AbbVie Inc. (ABBV)

R&D Day 2016

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Jun 3, 2016

Good morning, everyone. For those of you who don't know me, I'm Mike Severino. I'm the Chief Scientific Officer at AbbVie. And I'd like to welcome you to AbbVie's first R and D Day. We've prepared what we hope will be a very informative program for you today, and we're going to cover a wide range of topics, including R and D strategy, updates on our late stage pipeline and highlights from selected discovery and early development efforts. But before we get started, I'd like to take care of a few housekeeping items. First, before we begin, let me remind you that during the course of the program today, we anticipate making projections and forward looking statements based on our current expectations. Our actual results could differ materially due to a number of factors, including those listed on this slide and those outlined in our latest Forms 10 ks and 10 Q filed with the SEC. 2nd, we have a very full agenda today and we have to stop at 1 p. M. In order to allow people time to get to ASCO. So because of this, we scheduled only one short break in the middle of our program that will be about 15 minutes. During that break, we have box lunches available that you can bring back into the meeting room with you. Of course, if you need to step out at other times, feel free to do so. So with that, let's turn to our program. I'd like to begin by introducing our CEO, Rick Gonzales for his opening remarks. Rick? Well, thank you, Mike, and good morning, everyone. I'd also like to welcome you and thank you for joining us on our AbbVie R and D Day. This seems like an absolutely fantastic idea back in October with that one little sentence that we made and what happened after that was a tremendous amount of work by a number of the people who you'll meet and many others who are behind the scenes developing the presentations that you'll go through today. So although I probably thought it was a great idea, I can tell you some of the audience or some of the people here probably thought it wasn't such a great idea once we got into it. But I think you will find it very informative. I think you'll get a much better insight into what AbbVie R and D looks like. And I think you'll have an opportunity to learn some new things, particularly some new things around our early stage programs. So our goal today is to spend some time framing for you AbbVie's R and D strategy and providing our vision for how our near term growth assets including 8 innovative derisked late stage medicines will fuel our growth in the coming years. We'll also highlight some of the most promising early and mid stage programs that we're working on, which have the potential to further restate key therapeutic areas, driving deep and durable response in a number of diseases. The combination of our late stage and our early stage pipeline is really designed to drive long term sustainable growth well beyond 2020. I'll talk more about that here in a moment. While our near term growth assets are designed to deliver significant improvements in standard of care. Our early stage programs are focused on dramatically resetting the bar as it relates to standard of care, and I think you'll see that. We're using unique and innovative approaches in oncology, immunology and neuroscience. Many of our early stage programs leverage the knowledge that we've gained over the years in genomics and biology, allowing us to identify novel ways to deliver new therapies with market changing profiles. Some of the exciting early stage programs you'll hear more about today, and this is just a small list of those, our next generation immuno oncology program, which are really designed to broaden and deepen response beyond what we've seen with the 1st wave of IO therapies. We're using novel approaches, for example, including things like our bispecific technology to elicit T cell activation in close proximity to tumor cells. Over the next 12 to 18 months, we'll have five next generation immuno oncology assets entering the clinic. We'll also share details on some of the innovative work we're doing in neuroscience, including new mechanisms like anti tau and RGMA, which have the potential to translate to disease modification in neurodegenerative disease conditions like Alzheimer's, MS and spinal cord injury. Both anti tau and RGMA are in active human clinical programs now. In immunology, an area where we are clearly the undisputed leader, we continue to advance novel approaches to dramatically improve the depth and breadth of response in diseases like RA and inflammatory bowel disease. We're leveraging innovative internally developed approaches, which you'll hear about today. But one example of that is our novel antibody steroid conjugates, which are designed to knock out the specific cells responsible for disease activity. These compounds are analogous to antibody drug conjugates in oncology, except the toxin is replaced with a novel steroid. We expect to enter the clinic with this novel program in the first half of twenty seventeen. Our recent acquisition of Stemcentrx gives AbbVie a highly attractive platform for solid tumors and an extremely exciting late stage asset in ROVATI. Now that we've completed the acquisition, I can tell you that we're extremely excited to have the members of the Stemcentrx leadership team who are with us here today here to be able to review the exciting data on rovaT as well as their cancer stem cell discovery platform. This platform, which has already demonstrated a high level of productivity selecting novel targets that have shown strong activity, I can tell you will be an an important component of our R and D efforts going forward. We believe our R and D engine combined with our highly effective business development strategy will ensure that AbbVie has a robust and sustainable pipeline, which will fuel our strong growth over the long term. When we launched our company 3.5 years ago, we dedicated ourselves to the mission that's presented on this slide. A critical element of our success has been the productivity of our R and D organization. Our business is dependent on our ability to generate a steady stream of innovative new medicines that address today's most critical diseases, many of which are debilitating or life threatening. Since our inception, we have dedicated considerable attention and resources to the development of our pipeline, both internally as well as this company. Our central focus is on developing medicines that make a real difference, medicines that offer distinct and compelling patient benefits, strong differentiated clinical performance and a strong value proposition, Delivering meaningful economic value in today's healthcare environment is absolutely critical. And although we're still early on in our journey, I can tell you that we are extremely proud of our track record and the tremendous progress we've made towards our strategic objectives. We produced strong clinical data across multiple programs and have a success rate that is well above industry average. We're focused on some of the most attractive segments of healthcare, including oncology, immunology, neuroscience and virology, with focused investments in other areas where we have either unique assets or a strong strategic fit. In oncology, we've established a strong position in hematological malignancies with IMBRUVICA and VENCLEXTA. These two therapies alone and in combination with other medicines are demonstrating extremely strong activity in a broad range of cancers, giving us the ability to create a leadership position in the hematological oncology market, a $27,000,000,000 market today expected to grow to $50,000,000,000 by 2020. In solid tumors and even larger market, we have several promising programs, including our newest asset, RovaT. RovaT is a DLL3 directed antibody drug conjugate that has the potential to significantly improve the treatment and survival of patients with small cell lung cancer, a disease with absolutely devastating outcomes. DL3 expression in other solid tumors gives us confidence that ROSA T will expand beyond just small cell lung cancer. It's our objective to rapidly advance ROSA and efficiently execute studies to move quickly into frontline therapy as well. In parallel, we'll be advancing studies to validate Boviti's activity in a number of other solid tumors. We also plan to rapidly advance a number of additional targets from the Stemcentrx pipeline. Clearly, Stemcentrx will play a very important role in achieving our objectives in solid tumors. We have several additional active programs in solid tumors, including our PARP inhibitor, vilipparib, ABT-four fourteen, antibody drug conjugate for glioblastoma multiforme as well as programs exploring the use of IMBRUVICA in combination with either chemotherapy or immunotherapy. The Stemcentrx discovery and early development platform, combined with AbbVie's ongoing discovery efforts in oncology, creates a powerful engine to produce a steady stream of new novel targets and agents in solid tumors. Our oncology discovery effort though is also further supplemented with our partner Calico. As evidenced by our on market presence, our late stage pipeline and our early discovery and development work, clearly, we have made a major strategic commitment to oncology. And oncology will be a major growth driver for AbbVie over the next 10 years and beyond, further diversifying our business. In immunology, we're leveraging our deep expertise to develop next generation biologics and small molecules that elevate standard of care. Here, as you know, we have 2 late stage assets, ABT-four ninety four and risatizumab, each of which has the potential to significantly advance standard of care in immune mediated conditions such as RA, psoriasis and Crohn's disease, covering the major market segments where we currently have a leadership position. In virology, our emphasis is really on addressing the remaining unmet medical needs through our highly competitive pangeontypic next generation HCV combination. We're on track to launch this asset in 2017, allowing us to grow our market share position in HCV. We have an emerging area of focus when it comes to neuroscience, where we placed a concerted effort to develop disease modifying therapies for Alzheimer's and other neurodegenerative conditions. And as I mentioned, we're exploring novel mechanisms like anti tau or RGMA in disease modifying approaches for Alzheimer's and MS. And we're placing targeted investments in a number of areas as well, with programs in women's health with alagolix, renal disease with atrasentan and cystic fibrosis through our collaboration with Galapagos. These represent segments where we believe we have unique strengths. For example, we have significant knowledge in endometriosis and elagolix represents a potential new medicine to address a large number of patients suffering the significant pain associated with this prevalent disease. We reported positive pivotal data illustrating the therapy's potential in an area where current treatment options are suboptimal at best. The data we disclosed to date gives us a high level of confidence that elagolix has the profile necessary to achieve multibillion dollar potential. We made tremendous progress in R and D since we became an independent company. It was a high priority for us. And we did this through a concerted effort to create a highly productive R and D engine at AbbVie. We invested in meaningful opportunities in our pipeline, rapidly moving them through development, registration and approval. Our R and D investment has been highly productive and it ranks favorable as a percentage of sales compared to many of our peers. We build upon our already strong capabilities that we had as part of AbbVie with the addition of new talent to our R and D organization. You'll meet some of those people today. The individuals we've added to the team bring with them strong expertise in specific core areas of focus for us. We've strengthened our discovery efforts through collaborations with leading academic and other institutions like Calico and C2N. We've augmented our pipeline through a concerted effort to identify promising new technologies and assets that fit our area of expertise. This includes our 2 most recent examples, STEMcentrx and our collaboration with BI. And over the past several years, we've seen data from most of our late stage pipeline that has increased our level of confidence substantially. As I mentioned a moment ago, the combination of our near term growth assets and our early stage pipeline are really designed to drive long term sustainable growth well beyond 2020. In addition to the near term growth assets, we have more than 50 additional development programs, some of which have already established strong proof of concept. We anticipate data readouts from several of these programs over the next 12 to 24 months. And we believe that the innovative early stage development work that you will see here today will produce innovative new assets, which will drive further growth beginning in the early 2020s and extend through the decade. Our near term growth assets have been significantly derisked. Each of these therapies has demonstrated compelling differentiated data relative to standard of care. Given the product profile of each of these assets, I can tell you we have a high level of confidence in our probability of regulatory success as well as commercial performance. And today you're going to hear more about each of these assets. AbbVie has achieved truly unprecedented success when it comes to HUMIRA. That's a testament to both the benefit that the drug provides to patients as well as the confidence that physicians have in that therapy. As we've indicated previously to the investment community, we believe HUMIRA will exceed peak revenues of $18,000,000,000 It is our objective to continue to further diversify AbbVie's revenue base and assets like IMBRUVICA, VICERA, VENCLEXTA have already started that diversification process. As you'll see through today's presentation, we have 8 late stage de risked assets, which collectively have the potential to generate $25,000,000,000 to $30,000,000,000 in peak nominal revenues, significantly reducing our concentration related to HUMIRA and further diversifying AbbVie. And although we have a very high level of confidence in HUMIRA's durability, I would also tell you that we have great confidence in our pipeline's ability to continue to grow through the evolution of HUMIRA. As we step back and we look at the company, we do believe AbbVie is a very unique investment opportunity. We have a compelling de risk late stage pipeline, which is poised to fuel strong long term growth. And our early stage pipeline includes programs with the potential to dramatically restate standard of care. We have a strong track record of execution, both financially as well as strategically. We offer an attractive return of capital, balanced between supporting our growth objectives and returning capital to our shareholders. We remain committed to delivering on the long term objectives that we outlined for you back in October. And we expect double digit EPS growth on average through the long range plan. In closing, I hope that you'll leave today's meeting with a deeper appreciation of our scientific leadership, our R and D productivity and innovation as well as our long term growth prospects, which will be driven by the strength of our pipeline going forward. So with that as an overview, I'll now turn the stage back over to Mike. Mike? All right. Thanks, Rick. So as I mentioned, we're going to cover a wide range of topics today and you'll get to hear directly from a number of the physicians and scientists who are leading our programs in our therapeutic areas today. But first, I'd like to start with a brief introduction and overview of our R and D strategy. So this slide shows a number of the considerations that we look at when we develop our R and D strategy. 1st and foremost at AbbVie, our R and D strategy always starts with unmet medical need. Discovering and developing therapies that have the potential to transform the standard of care for people battling serious and often life threatening illnesses is our core mission. In addition, we believe that providing therapies that deliver value to patients, physicians, the healthcare system and ultimately to society is the only path to long term success in our industry and should be at the heart of an innovative science driven biopharma like AbbVie. As we set out to achieve this mission, we're fortunate that the last 2 decades have witnessed an unprecedented expansion in our understanding of human biology. Advances in areas like human genetics, cancer genomics, stem cell biology, bioinformatics and systems biology point the way to new therapies. At AbbVie, we're committed to investing in this novel biology to drive innovation within our pipeline. Over the course of today's program, we'll highlight a number of examples of this sort of investment. In addition, we believe that it's important to access the best external innovation as well. And we're doing so through partnerships with leading academic institutions around the world and through our licensing and acquisition activities. In addition to new biology, we must consider areas in which new technologies bring previously inaccessible therapeutic targets within our grasp. An example of this from our past is VENCLEXTA, our recently approved BCL-two inhibitor. VENCLEXTA is a small molecule that blocks protein protein interactions between BCL-two and other family members that regulate apoptosis or programmed cell death. Until recently it was not thought possible to drug protein interactions with a small molecule. But advances in medicinal chemistry and real time molecular modeling, many of which were made in our own laboratories made VENCLEXTA a reality. In the future, advances not only in medicinal chemistry, but in areas such as protein engineering, antibody drug conjugates and novel technologies such as bispecifics, T cell receptor based therapies and in other areas will bring new targets into our sites. In addition, focus is a core element of our R and D strategy. At AbbVie, we will focus on areas of biology and technology that are a good fit for our core capabilities. Areas where we believe we possess or can build a competitive advantage. Areas where we believe we are the right company to bring forward into advance. Lastly, we will focus on areas in which the path to clinical translation is clear, where the considerations that I have just outlined point the way to a new therapeutic. So based on these considerations, our discovery efforts are focused in 3 main areas, oncology, immunology and neuroscience. In each of these areas, we've identified a number of strategic priorities. In oncology, we'll grow our already strong position in hematologic malignancies. We'll establish a strong foundation in solid tumors and we'll leverage our experience in immunology to develop the next generation of IO assets. In immunology, we'll use our core skills to develop therapies that elevate the standard of care in disease areas like rheumatology, dermatology and gastroenterology. And in neuroscience, we'll capitalize on emerging biology and new technology to expand into Alzheimer's disease and the neurodegenerative components of MS. In addition, as Rick mentioned, we will continue to pursue areas that are a strong fit for our core strengths. Areas like chronic HCV infection, where we will develop next generation regimens that address the remaining unmet medical need, such as providing high cure rates to patients with difficult to treat genotype 3 infections or patients who have failed previous therapy with directly acting antivirals or DAAs. You'll see some examples of this from our next generation pan genotypic program later on in the program. And with programs like elagolix, we will bring an important new treatment option to women with endometriosis and uterine fibroids, 2 chronic conditions in which the current standard of care provides insufficient relief. And in cystic fibrosis, where we will explore whether new insights in biology and medicinal chemistry can lead the way to a transformational new therapy. So as the title of this slide says, strong talent is an essential part of this strategy. We've been fortunate as Rick mentioned, to recruit a number of talented individuals to AbbVie from the outside and we've continued to develop our internal talent base. This slide highlights a number of individuals who are either new to AbbVie or in newly expanded roles within R and D. You'll be hearing from a number of them over the course of the program today. Based on our focus on talent and innovation, we have recently decided to increase our presence in the San Francisco Bay Area and in Cambridge, Massachusetts, 2 important hubs of biotechnology and biomedical research. For oncology, this includes the creation of a new role to head our oncology discovery and early development efforts. We were very fortunate to recruit Tom Hudson for this role. Tom, who joined us just 2 weeks ago, is an internationally recognized leader in human genetics, cancer genomics and cancer biology. He'll be based in Redwood City, California and you'll get a chance to hear from Tom later on in the program. In neuroscience, we recently opened a new discovery center focused on Alzheimer's disease in Cambridge, Massachusetts. This facility, which we call our foundational neuroscience center is headed by Eric Caron, a leading figure in Alzheimer's research who joined us earlier this year from his prior role as Chief Scientific Officer of Alzheimer's Research UK. You'll also get a chance to hear from Eric a little bit later on. And while we are committed to innovation within AbbVie, we also recognize that we must access external innovation as well. And we're doing so through a wide range of partnerships. These include collaborations with world leading institutions like the Broad Institute of Harvard and MIT, which we're collaborating with in functional genomics, Yale University in Immunology, the Mass General Hospital and Washington University in St. Louis in Alzheimer's disease and the MD Anderson Cancer Center in oncology and immuno oncology just to name a few. In addition, we will pursue a range of industry partnerships based on basic science like our Calico collaboration, based on enabling technologies like our recently announced collaboration with CytomX and to access promising pipeline programs like our in licensing of rasankizumab, which is an anti IL-twenty three monoclonal antibody from Boehringer Ingelheim earlier this year. So I think our almost 2 year old partnership with Calico is a good example of our commitment to innovation. Our Calico collaboration allows us to explore a number of basic biological mechanisms that are altered as we age and underlie important disease areas like oncology and neuroscience that are a strong fit for AbbVie and for our pipeline. Working together, Calico and AbbVie scientists have created a portfolio of approximately 20 discovery programs that cover a wide range of areas and will offer an additional source of innovative clinical opportunities over the next several years. This will complement the innovative activities that are already ongoing in our laboratories. So as this slide shows, our R and D strategy is supported by strong financial commitment. The left hand panel shows that our investment in R and D has grown from approximately $2,800,000,000 in 2013 to more than $3,600,000,000 in 2015. In 2016, we expect to commit approximately $4,000,000,000 to our R and D efforts. As we have made this investment, we've been fortunate to be able to leverage a growing top line with R and D spending as a percentage of sales shown on the right. Of course, this financial commitment must be tied to tangible results. This slide shows the results of an internal look we performed to assess our Phase 2 and Phase 3 success rates in comparison to industry benchmarks. As you can see our recent 44% success rate in Phase 2 development and 83% success rate in Phase 3 development compare well to industry norms. In aggregate, these efforts have allowed us to build a pipeline that supports our future growth. Unfortunately, we won't have time to discuss all of these programs today, but you'll hear updates on many of them. And in particular, I'd like to call your attention to our late stage pipeline, which as Rick mentioned, contains 8 programs that have been substantially derisked based on clinical data that we have in hand. Each of these programs is either in registrational studies or has recently been launched. In addition, our pipeline has the potential to launch more than 20 new products or major new indications by the year 2020. And so while our 1st 3 years have been very productive, the next several years will be busier still. This chart provides a high level news flow for major pipeline This slide shows the agenda for the remainder of the program. Given recent developments in our pipeline, the acquisition of Stemcentrx and our newly announced West Coast discovery and early development hub for oncology, we'll spend a fair amount of time in oncology today. We'll then turn our focus to immunology, an area that has been and will continue to be very important for AbbVie with an update on our late pipeline and highlights of some promising discovery efforts. This will be followed by updates on our HCV and elagolix program and we will conclude with some exciting work that we're doing in neuroscience. So with that, let's turn our attention to oncology. The roots of AbbVie's oncology franchise go back almost 2 decades to the beginning of the work that ultimately led to the approval of VENCLEXTA, our novel BCL-two inhibitor just a few months ago. Over that time, we've built expertise in a number of areas of cancer biology and also in the enabling a little over a year ago and again by our acquisition of Stemcentrx, a little over a year ago and again by our acquisition of Stemcentrx, which was completed just 2 days ago. Based on the strategic considerations that I outlined in the beginning of my talk, unmet medical need, the emergence of new and exciting biology, the availability of enabling technologies and a clear path to clinical translation. We believe that oncology is an outstanding fit for AbbVie that will be a major growth platform in the coming years. The past several years have witnessed considerable success in