Good morning, everyone. Thank you for joining us for our Investor R and D Day. I'm Mike Henke in Investor Relations. Before we begin, I would like to point out that we will be making forward looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties.
I encourage you to consult the risk factors in our SEC filings for additional detail. We're excited to share with you today the progress we are making in R and D across neuroscience. Today's program will include multiple live presentations, followed by a live Q and A session. The slides presented today can be found on the Investors section of our website. We will begin with presentations from our Chief Executive Officer, Michelle Bounatsos and Al Sandrock, our Head of R and D.
You will then hear from a number of other senior leaders across therapeutic areas and we will conclude with a Q and A session. We will take a short break at approximately 11:30 a. M. And we aim to conclude today's event at approximately 1:45 p. M.
You may notice today that we are socially distanced in separate rooms. I would also like to point out But yesterday, we posted 9 pre recorded on demand presentations on our website. These presentations cover additional therapeutic areas, Some of our early research programs as well as several of our core capabilities and enabling technologies. If you haven't already, I encourage you to review these presentations after today's event. Please note that Questions can be submitted at any time during today's presentations through the box in the upper right of your screen.
We ask that you limit your questions to the R and D topics discussed either today or in the pre recorded presentations. Thank you again for your attention. And with that, I'm pleased to welcome our Chief Executive Officer, Michelle Brunazos.
We are now 9 months into 2021. And as I stated in the past, we believe this is a transformative year for our company. We have achieved a number of positive clinical and regulatory milestones, while we are diligently working to address The near term challenges with the launch of Adjohelm. Today, we're excited to showcase for you our R and D pipeline And our scientific talent. I would like to start with our reason for pursuing scientific advancement in neuroscience, the patients.
There remains a vast landscape of significant unmet need in neuroscience, which has historically been a very challenging area. However, I believe that our specialization in terms of people, capabilities and programs Could enable us to help address these unmet needs? Just consider the following statistics. Today, it is estimated that over 30,000,000 people worldwide suffer from Alzheimer's disease and 10,000,000 people suffer from Parkinson's disease. Approximately 260,000,000 people worldwide suffer from depression with no meaningful breakthrough in treatments Since the SSRI revolution of the 80s 90s, as we know, COVID-nineteen has led to a 4x increase In the rate of depression among U.
S. Adults since 2019. Stroke is the 5th leading cause of death in the U. S. And researchers estimate that due to COVID-nineteen, this number has significantly increased from pre pandemic levels to now.
Patients with these conditions are underserved. They're living with the limitation of the therapeutics that are currently available And in many instances, the burden of disease falls to the family members and caregivers. This must change. Today, we will share with you how our scientific capabilities and our pipeline of new potential therapies is advancing. As you listen throughout the day, I would like to underscore a few points we will be highlighting.
1st, as I discussed, Neuroscience is a field with significant unmet needs. 2nd, Biogen is the established leader in neuroscience. We have a robust and diversified pipeline across multiple disease areas and therapeutic modalities. 3rd, neuroscience is experiencing a wave of scientific And technological breakthroughs. Biogen is at the forefront of exciting developments across biomarkers, new modalities, Advances in digital technologies and a better understanding of disease biology, including human genetics.
This is providing increasingly powerful ways to potentially mitigate risks and increase the probability of success. These same advances are also creating opportunities for early and targeted treatments Towards prevention by intervening in a disease even before symptom onset. 4th, we have very strong talent and specialized expertise. Finally, our pipeline has matured with multiple near and midterm opportunities. Let me highlight the importance of the inflection we believe we are seeing in neuroscience, which has the potential to increase R and D productivity Over the coming years, we have gained a much broader understanding of disease biology aided by advances in human genetics, Which is now helping us select the right targets and the right molecules.
The introduction of new technologies, Such as imaging and fluid biomarkers may further enable us to select the right patients and track disease progression over time. For example, we are the 1st company to use a blood based biomarker to potentially enable therapeutic intervention Before symptoms onset in ALS, new modalities and delivery technologies are starting to enable viable therapeutic approaches for diseases and targets once believed to be intractable. We once believed that large molecules could not sufficiently cross the blood brain barrier to exert a therapeutic effect. Yet, we have demonstrated that Aduhelm administered intravenously can exert a biological change in the brain. Furthermore, at Biogen, both internally and also with Denali, We are developing innovative delivery platforms.
