Good morning, everyone. For those of you who don't know me, I'm Mike Severino. I'm the Chief Scientific Officer at AbbVie. I'd like to welcome you to AbbVie's first R&D Day. We've prepared what we hope will be a very informative program for you today. We're going to cover a wide range of topics, including R&D strategy, updates on our late-stage pipeline, and highlights from selected discovery and early development efforts. 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-K and 10-Q filed with the SEC.
Second, we have a very full agenda today, and we have to stop at 1:00 P.M. in order to allow people time to get to ASCO. Because of this, we've scheduled only one short break in the middle of our program. It'll be about 15 minutes. During that break, we have boxed 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. With that, let's turn to our program. I'd like to begin by introducing our CEO, Rick Gonzalez, for his opening remarks. Rick.
Appreciate it. 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&D Day. This seemed 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. Although I probably thought it was a great idea, I can tell you some of the people here probably thought it wasn't such a great idea once we got into it. I think you will find it very informative.
I think you'll get a much better insight into what AbbVie R&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. Our goal today is to spend some time framing for you AbbVie's R&D strategy and providing our vision for how our near-term growth assets, including eight innovative, de-risked 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, are next-generation immuno-oncology programs, which are really designed to broaden and deepen response beyond what we've seen with the first wave of biotherapies. 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 12-18 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 ABBV-8E12 and RGMA, which have the potential to translate to disease modification in neurodegenerative disease conditions like Alzheimer's, MS, and spinal cord injury. Both ABBV-8E12 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. 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 2017. Our recent acquisition of Stemcentrx gives AbbVie a highly attractive platform for solid tumors and an extremely exciting late-stage asset in Rova-T. 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 Rova-T 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 important component of our R&D efforts going forward.
We believe our R&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 three and a half 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&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 externally. Science and innovation are the core of the work we do every day. They are really the lifeblood of 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. 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've 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, 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 billion market today, expected to grow to $50 billion by 2020. In solid tumors, an even larger market, we have several promising programs, including our newest asset, Rova-T. Rova-T 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. DLL3 expression in other solid tumors gives us confidence that Rova-T will expand beyond just small-cell lung cancer. It's our objective to rapidly advance Rova-T into relapsed refractory small-cell lung cancer and efficiently execute studies to move quickly into frontline therapy as well.
In parallel, we'll be advancing studies to validate Rova-T'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, veliparib, ABT-414, our 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 in combination 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. 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 two late-stage assets, ABT-494 and risankizumab, 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 pangenotypic 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've placed a concerted effort to develop disease-modifying therapies for Alzheimer's and other neurodegenerative conditions. As I mentioned, we're exploring novel mechanisms like anti-tau or RGMA in disease-modifying approaches for Alzheimer's and MS. We're placing targeted investments in a number of areas as well, with programs in women's health with elagolix, 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&D since we became an independent company. It was a high priority for us, we did this through a concerted effort to create a highly productive R&D engine at AbbVie. We invested in meaningful opportunities in our pipeline, rapidly moving them through development, registration, and approval. Our R&D investment has been highly productive, it ranks favorable as a percentage of sales compared to many of our peers. We built upon our already strong capabilities that we had as part of AbbVie with the addition of new talent to our R&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 two most recent examples, Stemcentrx and our collaboration with BI. 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 12-24 months. 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 de-risked. 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. 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 billion. It is our objective to continue to further diversify AbbVie's revenue base, assets like IMBRUVICA, VIEKIRA, VENCLEXTA have already started that diversification process. As you'll see through today's presentation, we have eight late-stage de-risked assets which collectively have the potential to generate $25 billion-$30 billion in peak nominal revenues, significantly reducing our concentration related to HUMIRA and further diversifying AbbVie. 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-risked late-stage pipeline, which is poised to fuel strong long-term growth. 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. We expect double-digit EPS growth on average through the long range plan.
In closing, I'd hope that you'll leave today's meeting with a deeper appreciation of our scientific leadership, our R&D productivity and innovation, as well as our long-term growth prospects, which will be driven by the strength of our pipeline going forward. With that as an overview, I'll now turn the stage back over to Mike. Mike?
All right. Thanks, Rick. 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. First, I'd like to start with a brief introduction and overview of our R&D strategy. This slide shows a number of the considerations that we look at when we develop our R&D strategy. First and foremost at AbbVie, our R&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 two 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-2 inhibitor. VENCLEXTA is a small molecule that blocks protein-protein interactions between BCL-2 and other family members that regulate apoptosis or programmed cell death. Until recently, it was not thought possible to drug protein-protein interactions with a small molecule. 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 sights. In addition, focus is a core element of our R&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 a new 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. Based on these considerations, our discovery efforts are focused in three 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 that we know well. Areas like rheumatology, dermatology, and gastroenterology. 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 pangenotypic program later on in the program. With programs like elagolix, where we'll bring an important new treatment option to women with endometriosis and uterine fibroids, two chronic conditions in which the current standard of care provides insufficient relief. In cystic fibrosis, where we will explore whether new insights in biology and medicinal chemistry can lead the way to a transformational new therapy. 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&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, two 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 two 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 Karran, 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. 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 MIT and Harvard, 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 risankizumab, which is an anti-IL-23 monoclonal antibody from Boehringer Ingelheim earlier this year. I think our almost two-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. As this slide shows, our R&D strategy is supported by strong financial commitment. The left-hand panel shows that our investment in R&D has grown from approximately $2.8 billion in 2013 to more than $3.6 billion in 2015. In 2016, we expect to commit approximately $4 billion to our R&D efforts.
We have made this investment, we've been fortunate to be able to leverage a growing top line with R&D spending as a % 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 II and phase III success rates in comparison to industry benchmarks. As you can see, our recent 44% success rate in phase II development and 83% success rate in phase III 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.
In particular, I'd like to call your attention to our late-stage pipeline, which, as Rick mentioned, contains eight programs that have been substantially de-risked 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. While our first three years have been very productive, the next several years will be busier still. This chart provides a high-level news flow for major pipeline events between now and 2018. With that, I'll conclude my opening remarks. 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 on 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. With that, let's turn our attention to oncology. The roots of AbbVie's oncology franchise go back almost two decades to the beginning of the work that ultimately led to the approval of VENCLEXTA, our novel BCL-2 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 technologies that underlie our portfolio today. Our presence in oncology was significantly accelerated by the acquisition of Pharmacyclics a little over one year ago, and again by our acquisition of Stemcentrx, which was completed just two 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. New areas such as immuno-oncology have burst onto the scene. 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 2030, the worldwide incidence is expected to double, resulting in a staggering 21 million new cancer diagnoses every year. Despite the availability of a wide range of therapies, clinical outcomes remain poor. 30% of all patients diagnosed with cancer will die within five years, and that number increases to 80% in cases of metastatic disease. In fact, in certain cancers, such as small cell lung cancer and glioblastoma multiforme, 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. 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 three 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 one 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 III 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 VENCLEXTA 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. 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. 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 to the accumulation of mutations that drive tumors. 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 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 Rova-T, an antibody-drug conjugate that targets DLL3 on the surface of neuroendocrine tumors. Rova-T, 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 four 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 Rova-T 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 ADCs is not new, 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're 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 pre-clinical 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. 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 pre-clinical systems, we can show that a bispecific that binds to two 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 two 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. 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. 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. 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. 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. CD40 agonists were limited in the clinic by systemic inflammation and by hepatotoxicity. 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.
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 to 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 two 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 two representative bispecifics interact with their target proteins.
The antigen-binding regions are coded in green and in purple, and the respective proteins are coded in blue and yellow. 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 on the cell surface. In the program that I just described, we had to screen more than 50 unique 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 antitumor 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. 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. 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 12-18 months. This number includes five 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. 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 Rova-T, 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. With that, we're very pleased to have with us today two of the co-founders of Stemcentrx, Brian Slingerland, their CEO, and Scott Dylla, their CSO. Brian and Scott will now tell us more about Rova-T, their pipeline, and the platform that they've built, and will 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.
Hey. 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 those synergies or what the potential could be as I go through our talk today. 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 improves survival. Before I start today, Stemcentrx, as the name implies, is very much based around the cancer stem cell paradigm, which came to a head maybe about 10 years ago in the lab I was post-doc-ing at at Stanford. It's really, you can break it down into three 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. 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.
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. Stemcentrx, as the name implies, is focused on identifying the cancer stem cell population and developing therapies that actively target and eliminate those cells. While a truly cancer stem cell-targeted therapy may not have an immediate impact on tumor burden, we do believe that that will ultimately impact survival. To introduce to you a little bit to Stemcentrx, we were founded in 2008 by Brian and I. We're located in South San Francisco. Among our core research platforms are patient-derived xenografts.
These are very simply human tumors grown exclusively in mice. 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. 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. In so doing, it allows us to identify targets that are tractable and develop targeted therapies against those. I'm going to be talking about a number of our clinical programs in just a moment. At Stemcentrx, we built an agnostic platform. When we started the company in 2008, we did not fully ascribe to the markers that were in the public domain.
We very simply built a large proteomic platform to identify and characterize tumor cell heterogeneity. 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. 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. In this work, and adding additional markers beyond CD46, we've been able to identify, over the last eight 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.
There are progeny non-tumorigenic cells. Both the progenitors and non-tumorigenic cells are progeny, ultimately, of the cancer stem cell population. Obviously, we're able to isolate and analyze the 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 eight different indications, and we've leveraged that ability to now look for targets. 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 up front, now a lot of that noise is removed. This next slide shows a representation of the power of this approach.
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. 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. 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 a subpopulation of tumor cells.
This is where Stemcentrx has gone hunting and why a number of the targets, in fact, all three 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. I briefly laid out a number, one or two 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've 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 about 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. 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. 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 five drugs in clinical development. I'm going to talk about three of those in just a moment. We also have a pipeline of programs moving into the clinic or coming close to clinical development and a number of other major unmet needs that we've not yet addressed clinically, and we'll talk about those a little bit.