cancer therapeutics. The number and pace of oncology approvals has steadily increased. Molecularly targeted and biomarker driven therapies are quickly becoming the norm and new areas such as immuno oncology have burst onto the scene. However, despite all of this progress, significant unmet need remains across a wide spectrum of cancers. The lifetime risk of cancer is estimated to be approximately 40% with an annual incidence rate that continues to rise. By 2,030 the worldwide incidence is expected to double resulting in a staggering 21,000,000 new cancer diagnoses every year. And despite the availability of a wide range of therapies, clinical increases to 80% in cases of metastatic disease. In fact, in certain cancers such as small cell lung cancer and glioblastoma multiforma, cancers in which AbbVie has active clinical programs, the long term survival is even worse than these averages. AbbVie's goal in oncology is to develop novel therapies and combinations that can drive long term remission or even cures whenever possible. And when cure is not possible to provide treatment options that allow for durable disease control that is substantially better than the current standard of care. As I mentioned at the beginning of my remarks, we've identified 3 strategic priorities in oncology. I'll take a moment to provide a bit more color on each of these. The first is to grow our already strong position in hematologic malignancies. With the acquisition of Pharmacyclics and its flagship molecule IMBRUVICA a little over a year ago and the registration of VENCLEXTA just a few months ago, AbbVie has a set of assets that is capable of transforming the treatment of a wide range of hematologic malignancies. We see this with recent Phase 3 results from the IMBRUVICA CLL program, which shows substantial reductions in the risk of progression or death when IMBRUVICA is used as monotherapy in the frontline setting or when IMBRUVICA is used as part of a combination with other agents in patients who have failed prior therapy. We also see this in the VENCLEXTA program, which has demonstrated high response rates in difficult to treat patient populations. Populations like the 17p deletion CLL and CLL patients who have failed prior therapy with a B cell receptor inhibitor. We see it again in clinical studies of VENCLEXTA when used in combination with other agents like Rituxan. This combination drives very high levels of response, including complete response and MRD negative response. Later on in the morning, we'll hear updates from both of these programs. In addition, we'll provide an update on studies of the combination of IMBRUVICA and VENCLEXTA, an area where we see great promise and have made considerable progress since the closing of our Pharmacyclics acquisition just about a year ago. Both IMBRUVICA and IMBRUVICA have significant potential beyond their current indications and we will show data that support the development of these agents in a wide range of cancers, including aggressive and indolent forms of non Hodgkin lymphoma, multiple myeloma, acute myelogenous leukemia and graft versus host disease. Of course, there are a number of additional programs in our early pipeline that hold promise in hematologic malignancies. While we don't have time to present all of these early heme programs today in detail, we will provide updates at upcoming medical meetings. So now let's turn our attention to solid tumors. Our solid tumor efforts have a foundation in areas of biology that we understand well, areas like apoptosis, epigenetics, DNA damage repair and others. But of course, we always keep an eye out for new and emerging areas of cancer biology, new targets that might be revealed by work in areas such as cancer genomics. We have known for many decades that cancer is a disease of the genome and that genomic instability leads the accumulation of mutations that drive tumors. But it is only recently that we've had the sequencing and analytic power to tackle this problem in a significant way. In his section, Tom Hudson will speak about the work he's done in this area and how it can be used to review to reveal new cancer targets. Cancer stem cell biology is another emerging area that holds great promise in helping us achieve our goals in oncology. Cancer stem cells are the cells that are responsible for the initiation, progression and spread of tumors. Stemcentrx has used their expertise in cancer stem cell biology to discover and develop RobaT, an antibody drug conjugate that targets DLL3 on the surface of neuroendocrine tumors. RobaT, which will serve as an anchor asset for our solid tumor efforts is currently in registrational trials for small cell lung cancer and is being studied broadly across a range of related tumor types. In addition, the acquisition of Stemcentrx brings with it a pipeline of 4 additional programs in clinical development as well as a talented team and a platform for target discovery that will significantly enhance our overall efforts. We are very pleased to welcome Stemcentrx to the AbbVie team and in just a few moments you'll get a chance to hear from them directly and learn more about Robitie and the platform that they've built. In addition to the efforts that I just described, we are continuing to explore new technologies that will extend our reach. One such technology is the ADC or antibody drug conjugate. An ADC takes a highly potent toxin, one that is too potent to be administered systemically and couples it to a monoclonal antibody so that it can be delivered directly to cancer cells, sparing normal tissue. The idea behind ABCs is not new, but it is only recently that progress in target identification, antibody engineering, linker chemistry and toxin technology have come together to make this a promising platform. In particular, we believe that ADCs are a good fit for AbbVie, given our strengths in discovering and developing highly specific monoclonal antibodies and our experience in small molecule chemistry and analytics. This can be seen in the progress that we're making with a number of ADCs in our portfolio and will be enhanced following the acquisition of Stemcentrx, who also use ADCs as a therapeutic modality. While we believe our current ADCs hold great promise, we are also seeking to develop the next generation of ADC technology. An example of this are our efforts to develop novel warheads for ADCs. No one warhead is active against all tumor types and it's necessary to compile a wide array of warheads to support a portfolio of programs that address a broad range of cancers. The panel on the right describes our efforts to develop a novel warhead based on our work in apoptosis. The figure at the bottom shows results from a preclinical model of non small cell lung cancer. Tumor volume is plotted on the vertical axis and time on the horizontal axis in days. As you can see, the tumor grows rapidly in untreated control animals, but tumor growth is dramatically inhibited following a single dose of ADC bearing this novel warhead. Another technology that we believe holds great promise is our bispecific platform. In the past, this has been referred to as our DVD or dual variable domain platform. But this is in fact a bit of a misnomer because we are capable of producing a wide range of different bispecific formats and DVDs is just a small portion of that. These bispecific formats have a broad range of protein binding and biologic characteristics. In oncology, we view our bispecific platform as a path to new biology rather than simply to combination therapy. For example, we are studying the use of our bispecifics to enhance the performance of ADCs. In preclinical systems, we can show that a bispecific that binds to 2 different portions of the same molecular target is taken up into cancer cells better than a traditional ADC. This offers the potential to deliver a greater toxin load thereby enhancing efficacy. Similarly, a bispecific that binds to 2 different molecular targets on the same cancer cell can be used to increase tumor specificity, allowing us to prosecute targets that have some degree of expression in normal tissue. An additional way that bispecifics can be used to generate new biology is shown in the right hand panel. And that is by directing cell cell interactions or by clustering proteins on a cell surface leading to activation. I'll give a specific example of such a use of bispecifics in the immuno oncology section, which will come next. So if we now turn our attention to IO, I think it's fair to say that this has been a very hot area in cancer biology over the past several years. The current generation of agents, the checkpoint inhibitors work by taking the brakes off an existing immune response. And while these agents have shown good results across a number of tumor types, the majority of patients still fail to achieve a long term good outcome and a number of tumor types have not yet been addressed by IO. Thus, we believe there is more work to do. So the panel on the right shows a simplified depiction of the steps that are involved in the generation, activation and regulation of an anti tumor immune response. AbbVie's work in immuno oncology is focused on a number of these areas, including efforts to address the tumor immunosuppressive environment. This includes programs like our anti GARP antibody recently in license from argenx. GARP is a protein that directly regulates suppressor T cell function and is one of the mechanisms that tumors use to evade the immune system. By inhibiting GARP, we hope to restore normal immune function and generate new anti tumor immune responses. Another approach that AbbVie is pursuing is the direct activation of tumor specific immunity by engaging activating receptors on T cells and other immune cells. In many cases, the broad activation of immunity is not desirable due to the risk of a systemic inflammatory response or of other toxicities. So we're pursuing programs that deliver this activating signal only in the tumor microenvironment. The next few slides show an example of how we're doing this in our CD40 program. It's been known for several years that CD40 activation restores cell mediated immunity in tumors. But CD40 agonists were limited in the clinic by systemic inflammation and by hepatotoxicity. So our approach to this problem capitalizes on the observation that finding a single CD40 receptor on the cell surface is insufficient to activate immune cells. Instead activation requires that a number of CD40 molecules are engaged and physically clustered on the cell surface. So we set out to develop a bispecific that binds CD40, but only creates this clustering in the presence of a second tumor specific antigen as shown in the panel on the right. As I mentioned, our bispecific platform can be used create a wide range of protein constructs leading to new biology with different mechanisms of action. This slide depicts a number of these potential formats. The different protein segments are color coded so that you can identify them. Each of these has differences in binding characteristics, mobility and other physical properties that can affect how they interact with other proteins. This slide shows about 2 dozen representative constructs, but we can in fact make more than 100 of these that maintain antibody like binding affinities and drug like properties. This next slide shows the results of a molecular model that demonstrates how 2 representative bispecifics interact with our target proteins. The antigen binding regions are coded in green and in purple and the respective proteins are coded in blue and yellow. So if we set this in motion for the first construct and then the second, you can see that the binding orientation and mobility are in fact quite different, leading to the potential for differing interactions constructs to identify one that had the desired properties. This next slide shows the results of preclinical studies that confirm that the selected bispecific retains the ability to activate anti tumor immunity while avoiding the toxicity associated with systemic CD40 agonism. This program along with a number of others from our IO efforts is set to enter human studies in 2016. In aggregate, these efforts have produced a strong oncology pipeline as indicated in this next slide. So this chart shows our pipeline as it stood at the beginning of this week. Most of you are familiar with the programs we have in late stage development. These are the programs on the right hand side of this chart. But we have added 6 additional programs in early clinical development and an additional 6 programs that are expected to enter the clinic over the next 12 months to 18 months. This number includes 5 potential IO assets and a number of additional programs that cover a wide range of cancer biology, many of the areas that we've discussed this morning. And of course, this was our pipeline before the close of the Stemcentrx acquisition. As we've said, Stemcentrx further strengthens our pipeline by the addition of Roviti, a number of early clinical programs and a powerful discovery engine. You can see the impact of Stemcentrx on our combined oncology portfolio in this chart. Of course, not all of the very early programs on the left hand side of this chart will become drugs, but the portfolio of the combined company gives us a large number of very novel, high quality assets from which to identify the next wave of AbbVie Oncology products. So with that, we're very pleased to have with us today 2 of the co founders of Stemcentrx, Brian Slingerland, their CEO and Scott Dilla, their CSO. Brian and Scott will now tell us more about Robitie, their pipeline and the platform that they've built. And we'll also talk about the way that we'll drive it together as a part of AbbVie. With that, I'd like to introduce Brian and Scott. Well, I'd like to thank Mike for the introduction. I must say the deal just closed a couple of days ago. We're extremely excited to be a part of AbbVie and we see strong synergies between the two companies. I hope you see some of the synergies or what the potential could be as I go through our talk today. And we do share a common mission and the mission of Stemcentrx like AbbVie is to discover and develop therapies for cancer in our case that cure significantly improved survival. So before I start today, Stemcentrx as the name implies is very much based around the cancer stem cell paradigm, which came to ahead maybe about 10 years ago in the lab I was post talking at Stanford. And really you can break it down into 3 central tenets. The first is that only stem cells can accumulate compounding mutations to result in overt cancer. The second is that only cancer stem cells are capable of fueling continued tumor growth. Most of the cells in tumors, it appears are simply bystanders in this process. They have a finite lifespan. And if you target those cells, you're really not going to impact survival. And third, and as it's most important as it relates to survival is that cancer stem cells are minimally impacted by therapies that are currently approved. So while response rates have really been a driver of drug approvals in the last 20 or 30 years and many of the drugs that are approved do a good job of shrinking tumors. Most of those drugs don't impact survival and we believe that's because they fail to address the underlying cause of recurrence, which is the cancer stem cell population. So Stemcentrx, as the name implies, is focused on identifying the cancer stem cell population and developing therapies to actively target and eliminate those cells. And while a truly cancer stem cell targeted therapy may not have an immediate impact on tumor burden, we do believe that will ultimately impact survival. So to introduce you a little bit to Stemcentrx, we were founded in 2,008 by Brian and I. We're located in South San Francisco. Among our core research platforms are patient derived xenografts. So these are very simply human tumors grown exclusively in mice. And Stemcentrx has one of the world's largest PDX tumor banks covering more than 21 different indications. A number of them are accumulated here at the bottom. But the reason for this large tumor bank is it allows us to study and understand subtypes of cancer, not only a particular subtype, but patient heterogeneity with each of those different subtypes and cancer stem cell identity within each of those different subtypes. And in so doing, it allows us to identify targets that are tractable and develop targeted therapies against those. And I'm going to be talking about a number of our clinical programs in just a moment. So at Stemcentrx, we built an agnostic platform. When we started the company in 2,008, we did not fully ascribe to the markers that were in the public domain. And so we very simply built a large proteomic platform to identify and characterize tumor cell heterogeneity. And you can see this antigen CD46. This is a flow cytometry plot where every dot represents a single cell is heterogeneously expressed in this colorectal tumor as an example. And when we isolate these respective subpopulations and transplant them into mice, you can see that the subpopulation of CD46 positive cells has all of the tumor initiating cell capacity whereas the CD46 negative population really does nothing when you transplant it into mice. So in this work and adding additional markers beyond CD46, we've been able to identify over the 8 years and characterize tumor cell heterogeneity and hierarchies, where we now can identify the cancer stem cell population, tumor progenitor cells, which are functionally tumorigenic in a primary transplant, but cannot generate tumors that can be serially transplanted. And then there are progeny non tumorigenic cells, both the progenitors and non tumorigenic cells are progeny ultimately of the cancer stem cell population. And then obviously, we're able to isolate and analyze stroma that's recruited into these tumors in mice, so we can also look at crosstalk between the tumor microenvironment and the tumor cells themselves. We've done this now for more than 8 different indications and we've leveraged that ability to now look for targets. So whereas most of academia and industry tries to identify targets by doing whole transcriptome sequencing, for example, in a whole tumor, If you do that, but you don't isolate subpopulations out, there's really a lot of noise, whereas if you isolate the cancer stem cell population front, now a lot of that noise is removed. And so this next slide shows a representation of the power of this approach. So shown here are 59 different genes and each color represents a different patient derived xenograft. There are a number of different solid tumor indications represented here. But what's clear is that there are a lot of genes that have been interesting and pursued clinically. A few approved drugs actually are represented by expression in this top quadrant. But you'll note that there are a lot of very important targets on that cancer stem cell population that have not been recognized as interesting before because they don't rise above the level of the noise because they are a subpopulation or expressed by subpopulation of tumor cells. So this is where Stemcentrx has gone hunting and why a number of the targets, in fact, all 3 I'm going to talk about today and the clinical results associated with them have never been ascribed to be important in cancer prior to our discoveries or have never been pursued before clinically. So I briefly laid out a number, 1 or 2 of the proteomic and genetic platforms that we've used to identify cancer stem cells and targets associated with those cells. Very early in the company's existence, we brought in the capabilities to build out our own bioinformatics platforms and IT tools to leverage both internal data sets and external data sets to identify targets and validate those. At this point, within the umbrella of AbbVie, we have approximately 180 employees. Most of those employees are involved in target discovery and target validation. We do have our own GMP manufacturing facility, I think the only of its kind in the world where you can make an entire antibody drug conjugate in one place. So we actually do the synthetic organic chemistry to make the payload. We produce the monoclonal antibody. We do the conjugation fill finish and ship directly to clinical trial sites. And what that allows us to do is bring innovative therapies into patients very quickly with much less cost than what traditionally has been done. We currently have 5 drugs in clinical development. I'm going to talk about 3 of those in just a moment. We also have a pipeline of programs moving into the clinic or coming close to clinical development in a number of other major unmet needs that we've not yet addressed clinically and we'll talk about those a little bit. So these are the 5 programs that we currently have in clinical development. I'm going to spend the most of my time speaking about DLL3, the pyrrolobenzodiazepine dimer conjugate otherwise known as Rovative or rovalpatezumabatezarin. I will then also talk about the PTK-seven, Orastat and then fRNA-four cleatromycin programs. Those were partnered with Pfizer back in 2011 when we only had 25 people and none of the capabilities we have today. But as you can see, we've already progressed further because of some of the streamlining we've done in producing of antibody drug conjugates, etcetera. And then there are 2 other programs that are in Phase Ia right now. We're not going to talk about those and we also have not yet disclosed those targets. So, rivopituzumab test screen or Rovative T, as many of you probably know, lung cancer is far and away the major cause of cancer related deaths, outnumbering colorectal, breast and pancreatic cancer combined. Small cell lung cancer, although it's a minority of cases among the broader umbrella of lung cancer, does afflict 81,000 patients in the U. S, EU and Japan and it by far and away has the worst survival metrics with less than 5% 5 year survival. So it's a very nasty disease. Most patients are diagnosed with broadly metastatic disease and the median OS from original diagnosis is approximately 10 months. The course of disease for these patients is the primary therapy in frontline is a platinum containing chemotherapy agent either carboplatin or cisplatin combined with etoposide. While there is a 70% response rate, there is a great toxicity, albeit manageable and however response there is a great toxicity, albeit manageable and however responses last only 3 or 4 months. So while it's effective at reducing tumor burden, it's not very effective at improving survival. In the second line, topotecan is the only approved drug. It only has a 7% to 17% response rate, also a great deal of toxicity. In fact, most physicians don't even like to use it. And then in the 3rd line setting, there is no approved drug. And so the data I'm going to share with you in a few minutes is a Phase I trial we ran in small cell lung cancer. These are patients with progressive disease in either the second or the third line, again, where outcomes are extremely poor. But let's take a step back. So during the course of normal lung development, the transcription factor ASCL1 and inhibition of the Notch pathway have both been demonstrated to drive neuroendocrine differentiation. In the context of small cell lung cancer where P53 and RB1 are almost universally mutated that transcription factor ASCL1 is driven to unnaturally high levels and inhibition of the notch pathway also drive neuroendocrine tumor genesis and this has been established in a number of publications. Now today I'm going to use the term tumor initiating cell. Very simply, it is a term that encompasses both the cancer stem cell population and the tumor progenitor cell. The functional difference between these two is that while both are tumor initiating, the tumors generated by a progenitor cell cannot be serially perpetuated because there are no cells within those tumors that have self renewal capacity, one of the defining characteristics of a stem cell. Using tumor initiating cells that we isolated from small cell lung cancer and large cell neuroendocrine carcinoma xenografts using markers that we've kept as a trade secret, we identified high delta like protein 3 expression within these cells relative to a number of normal tissues including normal lung. And this is whole transcriptome or RNA seek data from these isolated populations of cells. Now DLL3 might sound familiar. It is a member of the notch receptor ligand family, but it is unlike all of its family members in that among the developmental biology literature has been shown to be and to redirect them to endosomes for destruction. And in so doing it, and to redirect them to endosomes for destruction. And in so doing, it's been shown to be a dominant inhibitor of Notch signaling. So unlike the other Notch receptor ligands that activate Notch signaling, DLL3 actually inhibits Notch signaling, which as I just touched on is a bit consistent with the role here in neuroendocrine tumorgenesis. There was a hairpin screen done by Doug Ball and colleagues at Johns Hopkins University where DLL3 appeared among the laundry list of genes that were down regulated when hairpins against ASCL1 were generated in a small cell cell line, suggesting that DLL3 is downstream and a transcriptional target of ASCL1. And we did show within our xenograft that there is a significant correlation between ASCL1 and DLL3 expression consistent with that published literature. I just told you on the previous slide that DLL3 inhibits notch receptor signaling and it stands to reason that DLL3 may actually unify these two previous observations by inhibiting NOTCH1 and therefore DLLL3 may actually drive neuroendocrine tumorigenesis. And consistent with its potential role as an oncogene in neuroendocrine tumors, when we try to knock down DL3 expression in small cell xenografts, the cells stop proliferating or they die, again suggesting that DLL3 is very important in the neuroendocrine tumorigenesis. Consistent with that, late last year, I think a month after our publication, there was a publication by Roman Thomas, a German scientist and a large consortium that sequenced more than 250 small cell lung cancer patients. And in 25% of those patients, they observed non synonymous notch mutations, which means mutations that would negatively impact signaling from the Notch receptor. So this is anti correlative, if you will, with DLL3 expression, which we've characterized to be present in about 80% of