So advances in digital technologies such as artificial intelligence and machine learning may open new opportunities across drug development, Diagnostics and Digital Therapeutics. This has all led to renewed interest in this field, and neuroscience is projected To be among the largest and fastest growing therapeutic areas. At Biogen, we have been steadfast in our focus. Over the last 5 years, we have invested over $11,000,000,000 in R and D, primarily within neuroscience. Many of our peers are investing selectively in neuroscience, choosing to focus on certain disease states and modalities.
At Biogen, we are differentiated from others. We have established a deep multimodality portfolio With the potential to deliver clinically meaningful treatments. At the core of our pioneering mindset is a central focus On the unmet needs. By placing patients first, we pursue opportunities with the greatest potential impact. We also have a deep commitment to equity, including a goal to increase the representation of underserved populations In our clinical trials, we have leveraged this approach to establish our leadership in MS and SMA.
And now we have an opportunity to do so in Alzheimer's disease. As pioneers, we embrace the most difficult And team, we have made significant progress developing and expanding our pipeline. It now includes 33 clinical programs Across a diversified set of disease areas and multiple modalities, we have added 25 clinical programs Due in part to the 27 business development transactions we have executed, importantly, our pipeline has matured With 12 programs in Phase III of filed. As I mentioned, 2021 is a transformative year for our company. We have achieved a number of milestones, including life cycle management initiatives, new product approvals, Positive readouts and new study initiations.
Admittedly, we have also had setbacks in some of our programs. Even so, we can apply learnings from these studies to deepen our understanding of the disease states, patient populations And potential for therapeutics. This is why our focus on neuroscience is so critical. It allows us to take these learnings And apply them across our pipeline. These accomplishments have progressed our strategy, And we are now working to translate this progress into new potential therapies for patients.
A good example of this is a recent approval of Abduhelm in the U. S. And looking forward, we have the potential to build new franchises in ALS, Depression, stroke, lupus and movement disorders. We have multiple upcoming milestones expected by the end of next year. This includes regulatory decisions for aducanumab outside the U.
S. And additional Phase III readouts For zuranolone in depression, BAN2401 olekalimab in Alzheimer's disease and tofersen in SOD1 ALS. We also look forward to expected proof of concept readouts in C9orf72 ALS And schizophrenia. In summary, at Biogen, we aim to advance science for the betterment of humanity. We strongly believe that neuroscience is at an inflection point for innovation and breakthrough despite the complexity And inherent risk in this space.
Today, you'll be hearing from some of our leading experts Across these areas, and I hope you will gain a better appreciation for both the depth of our pipeline and the richness Now let me welcome Doctor. Al Sandroch, Head of Research and Development at Biogen.
Hi, everyone. Apologies. We're experiencing a few technical delays, so we'll be right back with you in a moment.
Good morning, everyone. We apologize for the delay due to technical issues, but I'm glad to be able to introduce our R and D Day. It's been a few years since we did this, And I'm very happy to introduce you to the very talented presenters that you're going to hear from today. As you know, we've decided to pioneer in neuroscience, and I'd like to begin by explaining why and why now. First, There is no greater unmet need.
The burden that neurological diseases impart on patients, caregivers and society is staggering and growing, As you heard from Michelle, when I was a practicing neurologist, there were very few, if any, treatments we could offer patients Suffering from some of the worst diseases that afflict human beings. One of the hardest things I had to do was to tell a person that they had ALS. I knew that there was little I could do to change the inevitable progression to death. Biogen has become an epicenter of people who are passionate about finding life changing medicines for people suffering from diseases of the nervous system. You will meet many of these talented scientists today.
The fact that a high unmet need remains means that it has been difficult to find effective drugs. There were few validated drug targets, drug development tools such as biomarkers were not readily available And there was no regulatory precedent to follow. But that is all changing and changing rapidly as we hope to show you today. We don't choose neuroscience because it's easy. We know that if we want to transform people's lives, we take on the risk of failure.
Another goal for today then is to show you how we're working to mitigate the risks. And we think we can do it again Because we've done it before as in MS, SMA and now Alzheimer's disease. In business terms, we take on Scientific and clinical risk in R and D, a risk we can mitigate, we believe we can mitigate with science and technology, So that there's less commercial risk, because we have faith that society will always reward innovative transformational medicines. Neuroscience is probably the final frontier of our industry. I say this because we know of nothing more complex in the universe Then the human nervous system.