These are the five 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 Rova-T or rovalpituzumab tesirine. I will also talk about the PTK7 auristatin and then ephrin-A4 calicheamicin programs. Those were partnered with Pfizer back in 2011 when we only had 25 people and none of the capabilities we have today. As you can see, we've already progressed further because of some of the streamlining we've done in producing of antibody drug conjugates, et cetera. There are two other programs that are in phase I-A right now. We're not going to talk about those, and we also have not yet disclosed those targets. Rovalpituzumab tesirine or Rova-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% percent five-year survival. 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 and 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 lasts only three or four months.
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 seven to 17% response rate. Also a great deal of toxicity. In fact, most physicians don't even like to use it. In the third-line setting, there is no approved drug. 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. Let's take a step back. 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 tumorigenesis, and this has been established in a number of publications. 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 tumor 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. This is whole transcriptome or RNA-Seq data from these isolated populations of cells. DLL3 might sound familiar. It is a member of the Notch receptor ligand family, it is unlike all of its family members in that among the developmental biology literature, has been shown to be retained in the Golgi apparatus. It does not reach the cell surface. It's been shown to interact with Notch1 and DLL1 and retain them inside the cell, inside the Golgi, and to redirect them to endosomes for destruction. In so doing, it's been shown to be a dominant inhibitor of Notch signaling.
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 tumorigenesis . There was a hairpin screen done by Doug Ball and colleagues at Johns Hopkins University, where DLL3 appeared among a laundry list of genes that were down-regulated when hairpins against ASCL1 were generated in a small cell line, suggesting that DLL3 is downstream in a transcriptional target of ASCL1. 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, it stands to reason that DLL3 may actually unify these two previous observations by inhibiting Notch1, therefore, DLL3 may actually drive neuroendocrine tumorigenesis .
Consistent with its potential role as an oncogene in neuroendocrine tumors, when we try to knock down DLL3 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. In 25% of those patients, they observed non-synonymous Notch receptor mutations, which means mutations that would negatively impact signaling from the Notch receptor. 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.
We are currently working with that German group and others to confirm that these are mutually exclusive, again, suggesting that this inhibition of the Notch pathway is a major driver of neuroendocrine tumorigenesis , the vast majority of patients have a manifestation of high DLL3 expression. 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 DLL3 does leak to the cell surface when it's overexpressed in cancer. 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 as high as you will need it to deliver efficacy.
We found that this antigen internalizes extremely fast, much faster than HER2, for example, which is the target of one of the approved antibody drug conjugates, KADCYLA. Using an FFPE-compatible immunohistochemistry antibody, we found high expression on small cell lung tumors. If we convert that membrane 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 cisplatin and etoposide, have at least intermediate to high levels of DLL3 expression. Importantly, normal tissue has absolutely no expression of DLL3, including normal lung. 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 overexpression.
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. 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 a valine alanine dipeptide-containing spacer. The importance of the valine alanine is that it is a substrate for cathepsin B, which is active and expressed in late endosomes. This linker will only be cleaved when it gets into the cell and it's routed into late endosomes. The drug to antibody ratio in Rova-T is two, so two drugs per antibody. Essentially we're using Rova-T as a Trojan horse to deliver that PBD dimer payload. I'm going to back up.
I worked hard on that animation. To route to the late endosome where that dipeptide will be cleaved and the payload will be released and kill the cell. That's the mechanism of action of Rova-T. Just to show the power of antibody drug conjugates, this is one of our tumor-bearing mice. It had a relatively large tumor burden. This is getting close to when we would euthanize an animal. This is a human tumor engrafted under the skin of a mouse. It's running around pretty happy. It knows it has something there, but they're not really bothered by it. Then we randomized these animals and treated them four times, once a week for four weeks. You can see after just four treatments, that entire pretty large mass completely went away, and it didn't come back for more than 70 days after the last treatment.
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. We're injecting the drug IP, the drug is systemic, and it's that systemic MOA of get it, tumor in the right cells in the tumor that are causing the cell death and efficacy. Preclinically, 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 three times at day zero, three, and seven, and with the targeted antibody drug conjugate, an appropriate control, an anti-hapten or non-specific antibody linked to the same toxin with the same number of drugs, or treated animals with the standard of care, cisplatin and etoposide. You can see very strong activity by Rova-T, 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, 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.
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, two animals per group. We transplanted human tumor cells in limiting dilution into another set of animals and used Poisson distribution statistics to calculate the residual tumor-initiating cell frequency at that point in time. You can see that Rova-T had a dramatic impact on cancer stem cells or tumor-initiating cells. 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.
We performed 13 different xenograft experiments to try and do what we call a phase I study in mice. You can see that while tumor growth inhibition was similar to both cisplatin, etoposide, and Rova-T, we did not see any recurrences in eight of the 13 xenografts that we assessed, and that response very much correlated with expression. Something we commonly do is look at expression response correlations preclinically. You'll also note that some PDX models have very low H-scores, manifest by the fact that their low percentage of cells express the target. If you hit the right cells, you can still have a dramatic impact on the course of treatment. 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 public disclosure of any data, and then again at ESMO or the European Cancer Conference in Vienna. This is the summary of all patients in the phase I-B portion where patients were dosed at 0.2 milligrams per kilogram at every three weeks for a total of three doses or 0.3 milligrams per kilogram every six weeks for a total of two doses. You'll notice that the DLL3-high patients. All of our responses were DLL3-high.
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. This is all data we presented at ESMO, again last fall. There will be updated response and survival data presented on Sunday, I hope you all attend. Importantly, we saw equal responses in both the second-line setting and the third-line setting, this is very important because there is no approved drug in the third line. Drugs typically don't work very well in that third line, I'll talk about that in a few slides. I thought it'd be very important to cover just two case studies quickly because I think they say a lot about the mechanism of action of Rova-T.
The first is a 54-year-old patient at Memorial Sloan Kettering. They were treated three times, once every six weeks, with 0.3 mg/kg. After that third dose, they had about a 50% tumor reduction. This is also a third-line small cell lung cancer patient who was told to get their affairs in order. 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% of the cells typically are Ki-67 positive, which means they're actively proliferating. This patient had one tumor left in the adrenal gland, the physicians decided to resect the tumor, this is a cross-section in H&E of that tumor. While there was a residual mass, this light pink really is just scar tissue and fibroblasts.
The only visible tumor cells left were these small islands of purple cells, the pathologist at Sloan Kettering, who's one of the top lung cancer pathologists in the world, noted that upon path review, we had more than a 95% treatment effect. Only 1% of these tumor cells was Ki-67 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. 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. We don't always need to see responses to see clinical benefit, I think this is really eye-opening.
This patient is a 60-year-old female at the University of Alabama at Birmingham. After the first three doses of drug, this patient was on the 0.2 mg/kg dose regimen every three weeks. They were dose reduced going into the third cycle because of a mild rash. Basically, since that point in time at day 42, this patient has had stable disease and has PET negative scans now for over 620 days. This patient has not received any drugs since day 42, is still working two jobs, doing well as of their last visit in April. This data, again, you'll get an update on that data on Sunday, has underlined the focus on the third line. We are now enrolling a third-line pivotal study for approval, for accelerated approval.
It is a trial that we call TRINITY, it is a single-arm study because, again, there is no approved drug, we've seen very substantial activity. 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 has only been 18% with about 51% clinical benefit. The median overall survival is only 4.7 months. I want you to remember that number. The median one-year survival is only 12% in this setting. Again, TRINITY is actively enrolling. We currently have 28 trial sites open, including sites in Europe, one right now, there are many more coming online. Our focus is moving this drug as fast as we can into the front-line setting where we will be starting maintenance studies.
I'm going to talk about our clinical development plans in a minute. Also we will be evaluating combinations with cisplatin etoposide, providing Rova-T ahead of or after CE and combining the two. I briefly wanted to talk about checkpoint inhibitors. 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 nivo, with a little worse median OS than the current standard of care in third line, for example. Both of these drugs have the same mechanism of action, impacting immune checkpoints. There's been recent data published that antibody drug conjugates, specifically those with certain payloads, can induce an immunogenic cell death.
We believe, are now generating pre-clinical data that shows substantial evidence for potential synergy between these drug classes. The idea is to induce immunogenic cell death with a targeted cancer stem cell agent like Rova-T, provide a lot more fodder for recognition by antigen presenting cells and T cells, 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. All I'll say right now is we have significant evidence pre-clinically for this, we'll be showing that data later this year. We're also going to be moving aggressively into those combo studies clinically. I'll cover that in a moment. DLL3 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, an aggressive form of thyroid cancer, and glioblastoma. This is an overview of our clinical development plans. 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 a different sequencing of that. The basket study in these other neuroendocrine indications will be starting soon, 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 I so we can select the regimen dosing. We will be initiating a first-line maintenance study where you debulk tumors with cisplatin etoposide, followed by Rova-T. This will be a phase III study and will be confirmatory. We intend to start that later this year. Finally, we're also going to be opening trials in Japan at the end of the year. I see I only have 2 minutes left. I hope that is enough time, or I might get another minute or 2. To talk briefly about the other 2 programs that are partnered with Pfizer. The first is a PTK7-targeted auristatin, a different payload than Rova-T leverages.
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 in 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. If we focus on the triangles on the right, which I'm using to demarcate patients with breast cancer or ovarian cancer, which do express the target. We had very early on, still in the phase I-A, 50% response rate in breast cancer.
The only ovarian cancer patient we treated at doses below the phase I-B expansion levels had a complete response. This is a patient who had failed four previous lines of chemotherapy with no better response than progressive disease. Again, they were dosed at below the phase I-B expansion dose, which is 2.8 mg/kg, and the PR was confirmed well out past six months. This is one of the triple-negative breast cancer patients who had a near CR. Again, at doses below the phase I-B level. Started with a 5-centimeter tumor, shrank to a half centimeter. Also had a confirmed response well out past six months. This drug has been extremely well-tolerated. There have been no, at least in the data reported at ESMO, no grade 4 or 5 toxicities.
The only grade 3 toxicities observed, even up to 3.7 mg/kg, which is more than double the level at ADCETRIS, which is the other approved antibody drug conjugate, was a fatigue, a severe headache, and two cases of neutropenia, which were reversible and consistent with the MOA of auristatin. Finally, talk briefly about ephrin-A4 calicheamicin. Ephrin-A4 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-claudin-low subset of triple-negative breast cancer, which accounts for 90% of triple-negative breast, had very strong responses preclinically, whereas the claudin-low subset and HER2 positive, which don't express the target, don't respond to the ADC.