patients and high in 65% of patients. And we are currently working with that German group and others to confirm that these are mutually exclusive. And again suggesting that this inhibition of the notch pathway is a major driver of neuroendocrine tumorigenesis and the vast majority of patients have a manifestation of high DLL3 expression. So we develop monoclonal antibodies specific to DLL3. This is just an ELISA assay showing you there's no reactivity to the other related family members. Using antibodies that we generated, we confirmed that DLF3 does leak to the cell surface when it's overexpressed in cancer. Now this is not very high expression in the antibody drug conjugate field. Most companies will tell you that's not a great target. It's not highly it's not as high as you will need it to deliver efficacy, but we found that this antigen internalizes extremely fast, much faster than HER2 for example, which is the target of 1 of the approved antibody drug conjugates Kedsyla. Using an FFP compatible immunohistochemistry antibody, we found high expression on small cell lung tumors. And if we convert that membranous expression to an H score and assess large tissue microarrays of small cell lung cancer patients, you can see that the majority of naive small cell lung cancer patients and even patients who are recurrent or refractory, so they've already failed cisplatinetoposide have at least intermediate to high levels of DLL3 expression. Now importantly, normal tissue has absolutely no expression of DLL3 including normal lung. So to recap, DLL3 is normally expressed in the Golgi during development. In the context of neuroendocrine tumors, it leaks to the cell surface because of its over expression. And there we're leveraging an antibody drug conjugate, to target and take advantage of the fact that it does leak to the cell surface in these diseases. And so, Rova T is an antibody drug conjugate comprised of a monoclonal antibody targeting DLL3. We generated this antibody in mice and humanized it. It's conjugated to a PBD dimer toxin, which has a cell cycle independent mechanism of action via valine alanine dipeptide containing spacer. Now the importance of the valine alanine is that it is a substrate for capsidin D, which is active and expressed in late endosomes. So this linker will only be cleaved when it gets into the cell and it's routed into late endosomes. The drug antibody drug to antibody ratio in Rovaty is 2, so 2 drugs per antibody. So essentially, we're using ROVA T as a Trojan horse to deliver that PBD dimer payload. I'm going to back up because I worked hard on that animation. To route to the late endosome where that dipeptide will be cleaved and then the payload will be released and kill the cell. That's the mechanism of action of Roviti. So just to show the power of antibody drug conjugates, this is one of our tumor bearing mice. It had a relatively large tumor burden. We would normally this is getting close to when we would euthanize an animal. So this is a human tumor engrafted under the skin of a mouse. It's running around pretty happy. It doesn't know that it has something there, but they're not really bothered by it. And then we randomized these animals and treated them 4 times once a week for 4 weeks. And you can see after just 4 treatments that entire pretty large mass completely went away and it didn't come back for more than 70 days after the last treatment. So that's pretty strong visual for the power of an antibody drug conjugate. In the meantime, the mouse is fine. It's not losing weight, it's running around happy. And we're injecting the drug IP. So the drug is systemic and it's that systemic MOA of getting tumor in the right cells in the tumor that are causing the cell death and efficacy. Pre clinically, we evaluated a spectrum of PDX tumor models that represented what we would expect to see clinically. This is one of those intermediate to high expressing PDX tumor models. We always treat animals when they are tumor bearing. So these are established tumors. Here we treated only 3 times at day 0, 37 and with the targeted antibody drug conjugate and appropriate control, so an anti haptan or non specific antibody linked to the same toxin with the same number of drugs or treated animals with the standard of Carisys plant and atop aside. So you can see very strong activity by Roviti more than 160 days and we didn't see any tumor recurrence in any of the animals. The appropriate control really didn't do much and the standard of care while it did have an immediate impact on tumor burden, those tumors came back very quickly, which unfortunately is also the course clinically. Now to prove to ourselves that we were eliminating cancer stem cells and that was the underlying reason for the lack of recurrence, we performed an experiment like this and a number of them actually where during the course of tumor response, we euthanized a representative number of animals, in this case 2 animals per group and then we transplanted human tumor cells and limiting dilution into another set of animals and used Poisson distribution statistics calculate the residual tumor initiating cell frequency at that point in time. And you can see that ROVAT had a dramatic impact on cancer stem cells or tumor initiating cells. And of course, that is underlying why we don't see recurrence, whereas the appropriate controls and even the standard of care really have no impact whatsoever on tumor initiating cell frequency. Now we performed, 13 different xenograft experiments to try and do what we call a Phase 1 study in mice. And you can see that while both tumor growth while tumor growth inhibition is similar to both cisplatinetopside and ROVITI, we did not see any recurrences in 8 of the 13 xenografts that we assessed. And that response was very much correlated with expression. So it's something we commonly do is look at expression response correlations preclinically. And you'll also note that some PDX models have very low H scores, manifest by the fact that there are low percentage of cells expressed the target. But if you hit the right cells, you can still have a dramatic impact on the course of treatment. So this is all preclinical data. Clinically, we presented data last year at the International Association for the Study of Lung Cancer Meeting in September, which was our first kind of public disclosure of any data and then again at ESMO or the European Cancer Conference in Vienna. And this is the summary of all patients in the Phase 1b portion where patients were dosed at 0.2 milligrams per kilogram at every 3 weeks for a total of 3 doses or 0.3 milligrams per kilogram every 6 weeks for a total of 2 doses and you can see the responses there. But you'll notice that the DLL3 high patients, all of our responses were DLL3 high. So if we focus on the patients who are DLL3 high, which represents 65% of patients with small cell lung cancer, you can see we had a 44% response rate and a 78% clinical benefit, which means an achievement of stable disease or better. So this is all data we presented at ESMO, again last fall. There will be updated response and survival data presented on Sunday and I hope you all attend. Importantly, we saw equal responses in both the second line setting and the third line setting and this is very important because there is no approved drug in the 3rd line. Drugs typically don't work very well in that 3rd line and I'll talk about that in a few slides. But I thought it'd be very important to cover just 2 case studies quickly because I think they say a lot about the mechanism of action of Rovaty. So the first is a 54 year old patient at Memorial Sloan Kettering. They were treated 3 times once every 6 weeks with 0.3 mgkg. After that 3rd dose, they had about a 50% tumor reduction. This is also sorry, a third line small cell lung cancer patient, who is told to get their affairs in order. And after that third scan, they had a PET scan and their tumor was PET negative, which is really unheard of in small cell where more than 90 percent of the cells typically are CHI-sixty seven positive, which means they're actively proliferating. This patient had one tumor left in the adrenal gland. So the physicians decided to resect the tumor and this is a cross section in H and E of that tumor. And so while there was a residual mass, this light pink, really is just scar tissue and fibroblast. The only visible tumor cells left were these small islands of purple cells and pathologists at Sloan Kettering, who is one of the top lung cancer pathologists in the world, noted that upon path review, we had more than a 95% treatment effect. Now only 1% of these tumor cells was TY-sixty seven positive. He also noted that they tended to have a more differentiated appearance. They didn't look like your classical small cell lung cancer and may in fact be differentiated. And they still did retain expression of DLL3. So we could have treated this patient again and maybe finished off those cells. That patient as of their last visit in March was at day 556 and hasn't had drug beyond that time point way back here. Now we don't always need to see responses to see clinical benefit and I think this is really eye opening. So this patient is a 60 year old female at the University of Alabama, Birmingham. After the first three doses of drug, this patient was on the 0.2 milligram per kilogram dose regimen every 3 weeks. They were dose reduced going into the 3rd cycle because of a mild rash. And basically since that point in time at day 42, this patient has had stable disease and the PET negative scans now for over 620 days. This patient has not received any drug since day 42, and is still working 2 jobs and doing well at their last visit in April. So this data, and again, you'll get an update on that data on Sunday, and has underlied the focus on the 3rd line. So we are now enrolling a 3rd line pivotal study for approval for accelerated approval. It is a trial that we call Trinity and it is a single arm study because again there is no approved drug and we've seen very substantial activity. Now just to compare the activity we've seen versus the historical means in the third line of small cell lung cancer, there was a retrospective analysis published late last year. The historical response rate in third line only been 18% with about 51% clinical benefit. The median overall survival is only 4.7 months. I want you to remember that number. And the median 1 year survival is only 12% in this setting. So again, Trinity is actively enrolling. We currently have 28 trial sites open including sites in Europe, one right now, but there are many more coming online. And our focus is moving this drug as fast as we can into the frontline setting where we will be starting maintenance studies. I'm going to talk about our clinical development plans in a minute. But also we will be evaluating combinations with cystplan and etoposide providing ROVAT ahead of or after CE and combining the 2. So I briefly wanted to talk about checkpoint inhibitors and while checkpoint inhibitors such as BMS data which will be updated on Saturday by the way, have had some success in small cell lung cancer. You can see the success has been moderate in the single agent EVO with a little worse median OS than the current standard of care in third line, for example. But both of these drugs have the same mechanism of action impacting immune checkpoints. There's been recent data published that antibody drug conjugates and specifically those with certain payloads can induce an immunogenic cell death. And we believe and are now generating preclinical data that shows substantial evidence for potential synergy between these drug classes. And so the idea is to induce immunogenic cell death with a targeted cancer stem cell agent like Rovaty, provide a lot more father for recognition by antigen presenting cells in T cells. And then if you further ramp up the immune system to recognize that increased release of cancer stem cell associated antigens, you should see an even stronger response in patients that are not responding to the immune checkpoint inhibitors and much better durability. So I'll say right now is we have significant evidence preclinically for this and we'll be showing that data later this year. But we're also going to be moving aggressively into those combo studies clinically. And I'll cover that in a moment. DL3 is expressed in a number of other high grade neuroendocrine tumors. This is just immunohistochemistry expression showing that expression in 50% of metastatic melanoma, neuroendocrine prostate, which is a fast growing indication actually as patients are refractory to ZYTIGA and one of the other inhibitors, neuroendocrine pancreatic colorectal medullary thyroid and aggressive form of thyroid cancer and glioblastoma. This is an overview of our clinical development plans. Again, Trinity is actively enrolling. We're also enrolling a pharmacokinetic study in patients independent of DLL3 status. We will be starting a first line trial to evaluate combinations with current standard of care or different sequencing of that. The Basket study and these other neuroendocrine indications will be starting soon and we do have a poster on Monday if you want to come by. I think it's poster 308. We also intend to start very soon the checkpoint inhibitor combination studies in Phase 1, so we can select the regimen dosing and then we will be initiating a first line maintenance study where you debulk tumors with cystlanta top side followed by ROV T and this will be a Phase 3 study and will be confirmatory. We intend to start that later this year. And then finally, we're also going to be opening trials in Japan at the end of the year. So I see I only have 2 minutes left. I hope that is enough time or I might get another minute or 2. And to talk briefly about the other 2 programs that are partnered with Pfizer. The first is a PTK-seven targeted orastatin, a different payload than ROVT leverages and this is an antigen that's expressed and that we identified a non small cell lung cancer, breast and ovarian cancer. Again, snapshot of preclinical data, one course of therapy in a week. We see very strong responses, a lack of tumor recurrence in most of the models that have high expression of the target. This is triple negative breast cancer, non small cell lung and ovarian cancer. The first clinical data around this ADC was shared at ESMO again last fall. This was an all comers study, so it did enroll a number of patients with indications that we do not think express PTK7. But if we focus on the triangles on the right, which I'm using to demarche patients with breast cancer or ovarian cancer, which do express the target. We had it very early on still in the Phase 1a, 50% response rate in breast cancer and the only ovarian cancer patient we treated at doses below the Phase Ib expansion levels had a complete response. So this is a patient who had failed 4 previous lines of chemotherapy with no better response than progressive disease. Again, they were dosed that below the Phase Ib expansion dose, which is 2.8 mgs per kg and the PR was confirmed out well out past 6 months. This is one of the triple negative breast cancer patients who had a near CR, again at doses below the Phase Ib level, started with a 5 centimeter tumor, shrank to a half centimeter, also had a confirmed response well out past 6 months. This drug has been extremely well tolerated. There have been no at least in the data reported at ESMO, no grade 4, 5 toxicities. The only grade 3 toxicities observed even up to 3.7 mgs per kg, which is more than double the level of ADCETRIS, which is the other approved antibody drug conjugate was a fatigue, a severe headache and 2 cases of neutropenia, which were reversible and consistent with MOA of orastatin. Finally, talk briefly about fRNA4 cleachyomycin. FRNA4 is another cancer stem cell associated target that we identified in triple negative breast and ovarian cancer. This is a snapshot of preclinical data. Again, one dosing regimen, tumors completely respond and don't recur out past 160 days. We evaluated a number of models preclinically and found that the triple negative or I should say the non clot and low sub of triple negative breast cancer, which accounts for 90% of triple negative breast had very strong responses preclinically whereas the clot and low subset and HER2 positive which don't express the target, don't respond to the ADC. Again, this Phase 1 trial was reported or early data was reported last year at ASCO in a poster. The triangles represent patients with ovarian cancer in pink or breast cancer in blue treated at doses above what we think is therapeutically relevant. And again, you can see some really nice early responses in the Phase 1a portion. Again, both this study in previous study and Roviti, all single agent data. Again, the tox profile here was also pretty good, a little bit of mucositis, thrombocytopenia and those were mitigated by moving to a weekly dosing regimen somewhat consistent with the clinical experience around Mylotarg, which also uses clechomycin. So at Stemcentrx, again, we have 5 clinical programs shown here. Here's kind of our scorecard where we have drugs 2 drugs in small cell lung cancer, 2 in triple negative, 3 in ovarian and 1 in melanoma non small cell. Over the next 18 months, we will be filling out the rest of the scorecard. We have 2 programs that will be entering the clinic this year. The first of those IND number 6 in ovarian and non small cell lung cancer and then we have some others coming for colorectal, pancreatic, gastric, luminal B breast cancer and another big unmet need and AML. So our vision ultimately is to develop cancer stem cell targeted therapies that are A, targeted and specific to patients who express the target. So a patient could come into the clinic, get their tumor biopsied, stained biochemistry. We do have companion diagnostics we're developing in parallel with all these programs and then match the patient to the right drug. It seems fairly simple and that's what we're working towards. In summary, 3 of our first three clinical programs are all showing strong single agent activity at tolerated doses. All 3 are targeting engines that have never before been pursued clinically. Our discovery pipeline is unveiling additional targets that can not only be leveraged by antibody drug conjugates, but also CAR T, CAR NK, TCR targeted therapies and small molecules. And this is part of why we're very excited to be collaborating and working very closely obviously with the AbbVie team because we can start to leverage a lot more of our discoveries to bring new drugs to the clinic. And then our milestones this year are to enroll the TRINITY study and ensure rapid enrollment, initiate a first line trial for a selection of a regimen to advance, but not wait and start that maintenance study as soon as we can, which will probably be in the Q4 early next year. Again, that will be a Phase 3 confirmatory study to confirm the TRINITY study. We also will be initiating the neuroendocrine basket study very soon and as soon as we can initiate checkpoint inhibitor combination studies, again for which we have very, very strong preclinical data for the synergy between these different MOA type drugs. So with that, I'll turn it back over to Mike. Great. Thanks, Pat. Okay. So I think you can see why we're all very excited about Stemcentrx and what it adds to our already innovative efforts. We're also excited about our pipeline and we'll now change gears to some updates on the later stage programs in our pipeline. We'll start with Danelle James. Danelle? Hi, good morning and thanks Mike. So today on behalf of the Pharmacyclics team, I'd like to update everybody on the status of the IMBRUVICA program and where we're going. And before I get into the BTK program specifically, I'd like to emphasize that despite the efficacy of the current standard of care, there's still considerable unmet medical need within CLL and non Hodgkin's lymphoma. And as you can see on the graph here on the left, no matter what the age of diagnosis, CLL still significantly impacts patients' life expectancy compared to normal age matched population. And if you look at non Hodgkin's lymphoma, we are still seeing a high proportion of patients dying from their disease with over 20,000 deaths in the United States annually. Now to BTK. From target validation to the frontline indications, here's a timeline depicting the rapid development of the inhibitor of Ibrutin's tyrosine kinase, ibrutinib. About 70 years ago, Colonel Ogden Brutin described a genetic disorder in young boys with agammaglobulinemia. And over 40 years later, the BTK gene was cloned and characterized. In 2005, the first synthesis of PCI-three thousand two hundred and sixty five occurred and here's Ibrutinib docking and covalently into the BTK active site at CYS481. And just in 2009, the first human was treated with ibrutinib and following that efficacy was demonstrated in several B cell malignancies. In 2013, we had we received 3 breakthrough therapy designations from the FDA. And in rapid succession, we converted those to approvals, with the first approval for Ibrutinib being just over 4 years after the patient first patient being dosed. All the primary research was published in the New England Journal of Medicine. And then more recently, we garnered a frontline approval for CLL, all lines of therapy in March 2016. And then just, over the past couple of weeks, we had an approval for all lines of SLL in May 2016. So the IMBRUVICA clinical development program as well as its license has given a broad safety experience to be incorporated into our label. So we've treated over 10,500 patients within our clinical trials and there's over 35,000 patients treated worldwide with the drug. Now obviously IMBRUVICA is an effective drug in CLL and mantle cell lymphoma. And today, I'm going to highlight some of the key parts of our program where we're trying to maximize IMBRUVICA in those indications. But in addition to CLL and MCL, we have a broad range of development within hematologic malignancy with many of our non Hodgkin's lymphoma programs being well into the Phase 3 development. And then at the end, I'll actually touch on some of the places where we're looking at IMBRUVICA outside of hematology and solid tumors and graft versus host disease. So now let's start with CLL. So IMBRUVICA has the potential to broadly transform the management of treatment naive CLL patients. And I think one of the key features of our development program was how quickly we got to this frontline indication. And this was based on the RESON-eight-two study, which looked at the largest population of treatment naive CLL patients, those that are 65 and older, looking at ibrutinib versus a traditional chemotherapy, sclerandisol. In this study, the data really clearly support the frontline use of IMBRUVICA. If you look here at the progression free survival curves, we see a 91% reduction in the risk of progression or death compared as assessed by the investigator. In addition, we see significant overall survival benefits. And within our USPI, we recently had an update in the label incorporating a new longer term survival analysis, which provides statistically significant benefits for overall survival, reducing the risk of death by 54% versus the control arm. And this was despite the crossover of 41 patients from the chlorambicile arm to the IMBRUVICA arm. This data set has supported NCCN Category 1 recommendation in several key frontline patient segments in addition to our Category 1 recommendation for all previously treated patients. We have a full FDA approval now for all CLL patients and SLL patients regardless of line of therapy or genetic subtype. And just recently this week, we received the European Commission approval for first line use in CLL as well. And we're setting IMBRUVICA in a comprehensive development program in treatment naive CLL and SLL. And there's several more Phase 3 studies that are ongoing, mostly being performed in the cooperative group setting. In the UK and the United States, there are 2 Phase 3 studies looking at patients who are younger and fit. The sibrutinib in combination with rituximab against the standard treatment with beta sarcophosphamide and rituximab or FBR. An intergroup study led by the alliance is looking at IMBRUVICA versus IMBRUVICA rituximab versus BR in patients who are 65 and older. This study has completed enrollment and will not only assess IMBRUVICA versus bendamustine rituximab in this population, but will also evaluate the additional contribution of rituximab in terms of extending PFS. Our company sponsored ILLUMINATE study has also fully enrolled. This is looking at different segments in the treatment naive population and is looking at Ibrutinib and obenituzumab or Gazyva versus the chemotherapy based combination with the antibody. And in the German CLL study group, they're performing a very important study. It's called CLL12 and it's looking at that watch and wait population to see if early treatment with IMBRUVICA can improve upon the outcomes of patients with high risk disease during their typical watch and wait period. And we anticipate data from these studies to be reading out between 2017 2019. Now moving on to the novel, novel combinations and the progress that we've made, I'd like to first touch on the rationale for combining IMBRUVICA and VENCLEXTA. Our goal is to combine these 2 oral medications with distinct and complementary mechanism of action to really induce profound responses and eradicate MRD in our patients. And this is supported by some robust ex vivo analysis. Here you can see at the top panel on your right, BCL-two expression evaluated in patients treated with IMBRUVICA by U. K. Investigators demonstrating persistently strong expression of BCL2 target of VENCLEXTA throughout IMBRUVICA treatment. And in some patients as denoted here by the MD Anderson investigators, we actually see increasing levels of the BCL-two protein in patients treated with IMBRUVICA. And when you take the leukein cells out of patients who are treated with IMBRUVICA, you see that they remain highly sensitive to apoptosis with VENCLEXTA. And this is compared here versus bendamustine, where VENCLEXTA has a very high level of inducing apoptosis. And so here's our ongoing clinical evaluation of the combination of imbuvipar and VENCLEXTA. And you see here 6 studies that are either ongoing or very soon to initiate, including one large Phase 3 study, the CLL13 study, which is looking at the combination versus FCR or VR. And in this study, they're testing the 3 drug combination of IMBRUVICA, VENCLEXTA and obinutuzumab versus SVRVR and also looking at vinclexa and obinutuzumab and vinclexa and rituximab in 2 other arms. There's a similar Phase 2 evaluation that's being done in treatment naive CLL patients with the deletion 17p. And in the U. K, there's an ongoing study called CLARITY that's looking at the 2 drug combination in patients with relapsed or refractory CLL. Internally, we're really excited about the PCYC1142 study, which is a fairly substantial Phase 2 study, that will look at the combination of IMBRUVICA and VENCLEXTA, to try to eradicate MRD and to give these patients treatment holidays in which they can then be retreated with these agents. And in the bottom, we see 2 studies in mantle cell lymphoma. One is looking at the 3 drug combination, the OASIS study that's ongoing in the UK. And the last study, the AIM study, I'll go through in the next slides. So the AIM study is looking at the combination of imbruvica and nexplexa in relapsedrefractory mantle cell lymphoma. And the first human data with this combination will be presented here at the annual meeting. The objective for the investigator is to determine the complete response rate and to really drive rapid deep responses in this high risk patient group. And in a limited number of patients in the abstract, they started 4 weeks before VENCLEXTA at the standard dose for mantle cell lymphoma 5 60 milligrams daily. VENCLEXTA is then added and given as per the USPI in the standard dose ramp up over 5 weeks. What you see here is that full doses of VENCLEXTA and IMBRUVICA were achieved in all patients, and it was safe and tolerable. And the efficacy seems to also be very promising. After the addition of VENCLEXTA, they saw stable diseases converting to responses and then responses converting complete responses with 3 evaluable patients. 