And yet our job is to fix it when it is diseased. Despite the complexity, we believe the time is right for major therapeutic advances. Why? First, our understanding of the molecular pathophysiology of human disease has grown exponentially in recent years, Owing in large part to human genetics that have pointed to causal biological pathways. Within these pathways, there are actionable targets For Drug Discovery and Development.
What do I mean by actionable? We used to rely Solely on small molecules to get past the blood brain barrier. But we have now shown unequivocally that biologics, including monoclonal antibodies, Can get into the brain and affect biology. Perhaps the clearest demonstration of this may have been when we showed that intravenous administration of aducanumab, A drug whose target resides exclusively in the brain led to a dose dependent clearance of amyloid plaque. We, along with our partners at Ionis, were also the first to show that intrathecally administered antisense oligonucleotides Distribute well enough in the central nervous system to affect clinically meaningful gene expression in spinal cord and brainstem motor neurons In Spinal Muscular Atrophy.
And now we have witnessed the advent of gene therapy products For diseases of the central nervous system, the retina and hopefully soon, skeletal muscle. The broad range of modalities at our disposal means that there may be no undruggable target in the nervous system and thus There may be unprecedented ability to induce the biological changes we seek in the CNS. We also have new measurement tools, including biomarkers such as imaging and fluid biomarkers To faithfully track biological changes in the central nervous system. We can now even draw blood and interrogate biological changes in the brain, Such as with plasma neurofilament light chain or abeta42:forty ratio. We were leaders in showing how plasma NfL can be used for The advent of digital Technologies will also help detect and quantify even subtle changes in neurological function that the patients themselves may not notice.
As such, I tend to include digital measurements under the rubric of biomarkers. Some of these measurement tools May also allow us to detect the right patients for our trials. The ability to increase the homogeneity of the patients we enroll in our clinical trials has and will continue to improve our ability to detect treatment effects. And after approval, these measurements will aid in the selection of appropriate patients for treatment by practicing physicians. And finally, There have been major advances in regulatory science enabled by the improved understanding of disease pathophysiology.
For example, based on advancements in imaging and fluid biomarkers, we now think of Alzheimer's disease as a continuum. And in 2018, FDA published a document entitled Early Alzheimer's Disease Developing Drugs for Treatment Guidance for Industry. This document defines 4 stages of Alzheimer's disease across the continuum with 2 of these stages occurring prior to functional impairment And contemplates how drugs could be approved for each of these stages. The treatment of neurodegenerative disease as early as possible, Which is likely to lead to the greatest benefit to patients is enabled by such advances in regulatory science. Despite these advancements and the unprecedented potential for innovation, as pioneers in neuroscience, we will encounter the risk of failure.
So the real question for us becomes, how do we mitigate this risk? Much of the rest of my presentation will be focused on how we are to mitigate the risks of pioneering in neuroscience. I want to begin by focusing on 2 specific aspects That I think are critical for optimizing the probability of success. First, the what, how to choose the right discovery and development programs And then I will talk about the how, how we are working to optimize the methodology of drug development to increase the probability of success. Beginning with the what, I will share the 4 factors we consider when we are evaluating whether or not to invest In a drug discovery or development program in R and D.
Let's begin with unmet need. In addition to understanding the incidence and prevalence, We also look at the seriousness of disease. Does the disease affect function and lifespan? Does it affect quality of life, A patient's ability to work and carry out activities of daily living. We listen to the voice of the patient and their caregivers.
If there are available therapies, we ask the prescribers how satisfied they are with the available options and how we could substantially improve upon them. And finally, we listen to the payers to understand how our products will be reimbursed. Based on the unmet need, we develop The other three factors I will speak about in the next then Are used to estimate the probability that product profile can be achieved. Next, we look to see if the molecular path Physiology is understood well enough to know whether or not the drug target under consideration is validated in humans. Especially if the drug is presumed to be disease modifying, we must see evidence that the drug target is in the causal biological pathway Leading to human disease.
For this, we rely heavily on human genetics, as human genetics always points to causal biology. It is rare to be able to use words like always in biology or medicine, and I don't use the word lightly, But I strongly believe it is appropriate to use it here. Histopathological studies of post mortem tissue Or biopsy specimens are helpful, but they cannot distinguish cause from effect. The same goes for laboratory tests or Human genetics, by always pointing to causation, therefore, Becomes a crucial key element of our choice of program. But that is not all we consider.