Again, this phase I 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. You can see some really nice early responses in the phase I-A portion. Again, both this study and the previous study and Rova-T, all single-agent data. Again, the tox profile here is 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 calicheamicin. At Stemcentrx, again, we have five clinical programs shown here. Here's kind of our scorecard, where we have two drugs in small cell lung cancer, two in triple negative, three in ovarian, and one in melanoma non-small cell.
Over the next 18 months, we will be filling out the rest of the scorecard. We have two programs that will be entering the clinic this year. The first of those, IND number 6 in ovarian and non-small cell lung cancer, we have some others coming for colorectal, pancreatic, gastric, luminal B breast cancer, another big unmet need, and AML. Our vision ultimately is to develop cancer stem cell-targeted therapies that are, A, targeted and specific to patients who express the target. A patient could come into the clinic, get their tumor biopsied, stained by immunohistochemistry. We do have companion diagnostics we're developing in parallel with all these programs, match the patient to the right drug. Seems fairly simple, and that's what we're working towards.
In summary, three of our first three clinical programs are all showing strong single-agent activity at tolerated doses. All three are targeting antigens 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. 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. 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 fourth quarter, early next year.
Again, that will be a phase III confirmatory study to confirm the TRINITY study. We also will be initiating the NEURON and basket study very soon, and as soon as we can, initiate checkpoint inhibitor combination studies, again, for which we have very strong preclinical data for the synergy between these different MOA-type drugs. With that, I'll turn it back over to Mike.
Great. Thanks, Scott. 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?
Thank you, Mike. Hi, good morning, and thanks, Mike. 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. 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. 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. If you look at non-Hodgkin's lymphoma, we are still seeing a high net proportion of patients dying from the disease, with over 20,000 deaths in the U.S. annually. Now to BTK.
From target validation to the frontline indications, here's a timeline depicting the rapid development of the inhibitor of Bruton's tyrosine kinase, ibrutinib. About 70 years ago, Colonel Ogden Bruton described a genetic disorder in young boys with agammaglobulinemia. Over 40 years later, the BTK gene was cloned and characterized. In 2005, the first synthesis of PCI-32765 occurred, and here's ibrutinib docking covalently into the BTK active site at Cys481. Just in 2009, the first human was treated with ibrutinib, and following that, efficacy was demonstrated in several B-cell malignancies. In 2013, we received three breakthrough therapy designations from the FDA. In rapid succession, we converted those to approvals, with the first approval for ibrutinib being just over four years after the first patient being dosed. All the primary research was published in The New England Journal of Medicine.
More recently, we garnered a frontline approval for CLL, all lines of therapy, in March 2016. Just over the past couple of weeks, we had an approval for all lines of SLL in May 2016. The IMBRUVICA clinical development program, as well as its license, has given a broad safety experience to be incorporated into our label. 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. Today, I'm going to highlight some of the key parts of our program where we're trying to maximize IMBRUVICA in those indications. 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 III development.
At the end, I'll actually touch on some of the places where we're looking at IMBRUVICA outside of hematology, in solid tumors and graft versus host disease. Now let's start with CLL. IMBRUVICA has the potential to broadly transform the management of treatment-naive CLL patients. I think one of the key features of our development program was how quickly we got to this frontline indication. This was based on the RESONATE-2 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, chlorambucil. In this study, the data really clearly supports 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 as assessed by the investigator. In addition, we see significant overall survival benefits.
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. This was despite the crossover of 41 patients from the chlorambucil 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. Just recently this week, we received the European Commission approval for first-line use in CLL as well. We're studying IMBRUVICA in a comprehensive development program in treatment-naive CLL and SLL.
There's several more phase III studies that are ongoing, mostly being performed in the cooperative group setting. In the U.K. and the U.S., there are 2 phase III studies looking at patients who are younger and fit with ibrutinib in combination with rituximab against the standard treatment with fludarabine, cyclophosphamide, and rituximab, or FCR. An inter-group 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 obinutuzumab, or GAZYVA, versus the chemotherapy-based combination with the antibody.
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. We anticipate data from these studies to be reading out between 2017 and 2019. Now, moving on to the 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. This is supported by some robust ex vivo analysis.
Here you can see at the top panel on your right, BCL-2 expression evaluated in patients treated with IMBRUVICA by U.K. investigators, demonstrating persistently strong expression of BCL-2, the target of VENCLEXTA, throughout IMBRUVICA treatment. In some patients, as denoted here by the MD Anderson investigators, we actually see increasing levels of the BCL-2 protein in patients treated with IMBRUVICA. When you take the leukemia 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.
Here's our ongoing clinical evaluation of the combination of IMBRUVICA and VENCLEXTA, you see here six studies that are either ongoing or very soon to initiate, including one large phase III study, the CLL13 study, which is looking at the combination versus FCR or BR. In this study, they're testing the three-drug combination of IMBRUVICA, VENCLEXTA, and obinutuzumab versus FCR, BR, and also looking at VENCLEXTA and obinutuzumab and VENCLEXTA and rituximab in two other arms. There's a similar phase II evaluation that's being done in treatment-naive CLL patients with a deletion 17p. In the U.K., there's an ongoing study called CLARITY that's looking at the two-drug combination in patients with relapsed or refractory CLL.
Internally, we're really excited about the PCYC-1142 study, which is a fairly substantial phase II 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. In the bottom, we see two studies in mantle cell lymphoma. One is looking at the three-drug combination, the OASIS study, that's ongoing in the U.K. The last study, the AIM study, I'll go through in the next slide. The AIM study is looking at the combination of IMBRUVICA and VENCLEXTA in relapsed and refractory 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.
In a limited number of patients, in the abstract, they describe an elderly population with high-risk disease. Ibrutinib is started four weeks before VENCLEXTA at the standard dose for mantle cell lymphoma, 560 milligrams daily. VENCLEXTA is then added and given as per the USPI in the standard dose ramp up over five weeks. What you see here is that full doses of VENCLEXTA and IMBRUVICA were achieved in all patients, it was safe and tolerable. The efficacy seems to also be very promising. After the addition of VENCLEXTA, they saw stable diseases converting to responses, then responses converting to complete responses with three valuable patients. Two of those three patients were actually PET negative and MRD negative, so showing absolutely no evidence of the disease.
This is really early experience, and it will be updated here at the annual meeting on Monday. It's really promising in terms of the efficacy and no unexpected safety signals, really paves the way for continued progress for this combination within CLL and non-Hodgkin's lymphoma. I've talked about the approvals in CLL, SLL, and Waldenström'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. IMBRUVICA has broad potential beyond CLL and mantle cell lymphoma. I'll be reviewing some of our progress in other pivotal development programs, including diffuse large B-cell lymphoma and follicular lymphoma. I'll go through some of the data in solid tumors. I'll touch on our first non-traditional oncology indication that we're evaluating IMBRUVICA, and that's chronic graft-versus-host disease.
If you take the largest segment of non-Hodgkin's lymphoma, it's diffuse large B-cell lymphoma. Early on in 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 IMBRUVICA can be safely combined with R-CHOP, and efficacy also looks promising in a phase I study. This set the stage for a large ongoing phase III study called the PHOENIX study, which is looking at IMBRUVICA in combination with R-CHOP in these treatment-naïve 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.
At the recent ASH, we demonstrated high activity of IMBRUVICA and rituximab in first-line follicular lymphoma. This is an early data set with a median duration of treatment of about two and a half, 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. The majority of these patients continue on treatment. We'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 and 2018. A common objective of many of our pivotal studies within non-Hodgkin's lymphoma is to enhance the activity significantly versus chemoimmunotherapy alone.
HELIOS, back in the CLL program, was the first of these phase III 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. 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 SLL. In non-Hodgkin's lymphoma, we have two very similarly designed studies. One is the SELENE study. It's a fully enrolled phase III study evaluating IMBRUVICA BR in previously treated indolent lymphoma. The STEIN study, a phase III study assessing IMBRUVICA and BR as first-line therapy in mantle cell lymphoma.
Turning to solid tumors, the rationale for IMBRUVICA in solid tumors is multifactorial. It includes the high-level expression of active BTK within the tumor-infiltrated leukocytes and the tumor microenvironment, as demonstrated here in a recent publication from Cancer Discovery in pancreatic adenocarcinoma. With higher-level expressions seen in the tumor microenvironment than they are seen in normal leukocytes within the human spleen. An additional rationale is the role of ITK. ITK is an analogous kinase that is expressed in T-cells analogous to BTK that's expressed in the non-T-cell component. By inhibiting ITK, we actually see a reduction in the immunosuppressive TH2 phenotype of T-cells, and an increase in the TH1 or pro-anti-tumor T-cells.
Taken together, this could increase the efficacy that we see in solid tumors. This has been proof of principle in many preclinical models, including the one 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 PNAS looking at IMBRUVICA in combination with checkpoint inhibitors where a phenomenon of prolonged overall survival was seen in the mice treated with the combination versus the single-agent checkpoint inhibitor alone. We're looking at IMBRUVICA in a broad but targeted fashion within solid tumors. We have two actively enrolling basket studies looking at IMBRUVICA in combination with standard of care chemotherapy or checkpoint inhibitors.
As well, we have one 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. 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. It's associated with substantial morbidity, and there are no approved therapies for this disease. It represents a significant unmet medical need. IMBRUVICA targets both the B and T-cell component of this disease and can lead to responses in high-risk patients. 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.
IMBRUVICA, in addition, targeting BTK, can inhibit the self-reactive B-cells, inhibit the production of the antibody complexes and the resultant fibrosis. Also through ITK, IMBRUVICA can inhibit several of the self-reactive T-cell subsets. What we've shown in a phase II 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. If we look at the news flow for IMBRUVICA, some of the upcoming milestones include, in CLL and SLL, a number of the phase III studies being read out 2018. If you include the IMBRUVICA and VENCLEXTA and GA101 combination, that will read out a little bit later.