2 of those 3 patients were actually PET negative and MRD negative, so showing absolutely no evidence of the disease. So this is really early experience, and it will be updated here at the Annual Meeting on Monday. But it's really promising in terms of the efficacy and no unexpected safety signals. So really paves the way for continued progress for this combination within CLL and non Hodgkin's lymphoma. And I've talked about the approvals in CLL, SLL and Waldenstrom's where we're improved in all lines of therapy including first line, we're approved in mantle cell lymphoma for any patient that has one prior line of therapy, but IMBRUVICA has broad potential beyond CLL and mantle cell lymphoma. And I'll be reviewing some of our progress and other pivotal development programs, including diffuse large B cell lymphoma and follicular lymphoma. I'll go through some of the data in solid tumors and then I'll touch on our first non traditional oncology indication, that we're evaluating IBRUVICA and that's chronic graft versus host disease. So if you take the largest segment of non Hodgkin's lymphoma, it's diffuse large B cell lymphoma. And early on our program, we realized that the single agent activity of IMBRUVICA was really most pronounced in those patients that had the more aggressive activated B cell subtype of diffuse large B cell lymphoma or the non germinal center B cell subtype of diffuse large B cell lymphoma. Later, we showed that imbibiculin can be safely combined with R CHOP and efficacy also looks promising in a Phase 1 study. And this sets the stage for a large ongoing Phase 3 study called the PHOENIX study, which is looking at imbiblica in combination with R CHOP and these treatment naive diffuse large B cell lymphoma patients with the goal to extend the event free survival of these patients and also increase the fraction of patients who are actually receiving curative first line therapy for their disease. And at the recent ASH, we demonstrated high activity of imbruvacad mirtuximab in first line follicular lymphoma. And this is an early data set with a median duration of treatment of about 2.5 or 12.5 months. As you can see here that every patient experienced reduction in their tumor burden and that a very high overall response rate was achieved with about a third of the patients achieving a complete response and the majority of these patients continue on treatment. So they'll continue to update this data and potentially IMBRUVICA rituximab can provide another option versus chemoimmunotherapy in this population. Our ongoing pivotal studies in indolent lymphoma, including marginal zone lymphoma and follicular lymphoma will read out between 2016 2018. And so a common objective in many of our pivotal studies within non Hodgkin's lymphoma is to enhance the activity significantly versus chemoimmunotherapy alone. And so HELIOS, back in the CLL program was the first of these Phase 3 studies to read out and it was overwhelmingly positive with an 80% reduction in the risk of progression or death when IMBRUVICA was added to BR versus the BR placebo arm. This combination data has recently been added to the USPI and so now physicians in the United States have an option to either prescribe IMBRUVICA as a single agent or in combination with chemotherapy for their patients with CLL or FLL. And so in non Hodgkin's lymphoma, we have 2 very similarly designed studies. One is the STELINE study. It's a fully enrolled Phase 3 study evaluating IMBRUVICA BR in previously treated indolent lymphoma and the Stein study, a Phase 3 study assessing IMBRUVICA in BR as first line therapy in mantle cell lymphoma. Now turning to solid tumors, the rationale for imbiblican solid tumors is multifactorial, and it includes the high level expression of active BTK within the tumor infiltrated leukocytes and the tumor microenvironment as demonstrated here at a recent publication from cancer discovery in pancreatic adenocarcinoma with higher level expressions seen in the tumor microenvironment than they are seeing in normal leukocytes within the human spleen. And then an additional rationale is the role of ITK. ITK is an analogous kinase and that is expressed in T cells analogous to BTK that's expressed in the non T cell component. And by inhibiting ITK, we actually see a reduction in the immunosuppressive Th2 phenotype of T cells and an increase in the Th1 or protantitumor T cells. And so taken together, this could increase the efficacy that we see in solid tumors. And this has been proof of principle in many preclinical models, including the ones shown here on the left, looking at IMBRUVICA either alone or in combination with gemcitabine in pancreatic adenocarcinoma, significantly improving the survival of those mice. Recently, we also had a publication with the TNAS looking at imbruvica in combination with checkpoint inhibitors or a similar phenomenon of prolonged overall survival was seen in the mice treated with a combination versus a single agent checkpoint inhibitor alone. And so we're looking at IMBRUVICA in a broad but targeted fashion within solid tumors. We have 2 actively enrolling basket studies looking at IMBRUVICA in combination with standard of care chemotherapy or checkpoint inhibitors. As well, we have 1 randomized study that's set to be registration enabling in first line metastatic pancreatic cancer looking at IMBRUVICA on top of gemcitabine and nab paclitaxel. And so if we turn to chronic GVHD, although it's not a traditional oncology indication, it is a common complication of stem cell transplant, which is used to manage cancer patients. And it's associated with substantial morbidity and there are no approved therapies for this disease. So it represents a significant unmet medical need. And so IMBRUVICA chart is both the B and C cell component of this disease and can lead to responses in high risk patients. And here's a cartoon schematic kind of demonstrating what that is. Overproduction of self reactive T cells and B cells from the donor attack the host tissues leading to an immune mediated clinical manifestations of chronic GVHD. And so imbruvucatinibition targeting BTK can inhibit the self reactive B cells, inhibit the production of the antibody complexes and the resultant fibrosis And also through ITK, IMBRUVICA can inhibit several of the self reactive T cell subsets. And what we've shown in a Phase 2 study that was recently presented at the European Bone Marrow Transplant Conference in 2016, We've shown that the majority of patients are responding to single agent Ibrutinib and that these responses are occurring in conjunction with reduction in toxic steroid doses and other immunosuppressive medications as well as reduction in their symptoms. So if we look at the news flow for IMBRUVICA, some of the upcoming milestones include in CLL and SLL, a number of the Phase 3 studies being read out 2018. And if you include the imbruvica, vinoplexda and GA-one hundred and one combination that will lead out a little bit later. We see in multiple myeloma, we have 2 randomized studies looking at IMBRUVICA in combination with pomalidomide or IMBRUVICA in combination with XELCADE. In non Hodgkin lymphoma, we have a number of pivotal programs that are slated to potentially read out over the next year and a half. Many of these are based on potential interim analysis timeline, so the actual timing of the data may vary. But we can see that SHINE, Celine and PHOENIX are all poised to read out over the next 6 to 18 months. And in solid tumors, we'll be seeing some of our first basket study data from the checkpoint inhibitors in the near term, and then later on top of the standard chemotherapies as well as an early interim analysis is potentially available for pancreatic cancer. And I think that's all I have for the IMBRUVICA program. I'd like to hand it over to Doctor. Gary Gordon, who will give you an update on the other late development oncology assets from AbbVie. So thank you, Danelle. I think Danelle has given you a very nice overview about how we're thinking about not only IMBRUVICA, but some insight into how we're thinking about putting together some of our other assets in the setting of hematologic malignancies. So as many of you know, AbbVie has been working in the area of apoptosis for approximately 2 decades. This is, as Mike has alluded to, a very important process in carcinogenesis as well as normal development. It's how the body gets rid of damaged cells or unneeded cells. It's a process that contributes not only to the development of cancer, the evolution of cancer, the progression of cancer, but it's a key process in developing resistance to chemotherapy. And the real accomplishment here was developing a small molecule that allows one to modulate how this process occurs in the setting of dysregulation. So, on the next slide here, you can see on your left hand side in the lower part of the panel is a picture representing some of the key proteins that exist in this family. So you can think of this as a family of proteins that have 2 large classes. One class promotes apoptosis or programmed cell death and those are the ones in red, so BIM, BED, BACs and BAC and the ones in blue are BCL-two, BCL XL and MCL-one. For purposes of our discussion, BCL-two is really the critical one. The normal function of BCL-two, this anti apoptotic member is to sequester the proapoptotic proteins as shown in the red on the diagram. When that happens, cells survive. When VENCLEXTA is administered, it has the ability to release the pro apoptotic family members and that can trigger the process of apoptosis and allow cells to die. And then setting of many of the hematologic malignancies, one of the mechanisms of failure to die is very high levels of the BCL2 family or the BCL2 protein specific. So what's shown on this slide is some of the areas where we think that VENCLEXTA can have important clinical activity. And what we're showing is not only CLL, non Hodgkin's lymphoma, multiple myeloma and acute myeloid leukemia. The areas in red are the areas where we have breakthrough designations. So in the setting of 17p deleted relapsed refractory CLL, the treatment of CLL in combination with Rituxan for patients who have progressed on earlier therapies and in the setting of AML and I'll get to some of these as we go through this. The other information on this slide is those areas where there's an asterisk indicates where there's going to be an update presented at this meeting. So if we first focus on CLL, remember this is a drug that we brought into the clinic in June of 2011. A little less than 5 years later, we received our first approval, so April of this year for the treatment of relapsedrefractory 17p deleted CLL. Remember, this is a disease setting where the 17p deletion identifies a patient population that responds poorly to traditional cytotoxic chemotherapy. Shown in the graphic in the first bar is the fact that under approved is that we had in this setting overall about an 80% response rate and we had a 7% complete response rate, meaning radiographic, physical exam, blood work, complete responses in these patients. And what is even more significant is 1, this occurred with a single agent 2, this occurred we also were able to show that patients became MRD negative. So the overall group of patients, 3% of them became MRD negative in the setting of complete response about 10% were MRD negative if you included partial responses and MRD is a, if you will, molecularly based means of detecting whether or not there are cancer cells. And we know from other studies that MRD negativity predicts for longer term responses in this patient even better than complete response does. Shown in the middle bar is that we have activity in the broad relapsedrefractory population, again, about an 80% response rate with 20% of patients receiving a complete response. And then setting the stage for the next study is when you combine venetoclax or VENCLEXTA with Rituxan and anti CD20, we in fact moved the response in terms of complete responses up to about 50% and about 50% of patients have MRD negativity, which is really quite remarkable. There are a number of 2 Phase 3 studies in frontline CLL that are ongoing. There is a pivotal study that has completed enrollment in relapsed refractory disease in combination with Rituxan and there'll be updates to this to the work and CLL presented on Monday, June 6 at Hall A. So I urge you to go over and take a look at that information. Another setting where VENCLEXTA has activity is in the setting of patients who have progressed following or on treatment with T cell receptor pathway inhibitors, specifically in this case, Idelic and IMBRUVICA. When patients progress on this sort of therapy, they have a particularly poor prognosis. They don't respond that well to cytotoxic. Their treatment options are limited. And really the point of this early data is to show these patients are sensitive to VENCLEXTA with overall response rates that are comparable to what I've shown you on the previous slide. And again, there'll be further information updated on Monday and we expect to read out the full Phase 2 study in 2017. So now I'm going to turn to some of the other areas where we're developing VENCLEXTA. Each of these sets are going to have the same setup. I'll talk a little bit about the disease, the epidemiology of the disease and then on the next slide show you a little bit of the data that supports that. So non Hodgkin's lymphoma, Danelle has already talked to you about this a little bit, about 72000 to 73000 cases a year in the U. S, roughly 20,000 deaths. You can see the numbers in terms of patients who receive chemotherapy. The median age of diagnosis is in the mid 60s. There were multiple types of non Hodgkin's lymphoma. Basically, there are 2 large buckets diffuse large B cell lymphoma, which is a more aggressive type, which is treated with anti CD20 therapy in combination with chemotherapy that does have about a 50% cure rate, but if you are not cured, you will buy diffuse large B cell lymphoma. The other bucket is indolent non Hodgkin's lymphoma in many the largest subset of that is follicular lymphoma. While it's called a more indolent disease, it remains incurable by current therapy, again, which is largely anti CD20 therapy or CHOP for bendamustine, rituxan, but it does have a more indolent course with a first line PFS progression free survival about 70 months. And what we're really looking to do in this disease is take advantage of the strong preclinical data that shows combinations with anti CD20 andENCLEXTA can improve responses in this disease. This is looking across some of our early data in a variety of patients with relapsed or refractory non Hodgkin's lymphoma, you can see the overall response rate is about 44% with about a quarter of those patients having complete responses. And you can see there is some variation in sensitivity across the different types of non Hodgkin's lymphoma with Waldenstrom's and mantle zone being among the most sensitive as well as mantle cell lymphoma. So there'll be there are several ongoing studies in frontline therapy in diffuse large B cell lymphoma. There's ongoing work looking at combinations with chemotherapy and relapsedrefractory follicular lymphoma. We expect readouts next year and there will also be further updates on where we are in the program, again, presented on Monday. Multiple myeloma is an area where we are very interested in this disease. It has about 30,000 cases per year. Again, the numbers of terms of treated patients are shown about 12,000 to 13000 patients die of this disease, median age of diagnosis is late 60s, 5 year survival about 50%. In spite of the introduction of new therapies, basically this disease remains incurable and can be a devastating disease to have. We do know there is a strong mechanistic underpinning for our interest in this disease because we know proteasome inhibitors and dexamethasone all modulate BCL-two family members in a way where some of the resistance factors such as MCL1 are down modulated. So in theory, increasing the sensitivity to VENCLEXTA. And on the next slide is showing some of our results that show we do have some we have single agent activity, which we reported on earlier, but we know that if you combine the 2 in clinical studies, particularly in patients who remain sensitive to VELCADE or bertesimib, we have response rates that are north of 70%. These are very good responses. We're very excited about moving this forward. There will be an update presented on Tuesday and we're starting a Phase 3 study in this setting in the second half of this year. So the last part of the VENCLEXTA program I'll talk about is AML. AML again is with most hematologic malignancies that we're dealing with median age diagnosis is in 60s. 5 year survival overall is not great at 27%, but if you're over the age of 65, it's less than 5%. It's an incurable disease for most patients unless you can undergo stem cell transplantation. There are approximately 20,000 patients a year diagnosed with acute myeloid leukemia, about half of them will die. We again have some fairly interesting preclinical data that shows that if you isolate AML cells from patients and study them ex vivo, they have a very many of them have a sensitivity profile very similar to that that we see in CLL and that encouraged us to move forward. And here's some of our data looking at responses to 2 of the kind of standard therapies that are used in this population. One of those are hypomethylating agents, so azacitabine or decitabine where the historical response rates are about 28%, You can see that we're achieving response rates well north of that, about 71% of the patients have CRs, complete responses or CRIs. And the other one that's actually very intriguing is low dose ARRIS C with a historical response rate is down at 10% or 11% and when used in combination, VENCLEXTA and LODAC, we're seeing very good complete response CRI rates of about 44%. And this will be presented as an oral presentation on tomorrow, June 4. And we will be also starting Phase 3 activity in this setting as well in the second half of the year. So this is the news flow for purposes of time. I'm not going to go through it in detail except to say stay tuned. It'll be pretty busy over the next year and then it'll get interesting in the following years as well. And what I'm going to turn to next are the 2 programs that I'd like to talk about in the solid tumor set. 1 is voliparib or PARP inhibitor, an oral agent and the second is ABT-four fourteen, an antibody drug conjugate EGFR and you've heard a lot already today about antibody drug conjugates and how they might work. So let me turn to voliparib. Voliparib is a drug that inhibits a class of enzymes called PARP. PARPs are enzymes that basically look for damage in DNA. When they find strand breaks on DNA, they bind to the DNA. When they bind to the DNA, they help build the scaffold that allows DNA damage to be repaired, particularly single strand breaks. The settings that we're very interested in studying PARP inhibitors are basically twofold. 1 is in the setting of pre existing known defects in DNA repair. So the BRCA, the BRCA type cancers, so BRCA breast and BRCA ovarian. And then the other is in settings where there is, there may be somatic changes in DNA repair and where there may be additional damage to DNA. So we're looking both as a single agent, we're looking at this in those two settings and we are particularly interested in being early in therapy and combining with chemotherapy, so we're in frontline settings. First thing we wanted to establish was single agent activity in the setting of BRCA mutations that's shown in box 1 where our activity in settings where we know there are BRCA mutations on average is about 40% response rate on par with any other PARP inhibitor. And the second is data from a randomized study in non small cell lung cancer where we combined PARP inhibition, vilipparib with backbone chemotherapy. And what we were able to show there is that in a group of individuals who smoke, so predefined, prespecified population with even more DNA damage to current smokers, their overall survival with chemotherapy alone was about 5.5 months. When we added voliparib, it went to 12.5 months. That encouraged us to move to a series of trials shown on the next slide, where we have 5 ongoing Phase III studies, 2 of those in all in combination with chemotherapy, 2 in the setting of where there's probably some pre existing limitations to DNA repair. So BRCA related breast cancer and ovarian cancer and then, 2 studies in non small cell lung cancer, one focused on squamous cell, the other focused on non squamous cell lung cancer and also in the setting of triple negative breast cancer and neoadjuvant trial, which was based on a positive study from the I SPY II trial. So in the last minute, I'll talk to you about ABT-four fourteen. ABT-four fourteen is an antibody drug conjugate against the epidermal growth factor. It's focused primarily on the treatment of glioblastoma. Glioblastoma is a disease that as I'm sure all of you know is a devastating disease. It's the most common brain tumor. The median survival even with aggressive surgery, chemotherapy and radiation therapy is abysmal. And when the disease recurs, it's even worse. It's The incidence around the world is about 28,000. ABT-four fourteen is an antibody drug conjugate shown on the lower left hand side and you learned a lot about how ADCs work and are targeted. ABT-four fourteen is unique in the sense that it only identifies an epitope in EGF that is in the EGF receptor that is exposed upon activation. Activation occurs when there's amplification of the gene or there's a specific mutation called the V3 mutation. This is common amplification in EGFR mutation occurring about 50% of GBM patients. So it's a very good disease to study this in. And because of that ability to specifically target only activated, we don't see the typical skin rash that comes with the usual EGFR inhibition. Most importantly shown in the lower panel is our ability to specifically deliver this antibody tumor. So this I know it's a little difficult to tell, but it's looking at a patient from the, if you will, neck up on the most left hand panel is immediately after a zirconium labeled version of ABT-four fourteen, the antibody is delivered to the patient. And what you can see is over the next 5 days in the area in red is the accumulation of the antibody in the area of the patient's tumor. Just to give you a flavor of the results, we're looking at a waterfall plot. Anything below the line is tumor shrinkage, anything above the line is increased in size. You can see about 50% of the patients have a response to the drug and tumor shrinkage. Based on this and other preclinical data, we've embarked on an aggressive program for ABT-four fourteen in the setting of glioblastoma. We now have 2 large international trials that are ongoing, one for patients who have relapsed disease, 1 in frontline disease and you can see that we're expecting readouts from these trials over the next couple of years. And I will just end with the consolidated news flow. And again, for purposes of time, I won't walk through this and I'll ask Mike to come back up and take us to the next part. Okay. As I mentioned at the start of the day this morning, we've created a new role. That role leads oncology discovery into early development across AbbVie and it will be based on the West Coast as part of our West Coast Oncology Hub. We're very fortunate to be able to recruit Tom Hudson for this role. Tom played a leading role in the determination of both the physical map of the human genome through the Human Genome Project and the genetic map of the genome through his leadership of the HapMap program during his days at MIT in the 1990s. He's gone on to have a very productive role in cancer genomics and cancer biology in a number of institutions. He joins us from the Ontario Institute of Cancer Research where he served as its founding President and Scientific Director. So here to tell us a little bit more about himself, about his background and about the ideas he'll bring to AbbVie Oncology is Tom Hudson. I'd like to introduce Tom. Good morning. Very grateful to be here. It's a little daunting after all these great presentations and since it's only day 6 for me at Ebbly, I'm going to be presenting a couple of ideas initiatives mostly that I've led in the last 10 years to give you a sense of experience and my experience, experience which I'm going to use as I manage the growth of oncology discovery and early development at AbbVie. We all know cancer is very common and 1 out of 4 Americans are going to die from cancer. His State of the Union address, President Obama invited Vice President Joe Biden to champion and spearhead a national effort, a moonshot in the fight against cancer. I think there has been some discussions in some papers whether this is really a moonshot. So there's always controversy about it, but this is really important. And really as an moonshot, there's a lot of new knowledge, new technologies that have been developed have been found and it's important to accelerate bringing these to patients so that ultimately we can bring benefits. So this is an important problem and there's a lot of opportunities and I think it's going to inspire as Joe Biden said a new generation of scientists to really bring and make an impact in the fight against cancer. So I'm a clinical immunologist, but most of my research has been in genomics and cancer research. And as Mike mentioned, I was part of the Human Genome Project. I was I think the first postdoc at MIT when the genome started got launched Genome project got launched in the U. S. And we worked a lot on technologies, but we also worked a lot on mapping the genome. I was in charge of the group that map did the physical map of the genome, the gene map of the genome. We eventually found the concepts for the haplotype map projects, which again were used by my I participated when I was at McGill in terms of making that map. The human genome project brought us a lot of discoveries in rare diseases. Over 2,000 genes were found within a few years of this information going out to the public domain. The HapMap itself also found several thousand loci for common diseases, an area of genetics which actually was difficult to probe before then at least drove successfully. It also brought technologies. We developed lots of robotics as you can see in an old picture, I used to have hair, but also developed the concepts of microarrays. To help design novel microarrays with IP metrics for expression SNP chips. And again, lots of discoveries and technologies and applications. Today, I'm going to talk mostly about the International Cancer Genome Consortium and the Ontario Institute For Cancer Research, 2 of the initiatives which I've been associated with the most in the last 10 years. The International Cancer Gym Consortium was a moonshot that was launched in 2007 by the global research community. I was asked by NIH to Welcome Trust to bring a think tank together which we had a meeting in 2007 which made some very bold decisions. We knew at the time that cancer, we call it the disease of the genome, as Mike has mentioned. We've known for many years under the microscope the karyotypes that almost always abnormal in most cancers. And here in this case, you can see a lot of chromosome 2s. You can see rearrangements. Is not a normal karyotype. So very common in cancer. We have discovered over 41 years that h translocation, BCR ABL, can actually give rise to a fusion gene. And if you inhibit that fusion gene with Gleevec, you can actually put patients in remission, long term remissions. You're not curing the disease, but people it becomes a chronic disease. So the concepts of cancer is a disease of the gene was important. The concept that would be mutations in cancer genomes that were yet to be discovered was very strong, but we didn't have the tools until then actually do a systematic search of cancer genomes. So and we want to find, of course, additional drivers to for drug development programs. So we decided to sequence 25,000 cancer genomes. 