Sometimes there's clinical experience to draw upon. The history of neurotherapeutics is full of serendipitous observations, clinicians noticing that drugs that were designed to treat one disorder Also treat another. These are potentially useful observations that can be pursued. Occasionally, clinician investigators have conducted pilot Studies or even controlled clinical trials with their therapies that have been approved for other indications, and the results of these are also worthy of scrutiny. Sometimes even clinical trials that on their face seem to have failed may provide clues to biological or even clinical activity.
In summary, it may seem onerous for a drug target to be considered validated at Biogen, but we think it is critically important to have Next, we estimate the feasibility of the clinical development program for the drug. No matter how valid the drug target is, if we cannot reduce uncertainty early and efficiently, We know that we're going to be delaying the reduction of uncertainty to later stages of development where the cost may not be worth the risk. We will be much more likely to pursue programs where there are drug development tools such as biomarkers That allow for the estimation of target engagement or pharmacodynamic effects. If they are not readily available, We examine the feasibility of discovering and validating new ones that we will need. We are also more likely to choose programs Where there are clinical outcome measures sensitive enough to detect clinically significant treatment effects.
And finally, we evaluate whether or not there is clarity on the regulatory path to approval and what it would take to gain that clarity. Path to approval and what it would take to gain that clarity. The last factor to assess is whether or not we have the right core to advance the program efficiently through research, the phases of clinical development and ultimately approval around the world. Do we have the expertise and competency to execute on the program? In other words, are we the rightful owners of the program?
We have been building the drug development disciplines needed in an R and D organization, as shown here, to be able to say yes For virtually every area of neuroscience, employing any therapeutic modality. We also welcome collaborations with partners Who bring their own capabilities, which are especially crucial when we enter new diseases adjacent to our core competencies. I have listed the 4 factors that we and R and D prioritize when we are making choices about which Programs deserve investment. I'm sure you'll agree that they represent a very high hurdle. Not all programs fully satisfy all four factors, but the discipline these factors impose on our decision making also means That we are aware of where the greatest risk lies and they inform how we will conduct our preclinical experiments And clinical studies to reduce the risk as early as possible in the life of the program.
Moreover, it reflects the great care we exercise As we invest our precious human and financial resources in R and D. We apply the same lens to drug discovery and development programs that we choose to initiate internally As well as those that we license in from the outside. The pace of innovation in neuroscience has quickened quite substantially in recent years, And that is why we have built the capabilities in R and D to evaluate external opportunities at scale. For example, in 2020 alone, we evaluated 661 external assets and performed technical diligence on 174 To end up with a total 20 deals signed. This slide shows some, but not all of the partnerships and acquisitions We have bolstered our portfolio and capabilities since 1995.
Some of the R and D programs we acquired are now marketed assets. Many are in the process of drug discovery and development. Some are capabilities we have brought in to enable our modality agnostic approach. External opportunities have been an important source of innovation for us over the years, and we believe they will continue to play a key role in our Now I want to turn to the how and highlight how Biogen has changed our approach to neuroscience R and D over the years. In the past, we would generally start with interesting biology or a molecule with interesting biological properties, such as a growth factor We're a molecule with neuroprotective properties in vitro.
To see if there would be any therapeutic applications, we would rely on animal models Where if it resulted in an improvement in some measure of efficacy such as a behavioral measurement or survival, we moved into the clinic. Whereas this approach may have been productive for symptomatic treatments, it has not been as productive for disease modifying therapies. So we have switched to a different way of thinking about drug development. Our approach these days is to start with the disease And ask the question, what are the causal biological pathways that lead to disease initiation and propagation? In step 1, Disease to biology.
We rely heavily on human genetics and look for drug targets within causal biological pathways implicated by genetics. We collaborate with top scientists around the world and use publicly available data wherever possible. We combine these data with our own proprietary data as well as insights we gain from human iPS cells and human tissue studies To gain confidence that the target is worthy of pursuit. After we have established the biological perturbations that cause disease, We determined the feasibility of making a drug against the target that can restore homeostasis. At Biogen, we are modality agnostic And we have at our disposal small molecule, biologic, nucleic acid and now gene therapy approaches.
This creates unprecedented opportunities for drug discovery. If we decide to invest in finding a drug against a target, We then form a program team. After a candidate drug has been discovered, the next step in this process is to verify first in animals, Then in humans, whether or not the drug engages the target in the appropriate cells and produces the biological change in the appropriate tissues. In step 3a, we use animals to understand the pharmacology of the drug, that is to determine the relationship between dose, Plasma exposure, tissue distribution, target engagement and pharmacodynamic effects. We don't necessarily need an animal model to accomplish This step, frequently wild type animals are sufficient.