We see in multiple myeloma, we have two randomized studies looking at IMBRUVICA in combination with pomalidomide or IMBRUVICA in combination with VELCADE. In non-Hodgkin's 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 timelines, the actual timing of the data may vary. SHINE, SELENE, and PHOENIX are all poised to read out over the next 6-18 months. In solid tumors, we'll be seeing some of our first basket study data from the checkpoint inhibitors in the near term, later on top of the standard chemotherapies, as well as an early interim analysis is potentially available for pancreatic cancer. I think that's all I have for the IMBRUVICA program.
I'd like to hand it over to Dr. Gary Gordon, who will give you an update on the other late development oncology assets from AbbVie.
Thank you, Danelle. I think Danelle's 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. As many of you know, AbbVie has been working in the area of apoptosis for approximately two 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. The real accomplishment here was developing a small molecule that allows one to modulate how this process occurs in the setting of dysregulation.
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. 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, BAD, BAX, and BAK. The ones in blue are BCL-2, BCL-XL, and MCL-1. For purposes of our discussion, BCL-2 is really the critical one. The normal function of BCL-2, this anti-apoptotic member, is to sequester the pro-apoptotic 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, that can trigger the process of apoptosis and allow cells to die.
In the setting of many of the hematologic malignancies, one of the mechanisms of failure to die is very high levels of the BCL-2 family or the BCL-2 protein specific. What's shown on this slide is some of the areas where we think that VENCLEXTA can have important clinical activity. What we're showing is not only CLL, non-Hodgkin's lymphoma, multiple myeloma, and AML. The areas in red are the areas where we have breakthrough designations, in the setting of 17p deleted relapse/refractory CLL, the treatment of CLL in combination with RITUXAN for patients who have progressed on earlier therapies, and in the setting of AML. 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.
If we first focus on CLL, remember this is a drug that we brought into the clinic in June 2011. A little less than five years later, we received our first approval, April of this year, for the treatment of relapse/refractory 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. What is even more significant is, one, this occurred with a single agent, two, we also were able to show that patients became MRD negative.
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. MRD is a, if you will, molecularly-based means of detecting whether or not there are cancer cells. 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 relapsed refractory population. Again, about an 80% response rate with 20% of patients achieving a complete response. Then setting the stage for the next study is when you combine venetoclax or VENCLEXTA with RITUXAN, an anti-CD20, we in fact move 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 two phase III studies in frontline CLL that are ongoing. There is a pivotal study that has completed enrollment in relapsed refractory disease in combination with RITUXAN. There'll be updates to the work in CLL presented on Monday, June 6th at Hall A. 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 B-cell receptor pathway inhibitors, specifically, in this case, ZYDELIG 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.
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. Again, there'll be further information updated on Monday, and we expect to read out the full phase II study in 2017. 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. Non-Hodgkin's lymphoma, Danelle has already talked to you about this a little bit, about 72,000-73,000 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 are 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. If you are not cured, you will die of diffuse large B-cell lymphoma. The other bucket is indolent non-Hodgkin's lymphoma. 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 or bendamustine RITUXAN. It does have a more indolent course with a first-line PFS, progression-free survival, about 70 months.
What we're really looking to do in this disease is to take advantage of the strong pre-clinical data that shows combinations with anti-CD20 and VENCLEXTA 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. You can see there is some variation in sensitivity across the different types of non-Hodgkin's lymphoma with Waldenström's and marginal zone being among the most sensitive, as well as mantle cell lymphoma. There are several ongoing studies in frontline therapy in diffuse large B-cell lymphoma. There's ongoing work looking at combinations with chemotherapy in relapsed refractory follicular lymphoma.
We expect readouts next year. 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 in terms of treated patients are shown. About 12,000-13,000 patients die of this disease. Median age of diagnosis is late 60s. Five-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-2 family members in a way where some of the resistance factors, such as MCL-1, are down-modulated, so in theory, increasing the sensitivity to VENCLEXTA.
On the next slide is showing some of our results that show we have single-agent activity, which we reported on earlier, but we know that if you combine the two in clinical studies, particularly in patients who remain sensitive to VELCADE or bortezomib, 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 III study in this setting in the second half of this year. The last part of the VENCLEXTA program I'll talk about is AML. AML, again, as with most hematologic malignancies that we're dealing with, the median age at diagnosis is in the 60s. Five-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, many of them have a sensitivity profile very similar to that that we see in CLL, and that encouraged us to move forward. Here's some of our data looking at responses to two of the standard therapies that are used in this population. One of those are hypomethylating agents, azacitidine 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.
The other one that's actually very intriguing is low-dose Ara-C, where the historical response rate is down at 10% or 11%, and when used in combination VENCLEXTA and LDAC, we're seeing very good complete response CRI rates of about 44%. This will be presented as an oral presentation tomorrow, June 4th, and we will be also starting phase III activity in this setting as well in the second half of the year. 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. What I'm going to turn to next are the two programs that I'd like to talk about in the solid tumor setting. One is veliparib, our PARP inhibitor. It's an oral agent.
The second is ABT-414, an antibody drug conjugate EGFR. You've heard a lot already today about antibody drug conjugates and how they might work. Let me turn to veliparib. Veliparib 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. One is in the setting of pre-existing known defects in DNA repair, the B-R-C-A, the BRCA-type cancers, BRCA breast and BRCA ovarian. The other is in settings where there may be somatic changes in DNA repair and where there may be additional damage to DNA.
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. The 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. The second is data from a randomized study in non-small cell lung cancer, where we combined PARP inhibition, veliparib, with backbone chemotherapy. What we were able to show there is that in a group of individuals who smoke, so a predefined, pre-specified population with even more DNA damage to current smokers, their overall survival with chemotherapy alone was about five and a half months.
When we added veliparib, it went to 12.5 months. That encouraged us to move to a series of trials shown on the next slide, where we have five ongoing phase III studies, two of those in All in combination with chemotherapy, two in the setting of where there's probably some preexisting limitations to DNA repair, so BRCA-related breast cancer and ovarian cancer, and then two 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 in neoadjuvant trial, which was based on a positive study from the I-SPY 2 trial. In the last minute, I'll talk to you about ABT-414. ABT-414 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. When the disease recurs, it's even worse. The incidence around the world is about 28,000. ABT-414 is an antibody drug conjugate, as shown on the lower left-hand side, and you've learned a lot about how ADCs work and are targeted. ABT-414 is unique in the sense that it only identifies an epitope 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 EGFRvIII mutation. This is common amplification in EGFR mutation occur in about 50% of GBM patients, so it's a very good disease to study this in.
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 to tumor. 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-414. The antibody is delivered to the patient, and what you can see is over the next five 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 increase 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-414 in the setting of glioblastoma. We now have two large international trials that are ongoing, one for patients who have relapsed disease, one in front-line disease, and you can see that we're expecting readouts from these trials over the next couple of years. I will just end with the consolidated news flow. 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.
All right. Thanks, Gary. Okay. As I mentioned at the start of the day this morning, we've created a new role. That role leads oncology discovery and early development across AbbVie, and it'll 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 '90s. He's gone on to have a very productive career and a leadership role in cancer genomics and cancer biology at a number of institutions. He joins us from the Ontario Institute for Cancer Research, where he served as its founding president and scientific director.
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, since it's only day six for me at AbbVie. 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, of my 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, one out of four Americans are going to die from cancer. In the 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's been some discussions in some papers whether this is really a moonshot. There's always controversy about it, this is really important.
Really, as a moonshot, there's a lot of new knowledge and 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. This is an important problem, and there's lots 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. I'm a clinical immunologist, but most of my research has been in genomics and cancer research. As Mike mentioned, I was part of the Human Genome Project. I think, the first postdoc at MIT, when the Genome Project got launched in the U.S. We worked a lot on technologies, but we also worked a lot on mapping the genome.
I was in charge of the groups that did the physical map of the genome, a gene map of the genome. We eventually found the concepts for the haplotype map projects, which, again, were used by 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 probe successfully. It also brought technologies. We developed lots of robotics, as you can see in an old picture. I used to have hair. Also developed the concepts of microarrays.
We helped design novel microarrays with Affymetrix for expression, SNP chips, 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, two of the initiatives which I've been associated with the most in the last 10 years. The International Cancer Genome Consortium was a moonshot that was launched in 2007 by the global research community. I was asked by NIH and Wellcome 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 are almost always abnormal in most cancers. Here in this case, you can see a lot of chromosome 2s.
You can see rearrangements. This is not a normal karyotype. Very common in cancer. We discovered over 41 years that each translocation, BCR-ABL, can actually give rise to a fusion gene. If you inhibit that fusion gene with Gleevec, you can actually put patients in long-term remissions. You're not curing the disease, but people, it becomes a chronic disease. The concepts of the cancer as a disease of the genome was important. The concept there would be mutations in cancer genomes that were yet to be discovered was very strong, but we didn't have the tools until then to actually do a systematic search of cancer genomes. We want to find, of course, additional drivers for drug development programs. 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 2007. We knew that technologies were coming. We knew people would be interested in this project. We realized those cancers are 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 is actually very healthy. It's 88 projects across the world. It was more than 50.
Each of these bullets here represents a big investment by a funding agency, a group of pathologists, clinicians, genome centers, computer scientists generating data and putting out in a public domain. You heard a bit earlier about the small cell lung carcinoma project in Germany by Roman Thomas. It's on 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. 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 types of 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. This information, as I said, is already going out to academic groups, but also to industry to identify new targets. This has led to discovery of many new pathways. 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 cancer stem cells, for example, mutations in the DNMT3A are actually reinitiating mutations. 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 genome is 10,000 somatic mutations. Most of them are passengers. We want to just find the ones which are drivers.
There's still a lot of work to sift through all the data sets to find the important ones, but many have been identified, many of the cancer genomes, and these are becoming biomarkers, seeds for new drug development projects, and precision medicine. What has been the impact so far of the ICGC? 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 under different types of cancers and put that out in the public domain as new insight about cancer. Science-wise, it's been a great project. It's also been a translation, and we've learned a lot by it on how to translate. I think one of the major things we're learning is that cancer genome is not just something of a genome center anymore.