25,000 cancer genomes really in concept was 50 different types of tumors across the world and we would collect 500 tumors and sequence them and put that information in public domain to accelerate the discovery of new targets. It was a moonshot because no cancer genome had been sequenced in 2,007. We knew that technologies were coming. We knew people would be interested in this project. We realized those cancer is a very different disease in different parts of the world, I'll mention on my next slide. And it was important to be able to tackle all types of cancers and do it in a systematic way. The iCGC today, so I just gave my role to someone else, but it's actually very healthy. It's 88 projects across the world, so it's more than 50. And each of these bullets here represents a big investment by a funding agency, a group of pathologists, clinicians, genome standards, computer scientists generating data and putting out in the public domain. You heard a bit earlier about the small cell lung carcinoma project in Germany by Roman Thomas. It's one of those projects on this slide. In Japan, we study liver cancer due to viruses. And in France, we study liver cancer due to alcohol. And they actually give rise to different mutations and actually should be treated differently. So of course, I'm not going to explain a lot, but we certainly see our study in the span of cancer genomes across the world and we're seeing a lot of similarities in some type of tachychambers cancers we didn't expect and we see a lot of differences in the ones that come from the same tissues. The data is being generated. We're more than halfway there by 2018, which is a deadline we'll reach the 25,000 cancer genomes. But this information, as I said, is already going out to academic groups, but also to industry to identify new targets. And this has led to discovery of many new pathways. We didn't understand we didn't expect to find a lot of genetic mutations in epigenetic genes. But in fact, it turns out that many of those mutations are very early like in AML and in cancer stem cells, for example, mutations in the MT3A or actually the initiating mutations. So these are really important insight we've had in splicing in many other mechanisms that we didn't know before we start exploring. The typical cancer cell to a couple of the cancer genome has 10,000 somatic mutations. Most of them are passengers. We wanted to find the ones which are drivers. So there's still a lot of work to sift through all the data sets on the important ones, but many have been identified, many of the cancer genomes and these are becoming biomarkers, seeds for new drug development drug development projects and precision medicine. So what has been the impact so far of the ICGC? Well, there's been great science and I'm not going to go through all the science because each of the groups have actually been able to publish major seminal papers into different types of cancers and put that out in the public domain as new insight about cancer. So science wise, it's been a great project. But it's also been a translation and it's translating. We've learned a lot about it on how to translate. And I think one of the major things we're learning is cancer genome is not just something of a genome center anymore. It's something that's going to happen in a past lab. Initially, we thought we would just want to discover the driver mutations and just sequence those genes. And for those for which there was an oncogene, we could which we could inhibit, we actually started therapies based on that. And so that was the original concept of what we were looking for. More and more we know we see a lot more in cancer genome, for example, genome instability. The more genome instability there is generally, the tumor is more aggressive. Even if you take an early prostate cancers, we published this in Nature Genetics last year, an early prostate cancer, where has the 1st genial alteration is the highest biomarker of aggressive disease. Maybe those patients should be treated more aggressively. Of course, we've heard about the DNN stability important for in processes right now for DNA damage, PARP inhibition, combination therapies in this area might be very interested in how we would treat patients for the future. But again, it depends on looking at that patient's genome to identify the index of genome instability. And finally, neoantigens in all our publications, we used to say how many mutations we found, how many were neoantigens, neoantigens, but it's only because of the rise in immunotherapy we also realized that the more neoantigens there are and specific ones we're trying to able to identify that the best ones, but the more they are, the more people respond to the novel immuno therapies. So the cancer genome is becoming something to be done to be used in a diagnosis of every patient. So the last 10 years, I've also been leading a new institute, a translation institute that was founded by the institute, a translation institute that was founded by the government of Ontario. There were a lot of similarities between the launch of OICR and what the moonshot was announced by President Obama, because very much it was about the same thing of identifying the great discoveries happening in labs and accelerating and bringing it to the clinic. It wasn't about just discovery research anymore, but it's actually accelerating the bringing the path to bringing novel therapies to patients. But it took a lot of effort to just form the collaborations of all the cancer centers in the province set up at each of the cancer hospital clinical trial group and bringing new researchers. Of course, we had some important new funding to stimulate not just the discovery, but the translation. Still a small institute, we did focus on difficult to treat cancers such as pancreas, GBM and AML. There are a lot of work on clinical biomarkers such as genomics I've just mentioned or a lot of biomarkers on early disease, early prostate, early breast cancer where we want to distinguish more aggressive forms, more indolent forms of cancers and also some population health studies. Just to give you an example, over 20 companies were launched with the support of OICR. So that's important. That creates jobs. That's important for the minister to actually see that these companies are having products and bringing jobs. But a lot of it is private sector investment, that's the second graph here, which continues to grow around. Once you have a good project, you're able to attract a new investment and not just government dollars. It is still great to find. So if you look at the number of papers in the top percent top 10 percentile or highest citation impact in terms of percentage, they come from OYCR as opposed to in comparison to 100 institutes in Canada. We've been able to attract scientists. We've been able to bring scientists at different centers working together, the 1700 clinician scientists and trainees and others working in these in our large programs. And then our population health project, which allowed us to identify reasons why people were not getting their colon cancer screen as they were supposed to and changed policy, changed guidelines based on some evidence we gathered and that actually improved the colon cancer screening rate by more than 15%, which is about 400 lives saved for the year. OICR is an academic biotech and I'm not here to do a presentation of OICR. I mostly want to do a presentation on kind of the experience that we've learned in translation. But we did develop biomarkers, novel therapies, very high risk ideas at the time and move them forward towards the clinic. I just thought I would take one example of an immunotherapy study. If you go back to 2,007, 2008 as we were launching decided to launch this program, immuno oncology was not hot. In fact, it was deemed to have overpromised, underdelivered and there were scientists that came to us into YCR said, hey, we can cure cancer in mice using next generation therapies, but we just can't get them to patients. So John Bell was one of them. He's a virologist involved in the 1st generation of alcoholic viruses. And he says, I and my colleagues all need to be able to show whether these things are going to work in humans. So that's so one of the 6 programs and projects inside there was actually developing a next generation oncolytic virus, but also bringing the concept of vaccination to create what we call a non COVID vaccine. 2 of the former students of John, which have their own labs, they did a lot of this work, data stored at the bottom, basically screened different types of RNA viruses across the world to actually find the ones with the best oncolytic activities. I didn't say the kind of the basis therapy, but at the base of all this, but cancer cells generally have defective innate immunity. So viruses can penetrate cancer cells better than normal cells. So what we are looking David was looking for the viruses across the world, which would have the most of this on clinic penetration on clinic activity. But then also decide to boost to insert in these vectors some tumor antigens. In addition to that, by Lichty at McMaster decided let's boost in person's immune system before we treat them. So for a month before you actually give the treatment to actually boost immune system against that 2 cells. So what OICR was able to do, which you can't do in traditional academia is to deal with GMP manufacturing of the agents to large scale primate studies, very advanced preclinical studies and eventually is doing a Phase I is right now in Phase I study. We learned a lot and this is what I want to say. We embed research in our clinical trials. Here we were doing a lot of biopsies, a lot of measures of what's happening in the immune system in the periphery in some of the organs. And here for example, we discovered a way to really boost the immune system T cell responses that are extremely high are happening. And in this case, we discovered that while we see that although tumor most tumors present antigen at the levels of the tumor, there's a lot of immunosuppression in the micro environment of the tumor. And this strategy boosts the immune system against tumor antigen in the spleen and that's why the responses are so good. So these are things we've learned and you wouldn't do it if you weren't embedding the scientists that made the discoveries in the clinical trial studies themselves. And Mike mentioned that we are that Abi is very interested in tumor microenvironment. There's a lot to be learned about that environment and how we could use potentiates some of these novel immuno oncologies. Maybe one before I get to my last slide, because I've been asked, why does that come to AbbVie? Well, I'm obviously very passionate about cancer research and I wanted to do more in the area of therapies. So I did look for organizations. It could have been in academia or in industry where there's a real commitment for cancer research, a real commitment for developing new therapies that would be based on science and on unmet clinical need. And I found this all all of this at AbbVie and more. It's a very bold company, but you've seen the projects, bringing in pharmacichlix stemcentrics, a very bold company, very committed to oncology, great capabilities and also a great culture of team science, which is also very important in the types of projects I want to develop. So looking forward, I see an opportunity to build on the experience that I bring from ICGC, OICR and moonshot to continue to inspire individuals and groups to think big, to stimulate creative thinking and risk taking, intensifies the interactions between the discovery teams and clinician researchers to accelerate this translation going from discovery right to patients and capitalize on all these new technologies and knowledge to again accelerate cancer research, bringing new therapies to patients. So my priorities will be again, I'm only on basics, but I can tell you right now, still the priority is to grow this existing AgG pipeline. We will do critical mass in immuno oncology. We're going to go beyond the concepts which are being developed at this point in the field. We will definitely try to unlock the potential of different types of immune cells. I also hope to explore the interaction between cancer genome signatures and immune response because both the cancer genome and immune response are at the heart of what we are talking about when we talk about precision medicine. So hopefully, all of this is going to bring long term benefits to individuals, especially cancer patients and society. So and the last speaker, the oncology section. The day is not over, but I think we're going to take a 15 minute break. There's coffee outside. There's food. You can bring some of the food boxed lunch inside the room. We'll be restarting in about 15 minutes. Thank you. Okay. The music stops. I think that's my cue to get us going again. I'll give a minute just for people to sit down. All right. So thanks for your attention this morning and for respecting our short break and we'll get back to our program. I think, yes, if we could advance slides. We're going to come back now with immunology. As I said, immunology is an area that has been very important to us and it will continue to be very important to us for quite some time. Here to talk about our immunology efforts, we have Shao Lee Lin from Clinical Development and joining her in just a moment will be Lisa Olson for discovery. So without further ado, I'll turn it over to Xiao Li. Thank you, Mike. AbbVie's leadership in immunology comes from over a decade of experience developing 13 indications worldwide for HUMIRA and treating actively almost a 1000000 patients today. AbbVie remains committed to being the leader in immunology with a pipeline of 20 new molecules being evaluated across 14 different disease states with almost 200 active studies ongoing in over 50 countries that leverage our global infrastructure, our extensive external network as well as our deep expertise in this field. Over the past decade, HUMIRA has played an integral part in defining the standard of care for multiple disease states across rheumatology, dermatology and gastroenterology. Looking to the future, we remain focused on raising the bar and redefining that standard of care across our core disease areas. Our primary goal across these areas is to achieve complete remission for the vast majority of our patients. In rheumatology, we still use measures such as low disease activity or 70% response rates and we call these high degrees of response. And in fact, a minority of our patients still are able even to achieve those response rates. Today, my colleague Lisa Olson and I will tell you about some innovative approach that AbbVie intends to take, both with single agents as well as combinations of agents to continue to raise this bar. In dermatology, our goal is full skin clearance with durable responses and also the search is on for oral treatment options for these disease states. And in gastroenterology, specifically inflammatory bowel disease, the less than half of patients achieve remission with initial induction of therapy and less than half of those actually maintain that response after a year of treatment. Clearly, in inflammatory bowel disease, there remains significant opportunity to improve those remission rates as well as ultimately achieve full mucosal healing. ABT-four ninety four and rizankizumab are our 2 most late stage programs within immunology that very much like HUMIRA have the potential across multiple disease states within our core areas of strength. ABT-four ninety four is in Phase 3 development for rheumatoid arthritis, rizankizumab for Phase 3 in psoriasis and both agents have are actually being tested in Crohn's disease and have potential within that disease stage. And I'll tell you more about each of those programs today. ABT-four ninety four is a highly potent and highly selective inhibitor of JAK1. The inhibition of Janus Kinase or JAK is a clinically validated and approved therapy for rheumatoid arthritis with tofacitinib. The problem with dosing tofacitinib has been relative to its safety profile, where it's been limited based on side effects such as anemia secondary to JAK2 inhibition. The hypothesis for next generation agents has been whether or not differential selectivity of JAK1 relative to JAK2 or JAK3 could actually provide the potential for higher exposures to JAK1 relative to those other 2 JAKs and therefore results in higher efficacy, while achieving a better safety profile from sparing the anemia associated with JAK2 as well as preserving the normal immune function associated with JAK3. ABT-four ninety four is a highly potent JAK1 selective inhibitor with single digit animal potency against JAK1, 74 fold selectivity of JAK1 over JAK2 and 19 fold selectivity over JAK3. The potential for ABT-four ninety four to demonstrate this increased efficacy is seen here in this model based meta analysis across available RA trials for ABT-four ninety four as well as the other JAK1 selective molecules that are currently in development. The 3 panels are ACR-two thousand and fifty and seventy scores. Highlighted in blue are the 2 doses of ABT-four ninety four that were studied in Phase II as twice daily doses and is currently being evaluated in Phase III as single once daily equivalents. The light blue box represents the low dose of AVP-four ninety four being studied in Phase 3. And as you can see, it compares it is at least as good as the high dose of each of the other JAK1 selective agents currently in development. Of particular interest is the dark blue box, which represents the high dose of ABT-four ninety four that's being studied in the Phase 3. And ultimately, these data suggest that that high dose consistently performs better than the other JAK1 selective inhibitors. We are particularly encouraged by our observed data for TNF inadequate responders. Our Phase 2 study enrolled particularly difficult to treat TNF inadequate responders, individuals who had failed 2 or even 3 biologic therapies before being entered into the study. And again, what you can see are the 3 panels of ACR-two thousand and fifty and seventy scores, blue highlighting the doses of ABT-four ninety four being studied in Phase 3. The lower dose again is light blue, which performs at least as well as the high dose of the only other JAK1 selective agent that's been tested in this difficult to see population to date. And the high dose of APT-four ninety four again performing consistently better. As you can imagine, we were very encouraged when we saw these results at the end of Phase 2 and eager to move to Phase 3. And in fact, by leveraging that global infrastructure, the vast network as well as our deep expertise in this field, we were able to move end of Phase 2 go decision to 1st subject dosed in Phase 3 in a matter of 3 months. The Phase 3 program for APT-four ninety four in rheumatoid arthritis is composed of 6 pivotal studies and they're designed to deliver a comprehensive label that will enable use from left to right on the table, first line in methotrexate naive, in use in inadequate responders to oral disease modifying agents such as methotrexate and other oral agents, and use of course in the most grievous unmet need, the biologically inadequate responder population. Within the context of these 6 studies, 2 of the studies are active comparator trials against adalimumab as well as abatacept and 2 of the studies have radiographic endpoints that will evaluate the ability of ABT-four ninety four to inhibit structural damage after a year of treatment. As we have done for HUMIRA, we intend to fully maximize the potential of ABT-four ninety four across multiple disease states within our core areas of strength. Next, I'd like to tell you a little bit more about rizankizumab. Rizankizumab is a monoclonal antibody against IL-twenty three that was recently licensed from Baragering and is currently in Phase 3 development for psoriasis. IL-twenty three signaling is up stream of TNF alpha and IL-seventeen and has been implicated in the inflammatory cascade across multiple autoimmune diseases, including psoriasis, Crohn's disease and psoriatic arthritis. Risankizumab binds the P19 subunit of IL-twenty three and thereby exhibits its signaling. This is in contrast to ustekinumab, which binds the common P40 subunit of IL-twelve and IL-twenty three and blocks both IL-twelve and IL-twenty three function. It was uncertain whether the clinical efficacy that's been seen with usukinumab was secondary to IL-twelve function, IL-twenty three function or blockade rather or both. And it wasn't until preclinical experiments targeting P35, the unique subunits to IL-twelve were performed and showed no efficacy that it was hypothesized that the next generation of agents that targeted T19 such as rizumkizumab could block solely IL-twenty three and could result in efficacy at least as good as ustekinumab, while sparing the normal immune function associated with IL-twelve. And in fact, rivankizumab has demonstrated in Phase 2 the potential to be a transformational new therapy in psoriasis. The panel on the left are PASI90 or 90% response rates at 12 weeks and the panel on the right 100% response rates for complete clearance of skin disease at the 12b time point. On the far right of each of those panels is a teal colored bar that is risankizumab. As you can see from the height of the teal colored bar, about 80% of people actually responded at a 90% response score at 12 weeks to this therapy. In addition, about 50% of people actually had total skin clearance at 12 weeks with risankizumab. This is in comparison to actually all of the other therapies that are currently available for psoriasis, which is currently certainly the biologic therapies. And from left to right, just to give you an idea, the anti TNFs in purple with Humira, IL-twelvetwenty three mechanism with STELARA in brown or orange, the IL-17s in blue and gray and other IL-23s that are in development in green and blue. The other very attractive feature of rizantizumab for psoriasis is its dosing paradigm, relative to the next most efficacious agent instance, which is the gray bar in the middle of each of these panels, the IL-seventeen ekizumab is dosed every other week, where rizumab is dosed every 12 In addition, brisankizumab has demonstrated very encouraging Phase 2 results in Crohn's disease. These were recently presented at the DDW meeting. Here, you see the clinical remission scores for rizankizumab in Crohn's disease relative to the same endpoint from other agents currently in development as well as currently available agents from their Phase 2 as well as Phase 3 studies. Ultimately, you can see from the length of the bar that risankizumab appears to perform at least as well, if not better than most of the agents that are currently in development and of the ones that are currently available. What was particularly encouraging about this study was that it also enrolled the most difficult to treat patients, most of whom had failed up to 3 TNF agents prior to entry into the study. And also most of whom had documented over 10 disease of active Crohn's disease. What's not shown on this slide is another piece of very encouraging data, which is that 20% of the subjects from this study actually demonstrated endoscopic remission at this early 12 week time. And hence, we intend to move Crohn's disease into Phase 3, and we expect that to happen later this year or early 2017. The Phase 3 program for psoriasis will cover about 2,000 patients, and consists of 4 pivotal trials. 