Here, our main goal is to verify that the drug has engaged the target and produced the biological effects, not necessarily a therapeutic effect. Effects, not necessarily a therapeutic effect. After conducting preclinical safety In order to understand safe use conditions for 1st in human studies, we transition the program from research to development And repeat step 3. This is a crucial step, but one that the field of neuroscience as it had historically often circumvented As it is not easy to assess biology in the nervous system, you can't biopsy the brain or spinal cord and CSF examinations required an invasive procedure. As a result, we have historically been unable to mitigate risk early during clinical development And we're therefore forced to carry risk to later stages.
This had led to many Phase 3 trials in neuroscience. Some of these failures undoubtedly occurred because drugs failed to engage target in the brain. Moreover, The field does not advance with these failures because we do not learn whether or not the therapeutic hypothesis was even tested. In step 3B, the goal then is to understand whether or not we can produce the desired biological effect in humans with the drug candidate At Safe and Tolerable Doses. As in the animals, the goal is to understand the relationship between dose, Plasma exposure, tissue distribution, target engagement and pharmacodynamic effects in humans.
The advent of modern imaging technologies as well as ultra sensitive blood biomarkers have revolutionized our ability To quantify biological changes in the nervous system and digital health technologies offer the promise of nearly continuous monitoring Of the physiological, functional and cognitive effects of drugs. Armed with these tools, we seek to understand clinical pharmacology of the drug. But because we are pioneers, we frequently find that new biomarkers have to be discovered or validated. For biomarkers downstream of drug effects in the nervous system, this requires special expertise. Moreover, the work on biomarker discovery and development must begin years prior to when they are needed.
Our focus on neuroscience allows us to build the needed expertise in our organization and invest in this work even before the final drug candidate has been nominated. In step 4, we hope to confirm that the biological changes we produce with the drug lead to clinically meaningful benefit for patients. By the time we reach this most expensive and time consuming step of the journey, since this is typically done in Phase 2, ideally with surrogate markers of Or in Phase 3 with clinical outcome measures, we hope to have substantially mitigated the risk of failure. Having explained our approach, I would like to now illustrate the 4 steps taken for the development of aducanumab. We've known for about a century that Alzheimer's disease is defined histopathologically by the presence of amyloid plaques and neurofibrillary tangles.
In the 1980s, biochemical studies of human brain tissue identified the abeta protein and the tau protein As the main constituents of amyloid plaques and neurofibrillary tangles, respectively. These observations were critically important, But they did not establish abeta or tau as causal in the disease. As Dominic Walsh discusses in his presentation, It was the human genetic studies that strongly pointed to Abeta as causal in the disease, both familial and sporadic. Finally, as Samantha Bud Heberlein will discuss in her presentation, human imaging and fluid biomarker studies have now shown That perturbations in abeta biology occur very early in the disease course, long before symptom onset and are thus consistent with the notion That Abeta represents a disease initiating biology. Thus, the path from disease to biology Pointed strongly toward the amyloid cascade hypothesis.
The path from biology to drug was taken by our partners at Neuroimmune, Who cloned aducanumab from human memory B cells. Biogen licensed aducanumab from Neuroimmune in 2,007. The path from drug to biology was shown in detail in a publication that appeared in the journal Nature 5 years ago. In Step 3a, we showed that aducanumab, when administered peripherally, entered the brain, engaged its target And produced a dose dependent reduction of abeta42 biochemically and removed amyloid plaque In age TG-two thousand five hundred and seventy six transgenic mice histologically. We used transgenic mice Because wild type mice don't express the drug target, namely aggregated forms of the abeta protein, we used age mice Because we wanted to see if aducanumab would clear plaques after they had already been established, a situation similar To what we would be encountering when conducting clinical trials with Alzheimer's disease patients.
For step 3b, we conducted Study 103. In this study, we used amyloid PET imaging to select patients for enrollment, And we went as early in the disease as we could. We showed the treatment with intravenous aducanumab removed amyloid plaques In a dose and time dependent manner. For step 4, we measured the effects of aducanumab on the 3 cardinal features of Alzheimer's disease, namely cognition, function and behavior. Samantha Budheberlein will show the results of treatment with aducanumab On amyloid plaque burden biped imaging as well as the effect on CDR sum of boxes, which measures the impact on cognition and function The MMSE and ADAS COG, which measure the impact on cognition and ADCS ADL MCI, Which measures the impact on function as well as NPI-ten, which measures the impact on behavior.