It's something that's going to happen in a path 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, which we could inhibit, we'd actually start therapies based on that. 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 cancer, we published this in Nature Genetics last year, an early prostate cancer where the % genome alteration is the highest biomarker of aggressive disease. Maybe those patients should be treated more aggressively.
Of course, we've heard about DNA instability important in processes right now for DNA damage, PARP inhibition, combination therapies in this area might be very interested in how we would treat patients in the future. Again, it depends on looking at that patient's genome to identify the index of genome instability. Finally, neoantigens. In all our publications, we used to say how many mutations we found, how many were neoantigens, novel proteins. It's only because of the rise in immunotherapy, we also realize that the more neoantigens there are, and specific ones we're trying to be able to identify the best ones, but the more there are, the more people respond to the novel immunotherapies. The cancer genome is becoming something to be used in a diagnosis of every patient.
The last 10 years, I've also been leading a new institute, a translation institute that was founded by the governor 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 lab and accelerating it, bringing it to the clinic. It wasn't about just discovery research anymore, but it's actually accelerating the path to bringing novel therapies to patients. 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 a clinical trial group and bring in 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. We did 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. That's important. That creates jobs. That's important for the minister to actually see that these companies are having products and bringing jobs. A lot of it 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 finds.
If you look at the number of papers in the top 10 percentile or highest citation impact in terms of percentage, they come from OICR 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. There's 1,700 clinician scientists and trainees and others working in our large programs. 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 change policy, change guidelines based on some evidence we gathered. That actually improved colon cancer screening rate by more than 15%, which is about 400 lives saved per year. OICR is an academic biotech, I'm not here to do any presentation of OICR.
I mostly want to do a presentation on the experience that we've learned in translation. We did develop biomarkers, novel therapies, very high-risk ideas at the time, and moved them forward towards the clinic. I just thought I would take one example of an immunotherapy to study. If you go back to 2007, 2008, as we were launching, decided to launch this program, immuno-oncology was not hot. In fact, it was deemed to have over-promised, under-delivered, there were scientists that came to us, came to OICR, said, "Hey, we can cure cancer in mice using next generation therapies, but we just can't get them to patients." John Bell was one of them.
He's a virologist, been involved in the first generation of oncolytic viruses, he says, "I and my colleagues all need to be able to show whether these things are going to work in humans." One of the six programs in projects inside there was actually developing a next generational oncolytic virus, but also bringing in the concept of vaccination to create what we called an oncovaccine. Two of the former students of John, which have their own labs, did a lot of this work. David Stojdl 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 basis therapy, but the basis of all this, cancer cells generally have defective innate immunity, viruses can penetrate cancer cells better than normal cells.
What David was looking for the viruses across the world which would have the most of this oncolytic activity. Also decide to insert in these vectors some tumor antigens. In addition to that, Brian Lichty at McMaster decided, let's boost the person's immune system before we treat them. For a month before you actually give the treatment, you actually boost the immune system against the two cells. What OICR was able to do, which you can't do in traditional academia, is to deal with GMP manufacturing of the agents, do large scale primate studies, very advanced pre-clinical studies, and eventually is doing a phase I. It is right now in phase I study. We learned a lot, 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. Here, for example, we discovered a way to really boost the immune system. T-cell responses that are extremely high are happening. In this case, we discovered that while we see that although most tumors present antigens at the levels of the tumor, there's a lot of immunosuppression in the microenvironment of the tumor. This strategy boosts the immune system against tumor antigen in the spleen, and that's why the responses are so good. 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. Mike mentioned that AbbVie is very interested in tumor microenvironment.
There's a lot to be learned about that environment and how we could use, potentiate some of these novel immuno-oncologies. Maybe one before I get to my last slide, because I've been asked, why did I come to AbbVie? I'm obviously very passionate about cancer research, and I wanted to do more in the area of therapies. 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. I found all of this at AbbVie and more. It's a very bold company, but you've seen the projects, bringing in Pharmacyclics, Stemcentrx. A very bold company, very committed to oncology, great capabilities, and also a great culture.
A great culture of team science, which is also very important in the types of projects I want to develop. 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, intensify 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. My priorities will be-- Again, I'm only on day six, but I can tell you right now, the priority is to grow this existing AbbVie pipeline. We will build critical mass in immuno-oncology. We're going to go beyond the concepts which are being developed at this point in the field.
We'll definitely try to unlock the potential of different types of immune cells. I also hope to explore the interactions between cancer genome signatures and immune response, because both the cancer genome and immune response are right at the heart of what we are talking about when we talk about precision medicine. Hopefully, all of this is going to bring long-term benefits to individuals, especially cancer patients and society. I'm the last speaker of 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 or box lunch inside the room. We'll be restarting in about 15 minutes. Thank you.
Okay. The music stopped. I think that's my cue to get us going again. I'll give a minute just for people to sit down. All right. Thanks for your attention this morning and for respecting our short break, and we'll get back to our program. If we could advance the 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 Xiaoli Lin from Clinical Development, and joining her in just a moment will be Lisa Olson for Discovery. Without further ado, I'll turn it over to Xiaoli.
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 million 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. In fact, a minority of our patients still are able even to achieve those response rates. Today, my colleague Lisa Olson will tell you about some innovative approaches 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. In gastroenterology, specifically inflammatory bowel disease. 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-494 and risankizumab are our two 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-494 is in phase III development for rheumatoid arthritis, risankizumab for phase III in psoriasis, and both agents are actually being tested in Crohn's disease and have potential within that disease state. I'll tell you more about each of those programs today. ABT-494 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 two JAKs, therefore result 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-494 is a highly potent JAK1 selective inhibitor with single-digit nanomolar potency against JAK1, 74-fold selectivity of JAK1 over JAK2, and 19-fold selectivity over JAK3.
The potential for ABT-494 to demonstrate this increased efficacy is seen here in this model-based meta-analysis across available RA trials for ABT-494, as well as the other JAK1 selective molecules that are currently in development. The three panels are ACR 20, 50, and 70 scores. Highlighted in blue are the two doses of ABT-494 that were studied in phase II as twice-daily doses and is currently being evaluated in phase III as single once-daily equivalence. The light blue box represents the low dose of ABT-494 being studied in phase III, as you can see, 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-494 that's being studied in the phase III.
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 II study enrolled particularly difficult-to-treat TNF inadequate responders, individuals who had failed two or even three biologic therapies before being entered into the study. Again, what you can see are the three panels of ACR 20, 50, and 70 scores, blue highlighting the doses of ABT-494 being studied in phase III. The lower dose, again, is in 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-treat population to date. The high dose of ABT-494, again, performing consistently better.
As you can imagine, we were very encouraged when we saw these results at the end of phase II and eager to move to phase III. In fact, by leveraging that global infrastructure, the vast network, as well as our deep expertise in this field, we were able to move from an end of phase II go decision to first subject dose in phase III in a matter of three months. The phase III program for ABT-494 in rheumatoid arthritis is composed of six pivotal studies. 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. Use, of course, in the most grievous unmet need, the biologic inadequate responder population.
Within the context of these six studies, two of the studies are active comparator trials against adalimumab as well as abatacept. Two of the studies have radiographic endpoints that will evaluate the ability of ABT-494 to inhibit structural damage after a year of treatment. As we have done for HUMIRA, we intend to fully maximize the potential of ABT-494 across multiple disease states within our core areas of strength. I'd like to tell you a little bit more about risankizumab. Risankizumab is a monoclonal antibody against IL-23 that was recently licensed from Boehringer Ingelheim is currently in phase III development for psoriasis. IL-23 signaling is upstream of TNF alpha and IL-17 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-23 thereby inhibits its signaling.
This is in contrast to ustekinumab, which binds the common p40 subunit of IL-12 and IL-23 blocks both IL-12 and IL-23 function. It was uncertain whether the clinical efficacy that's been seen with ustekinumab was secondary to IL-12 function, IL-23 function, or blockade rather, or both. It wasn't until pre-clinical experiments targeting p35, the unique subunit to IL-12, were performed, showed no efficacy, that it was hypothesized that the next generation of agents that targeted p19, such as risankizumab, could block solely IL-23 could result in efficacy at least as good as ustekinumab while sparing the normal immune function associated with IL-12. In fact, risankizumab has demonstrated in phase II the potential to be a transformational new therapy in psoriasis.
The panel on the left are PASI 90 or 90% response rates at 12 weeks. The panel on the right, 100% response rates or complete clearance of skin disease at the 12-week time point. On the far right of each of those panels is a teal-colored bar that is risankizumab. 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, certainly the biologic therapies.
From left to right, just to give you an idea, the anti-TNFs in purple with HUMIRA, IL-12/23 mechanism with STELARA in brown or orange, the IL-17s in blue and gray. Other IL-23s that are in development in green and blue. The other very attractive feature of risankizumab for psoriasis is its dosing paradigm. Relative to the next most efficacious agent, for instance, which is the gray bar in the middle of each of these panels, the IL-17a ixekizumab is dosed every other week, where risankizumab is dosed every 12 weeks. In addition, risankizumab has demonstrated very encouraging phase II results in Crohn's disease, these were recently presented at the DDW meeting.
Here, you see the clinical remission scores for risankizumab in Crohn's disease relative to the same endpoint from other agents currently in development, as well as currently available agents from their phase II as well as phase III 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 three TNF agents prior to entry into the study. 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 point. Hence, we intend to move Crohn's disease into phase III, and we expect that to happen later this year or early 2017. The phase III program for psoriasis will cover about 2,000 patients and consist of four pivotal trials. Two of those pivotal studies are head-to-head comparisons versus STELARA. One is a withdrawal and retreat study, and one is a comparator against adalimumab. All three studies are ongoing and enrolling rapidly. As for HUMIRA and for ABT-494, we fully intend to maximize the potential of risankizumab across our core areas of strength in addition to the phase III study that's ongoing in psoriasis, the phase II in Crohn's disease.