2 of those pivotal studies are head to head comparisons versus STELARA. 1 is a withdrawal of the treatment study and 1 is a comparator against adalimumab. All three studies are ongoing and enrolling rapidly. As for HUMIRA and for ABT-four ninety four, we fully intend to maximize the potential of brisankizumab across our core areas of strength in addition to the Phase 3 study that's ongoing in psoriasis. The Phase 2 in Crohn's disease is a Phase 2 study that is also ongoing in psoriatic arthritis and we intend to study rizumizumab also in ulcerative colitis. The data readouts for both of these late stage programs will happen within the next 1, 2 3 year timeframe. And we believe that these agents even of themselves provide the opportunity for sustained growth for our immunology franchise. However, in addition, we have a number of Phase 2 assets that we'll be reading out within the next 1 to 2 years. These include our bispecific approaches to TNF and IL-seventeen as well as IL-one alpha beta, an antibody approach to IL-six as well as an antibody against IL-thirteen. With that, I would like to turn over the next several slides to my colleague Lisa Olson, who will tell you about some very exciting early programs within immunology. Lisa? Thank you, Shao Lee. So now I'd like to turn your attention to 3 discovery programs that continue to drive the search for transformational efficacy in our 3 key disease areas. 2 of these programs 2 of the programs, the anti TNF steroid ADC and the combination of JAK and BTK small molecule inhibitors are striving to achieve deep remission in rheumatology, with the anti TNF steroid ADC also having the potential to drive remission in IBD. The 3rd program is a small molecule inhibitor of ROR gamma T and holds the promise of an oral agent with high efficacy for psoriasis. So our anti TNF steroid ADC project really combines our deep understanding of TNF biology with the experience that we've gained in developing the antibody drug conjugate platform in oncology. And it's not usual to think of an ADC in immunology. So I'd like to share the story of how this came about. We know that one of the earliest activation events in immune cells is the expression of TNF and the placement of that TNF on the cell surface membrane. We know from studying anti TNF for over 10 years that ligating that membrane TNF with an antibody results in rapid internalization of the entire complex inside the cell. This biology will be depicted on the video where you'll see an anti TNF antibody labeled in red being taken up by a macrophage following binding to membrane TNF and ending up in the lysosome of the cell, which is stained in blue. Well, there we go. So one of the key characteristics of an ADC project, is high density expression of the ligand on the health surface membrane and rapid internalization as we heard earlier, from our Stemcentrx colleagues. What you saw just there is an example of a target that would be a very attractive candidate for an ADC project. The second important consideration is the payload. And in our case, we chose steroids because steroids have been extremely effective anti inflammatory agents for a number of autoimmune and inflammatory conditions. But their use is restricted because of side effects that limit not only the dose that's used, but the duration of dosing for the patient. So our creative biologics architects created a molecule, which has an anti TNF monoclonal antibody backbone coupled with a novel highly potent steroid. This molecule binds systemic TNF, but also binds membrane bound TNF and delivers the steroid directly to the activated cell, where following internalization, it can suppress that cellular inflammation. The 3rd most important characteristic of a successful ADC project is that it works. What I'm showing you here is the preclinical data that supports the promise of the ADC project delivering deep remission for RA. On the left hand side is the results of therapeutic dosing in a mouse arthritis model with paw swelling as the indicator of inflammation on the axis over the course of the experiment. Relative to vehicle shown in black, a single dose of systemic steroid is shown in blue, is quite effective in resolving inflammation in the model. However, its effectiveness is relatively short lived, as you can see. Treatment of the mice with an anti TNF antibody shown in green delivers consistent about 50% suppression of inflammation. The treatment of the mice with a single dose of the TNF steroid ADC resolves this disease for an extended period of time. This efficacy was extremely compelling to us because it came without the side effects that are normally observed with systemic steroids. And that data is shown on the right hand panel. Here, we've used an acute model of inflammation to compare systemic steroids shown in blue with the TNF ADC construct. As you can see, both molecules are about equally effective in suppressing inflammation in the model. But the systemic steroid has very potent suppressive effect, both on bone and on the pituitary axis, which is not shared by the TNF ADC at doses that delivered the compelling efficacy that you see on the right. We are extremely eager to test the promise of this molecule and we're advancing it into clinical testing early next year. The second program I'd like to share with you is a different way of doing combination therapy and that's combining 2 small molecule inhibitors. So we know that rheumatologists are very comfortable with combination therapy as a means to achieve greater disease management. Indeed, the standard of care in RA is a combination. The combination of an anti TNF antibody with methotrexate. What this really suggests to us in discovery is that it's in a complex disease like RA, it's likely that one needs to inhibit 2 complementary mechanisms to get full management of the disease. Shao Lee shared with you the compelling data with our JAK1 molecule in RA, which gives pretty broad spectrum inhibition of T cell responses. We're fortunate at AbbVie to have a novel suite of BTK inhibitors, which themselves will inhibit both B cell and myeloid cell mechanisms, 2 mechanisms that we know play a role in a number of autoimmune diseases including RA. Therefore, we generated the hypothesis that actually combining inhibitors of these 2 complementary but distinct mechanisms would deliver additive efficacy for autoimmunity. And the data preclinical data that supports that hypothesis is shown on your right. We are combining 2 low doses of the JAK1 inhibitor with the BTK inhibitor shown in red, delivers substantially greater efficacy than what's observed with each of the individual components alone. This program, we're advancing into RA again early in 2017. The last program I'd like to share with you is our ROR gamma T inverse agonist small molecule inhibitor. And I think what has been extremely interesting as an immunologist over the last 3 or 4 years is to see the efficacy in psoriasis, this chronic inflammation of skin disease when with inhibitors of both the IL-twenty three and IL-seventeen pathway. We believe that there is a big opportunity for an oral small molecule inhibitor of this pathway, which is so central to the pathogenesis of that disease. And the first program that is emerging from discovery is the ROR gamma T program. ROR gamma T is an obligatory transcription factor for the development of Th17 cells, the cells that produce the majority of IL-seventeen in an inflamed condition. It's also essential for the actual transcription of the cytokines themselves. So inhibition of this pathway would result in both lower numbers cells and therefore also lower amount of cytokines. We've demonstrated preclinically that using our Rgamma T inverse agonist is very effective in inhibiting IL-twenty three driven inflammation, as shown in the histology sections at the bottom part of the slide. Treatment of mice with ROR gamma T results in a suppression of IL-twenty three driven inflammation and brings the swelling down to the level of vehicle treated control. Along with that suppression of inflammation, we can measure complete inhibition of the numbers of IL-seventeen producing cells, suggesting that this oral intervention in this pathway will be very effective in inhibiting pathogenesis driven by this pathway and very effective, we're hopeful, in psoriasis. This lead molecule will advance into humans this year. So now I'd like to invite Shelby back up to give you a summary of our overall immunology pipeline. Thank you, Lisa. We've shared with you today across immunology a number of exciting data sets both for ABT-four ninety four and rasinkizumab, our late stage programs that we think ultimately will position these molecules well to bring advancements in rheumatology, in RA, in Crohn's disease as well as in psoriasis. And we have again data reading out in the next 1, 2 3 years for those programs. In addition, we've talked about some near term readouts for Phase 2 as well as giving you some exciting preclinical data from these early stage programs that Lisa just covered, which will enter the clinic in the next year and have clinical data in the next 2 year timeframe for us to evaluate. Overall, we believe that this steady stream of activity across our late stage as well as early stage immunology assets positions AbbVie well for continued leadership in immunology both now as well as into the future. With that, I'll conclude our immunology section and actually introduce myself to tell you more about hepatitis C as well as inagolix, hepatitis C first. So AbbVie is also committed to advancing the next generation of hep C cure. Current therapies have been nothing short of transformational for patients with chronic hepatitis C with over 1,000,000 patients cured to date and cure rates that have been greater than 95% for many of the genotypes. However, there definitely remains unmet need. The World Health Organization in fact estimates that over 100,000,000 patients remain chronically infected with hepatitis C. We need agents that treat all genotypes. We need agents that ultimately will address the resistance associated variants that occur at baseline as well as secondary to our 1st generation agents. We need agents that will address the difficult to treat populations like genotype 3 and cirrhotic patients. And we would like to provide our patients with shorter treatment durations. Ultimately, AbbVie's next generation hep C cure can meet this challenge. It is a once daily oral combination of ABT530, a novel NS5a inhibitor as well as ABT493, a novel NS3 4a protease inhibitor. To give you an example of the high degree of potency that's going to be available in this combination, this is actually in vitro data that compares the activity of ABT530 or NS5a inhibitor versus currently available NS5a inhibitors shown in the other panels. The x axis are common resistance associated variants and the y axis is degree of potency, where the shorter the bar, the higher the potency or the greater the activity against the given variant. And the higher the bar, the lower the potency or the more permissive that agent is relative to the replication of a given variant. And in the upper left hand panel, you can see that APT-five thirty has a lot of white space. Ultimately, the bars are very short and that designates that it has a high degree of activity against a wide variety of the common resistance associated variants. This includes the Y93 to H variant, which is the 2nd bar on the right in each of these panels. It's a common variant that's found in urologic failures to NS5a. In addition, this high degree of potency to baseline resistance has been demonstrated in patients. So this is the Magellan results from the Magellan 1 study that was recently presented at EASL in Barcelona and demonstrated high cure rates in patients with baseline resistance, where 82% of patients had resistance associated variants or RAB at NS3 or NS5a, 32% had both and 24% had triple or double mutations of NS5a. As you can see from the highlighted brown box, AbbVie's next gen hep C cure was able to achieve 95% SVR whether it was in the presence of riboviruses or not. In fact, we've been able to achieve high cure rates across all of the patient populations that we've evaluated in Phase 2. In addition to the GEDA type 1 direct acting antiviral experienced treatment failure or 1st generation treatment failures that I just showed you, which was MAGELLA-one study. We've also evaluated the difficult to treat genotype 3 non cirrhotic patient population and achieved 100% SDR as well as the genotype 3 compensated cirrhotic patients and also achieved 100% SVR. With regards to duration, in genotype 12 treatment naive as well as experience, we've been able to take the duration of treatment down to 8 weeks and still achieve 100% sustained urologic response. In genotype 3 treatment naive, this is true as well. And in genotype 4 through 6 treatment naive and experienced, we've been able to do this with 12 weeks of duration in Phase 2 with an 8 week regimen that's being tested in Phase 3. Overall, we believe that AbbVie's next gen hep C Qur and the Phase 3 program associated with it will be able to address the residual unmet medical need within the context of hepatitis C cure. In addition to testing treatment durations as short as 8 weeks, we're looking at all the patient relevant populations, including the treatment naive, the direct acting antiviral experience, special populations such as in renal impairment and cirrhotic patients and the difficult to treat, again, genotype 3 in cirrhotics. In addition, within the context of the Phase 3 program, there's also a head to head study in genotype 3 non cirrhotic treatment naive subjects versus sofosbuvir, the classifier. We anticipate that the next gen hep C cure will be commercialized in 2017. Finally, I'd like to share with you data from our elagolix program that we're very excited about. Elagolix is an orally active venetrotrophin releasing hormone antagonist. And the data that I'll show you will demonstrate that it has dose dependent suppression of estrogen and progesterone. With low doses of elagolix actually resulting in partial suppression and high doses resulting in more maximal suppression. Emagolix has a rapid onset of action and is readily reversible when therapy has stopped. And therefore, we believe that it has significant potential for the management of hormonally mediated conditions such as endometriosis and uterine fibroids. So what is endometriosis? Endometriosis is actually when the normal lining or endometrium of the uterus actually is found outside of the uterus. This tissue is responsive to estrogen and therefore with monthly cycles, you could have growth of this tissue as well as inflammation outside of the uterus, which results in menstrual pain associated with menses or dysmenorrhea. Endometriosis can also be associated with chronic non menstrual pelvic pain and about 50% of infertility in women is actually associated with endometriosis. Endometriosis affects about 6% to 10% of women with and therefore an estimated 176,000,000 women worldwide. The treatment options for endometriosis are quite limited and are depicted in this graphic with an x axis designating degrees of invasiveness, if you will, with higher degrees of invasiveness sort of towards the right and the y axis denoting degrees of efficacy with improved efficacy going up on the vertical axis. In the lower left hand corner are really the main phase of therapy, which have minimal invasiveness, but also minimal efficacy. And these are chronic analgesics, oral contraceptives, which have particularly low efficacy when associated with non menstrual pelvic pain as well as the progestins such as Depo Provera, which is associated with weight gain, mood changes as well as bleeding. High up on the efficacy scale, but more invasive are the gonadotropin releasing hormone agonists. In the U. S, that's primarily Lupron. Lupron is associated with complete hormone suppression. It's effectively an overdrive system of the hormonal axis. It's dosed subcutaneously once every month or once every 3 months. And we'll talk more about Lupron in a moment. In addition, there are surgical options such as laparoscopy that are obviously invasive and unfortunately are also associated with a high 1 year recurrence rate. And by the procedure itself can be associated with adhesions that also in and of themselves can lead to chronic pelvic pain. So the unmet medical need in endometriosis is significant. We really need something that is minimally invasive that has a high degree of efficacy that ultimately can occupy that uplift left hand corner of this graphic. Ideally, that would be an oral agent that's rapidly reversible in the event that, for instance, that a woman would become would want to become pregnant, had a high degree of efficacy or significant pain reduction, did not require laparoscopy to initiate treatment and ultimately can provide long term efficacy. We believe that elagolix has this potential and I'll show you the data that we believe supports this. So elagolix has been studied in 2 Phase 3 pivotal studies to date with 6 months of data available so far. The primary endpoint for these studies is pain at menses, a change from baseline in pain associated with menses or dysmenorrhea. The teal colored bars here are the placebo group. The purple bars are the low dose of elagolix, again associated with partial suppression of the axis and achieving about a 45% response rate relative to reduction in pain associated with menses. And the blue bars are the high dose of hemodoics or 200 milligrams twice daily, which is associated with about a 75% response rate with regards to decreased in pain. These responses were seen as early as 3 months and were maintained out to the 6 month time point. And as you can see across the two panels, they were highly reproducible across the 2 pivotal studies. When we look at a key secondary the key secondary endpoint of non menstrual pelvic pain, again, within the context of the 2 pivotal studies, you can see that the low dose of elagolix is associated with about a 50% response and decrease in non menstrual pelvic pain and the high dose about a 60% response, again highly reproducible across the two studies. The suppression of the estrogen and progesterone hormonal axis is known to be associated with the decrease in bone mineral density, which is an anticipated side effect. And here you can see the mean percent change in terms of base from baseline in terms of bone density for the low dose of elagolix, which is somewhat limited, a limited decrease and the higher dose of elagolix in blue, which is a higher decrease. And to put this more in perspective, I'll show you the bone density decrease that's associated with treatment of Lupron, which again remember completely inhibits this axis. And therefore is associated with the largest degree of loss of bone density. Lupron is approved for use as a single agent for about 6 months. And ultimately, if needed beyond 6 months, it can be used within the context of hormonal add back therapy, which is the light blue bar on the far right here. As you can see, hormonal add back therapy is actually quite effective in preventing the bone density loss from Lupron. And options for bone protection are currently under evaluation for the high dose of eladzellimax that includes the potential for hormonal add back therapy among other considerations. In addition, I'll next talk to you about uterine fibroids and I'll show you how elagolix plus hormonal add back actually is successful in regards to inhibiting this loss of protein. So uterine fibroids, what are they? They are benign tumors of the uterus that can occur singly or multiply within the muscle layer of the uterus. These tumors are responsive to both estrogen and progesterone and they're associated with heavy menstrual bleeding. And what I mean by heavy menstrual bleeding is that women can get on the order of a liter of blood loss with where a normal menses might be 40 millimeters. Hence, you can imagine that this disease state is often associated with anemia. In addition, they are just by the sheer mass of these tumors, they can be associated with bulk symptoms such as pelvic pressure and urinary frequency. They can also be associated with early pregnancy loss as well as infertility. And it is estimated that the lifetime instance of uterine fibroids in premenopausal women is on the order of 50% to 80%. Similar to endometriosis, there are very limited treatment options for uterine fibroids, again with a very similar graphic and actually the very similar treatment options. In the lower left hand corner, again are oral contraceptive and progesterone, here with only short term use and even more limited efficacy. In the green box, the natotrophin releasing hormone agonist, such as Neupron, which is only approved for a short term course preoperatively with no approved add back therapy. And surgical options such as hysterectomy exists, which is the full surgical removal of the uterus, obviously associated with fertility loss, as well as the risk of general surgery or myomectomy, which is the surgical removal of the muscle lining of the uterus, which unfortunately is also associated with a high 1 year recurrence rate. Hence, the unmet medical need in uterine fibroids is clear that we need something that has the potential for long term FFSD, ultimately without the need for surgery. And again, we think that we have some data that will support why elodolix may meet this unmet medical need. Here, I'm showing you the Phase 2b data for elazolix in uterine fibroids, specifically addressing the potential to decrease the amount of bleeding associated with Bensley. Green the green bars are placebo. The purple bars are elagolix. And you can see that a high dose of elagolix, 300 milligrams twice daily, achieves over a 90% of people actually achieve a response with regards to heavy menstrual bleeding. And the response here was a decrease in bleeding to less than 80 milliliters for menses and a 50% reduction from baseline bleeding. As is anticipated, this degree of suppression of the axis was associated with bone density loss, which is seen on the right hand panel. And because this study was specifically designed to push to achieve maximal efficacy with elagolix, It was also designed from the get go to include add back therapy as you can see in the blue bar. And the good news is that we get only a modest loss of efficacy with the addition of add back there to PD elagolix. So from a 90% response rate down to an 80% response rate, but we actually get market protection with regards to bone density in the far right hand panel. Hence, overall, we believe that elagolix has the potential to meet the unmet medical needs associated with both endometriosis as well as uterine fibroid. Elagolix is an orally active agent that has demonstrated significant efficacy in both of these disease states as I've just shown you. And we believe has long term potential certainly as a low dose and likely as a high dose in the context of bone protection. We also think that we've demonstrated that that bone protection can occur with hormonal add back therapy. The 12 month data from the 2nd pivotal study for endometriosis, the SELSA study, will read out later this year and that will put elagolix on track to be the first approval for endometriosis since Lupron in 1990. With that, I would like to introduce my neuroscience colleagues, Doctors Laura Gault from Development and Doctor. Eric Herron from Discovery will tell us about their neuroscience program. Laura? So as Rick mentioned in his introduction, neuroscience is an emerging area of focus for AbbVie. AbbVie neuroscience is committed to providing novel and effective treatments for patients with neurodegenerative disorders. We're focused on areas where there's high unmet medical need, including Parkinson's disease, multiple sclerosis and Alzheimer's disease. In Parkinson's disease, where our product DUADOPADUOPA is already marketed worldwide, we continue to look for less invasive, efficacious symptomatic treatment options for these patients. In addition, we're interested in pursuing therapies that would slow or halt the progression of the disease. In multiple sclerosis, we're interested in developing immunomodulatory agents that deliver a high degree of efficacy with manageable safety profiles. And we're also interested in developing drugs that actually help the central nervous system repair after the injury of multiple sclerosis and improve the function of patients with this disease. In Alzheimer's disease, we're also interested in drugs that would slower help the course of the disease and maintain patients' level of function at the highest level possible for as long as possible. We're very aware of the challenge in this field of identifying the appropriate time to treat patients given the target that you're pursuing and that's something that we're focusing discovery efforts on and that Eric Caron will discuss later. This slide shows our marketed products and some of our select early clinical development programs. In Parkinson's disease, DUOPADUADUDA is a levodopacarbidopa gel that's delivered directly into the intestine. And it maintains a consistent plasma level of levodopa leading to a decrease in off time and an increase in dyskinesia free on time in patients with advanced Parkinson's disease. Overall, this leads to an improvement in their functioning. This drug is marketed worldwide and provides a foothold for AbbVie neuroscience. In multiple sclerosis, we're really pleased to announce the recent approval of Zimbryta by the FDA last week. This project is partnered with Biogen and it is a novel immunomodulatory approach in MS. This is an anti CD25 monoclonal antibody that's demonstrated high efficacy in reducing relapses and disability progression. Now I'll give you a little bit more data on that in a few moments. As