Throughout our drug development process, there are talented individuals driving the success of each step. Starting at step 1, the step from disease to biology, Chris Henderson, Our Head of Research and Sally John, our Head of Genetics and Translational Biology, have prerecorded 2 excellent presentations And how we take this step at Biogen in collaboration with leading scientists and consortia around the world. Additionally, Dominic Walsh, the Head of our neurodegeneration research unit, talked about future prospects for drug development In Alzheimer's disease. Step 2, how we step from biology to drug, is beautifully discussed in a prerecorded presentation by Annabella Villalobos, our Head of Biotherapeutics and Medicinal Sciences. Additionally, Jung Hae Soo, the Head of our Gene Therapy Accelerated Unit delves further into how we have developed our gene therapy capabilities In order to build a robust preclinical pipeline across multiple disease.
Zheng He's presentation is also One of the several on demand presentations that I encourage you to view. To take step 3 from drug to biology, we begin with animal pharmacology. Chris Henderson in his on demand presentation shows how we take this step, illustrating a beautiful example of this when he talks about Angelman syndrome And the seamless transition from biological measurements in animals to biological measurements we plan to use in our human studies. After transitioning from research to development, we repeat step 3 in humans. In order to succeed as pioneers in neuroscience, we must be equally pioneering in step 3, which requires the use of validated, High fidelity biomarkers that can be used in human studies and John Beaver, the Head of our Biomarker Group, has prerecorded a presentation that shows how we do that at Biogen.
The advent of digital devices has provided new approaches to precisely measure even subtle physiological effects of drugs in humans. And Martin Dubuque, the Head of the Biogen Digital Health Unit and members of his team talk about how we are developing these for use in early stage clinical trials, As well as eventual use in the real world setting. Step 3 in humans and step 4, Namely, clinical development are led by our development unit heads. Samantha Bud Heberlein, the Head of our neurodegeneration development unit, We'll review our clinical stage programs in Alzheimer's disease. And we're extremely fortunate that she will be joined by Lynn Kramer, the Chief Clinical Officer at Eisai, who will review the lecanumab program.
In prerecorded presentations, Tian Dom, Senior Director in the Neurodegeneration Unit, reviews our clinical stage programs and movement disorders and she is joined by Carol Ho, Chief Medical Officer At Denali, who has kindly provided a review of the LORC-two program, which is poised to enter late stage clinical trials. Later today, Mona Kotecha, Senior Medical Director in the Therapeutics Development Unit, We'll review our clinical stage neuropsychiatry programs, and we're delighted that you'll be joined by Jim Dougherty, Chief Research Officer At Sage Therapeutics, who will review ziranolone Josh Bell, Medical Director in the Therapeutics Development Unit, We'll provide an overview of our neurovascular programs today, which will include a discussion of the results of the TMS-seven program An acute ischemic stroke that led us to exercise our option to in license the asset. Also today, Toby Ferguson, the Head of our Neuromuscular Development Unit, will review our cutting edge clinical stage programs in ALS And Natalie Franschimont, our Head of the MS and Immunology Development Unit, will talk about our exciting programs in lupus, where she will discuss our anti BDCA II program in some depth. Jaron Hana, Senior Director in Natalie's unit, As provided an overview of our clinical stage MS programs in a prerecorded presentation.
We are
very fortunate at Biogen to be able to recruit top notch scientists and experts in all the disciplines required for drug development. This slide shows just some of the very talented people who've been able we've been able to recruit in the past few years. These leaders and many others Many others, too numerous to fit into one slide, have come to Biogen to make a difference in the lives of people with neurological diseases. For some, this means leaving established academic labs and prestigious institutions. For others, it means leaving some of the best R and D organizations in the industry, but they all came to Biogen because they share our passion for making medicines For diseases where there is tremendous need and few options.
I have talked about the importance So the what and the how of the drug discovery and development process, and I have also highlighted the passion and expertise of the people at Biogen, many of whom you will hear from today as an indispensable element of our strategy. The 4th element, focus, is also important. Our focus creates a nidus for talented scientists to come to work at Biogen And for many groups outside of Biogen who want to collaborate with us. Our focus exploits the interconnectivity of biology across our disease areas And it enables a deeper understanding of molecular pathophysiology. Importantly, this enables our ability to select the right And if these tools were not available are not available, Our focus brings the expertise and forward looking investments that are required to assure their validation in time for use Critical decision making for our R and D programs.