There's a phase II study that was also ongoing in psoriatic arthritis, and we intend to study risankizumab also in ulcerative colitis. The data readouts for both of these late-stage programs will happen within the next one, two, and three-year timeframe. 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 II assets that will be reading out within the next one to two years. These include our bispecific approaches to TNF and IL-17, as well as IL-1 alpha beta, an antibody approach to IL-6, as well as an antibody against IL-13. 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, Xiaoli. Now I'd like to turn your attention to three discovery programs that continue to drive the search for transformational efficacy in our three key disease areas. Two 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 third program is a small molecule inhibitor of RORγt, and holds the promise of an oral agent with high efficacy for psoriasis. 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. 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. One of the key characteristics of an ADC project is high-density expression of the ligand on the cell 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. 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 third 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 y-axis over the course of the experiment. Relative to vehicle, shown in black, a single dose of systemic steroid, 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. The systemic steroid has very potent suppressive effects 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 two small molecule inhibitors.
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. It is a combination of an anti-TNF antibody with methotrexate. What this really suggests to us in discovery is that in a complex disease like RA, it is likely that one needs to inhibit two complementary mechanisms to get full management of the disease. Xiaoli shared with you the compelling data with our JAK1 molecule in RA, which gives pretty broad-spectrum inhibition of T cell responses. We are fortunate at AbbVie to have a novel suite of BTK inhibitors, which themselves will inhibit both B cell and myeloid cell mechanisms, two 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 two complementary but distinct mechanisms would deliver additive efficacy for autoimmunity. The preclinical data that supports that hypothesis is shown on your right, where combining two low doses of the JAK1 inhibitor with a BTK inhibitor, shown in red, delivers substantially greater efficacy than what is observed with each of the individual components alone. This program we are advancing into RA, again, early in 2017. The last program I would like to share with you is our RORγt inverse agonist small molecule inhibitor. I think what has been extremely interesting as an immunologist over the last three or four years is to see the efficacy in psoriasis, this chronic inflammation of skin disease, with inhibitors of both the IL-23 and IL-17 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. The first program that is emerging from discovery is the RORγt program. RORγt is an obligatory transcription factor for the development of Th17 cells, the cells that produce the majority of IL-17 in an inflamed condition. It is also essential for the actual transcription of the cytokines themselves. Inhibition of this pathway would result in both lower numbers of cells and therefore also lower amounts of cytokines. We have demonstrated preclinically that using our RORγt inverse agonist is very effective in inhibiting IL-23-driven inflammation, as shown in the histology sections at the bottom part of the slide. Treatment of mice with RORγt results in a suppression of IL-23-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-17-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 are hopeful, in psoriasis. This lead molecule will advance into humans this year. Now I would like to invite Xiaoli 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-494 and risankizumab, our late-stage program, 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. We have, again, data reading out in the next one, two, and three years for those programs. In addition, we've talked about some near-term readouts for phase II, as well as given you some exciting preclinical data from these early-stage programs that Lisa's just covered, which will enter the clinic in the next year and have clinical data in the next two-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 elagolix. Hepatitis C first. 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 million 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 million 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 first-generation agents. We need agents that will address the difficult-to-treat populations like genotype 3 and cirrhotic patients. 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 ABT-530, a novel NS5A inhibitor, as well as ABT-493, 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 ABT-530, our 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 a given variant. The higher the bar, the lower the potency or the more permissive that agent is relative to the replication of a given variant. In the upper left-hand panel, you can see that ABT-530 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 Y93H variant, which is the second bar from the right in each of these panels. It's a common variant that's found in virologic failures to NS5As. In addition, this high degree of potency to baseline resistance has been demonstrated in patients.
This is the 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 RAV, 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 ribavirin 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 II. In addition to the genotype 1 direct-acting antiviral-experienced treatment failure or first generation treatment failures that I just showed you, which was MAGELLAN-1 study, we've also evaluated the difficult to treat genotype 3 non-cirrhotic patient population, and it achieved 100% SVR.
As well as the genotype 3 compensated cirrhotic patients and also achieved 100% SVR. With regards to duration, in genotype 1 and 2 treatment-naive as well as experienced, we've been able to take the duration of treatment down to eight weeks and still achieve 100% sustained virologic 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 II with an eight-week regimen that's being tested in phase III. Overall, we believe that AbbVie's next gen hep C cure and the phase III 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 eight weeks, we're looking at all the relevant patient populations, including the treatment-naive, the direct-acting antiviral experienced, special populations such as in renal impairment, and cirrhotic patients and the difficult to treat, again, genotype 3 and cirrhotics. In addition, within the context of the phase III program, there's also a head-to-head study in genotype 3 non-cirrhotic treatment-naive subjects versus sofosbuvir/velpatasvir. 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 gonadotropin-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.
Elagolix has a rapid onset of action and is readily reversible when therapy is stopped, therefore, we believe that it has significant potential for the management of hormonally mediated conditions such as endometriosis and uterine fibroids. 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 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%-10% of women, and therefore an estimated 176 million 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 towards the right. 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 mainstays of therapy, which have minimal invasiveness but also minimal efficacy. 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 hormonal suppression. It's effectively an overdrive system of the hormonal axis.
It's dosed subcutaneously once every month or once every 3 months. We'll talk more about Lupron in a moment. In addition, there's surgical options such as laparoscopy that are obviously invasive, and unfortunately are also associated with a high 1-year recurrence rate. By the procedure itself can be associated with adhesions that also in and of themselves can lead to chronic pelvic pain. The unmet medical need in endometriosis is significant. We really need something that is minimally invasive and has a high degree of efficacy that ultimately can occupy that upper 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 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, I'll show you the data that we believe supports this. Elagolix has been studied in 2 phase II pivotal studies to date, with 6 months of data available so far. The primary endpoint for these studies is 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. The blue bars are the high dose of elagolix, or 200 mg twice daily, which is associated with about a 75% response rate, with regards to decrease in pain.
These responses were seen as early as 3 months and were maintained out to the 6-month time point, As you can see across the 2 panels, they were highly reproducible across the 2 pivotal studies. When we look at 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 in decrease in non-menstrual pelvic pain, and the high dose about a 60% response. Again, highly reproducible across the 2 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.
Here you can see the mean % change from baseline in terms of bone density for the low dose of elagolix, which is a limited decrease, and the higher dose of elagolix in blue, which is a higher decrease. 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 six months. Ultimately, if needed beyond six months, it can be used within the context of hormonal add-back therapy, which is the light blue bar on the far right here. You can see, hormonal add-back therapy is actually quite effective in preventing the bone density loss from Lupron.
Options for bone protection are currently under evaluation for the high dose of elagolix that include the potential for hormonal add-back therapy, among other considerations. In addition, I'll next talk to you about uterine fibroids, I'll show you how elagolix plus hormonal add-back actually is successful in regards to inhibiting this loss of bone density. 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, they're associated with heavy menstrual bleeding. What I mean by heavy menstrual bleeding is that women can get on the order of a liter of blood loss with menses, where a normal menses might be 40 milliliters. Hence, you can imagine that this disease state is often associated with anemia.
In addition, 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. It is estimated that the lifetime instance of uterine fibroids in premenopausal women is on the order of 50%-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 contraceptives and progestins. Here, with only short-term use and even more limited efficacy. In the green box, gonadotropin-releasing hormone agonists, such as Lupron, which is only approved for a short-term course preoperatively with no approved add-back therapy.
Surgical options such as hysterectomy exist, 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 one-year recurrence rate. Hence, the unmet medical need in uterine fibroids is clear, that we need something that has the potential for long-term efficacy, ultimately without the need for surgery. Again, we think that we have some data that will support why elagolix may meet this unmet medical need. Here, I'm showing you the phase II-B data for elagolix in uterine fibroids, specifically addressing the potential to decrease the amount of bleeding associated with menses. The green bars are placebo. The purple bars are elagolix.
You can see that a high dose of elagolix, 300 milligrams twice daily, 90% of people actually achieve a response with regards to heavy menstrual bleeding. A response here was a decrease in bleeding to less than 80 milliliters per menses and a 50% reduction from baseline bleeding risk. As is anticipated, this degree of suppression of the axis was associated with bone density loss, which is seen on the right-hand panel. 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. The good news is that we get only a modest loss of efficacy with the addition of add-back therapy to elagolix. From a 90% response rate down to an 80% response rate.
We actually get marked 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 fibroids. 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 second pivotal study for endometriosis, the [inaudible] , 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, Dr. Laura Gault from Development, and Dr. Eric Karran from Discovery, who will tell us about their neuroscience approach. Laura?
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 DUODOPA/DUOPA 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. 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 slow or halt 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 Karran will discuss later. This slide shows our marketed products and some of our select early clinical development programs. In Parkinson's disease, DUOPA/DUODOPA is a levodopa/carbidopa gel that's delivered directly into the intestine. 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 Zinbryta 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. 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-555 is one such potential agent that's currently in phase I. This is work that's based on pioneering biology conducted at AbbVie, where we've demonstrated extensive pre-clinical evidence for neuroprotection and regeneration. Finally, in Alzheimer's disease, we're approaching this disorder with an anti-tau monoclonal antibody.
The antibody was initially developed in the lab of Dr. David Holtzman at Washington University, and we continue to collaborate with Washington University and C2N Diagnostics to develop this antibody. It's currently in phase I, targets tau pathology, and is in development for Alzheimer's disease and progressive supranuclear palsy, another neurodegenerative disorder. I will focus on the two products in our MS pipeline, and Eric will follow and discuss our AD pipeline as well as the anti-tau program. MS is an unpredictable, progressive, chronic disorder of the nervous system that strikes patients between the ages of 20 and 40, females more commonly than males, and it affects about 2 million people worldwide. In MS, the immune system actually attacks a protein called myelin, which forms a protective sheath around nerve fibers. What myelin typically does is it actually increases the efficiency of communication from neuron to neuron.
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. 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.