I mentioned, we're also interested in developing drugs that actually promote neuronal protection or regeneration in MS and in other injuries of the nervous system. ABT-five fifty five is one such potential agent that's currently in Phase 1. And this is work that's based on pioneering biology conducted at AbbVie where we've demonstrated extensive preclinical evidence for neuroprotection and regeneration. And finally, in Alzheimer's disease, we're approaching this disorder with an anti chal monoclonal antibody. The antibody was initially developed in the lab of Doctor. David Holtzman at Washington University, and we continue to collaborate with Washington University and CTWAN Diagnostics to develop this antibody. It's currently in Phase 1, targets tau pathology and is in development for Alzheimer's disease and progressive supranuclear palsy, another neurodegenerative disorder. So I will focus on the 2 products in our MS pipeline and Eric will follow and discuss our AD pipeline as well as the anti tel program. So MS is an unpredictable progressive chronic disorder of the nervous system that strikes patients between the ages of 2040, females more commonly than males, and it affects about 2,000,000 people worldwide. In MS, the immune system actually attacks a protein called myelin, which is a form of protective sheet around nerve fibers. And what myelin typically does is actually increases the efficiency of communication from neurons to neuron. And when myelin is damaged by disorders like MS, neurons can't communicate effectively and that leads to the symptoms that patients manifest. Initially in the disease, patients have frequent inflammatory relapses that cause a lot of inflammation in the CNS. But over time, the number of these relapses tends to decrease. Unfortunately, so does the ability of the nervous system to regenerate in the face of these insults, leading to an accumulation of neuronal loss and atrophy over time, which results in the progressive disability that these patients exhibit. Current treatments for MS are immunomodulatory and reduce the frequency of inflammatory relapses, but they don't directly address the changes in neuroregeneration or offer the opportunity for neuroprotection. AbbVie sees a future treatment paradigm with drugs that promote remyelination and facilitate neuronal regeneration as an important choice for patients. So we're committed to meeting all of the needs of patients with MS. We're currently supporting SYMBRITEA, which is a novel immunomodulatory treatment option for patients with MS and advancing ABT-five fifty five as a novel agent for neuroprotection and neuroregeneration. People with MS need additional innovative immunomodulatory therapies. With an average age of onset in the 30s and progression over several decades, patients often have relapses on their initial therapy that prompts them to switch to other medication. Higher efficacy medications often have higher safety liability and it's important for physicians and patients to choose the medication that has the right efficacy safety profile for each individual patient. Providing new treatments that have novel mechanisms of action with different efficacy safety profiles is really needed to ensure that patients have individualized treatment options. ZYNBRA is one such new treatment option available to patients. It's a humanized IgG1 monoclonal antibody that binds specifically to the CD25 subunit of the interleukin 2 receptor. In MS and other autoimmune disorders, interleukin 2 is often elevated, leading to the symptoms that are exhibited. By selectively blocking high affinity IL-two receptors, ZimbriTA inhibits activated effector T cells, expands immunoregulatory CD56 Brite and K cells and decreases the activity of T regulatory cells. Overall, ZYNBRIGHT is associated with immunomodulatory effect without broad immune cell depletion. Zimbrieta has demonstrated efficacy in 2 pivotal trials, the SELECT study and the DECIDE study. In the SELECT study, 2 doses of ZYMBRATA 150 milligrams and 300 milligrams monthly were evaluated versus placebo. And both doses of ZYMBRYTA resulted in a 50% or greater reduction in the annualized relapse rate compared to placebo over the 52 week treatment period. The DECIDE study is the largest and longest study in MS that's ever been performed. And in this study, a single dose of ZYMBRITA 150 milligrams was compared to an active comparator interferon beta-one aravenex. In this trial, SYNBRA demonstrated a 45% reduction in annualized relapse rate versus the active comparator. The impressive results seen in the reduction in annualized relapse rates were also recapitulated in other important secondary endpoints like evidence of disease activity on MRI. In addition, preventing disability progression is a very important treatment goal in patients with MS, and we examined this in both trials. In the select study, ZYMBRITA resulted in a 57% relative risk reduction for confirmed disability progression. And in the DECIDE study, patients treated with ZYMBRATA had a lower risk of progression compared to the active comparator group. Symbrite exhibited a positive benefit risk profile in these studies consistent with other high efficacy agents. It has a large safety data set of approximately 4,100 patient years with more than 2,000 patients treated with SYMBRATA for up to 6 years. FOX warnings include warnings for hepatic injury, immune mediated disorders. And there are a number of other common adverse reactions that are reflected in the warnings and precautions as well, including acute hypersensitivity, infections and depression and suicide. Overall, the risks and side effects associated with SYMBRYTA are generally manageable and REMS plan has been established to educate patients and physicians about the risks associated with SYMBRYTA and the need for appropriate monitoring. Overall, the SYMBRYTA is a new efficacious treatment option for patients with relapsing forms of multiple sclerosis. It's a novel mechanism of action that inhibits activated T cells while preserving major immune cell subsets within the normal range. ZYNBRITA has demonstrated superior sustained efficacy versus an active comparator for treatment durations of up to 3 years. The risks and side effects are generally manageable and a REMS program has been established to support citizens and patients in the appropriate use of the drug. And finally, SYMBRYTA is available in a convenient monthly self administered subcutaneous dosing form. So in addition to developing immunomodulatory treatments, AbbVie is also focused on developing treatments that offer the opportunity for neuroprotection or neuroregeneration in patients with MS and other disorders of the nervous system. One such agent is ABT555. So when the nervous system is injured either by MS or by spinal cord injury, there's an increase in a protein called RGMA or repulsive guidance molecule A. This is expressed on the surface of cells and it actually inhibits axonal regrowth and remyelination. ABT-five fifty five binds to RGMA and blocks its effect enabling axonal regeneration and remyelination to occur. This mechanism of action is really quite revolutionary in treating MS and is different in its characteristics from other approaches that you may have heard of like LINGO-one. While LINGO-one has shown strong preclinical evidence for remyelination, it has not demonstrated strong effect for axonal regrowth or neuronal sorry, or neuroprotection. This slide shows some of the preclinical data that has been generated in our labs with anti RGMA antibodies. The panel on the left shows results from a targeted optic nerve model, where inflammatory cytokines are injected into the optic nerve. When this paradigm is performed, as you can see from the 2 upper panels, inflammatory cells and inflammation results in the area of the injection. The bottom two panels show staining in the same region with an antibody directed against GAP43, which shows neurons and neuronal fibers. In this experimental model, RASA received the control antibody, so very little staining in the region of the inflammatory lesion. In contrast, on the right lower panel, animals that receive the anti RGMA antibody show robust neuronal staining and neuronal process staining that shows increased growth of nerve fibers into the inflammatory lesion. But it's not enough to show that these neurons and their fibers are in the region. You also need to show that they're able to promote a functional effect. And that's what's shown in the panel in the right in a slightly different model where inflammatory cytokines are injected into the rat's spinal cord. In this model, the treatment occurred at day 0 with the inflammatory cytokine and administration of antibodies occurred at day 7, 1421. So 7 days the first dose was 7 days after the injection. What you can see on the x axis is time and on the y axis is a motoric score showing motor impairment. The purple line shows the results for antibodies that received for rats that received the control antibody. And in this experiment, those rats showed a decrement in motor function over the course of the 1st week that was preserved over the rest of the observation period. And their impairment was rather severe and included an inability to move their tail or to turnover. In contrast, the rats that received the antibody directed against RGMA showed an initial decrement in function, but it was attenuated relative to the control group. And they actually showed recovery over the remainder of the observation period and by the end were functioning at their baseline levels. So this demonstrates that the changes you see in the panels on the left can actually be translated into functional changes in rats. In another model that recapitulates aspects of optic neuritis, which is a common presenting symptom in patients with MS, the optic nerve was injured and animals received either a control antibody or the anti RGMA antibody. The panel on the left shows staining for retinal ganglion fibers in the normal retina. And you can see that many of these fibers are present and are progressing towards the optic disc. In the injury model, animals that receive the control antibody have lost over 90% of these fibers. And in fact, the blue sitting that you now see reflects blood vessels that were behind this cell layer and are now apparent. In the right, animals that received the RGMA antibody had a relative preservation of these fibers with about 80% to 90% of them still present after treatment. We confirmed these results using a different way of measuring retinal fiber layer using a method called optical coherence tomography. And this is really important because this is a technique that can actually be used in the clinic to look for similar effects in patients. So ABT-five fifty five will be entering the clinic in patients with MS this year and in spinal cord injury next year with initial evidence of biologic activity anticipated in 2018. I'd now like to turn the podium to Eric Herron, who will tell you more about our discovery efforts in AD and the anti tau antibody program. Thanks a lot, Laura. Age is the most significant risk factor for Alzheimer's disease. And as the world moves to increasingly elderly population, unless we find therapies that either delay or deflect the course of the disease, By 2,050, there will be 115,000,000 Alzheimer's disease patients worldwide. That will be an absolute calamity clearly for those patients, but also for their caregivers, the societies at large and also for health care providers who will struggle to be able to afford to pay for the cost of care. Now I've been sitting at the side and been tremendously humbled by the therapeutic success that my colleagues are having in their therapeutic areas. I've been humbled, but I've also been very energized because clearly we need to replicate that success for neurodegenerative disease as well. Now over the course of about 20 or more years, Alzheimer's disease will destroy 30% of the human brain. The first phase of this disease is asymptomatic, during which time the pathologies of Alzheimer's disease, which is plaques and tangles accumulate in the brain. Plaques are comprised of the abasopeptide that probably has no physiological role. Tangles are made from the protein tau, which becomes heavily hypophosphorylated, and tau plays an important role in neuronal physiology, as I'll come on to describe. Now we've known for many, many years that amyloid plaques in terms of their amount around the brain, their regional distribution does not correlate at all with clinical symptomatology or neuronal death. Tau pathology on the other hand correlates actually very well indeed. One can think of the disease process in 3 phases. There's a biochemical phase, during which time these proteins accumulate inside and outside of cells in the brain. There's then a cellular phase during which neuronal networks are degraded and ultimately the capacity of the human brain is overwhelmed and we enter the clinical phase when people manifest the signs and symptoms of the disease. Now there have been some significant changes to the AD scientific landscape this decade, which I'll take you through. Firstly, the genetic architecture of the disease has been pretty well delineated and that is giving us better opportunities to explore new biological pathways that ultimately will lead I think to greater target diversity. We're now able to image the major pathologies in the human brain in living people and moreover look at the effects of those pathologies on brain metabolism. And these and other biomarkers are enabling us to diagnose AD patients with far better accuracy, which of course is critically important for clinical trial recruitment purposes. Purposes. And clinical trial designs, which were hypothesized to be able to demonstrate true disease modification of therapeutics, they've been around for a long time. They are now being looked at in terms of Alzheimer's disease as well. So what I've just explained really is that we have incredible unmet medical need. We have breaking biology. We have new technologies. We have a clinical pathway. And that means that 4 of the 5 principles that Mike alluded to earlier that underpin AbbVie's R and D strategy has been satisfied. The one missing component from this list is core capability. Now to that end, AbbVie have inaugurated the foundational neuroscience center. It's located in Cambridge, Massachusetts. Putting it in Cambridge gives us fantastic access to talent, both to recruit from and also to collaborate with. We will initially focus on 3 areas: biology, tau biology, the neuroinflammatory response of the brain and also an area called autophagy, which is the process by which cells are normally able to rid themselves of damaged proteins, which clearly goes awry in Alzheimer's disease and other neurodegenerative diseases. Now unlike our peers, AbbVie does not have an abatore amyloid directed therapeutic. It isn't because we haven't been paying attention to that field. Indeed, over the last few years, I've authored and co authored a number of review articles and commentaries that seek to explore and explain the role of amyloid and A beta in the disease process. So I think we have a reasonable understanding of the field. I'd just like to expand upon this. This is a very simple diagram showing the clinical course of sporadic Alzheimer's disease. There is an age of onset and there is a duration of disease from symptom onset to death. The duration of the disease is about 8 years. Now we've known for some time that there are these rare cause of mutations that you can inherit from your parents that give you an early onset form of the disease, and it's called familial AD or genetic AD. And this is pathologically and symptomatologically identical to the sporadic form. There is a much earlier age of onset of this disease, but actually and quite strikingly, the duration of the disease is not different from sporadic AD. It's not a faster disease process. What do these causal mutations do? Well, they all increase the probability to 100% that amyloid will be deposited in the brain. So what does this tell you about the role of amyloid in Alzheimer's disease? Well, I think this is highly consistent with amyloid playing a role in triggering the disease process, but not necessarily driving the disease process once the process has started. Because otherwise, one would anticipate that with familial genetically caused AD, there would be a far more rapid course of disease and there is absolutely no evidence for that. So just to expand upon this idea and to juxtapose tau pathology into this diagram. We've known for many years that amyloid pathology precedes tau pathology by maybe a decade. And by the time people enter the very first symptoms of Alzheimer's disease of mild cognitive impairment, that amyloid pathology has reached a maximum, has reached an asymptote. Tau pathology actually still has some way to go in terms of its destructive capability in the brain. I've told you about familial AD where cause mutations shift this whole pattern to the left, but the overall course of the disease is unaltered. So it seems to be logical to me that if you wanted to accrue the best possible therapeutic benefit from an amyloid based therapeutic, You should really be administering them at or prior to the trigger points as I've described it. Now all of the Phase III trials on amyloid directed therapeutics that I've read out to date have been conducted in this phase of the disease process in the mild to moderate space. And as I've just told you at this point, amyloid has actually already reached the maximum. Now clearly, we need to be able to conduct Phase III trials earlier and earlier and preferably to do primary prevention studies. Now if you look at clinical development of agents coming through, they are going earlier and earlier. Some of the base inhibitors are being tested in asymptomatic at risk patients. But we think that it will be many years before we get to the primary prevention studies, firstly. Secondly, we don't think that amyloid based therapeutics will provide all of the therapeutic benefit that patients will need. And thirdly, AbbVie would not anticipate entering into this particular therapeutic arena of amyloid based therapeutics unless we were really confident that we had a mechanistic approach that was far, far superior or had the promise of superior efficacy in the 10 or more agents that are currently in clinical development. So that brings me on to tau. Neurons are quite unusual to cells insofar as they have these very long extensions, which people like me call axons. To give you a frame of reference, if the cell body was the size of the basketball, then the synapses on the right hand side would be up to 2 miles away. Now to sustain communication between the cell body and the synapse, neurons have these things called microtubules that you can think of as being intracellular conduits. Tau plays a very important role in stabilizing these microtubules. Now for reasons we don't really understand in Alzheimer's disease and other tauopathies, in fact, tau will dissociate from the microtubule, become heavily phosphorylated and then form intracellular aggregates called either PHFs or NFTs, neurofibrillary tangles. So there's probably 2 things going on here. There is a loss of normal function, which I think is probably quite modest. But the gain of aberrant function as these NFTs fill up the cell body, I think is very important to the pathology. And to give you an idea of what this might look like, this is an immunohistochemical slide. Those sort of triangular shaped are cell bodies. They're stained in brown and black with for aggregated tau. And you can see that they are absolutely full of tau. And I think if you were a neuron, you'd probably be feeling very uncomfortable in that position. So let's just talk about the potential for tau Therapeutics. This panel really shows you tau PET imaging in a range of pretty rare Alzheimer's disease variants. And what it basically says is the type of symptomatology that you get is predicated on where the tau pathology exists in your brain. If you look in the top left hand panel there, at posterior cortical atrophy, you will note that that red spot is at the back of the brain. That is the visual cortex. And the earliest symptoms of PCA are visual disturbances. Let's contrast that in the right panel where a patient has been imaged with both PAL imaging agents, amyloid imaging agents and also a measure of glucose utilization, a measure of brain metabolism. So at the top, you can see tau pathology in the back of the brain. That is also coincident with where you get the metabolic disturbance. But when you look at amyloid in the very bottom there, you can see that it is actually distributed all over the brain and doesn't correlate at all with the clinical symptomatology. And so these and a lot of other data actually really lead us to believe that tau is the most proximate biomarker for neuronal damage and symptomatology. Now neuropathologists for some time have used the BRAQ staging system to be able to assess the extent of tau pathology in the brain. It goes from 1 through to 6. And if you correlate BRAF stage, in other words, a measure of tau pathology with cognition here measured by the Mini Mental State Exam, you actually get a pretty good correlation. And this diagram really implies that if you were able to administer an effective tau therapeutic early on in the disease, you will preserve a lot of cognition in patients. But I think it also implies that it might be feasible to dose later on in the disease course and still give patients a very valuable therapeutic benefit. And I think ultimately, it's this feature that will distinguish tau therapeutics from abasor therapeutic. Now AbbVie have their own human monoclonal antibody against tauAT12, which was in license from C2N. And we and others in the field believe that tau pathology spreads through the brain from the release and uptake of misfolded tau sees as synapses. And we think that the anti tau antibody that we have in some way intercedes in this process, although mechanistically, we're not quite sure how that happens yet. Nevertheless, here is some data, some preclinical data with some antibodies that are quite similar in their nature to 8012. The green line at the top there is control antibody. And you can see that in this system, which is a cell based system measuring the uptake of tau aggregates, that these antibodies are able in a dose related manner to slow or stop that process. And this feature is manifested by an overall reduction in tau pathology in a mouse model, a mouse tauopathy model as shown on the right hand side. So we think this is going to be a very valuable approach to take in the future. In terms of clinical development, we plan to enter Phase II with AT12 in both progressive supranuclear palsy, which as Laura said is a pretty pure form of tauopathy and Alzheimer's disease as well. So to sum up, the inauguration of the FMC, I think is a measure of our ambition in this area. We're going to grow this group over the next 2 years to be able to deliver novel therapeutic targets to the organization. And in the meantime, neuroscience is developing a suite of anti tau antibodies to follow-up on our first foray in the clinic with AT12. And with that, I'll hand back to Mike. All right. We'll now move to the Q and A portion. Well actually, Eric, you can stay because we'll invite our speakers up onto the stage. In order to save time, we'll do this without a break. They'll come in and set up some chairs for the panel right now. But as we get ready to do that, we'll get set for our first few questions. All right. So as our panel gets seated, Larry, can you bring up the first questioner for us? Hi, it's Jeff Holford from Jefferies. Thanks very much for doing this meeting today. I'll just try and keep the two questions in the interest of time. So on Rova T, it's obviously a very exciting molecule. It sounds like there's lots of exciting data coming. Could you talk about the potential for a more accelerated filing than the 2017 time line that you have? Do you have data a setting where there's no treatment? We have a breakthrough therapy designation application in progress. I wonder if you can talk about the potential around that for a more accelerated filing in 2017 that you talked about in your guidance. And then secondly, just a bit more broadly about the oncology program in terms of the strategy around immuno oncology. You've identified a few molecules that might need to work with PD-one in the best case, and you've talked about some earlier stage micro tumor environment IO approaches. Do you think you're going to need to build a broader IO platform, including your own backbone PD-one or do you not subscribe to that being important? Okay. So 2 very distinct questions. Robitie question, we'll take first. We are committed to driving Robitie forward as rapidly as possible. And that program is moving forward on all fronts with a number of studies either up and running or to be up and running very, very shortly. Perhaps for the specifics, I'll hand it over to Brian. Sure. Yes. So we have a study called TRINITY that's up and running. It's a single arm study with about 125 to 150 patients and that will enroll mostly this year with a planned filing next year. So that is the absolute fastest that we think it would be possible. Again, it is a single arm study. The endpoint is confirmed response rate. Yes. And we'll be moving forward aggressively across other elements of that program as well. That'll be important additions like the frontline studies as Brian and Scott have both mentioned in other settings. So turning to immuno oncology, there's a lot to your question. So do we ascribe to PD-one? I mean, we think clearly that the PD-one, PD L1 access plays a very clear role. I think that's been demonstrated across a number of tumor types. And in a number of the approaches that we are pursuing, one could envision working well in combination with PD-one. We will certainly explore that in clinical development. We'll also explore the right way to advance those combinations in the long term, whether that's with our own PD-one over time. But we're exploring a broad range of programs. I gave you a couple of examples. I would bucket them in terms of the categories that I put on that slide in my introductory remarks. They are either programs that are aimed at tumor immunosuppressive environment that might be aimed at Treg function, that might