Focus also allows us to learn from failures in neuroscience drug development, Including our own. You can't dabble in neuroscience and expect to be successful. Our focus creates the capabilities To increase the probability of success as we pioneer in this final frontier of drug development. I'd like to now turn briefly to how we envision the future of neuroscience. How will we be treating diseases of the nervous system in the decades to come?
Several recent advancements in science and technology deserve attention. I have underscored repeatedly how important human genetics has been to our field. For diseases or disease subtypes Driven by single genes, the biological pathways to pursue for disease modification or prevention are clearly eliminated. But what about sporadic diseases, which are influenced by multiple genetic variations? In her presentation, Sally John shows how we use genetics And computational biology combined with data from human cells and tissues to find drug targets for polygenic diseases.
Here I show some data from a paper that appeared a couple of years ago that shows that precision phenotyping will also help unravel the complexity of polygenic Diseases. In reality, the pathophysiology of many diseases that we currently regard as single diseases We're actually heterogeneous, and this heterogeneity hampers drug development as well as clinical medicine. And drugs that target certain specific biologies will likely only be effective in a subset of patients. This slide shows 2 figures from a paper published in 2018 by Alexandra Young and colleagues in which they used cross sectional regional brain volumes From MRI data in the genetic frontotemporal dementia initiative or Genphi. Genphi investigates biomarker changes in carriers of mutations In pro granulan, tau and C9orf genes, which are known to be single gene drivers of FTD.
They used a machine learning algorithm called subtype and stage inference or SUSTAIN, which identifies patient subgroups With common patterns of disease progression. This unsupervised clustering algorithm incorporates data driven disease progression modeling, Which enables the grouping of individuals with common phenotypes across a range of disease stages. In other words, It's an algorithm that subtypes disease, unconfounded by stage or severity of disease. Panel A shows the Progression pattern of 4 subtypes of FTD identified by SUSTAIN. What was striking Was that the 4 subtypes identified by volumetric data from MRI images taken at a single point in time segregated by genotype, As shown in Panel B.
In other words, the 4 subtypes identified purely by imaging correspond to the 4 different biologies Underpinning genetic frontotemporal dementia, remarkable. We now know that by the time patients with neurodegenerative diseases become symptomatic, the underlying biology has been progressing for many years, Even decades. Since it is theoretically feasible to perform genetic testing as well as blood And digital biomarker assessments at scale across a broad population, I believe we will soon be using genetics and precision Phenotyping in virtually everybody, which may allow for the detection of the onset of pathophysiology long before the first symptoms. This is similar in concept to the way we screen for the major risk factors of cardiovascular disease by checking blood pressure With emerging therapies that target the underlying biology of these diseases, It should be possible to treat early to prevent disease, especially for diseases of the central nervous system, Which is precluded biologically from replacing lost cells or forming new connections between cells, Early treatment will undoubtedly lead to better outcomes. I believe that in the near future, We will be treating people rather than patients, initiating treatment targeted at specific biological processes Based on genetic risk score and precision phenotyping.
Research and development In neuroscience is not for the faint of heart, but the prospect of being able to help patients suffering from terrible diseases Drive us to work at Biogen. We believe we are building the capabilities that will allow us to exploit the science and technology That will enable the future of neurotherapeutics. The science is breaking and the technologies are at hand. We believe this is exactly the right time to be pioneers in neuroscience. I'll now hand it over To Samantha Bud Heberlein, who will discuss our Alzheimer's disease clinical portfolio.
Thank you, Al. Good morning. I'm Samantha Bud Hablein, Head of the Neurodegeneration Development Unit at Biogen. Today, I will be presenting some highlights of our Alzheimer's disease clinical portfolio. And I'll be joined by Lynne Kramer, Chief Clinical Officer from Eisai.
Our Alzheimer's disease clinical portfolio includes 2 anti abeta antibodies, aducanumab and lekanumab. These both reduce amyloid beta plaque significantly by 18 months, and their reduction in amyloid beta plaque Is associated with a reduction in clinical decline. The lekanamab off treatment data, which you will hear about from Lynne, Show that when treatment is initiated later in disease, patients do not catch up clinically and that amyloid beta plaque, once lowered, We're stable for approximately 2 years off treatment. Further, the blood biomarker data Suggests that the disease biology starts to rebound after stopping treatment at 18 months. These data suggest That additional data is needed to inform on the optimal duration of treatment with anti A beta antibodies.