We're committed to meeting all of the needs of patients with MS. We're currently supporting Zinbryta, which is a novel immunomodulatory treatment option for patients with MS, and advancing ABT-555 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 medications. 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. Zinbryta 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-2 receptors, Zinbryta inhibits activated effector T cells, expands immunoregulatory CD56 bright NK cells, and decreases the activity of T regulatory cells. Overall, Zinbryta is associated with immunomodulatory effect without broad immune cell depletion. Zinbryta has demonstrated efficacy in two pivotal trials, the SELECT study and the DECIDE study. In the SELECT study, two doses of Zinbryta, 150 milligrams and 300 milligrams monthly, were evaluated versus placebo, and both doses of Zinbryta 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, in this study, a single dose of Zinbryta, 150 milligrams, was compared to an active comparator, interferon beta-1a or AVONEX. In this trial, Zinbryta 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 examine this in both trials. In the SELECT study, Zinbryta resulted in a 57% relative risk reduction for confirmed disability progression. In the DECIDE study, patients treated with Zinbryta had a lower risk of progression compared to the active comparator group.
Zinbryta 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 Zinbryta for up to six years. Boxed 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 Zinbryta are generally manageable, and a REMS plan has been established to educate patients and physicians about the risks associated with Zinbryta and the need for appropriate monitoring. Overall, Zinbryta 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.
ZINBRYTA has demonstrated superior sustained efficacy versus an active comparator for treatment durations of up to three years. The risks and side effects are generally manageable, and a REMS program has been established to support physicians and patients in the appropriate use of the drug. Finally, ZINBRYTA is available in a convenient monthly self-administered subcutaneous dosing form. 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 ABT-555. 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-555 binds to RGMA and blocks its effects, 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-1. While LINGO-1 has shown strong preclinical evidence for remyelination, it has not demonstrated strong effects for axonal regrowth 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 two 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 GAP-43, which shows neurons and neuronal fibers. In this experimental model, rats who received a control antibody saw 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. 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 zero with the inflammatory cytokine, and administration of antibodies occurred at day seven, 14, and 21. The first dose was seven 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 rats that received the control antibody. In this experiment, those rats showed a decrement in motor function over the course of the first week that was preserved over the rest of the observation period. Their impairment was rather severe and included an inability to move their tail or to turn over. 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.
They actually showed recovery over the remainder of the observation period, and by the end, were functioning at their baseline levels. 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 received the control antibody have lost over 90% of these fibers.
In fact, the blue staining 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%-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. This is really important because this is a technique that can actually be used in the clinic to look for similar effects in patients. ABT-555 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 Karran, 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. As the world moves to increasingly elderly population, unless we find therapies that either delay or deflect the course of the disease, by 2050, there will be 115 million Alzheimer's disease patients worldwide. That will be an absolute calamity, clearly for those patients, but also for their caregivers, for societies at large, and also for healthcare providers who will struggle to be able to afford to pay for the cost of care. 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, I've also been very energized because clearly we need to replicate that success for neurodegenerative disease as well.
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 A-beta peptide that probably has no physiological role. Tangles are made from the protein tau, which becomes heavily hyperphosphorylated, and tau plays an important role in neuronal physiology, as I'll come on to describe. 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 three 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 plasticity of the human brain is overwhelmed, and we enter the clinical phase when people manifest the signs and symptoms of the disease. 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, moreover, look at the effects of those pathologies on brain metabolism.
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. Clinical trial designs, which were hypothesized to be able to demonstrate true disease modification of therapeutics, though been around for a long time, they are now being looked at in terms of Alzheimer's disease as well. 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. That means that four of the five principles that Mike alluded to earlier that underpin AbbVie's R&D strategy have been satisfied. The one missing component from this list is core capability. 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 three areas of 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. Unlike our peers, AbbVie does not have an Aβ or 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 Aβ in the disease process. 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 eight years. We've known for some time that there are these rare causal 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. This is pathologically and symptomatologically identical to the sporadic form. There is a much earlier age of onset of this disease, actually, 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.
What does this tell you about the role of amyloid in Alzheimer's disease? I think this is highly consistent with amyloid playing a role in triggering the disease process, not necessarily driving the disease process once the process has started. 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. 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 that by the time people enter the very first symptoms of Alzheimer's disease of mild cognitive impairment, that amyloid pathology has reached a maximum. It's 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 causal mutations shift this whole pattern to the left, the overall course of the disease is unaltered. 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 point, as I've described it. All of the phase III trials on amyloid-directed therapeutics that have read out to date have been conducted in this phase of the disease process, in the mild to moderate space. As I've just told you, at this point, amyloid has actually already reached a maximum. Clearly, we need to be able to conduct phase III trials earlier and earlier, and preferably to do primary prevention studies.
If you look at clinical development of agents coming through, they are going earlier and earlier. Some of the BACE inhibitors are being tested in asymptomatic at-risk patients. 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. 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 to the 10 or more agents that are currently in clinical development. That brings me onto tau. Neurons are quite unusual 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 a basketball, then the synapses on the right-hand side would be up to two miles away. 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. 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, then form intracellular aggregates called either PHFs or NFTs, neurofibrillary tangles. There's probably two things going on here. There is a loss of normal function, which I think is probably quite modest. The gain of aberrant function as these NFTs fill up the cell body, I think is very important to the pathology.
To give you an idea of what this might look like, this is an immunohistochemical slide. Those sorts of triangular shapes are cell bodies. They're stained in brown and black for aggregated tau, and you can see that they are absolutely full of tau. I think if you were a neuron, you'd probably be feeling very uncomfortable in that position. 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. 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.
The earliest symptoms of PCA are visual disturbances. Let's contrast that in the right panel where a patient has been imaged with both tau imaging agents, amyloid imaging agents, and also a measure of glucose utilization, a measure of brain metabolism. 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. 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. 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.
Neuropathologists for some time have used the Braak staging system to be able to assess the extent of tau pathology in the brain. It goes from one through to six. If you correlate Braak stage, in other words, a measure of tau pathology, with cognition, here measured by the Mini-Mental State Examination, you actually get a pretty good correlation. This diagram really implies that if you were able to administer an effective tau therapeutic early on in the disease, you would preserve a lot of cognition in patients. 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. I think ultimately, it's this feature that will distinguish tau therapeutics from Abeta therapeutics. AbbVie have their own human monoclonal antibody against tau AT12, which was in-licensed from C2N.
We and others in the field believe that tau pathology spreads through the brain from the release and uptake of misfolded tau seeds at synapses. 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 AT12. The green line at the top there is a control antibody. 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. This feature is manifested by an overall reduction in tau pathology in a mouse tauopathy model, as shown on the right-hand side.
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 Gault said, is a pretty pure form of a tauopathy, and Alzheimer's disease as well. To sum up, the inauguration of the FNC, I think is a measure of our ambition in this area. We're going to grow this group over the next two years to be able to deliver novel therapeutic targets to the organization. In the meantime, neuroscience is developing a suite of anti-tau antibodies to follow up on our first foray in the clinic with AT12. With that, I'll hand back to Mike.
All right. We'll now move to the Q&A portion. Well, actually, Eric Karran, 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. As we get ready to do that, we'll get set for our first few questions.
That was good.
Thank you.
Very good. Thank you. Should we do it in order? You and Laura want to go there?
Yeah, that makes sense.
Yeah, doesn't it?
All right. 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 to two questions in the interest of time. On Rova-T, it's obviously a very exciting molecule. Sounds like we've got some exciting data coming. Could you talk about the potential for a more accelerated filing than the 2017 timeline that you have? Do you have data in a setting where there's no treatment? I believe you have a breakthrough therapy designation application in progress. I wonder if you can talk about the potential around that for a more accelerated filing than 2017 that you talked about in your guidance. Secondly, just talk 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 a PD-1 in the best case, and you've talked about some earlier stage microtumor environment IO approaches. Do you think you're going to need to build a broader IO platform, including your own backbone PD-1, or do you not subscribe to that being important?
Two very distinct questions. Rova-T question we'll take first. We are committed to driving Rova-T forward as rapidly as possible. That program is moving forward on all fronts with a number of studies either up and running or to be up and running very shortly. Perhaps for the specifics, I'll hand it over to Brian.
Sure.
Yes. We have a study called TRINITY that's up and running. It's a single-arm study with about 125-150 patients, that will enroll mostly this year with a planned filing next year. 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.
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. Turning to immuno-oncology, there's a lot to your question. Do we ascribe to PD-1? We think clearly that the PD-1, PD-L1 axis plays a very clear role. I think that's been demonstrated across a number of tumor types. A number of the approaches that we are pursuing, one could envision working well in combination with PD-1. 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-1 over time. 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 the tumor immunosuppressive environment that might be aimed at T reg function, that might be aimed at restoring immunity through dendritic cell function in other ways that would generate new immune responses. I think that there are several programs that we'll be able to bring forward in the coming, say, 12 to 18 months, would share those mechanistic characteristics. I showed you two 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. There are also programs that address the tumor immunosuppressive environment in other ways. Stromal-directed agents, for example, that might enhance immunity and enhance neoantigen presentation to the immune system.
It'll be a wide range of approaches that we're exploring. We'll have about five mechanisms in the clinic in 2017. We're going to be exploring 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 the descriptions that I just gave, but other sorts of mechanisms as well. Tom, I don't know if you want to say anything further to that. You should be loud, if you can.
Oh, yes. I'd just like to say that I think that with just two weeks on the job, I'm still doing assessment of the different programs. I've met a lot of what I call drivers of projects, which have not been discussed today, which are sort of looking at other ways, again, to stimulate T cells, to look at other cell types, dendritic cells, macrophages. As I finish my assessment, I think we also want to do additional recruitment because this is going to be a long-term strategy of AbbVie to actually have a very long, healthy pipeline in immuno-oncology. That's all I can say, I think, at this point.
Okay. All right. Thanks. We have another question over here. Liz?
Hi. Jami 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 Stemcentrx.
Yeah. What I indicated in my remarks was on average, so it would mean just that across the average. There could be some years where we're slightly below that, and there could be years where we're substantially above that. I wouldn't expect years where we were dramatically below that. Again, it will be dictated to some extent by our interest in driving programs more broadly from an R&D standpoint. One of the things we won't do is we won't cut back on R&D to manage the bottom line. We may cut back in other areas to try to make sure we manage our bottom line appropriately. 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 at least you saw over the course of the day is we have a very productive R&D engine here at AbbVie.