be aimed at restoring immunity through dendritic cell function in other ways that would generate new immune responses. And, I think that there are several programs that we'll be able to bring forward in the coming say 12 months to 18 months would share those mechanistic characteristics. I showed you 2 examples during my presentation. There are also direct T cell agonists that we'll be exploring. And there are a number of those in our pipeline. And there are also programs that address the tumor immunos environment in other ways. So stromal directed agents, for example, that might enhance immunity and enhance neoantigen presentation to the immune system. So it'll be a wide range of approaches that we're exploring. We'll have about 5 mechanisms in the clinic in 2017. We're going to be exploring many, many more in our discovery labs. It's a main focus of Tom to continue to accelerate our efforts and to bring in not only programs that match descriptions that I just gave, but other sorts of mechanisms as well. Tom, I don't know if you want to add anything further to that. There should be a lot. You can Yes. Well, I'd just like to say that I think that we're just 2 weeks on the job. I'm still trying to do assessment of the different programs, but I've met a lot of what I call drivers of projects, which have not been discussed today, which is sort of looking at other ways again to stimulate T cells to look at other cell types, dendritic cells, macrophages. And as I finished my assessment, I think we also want to do additional recruitment because this is going to be a long term strategy AbbVie to actually have a very, very long healthy pipeline in immuno oncology. So that's all I can say at this point. Okay. All right. So thanks. We have another question over here. Jamie Rubin with Goldman Sachs. Rick, first a question for you. One of your bullets you highlighted that you expected double digit earnings growth on average through 2020. Is that every year through 2020 or is that compounded annually from 2015 to 2020? And then I have some follow-up questions on Semcentriq. Yes. I mean what I indicated in my remarks was on average. So it wouldn't just that across the average. There could be some years where we're slightly below that and there could be years where substantially above that. I wouldn't expect years where we were dramatically below that. And again, it will be dictated some extent by our interest in driving programs more broadly from an R and D standpoint. One of the things we won't do is we won't cut back on R and D to manage the bottom line. We may cut back in other areas to try to make sure we manage our bottom line appropriately. But certainly as we see an opportunity to drive promising programs into pivotal development, we're going to pursue those opportunities. I think one of the things you saw, I hope it was just over the course of the day is we have a very productive R and D engine here at AbbVie. Just to follow-up on ROVITI, which does look very exciting, especially in the DLL3 overexpressors. Is there a commonly used biomarker available to test DLL3 expression in small cell lung cancer patients? And just curious what percent of patients are currently tested for DLL3? Does it require a new biopsy or can you use old biopsy samples to test for this? And then just generally, is the PDX tissue library totally unique and differentiated giving you a competitive lead for future discovery? Yes. So Brian, maybe just before we start, in terms of whether people are being tested today, in routine clinical practice, people wouldn't be tested today because there's not an agent available. But the methods are very standard and those same methods can be applied to using to a DLL3 test, which is being developed by stem cells. It's a very simple immunohistochemistry assay just like with Herceptin. So, the antibody was developed by us. We're working with Roche Diagnostics for the actual clinical diagnostic and it does, it does not require a fresh biopsy. So all of these samples you've seen are from the original diagnosis and it does we have seen that DLL free expression does hold from that point even after patients get through rounds of chemotherapy. Maybe you can comment on the PDX library? Sure. So the PDX library, I think, is one of the largest of its kind. We don't know many others that have built a library like this. We do think it gives us competitive advantage. And I think as manifesting in the trial data we're seeing now, we've certainly gained a lot of confidence in the preclinical data now seeing it translate clinically. All right. So thanks, Jamie, for that. And I think, Larry, we'll go to you in the back. Yes. This is for Brian or Scott. As you think about how long patients live today, the competitive environment in your own data, how do you think about weighing the importance of overall response rate, total clinical benefit and survival? So it really depends on the line of therapy. I think right now we're focused on getting the drug to approval in third line. And Scott showed the data earlier today where the historical response rate has been in the 15% to 18% range. And at a year about 12% of patients are alive. I think the median OS is in the 4.5 month range. And so we've been focused on looking at our Phase 1 data and going into this study. The endpoint for TRINITY as I just mentioned is confirmed response rate and we also want to show and we can't talk about it now, but the data that will be presented on Sunday, you should we'd be looking at response rate differential versus standard of care as well as the survival rate at a year relative to standard of care is sort of the most important metrics for that particular study. Going forward as we move into the frontline setting then metrics like the median OS and looking at that rent relative to chemo or placebo in the case of the maintenance consolidation would be obviously the most important metric there. And I think one of the things that has really plagued studies in this disease a lot like in actually even more so than in pancreatic cancer is that response rates have been relatively high, but survival has not. And so we've been striving to really develop a therapy that has a very strong response rate, but also follows through with having nice tail on the curve and durability of survival. And we'd like to see that differential even stronger in survival. So that's hopefully clear as it relates to the first study endpoints are very different from the frontline study. And the one thing that I would add or really emphasize because you did touch on this, Brian, is it's those long term good outcomes that we're really trying to drive and that's lacking in therapies for this disease in particular and for many oncology conditions. And so those landmark analyses, those long term good outcomes are something really to focus on. And in the case studies, Scott during his presentation showed you a couple of patients who have very durable disease control out quite some time now. And that's one of the features that makes us very excited about potential of this method. I think the last thing is just the idea of as we focus on the frontline and developing new frontline regimens that the combinations with an immune checkpoint inhibitor could really drive compelling survival over time. And if you look at nivo by itself and in this setting in small cell has I think about a 3.5 month median OS and but when combined with ipi that goes to 7 or 7.5 months. And so we're very anxious to see the combination of our agents with an immune checkpoint inhibitor as well to hopefully really drive that survival. Great. Thanks. So, we're going to go over here. Thanks. Dave Risinger from Morgan Stanley. And first of all, thanks so much for having the Investor Day today. I wanted to ask some questions even though we're right ahead of ASCO about some of the other candidates beyond oncology. First, the JAK efficacy cross trial comparisons were very helpful. I was hoping that you could comment on the safety of your JAK relative to pipeline competitors, and I'm not thinking about versus Xeljanz, specifically, 494's impact on hemoglobin relative to baricitinib and 494's impact on NK cells relative to Galapagos' JAK. Those are 2 areas of some uncertainty. Regarding elagolix, could you discuss the dosing duration scenarios and the data readouts to watch, which will inform that over the next year or so. And then I thought your comments on Alzheimer's were quite interesting. Could you just provide a little bit more perspective on why the industry has struggled to bring candidates forward to successfully target tau to date. And then with respect to 8e12 on Phase II, I'm guessing we should see an efficacy readout in 2018 or so? And what will you be using as your primary endpoint or endpoints there? Thank you. Okay. So there's a lot to that. I might need to come back to you to make sure we've covered some of those questions. First one was 494 in safety. We have shown safety data from that program at a top line level and then in our ACR presentation in the second half of last year. And we believe that the safety that we're observing is very consistent with the JAK1 selective hypothesis. One thing that once you keep in mind when you look at those data is that we export a very, very broad dose range of 494 in Phase 2. We did that on purpose and we pushed the levels that we knew would be above the JAK2 selectivity threshold. We didn't advance those levels, but we tested them in Phase II specifically because we wanted to be able to make that determination of the optimal benefit risk. But the impacts that we're seeing on hemoglobin within the dose range that we're going to be exploring in Phase III were quite favorable in our minds as was the effect on not only NK cells, but on immune function. So, Shirley, I don't know if you want to say anything further about that. Yes. I can add some additional color, Mike. Exactly as Mike said, from our perspective in terms of the mean hemoglobin changes, ultimately we tested a broad dose range. And despite that, the hemoglobin act changes actually were within normal range throughout that dose range. In addition, your comment about NK cells, I think that we did push the dose to try to that can be determined when we could break the barrier, if you will, between JAK1 selectivity and JAK3. We did see that across our broad dose range. That having been said, I think the most relevant clinical outcome of that is the is whether or not there's an impact on infection. And what I can tell you is that across our Phase II studies that ultimately infections were relatively mild. And I think there were only 2 serious infections within the context of both studies, one was in placebo and one was in active treatment. So then with respect to elagolix, I think your question was about dosing scenarios, dosing duration in the various dose levels that we could select the low dose and the high dose. In endometriosis, we think that the lower dose clearly has potential for longer term therapy based on the relatively modest effects on bone that we showed during the presentation. The higher dose as we anticipated and as we design gives a greater degree of suppression in the hormonal axis and with that comes a greater degree of bone suppression as well. It's still less than Lupron. Lupron is approved for 6 months. So clearly we would see that safety profile as something that would be approvable at that duration at a minimum based on our expectation. And longer term data will tell us whether there's potential beyond that for the basic higher dose program. And then there are the components of the program that Shao Lee described that look at various ways to protect bone, one of which is hormonal add back therapy, which we've shown is very effective in protecting bone in both uterine fibroids component of the program and also based on our experience with Lupron. So we'd expect to have the same sort of success with that add back program within endometriosis and that could be a path even longer term administration of that agent. So maybe, Shelly, if there's anything you want to add? No. Just I think part of your question was about timing. The data timing, why don't you give that? So ultimately, we wouldn't hold up a filing because we think that elagolix as a single agent has the potential for significant benefit in endometriosis as well as your fibroids. So we'll move forward with those filings as a single agent. And I will come back as we're exploring the best option with regards to how to protect against bone, whether that's hormonal add back or others such as bisphosphates, etcetera, with a separate program. Yes. And then I think your last question was about tau and why it's been so difficult to advance a successful candidate in tau. So maybe I'll just turn that back to you. Yes. I mean it's an interesting question. I think you have to take historical perspective of this. In 1991, there was genetic human genetics that showed that mutations to that resulted in a different form of amyloid being produced could cause Alzheimer's disease with a full panoply of both plaque pathology and tau pathology with 100% certainty. And pharmaceutical companies in the rest of the field understood that if they could find molecules to prevent the production of amyloid, they may have therapeutic. And the discovery of the human mutation also enabled the field to get transgenic models, which actually displayed plaque pathology. So we had an in vivo model to use to progress those targets. That just did not exist for tau. So the first tau mutation was discovered in the mid-90s by Mike Houghton. Then we had the wherewithal to make transgenic models that had tau pathology. And then we had the systems in place to be able to test tau therapeutics. But the targets for tau have not been obvious. People have looked at kinase inhibitors, which have been shown to be universally toxic so far. I would address though your point there is, of course, a tauRx in Phase III currently for tauopathy. So I think really the shorter answer is the field have put a lot of effort into amyloid, the amyloid cascade hypothesis, which actually I'm an advocate of as well. And it's only later that we've had the drug discovery tools that we need to address tau and that's coming on now. I think Laura there was something about the trial. Yes. So to add to what Eric said with regard to tau, it's also the case that translational tools are emerging. And while amyloid PET has been available for a number of years, tau PET ligands are still in development. And as those continue to progress, that will enable the field to better evaluate agents that are directed against. Okay, great. So I think we'll go to Larry in the back. It's Geoff Meacham, Barclays. So I have 2 oncology questions. The first one is, how do you think that there's a response to IMBRUVICA and venetoclax combo therapies with respect to price as they're effective as single agents and what incremental clinical benefit do you think is needed? And the second question is for the PARP, clearly the landscape there is competitive today and it's getting more competitive. How do you guys look at differentiation? How do you maximize that? Or is the focus just speed to market indications that aren't really addressed today such as lung cancer? Okay. So on the first question with respect to, if I heard you correctly, how payers will respond in the combination of IMBRUVICA and venetoclax or VENCLEXTA. First and foremost, we are focused on driving the studies to show that there is real value here in patients. And you saw, as an example, this is of course monotherapy, the sorts of results that have been seen with RESNA-two or in combination therapy, the sorts of results we see with Healios, where we're driving very, very clear differences between the experimental regimen and standard of care. And when you have those big differences, when you're providing a real impact on the risk of progression on mortality, then you can demonstrate the sort of value you need to satisfy payers. And so that is a primary consideration in both combo studies. We think the combo of VENCLEXTA and IMBRUVICA has the potential to drive that sort of transformational efficacy. And we'll be very focused on demonstrating that. Beyond that, Rick, I don't know if you want to comment. No, I mean, I think what you described is really the critical part. We have to see the data. If you fundamentally believe and we see that this is a transformational therapy, Obviously, payers are going to be interested in collecting the data that demonstrate that the downstream costs associated with the disease are also reduced based on the cost of the therapy. And I think sometimes in oncology, it gets lost, the ancillary cost of treating patients, that have these kinds of outcomes and require this kind of medical intervention and follow-up therapy. And so collecting that data out of the traditional system of physician visits, hospitalization, all of the supporting care that is necessary for an oncology patient. I think many people are surprised by what that cost is. And if you can get a patient with a cure or a very deep response where they live basically a normal life without a tremendous amount of medical intervention going forward for many, many years, There's a savings to the system associated with that. That is the economic value proposition that I think is the new wave of the kind of medicine that we want to try to create in this industry. Okay. And then your second question about PARP in terms of how we would differentiate our PARF versus others that are in development. We have a different hypothesis or at least a different hypothesis drives our PARF program that has driven the development programs of others. There's so PARP is a DNA repair mechanism. And in patients who have an inherited deficiency in a different DNA repair mechanism, BRCA, there's the concept of synthetically valid between that and PARP inhibition. That's been proven in the clinic, in BRCA carriers, both with other agents and with ours. And that's an important component of our program. But there's a second component of our program, which is that first hit doesn't have to come from an inherited mutation. It can come from DNA damaging chemotherapy. And so we are studying our molecule in a combination setting, in places where DNA damaging therapy is used in places like triple negative breast cancer and lung cancer and other settings. And it is those data that will determine the long term utility of bliparib. Those studies are underway. They'll be reading out over the course of the next year or so. Over the course of 2017, we'll get a lot more data. And so that will tell us the differentiation. Gary, I don't know if you want to say. No, I think you've summarized that nicely that we're really focused on trying to be as early in combination with chemotherapy as we can to maximize the benefit and avoid the development of cross resistance, for instance, between platinum and PARP. Okay. So we'll go to Liz next. Good afternoon, folks. Alex Sarfait with BMO Capital Markets. First question on Robid T, obviously significant activity in DLL3 positive patients. The question is how confident are you that these are in fact these represent 65% to 80% of the patients out there. We've heard that number a few times. I'm not sure if there's a published report, but if you could help us gain more comfort regarding the size of that market. And then the second question is on elagolix. We spoke with a few physicians who said the younger patients with endometriosis are being treated with birth control and NSAID. Your Phase III trials are placebo controlled. So I'm just wondering how you plan to position elagolix versus some of the cheaper alternatives for pain management? Thank you. Okay. So Brian, if you want to throw it to you. Sure. Yes, we feel very confident about those numbers. So the 65% are the portion of patients that have high levels of CLL3 expression. And that's greater than 50% of cells expressed in target and 80% includes all patients that have any levels of CLL3 expression. And we initially discovered this and looked at our own data sets and those numbers were roughly in line with the 6580. We've also extrapolated and have collaborated with many different academic groups and have received tissue microarrays of hundreds of patients. And also in working with Ventana, our diagnostic partner and the samples they've looked at, the incidences at least at those levels. We feel really comfortable in that. It's not just our own data, it's been validated by external academic collaborations and even what we've seen now in our clinical trial. We're pretty comfortable in those levels. Okay, great. Thanks. And your question on elagolix, OCPs are used frontline. They're used obviously because there's a tremendous body of clinical experience and they're very well tolerated agent. What we know is that they don't work very well for a large majority of patients. There are many women who go on to have continued symptoms despite being placed on OCPs. And so new treatment options are clearly needed. With respect to NSAIDs, NSAIDs and other analgesics are used across that spectrum. And NSAIDs were allowed in our trial. So you're seeing a benefit over and above NSAIDs. And in fact, the effects that you're seeing are controlled for the use of NSAIDs. In other words, there's no increase in the use of NSAIDs and they in fact go down when one puts an effective therapy on board. And the chronic use of NSAIDs is not without its own complications as well. So the short answer to positioning is we wouldn't intend to position this ahead of OCPs. That just doesn't seem practical for this sort of therapy nor does it seem medically appropriate in large majority of cases. But many, many women go on to fail OCPs. And so they will cycle through and need an option like elagolix before they go to the things that are on the right hand panel of that slide that Shelly described, much more intensive hormonal blockade, pharmacologic menopause, that one would induce with Lupron, or the surgical options, which are obviously invasive and have their own downsides. So we believe that there is a very real place for elagolix. So Larry? Hi, Tony Butler from Guggenheim again on CEMCitrix for the group. Two questions. One is, when DLL leaks from the cell and this may get to this low high question, how many molecules or do you know how many molecules actually decorate the cell in a high versus low quantitative? And then second, if I understand the hypothesis correctly, the OLL is actually down regulating or causing a reduction in notch through the notch pathway. In some cancers, you actually see an increase in the NOTCH pathway or NOTCH activity, for example, in colorectal cancer. Any hypothesis what the difference might be? Is it totally EOL? Or is it something else that actually causes an up regulation versus a down regulation? Thank you. Yes. On the latter, it's very clear that inhibition of the notch pathway drives neuroendocrine cell phase, which is the opposite of epithelial. So high notch signaling drives epithelial cell phase. So notch is a switch that controls epithelial and that's where you see it higher in epithelial tumor types. With regards to the first question, DLL3 high and low is defined by the percentage of cells that have expression. So the cells that do have expression where we've quantified the receptors, to get at the other aspect of the question, we think there's about 5000 to 10000 receptors per cell. Unlike a lot of the other ADCs that target proteins that have high levels of receptors, especially 50,000 or greater, PLF3 internalizes much, much faster than those. So you're essentially delivering the same amount of drug because those few receptors are moving in faster. Okay. I think we have time for just one last question, unfortunately. Great. Chris Schott at JPMorgan. Just two quick ones. Maybe first on IL-twenty three and the psoriasis market. When we think about dynamics relative to the TNFs and the IL-17s, by the time you launch, do you see most of the opportunity for AbbVie as taking share from those existing agents? Or do you still see an opportunity when we look out a few years that there is growth in the category and just continue to bring kind of biologics to a broader spectrum of that market. The second question was on ROSA T and the combo program you're going to be starting. Will that just look at small cell or will you explore a number of different tumor types of the initial program in conjunction with PD-one? Okay. Rick, do you just want to comment just this time on the market dynamics? I mean quickly if you think about this particular market, I think there's still an opportunity to see significant growth and we're seeing it right now. As we saw mild to moderate products that were relatively low efficacy move into the space, what we've seen is the market growth rate has ramped up dramatically. Yet many of those patients end up failing and ultimately rotate over to another biologic. And so I think we will continue to see a significant amount of growth. I mean, the derm space, the psoriasis space specifically is still at a penetration level that's down in the high single digit range compared to other areas like RA or GI, which is up in the 25% to 30 percent biologic penetration rate. So I think there's plenty of opportunity to grow if you have the right kinds of agents. And in terms of the combo strategy, our strategy has been to demonstrate single agent activity first and then move into combination. And so that's what we're doing with small cell. Obviously, that was also a Phase 1 trial where we were looking for safety and we weren't ready to combine. And so we actually were very sure about the safety profile and the efficacy in the main disease of small cell. In this basket trial, we have 8 arms that will enroll a variety of different neuroendocrine cancers. And once we start to see a signal as a monotherapy then I think we would more quickly expand into combinations. And that will also be true of everything else in the pipeline. And this is a play that we'll keep running over and over because each of these targets in the pipeline albeit in different diseases still have the potential to synergize with a checkpoint inhibitor or other immunotherapy. All right. Well, with that unfortunately we have to bring our Q and A session to an end. But thank you for your time and attention and thank you for participating in our R and D Day.

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