Just to follow up on Rova-T, which does look very exciting, especially in the DLL3 overexpressers. Is there a commonly used biomarker available to test DLL3 expression in small-cell lung cancer patients? Just curious what % of patients are currently tested for DLL3. Does it require a new biopsy, or can you use old biopsy samples to test for this? Just generally, is the PDX tissue library totally unique and differentiated, giving you a competitive lead for future discovery?
Yeah.
Right.
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. The methods are very standard, and those same methods can be applied to a DLL3 test, which is being developed by Stemcentrx.
Right. It's a very simple immunohistochemistry assay, just like with Herceptin. The antibody was developed by us. We're working with Roche Diagnostics for the actual clinical diagnostic, and it does not require a fresh biopsy. All of these samples you've seen are from the original diagnosis, and we have seen that DLL3 expression does hold from that point, even after patients get through rounds of chemotherapy. Maybe you can comment on the PDX library?
Sure. The PDX library, we think, is one of the largest of its kind. We don't know of many others that have built a library like this. We do think it gives us competitive advantage, I think that's 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.
Thanks, Jami, for that. I think, Larry, we'll go to you in the back.
Yeah, 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?
It really depends on the line of therapy. I think right now we're focused on getting the drug to approval in third line. Scott showed the data earlier today where the historical response rate has been in the 15%-18% range. At a year, about 12% of patients are alive. I think the median OS is in the four and a half month range. We've been focused on looking at our phase I data and going into this study. The endpoint for TRINITY, as I just mentioned, is confirmed response rate.
We also want to show, and we can't talk about it now, the data that will be presented on Sunday, 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 as sort of the most important metrics for that particular study. Going forward, as we move into the frontline setting, metrics like the median OS and looking at that relative to chemo or placebo in the case of the maintenance consolidation would be obviously the most important metric there. I think one of the things that has really plagued studies in this disease, actually even more so than in pancreatic cancer, is that response rates have been relatively high, survival has not.
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 be even stronger in survival. That's hopefully clear as it relates to the first study endpoints are very different from the frontline study.
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 what's lacking in therapies for this disease in particular, and for many oncology conditions. Those landmark analyses, those long-term good outcomes are something really to focus on. 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 the 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. You look at nivolumab by itself, and in this setting, in small cell, has I think about a three and a half month median OS, but when combined with ipi, that goes to seven or seven and a half months. 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.
Liz, we're going to go over here.
Thanks. David Risinger from Morgan Stanley. 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. 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 two 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? 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? Then with respect to ABBV-8E12 on phase II, I'm guessing we should see an efficacy readout in 2018 or so. What will you be using as your primary endpoint or endpoints there? Thank you.
Okay, 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 and 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. We believe that the safety that we're observing is very consistent with the JAK1 selective hypothesis. One thing that one should keep in mind when you look at those data is that we explored a very broad dose range of 494 in phase II. We did that on purpose. We pushed to 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.
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. Xiaoli, I don't know if you want to say anything further about that.
Yeah, 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 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 effectively determine 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 whether or not there's an impact on infections. What I can tell you is that across our phase II studies, that ultimately infections were relatively mild. I think there were only two serious infections within the context of both studies.
One was in placebo and one was in active treatment.
With respect to elagolix, I think your question was about dosing scenarios, dosing duration, and 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 designed, gives a greater degree of suppression of the hormonal axis, and with that comes a greater degree of bone suppression as well. That's still less than LUPRON. LUPRON is approved for six 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. Longer-term data will tell us whether there's potential beyond that for the basic higher dose program.
There are the components of the program that Shelley 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 the uterine fibroids component of the program and also based on our experience with LUPRON. We'd expect to have the same sort of success with that add-back program within endometriosis, and that could be a path to even longer-term administration of that agent. Maybe, Shelley, if there's anything you want to add?
No, just I think part of your question was about timing.
Oh, the data timing. Why don't you give that?
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 uterine fibroids. 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 bisphosphonates, et cetera, with a separate program.
Yeah. I think your last question was about tau and why it's been so difficult to advance a successful candidate in tau. Maybe I'll just turn that directly over to Eric.
Yeah. It's an interesting question. I think you have to take a historical perspective of this. In 1991, there was human genetics that showed that mutations 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. Pharmaceutical companies and the rest of the field understood that if they could find molecules to prevent the production of amyloid, they may have therapeutics. The discovery of the human mutation also enabled the field to get transgenic models, which actually displayed plaque pathology. We had an in vivo model to use to progress those targets. That just did not exist for tau. The first tau mutation was discovered in the mid-'90s by Mike Hutton.
We had the wherewithal to make transgenic models that had tau pathology, and 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. I think really that the short answer is the field have put a lot of effort into the amyloid cascade hypothesis, which actually I'm an advocate of as well. 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 clinical trials.
To add to what Eric Karran said with regard to tau, it's also the case that translational tools are emerging. While amyloid PET has been available for a number of years, tau PET ligands are still in development. As those continue to progress, that will enable the field to better evaluate agents that are directed against tau.
Great. I think we'll go to Larry in the back.
It's Geoff Meacham, Barclays. I have two oncology questions. The first one is, how are you thinking payers will respond to IMBRUVICA and VENCLEXTA combo therapies with respect to price as they're effective as single agents, what incremental clinical benefit do you think is needed? The second question is for the PARP. Clearly the landscape there is competitive today and is getting more competitive. How do you guys look at differentiation? How do you maximize that? Is the focus just speed to market and indications that aren't really addressed today, such as lung cancer?
On the first question with respect to, if I heard you correctly, how payers will respond to the combination of IMBRUVICA and VENCLEXTA or VENCLEXTA. First and foremost, we are focused on driving the studies to show that there is real value here for patients. You saw, as an example, and this is, of course, monotherapy, the sorts of results that have been seen with RESONATE-2 or in combination therapy, the sorts of results we see with HELIOS, where we're driving very clear differences between the experimental regimen and standard of care. 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. That is our primary consideration in those 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 further.
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 want 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. 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. Collecting that data out of the traditional system of physician visits, hospitalizations, all of the supporting care that is necessary for an oncology patient, I think many people are surprised by what that cost is.
If you can get a patient to 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 years, there's a savings to the system associated with 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.
Your second question about PARP in terms of how we would differentiate our PARP versus others that are in development. We have a different hypothesis, or at least a different hypothesis drives our PARP program than has driven the development programs of others. 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 synthetic lethality 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. 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. 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. It is those data that will determine the long-term utility of veliparib. 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. That will tell us the differentiation that exists. Gary, I don't know if you want to say-
No, I think you've summarized it 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, we'll go to Liz next.
Good afternoon, folks. Alex Arfaei with BMO Capital Markets. First question on Rova-T, obviously significant activity in DLL3 positive patients. The question is, how confident are you that these are in fact, these represent 65%-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. The second question is on elagolix. We spoke with a few physicians who said that younger patients with endometriosis are being treated with birth control and NSAIDs. Your phase III trials are placebo-controlled, I'm just wondering how you plan to position elagolix versus some of the cheaper alternatives for pain management. Thank you.
Okay. Brian, if you want to take the Rova-T question.
Sure. Yeah, we feel very confident about those numbers. The 65% are the portion of patients that have high levels of DLL3 expression, and that's greater than 50% of cells expressed at target, 80% includes all patients that have any levels of DLL3 expression. We initially discovered this and looked at our own data sets, and those numbers were roughly in line with the 65 and 80. We've also extrapolated and have collaborated with many different academic groups and have received tissue microarrays of hundreds of patients. Also in working with Ventana, our diagnostic partner, and the samples they've looked at, the incidence is 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. Your question on elagolix. OCPs are used front line. They're used obviously because there's a tremendous body of clinical experience, and they're a 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, new treatment options are clearly needed. With respect to NSAIDs and other analgesics are used across that spectrum. 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.
The chronic use of NSAIDs is not without its own complications as well. 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 the large majority of cases. Many women go on to fail OCPs, they will cycle through and need an option like elagolix before they go to the things that were on the right-hand panel of that slide that Xiaoli described. Much more intensive hormonal blockade, effectively pharmacologic menopause that one would induce with LUPRON, or the surgical options, which are obviously invasive and have their own downsides. We believe that there is a very real place for elagolix. Larry.
Hi, Tony Butler from Guggenheim, again on Stemcentrx for the group. Two questions. One is, when DLL3 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 quantitatively? Second, if I understand the hypothesis correctly, DLL3 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 DLL3, or is it something else that actually causes an upregulation versus a downregulation? Thank you.
Yeah, on the latter, it is very clear that inhibition of the Notch pathway drives neuroendocrine cell fate, which is the opposite of epithelial. High Notch signaling drives epithelial cell fate. Notch is a switch that controls epithelial, and that is 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. The cells that do have expression, where we have quantified the receptors to get at the other aspect of the question, we think there is about 5,000 to 10,000 receptors per cell. Unlike a lot of the other ADCs that target proteins that have high levels of receptor expression, 50,000 or greater, DLL3 internalizes much faster than those. You are 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. Thanks. Chris Schott at J.P. Morgan. Just two quick ones. Dave, first on IL-23 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 you just continue to bring biologics to a broader spectrum of that market? The second question was on Rova-T and the combo program you are going to be starting. Will that just look at small cell, or will you explore a number of different tumor types for that initial program in conjunction with PD-1?
Okay. Rick, do you just want to comment, spend some time on the market dynamics?
Quickly, if you think about this particular market, I think there's still an opportunity to see significant growth. 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. I think we will continue to see a significant amount of growth. 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%-30% biologic penetration rate. I think there's plenty of opportunity to grow if you have the right kinds of agents.
Brian, you want to
In terms of the combo strategy, our strategy has been to demonstrate single agent activity first and then move into combinations. That's what we're doing with small cell. Obviously, that was also a phase I trial where we were looking for safety, and we weren't ready to combine until we actually were very sure about the safety profile and the efficacy in the main disease, small cell. In this basket trial, we have eight arms that will enroll a variety of different neuroendocrine cancers. Once we start to see a signal as a monotherapy, then I think we would more quickly expand into combinations. That will also be true of everything else in the pipeline.
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&A session to an end. Thank you for your time and attention, and thank you for participating in our R&D Day.