In regards to tau mechanisms, so far, extracellular anti tau antibodies have not impacted pathology or disease progression. Lowering of tau protein, which is designed to reduce all forms of toxic tau, Has been achieved in our Alzheimer's disease patients with our antisense oligonucleotide, BIIB080. And I will share the recent Phase 1 data with BIIB080. As is presented by my colleagues in the on demand sessions, Biogen has the capabilities, experience and rich portfolio as we work to address Alzheimer's disease. As Dominic Walsh mentioned in his presentation, we have a robust research pipeline in Alzheimer's disease, Which focuses on advancing the next generation of anti abeta therapies, growing the tau pipeline, Progressing drug discovery on genetic targets and enabling development of combination therapies.
Of our clinical programs in Alzheimer's disease, I will present BIVATEI and aducanumab and Lynne Kramer will present lecanumab. Alzheimer's disease is defined by the presence at autopsy of 2 pathologies: beta amyloid plaques And neurofibrillary tangles comprised of tau protein. With the advances in PET imaging, Both of these pathologies are now possible to detect and follow in living patients. Genetics And imaging data suggests that the disease cascade begins with amyloid beta, which is released from neurons And aggregates outside of neurons, forming oligomers, fibrils and eventually large insoluble plaques. Amyloid pathology triggers pathways that lead to the phosphorylation and aggregation of tau in the neuronal cell body.
This pathological cascade triggered by amyloid beta leads to dysfunction in neuronal and synaptic activity, Inflammation and neuronal death. Given the strong rationale, there have been multiple efforts Aimed at targeting removal of amyloid beta pathology. The very first generation of anti amyloid antibodies, Bapanezumab, crinizumab and solanezumab, as they each published, did not lower amyloid Moreover, trials with these antibodies were done at a time When clinical studies were conducted in patients at later stages of Alzheimer's disease and was prior to the use of amyloid PET imaging. As a consequence, these trials also included individuals without evidence of amyloid beta pathology, I. E, patients without Alzheimer's disease.
Our understanding today of the molecular pathophysiology of Alzheimer's disease Comes from decades of research into these pathways and in particular is informed by fluid and imaging biomarkers. As you heard from John Beaver, pet imaging has been among the most notable technical advances in CNS research And has transformed our understanding of disease and how we conduct clinical trials in Alzheimer's disease. Longitudinal studies in both sporadic and autosomal dominant Alzheimer's patients have contributed to our understanding of the disease As a continuum, as illustrated by the model shown here, the curves by Cliff Jack. We know from this work that amyloid beta disposition, the red line to the left, precedes clinical symptoms by decades. Subsequent markers of tau pathology and neurodegeneration increase continuously throughout disease progression.
The symptoms in Alzheimer's disease then represent the latter stage of a disease continuum, And early clinical signs correspond to an already advanced pathologic disease state. For therapeutics targeting underlying disease processes, intervention earlier in the disease continuum has the greatest promise To preserve cognition, function and autonomy. Anti amyloid beta And programs targeting tau have therapeutic windows aligned with the pathologies they target. Advancement of our Alzheimer's disease portfolio is supported by a number of strategic capabilities, Including accelerating clinical development with biomarkers, blood, digital and imaging Using the deep data generated by our clinical trials to increase our understanding of Alzheimer's disease pathophysiology And the amyloid tau neurodegeneration or ATN biomarker profile to inform future treatment paradigms And maximizing the potential of the portfolio through acceleration of tau programs and combinational add on approaches. Moving now to aducanumab.
Aducanumab was the 1st anti amyloid monoclonal antibody To show in early clinical trials a robust time and dose dependent reduction in amyloid beta plaques In patients with Alzheimer's disease. Aducanumab is the 1st anti abeta antibody that reduces amyloid beta plaque To have clinical data from Phase 3 trials. Aducanumab was approved by the FDA in June Under the provisions of accelerated approval regulations. Aduhelm is an amyloid beta directed antibody Indicated for the treatment of Alzheimer's disease. Treatment with Aduhelm should be initiated in patients with mild cognitive impairment On mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than was studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with Aduhelm. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. Aducanumab has a very shallow and compact binding cleft. And in contrast to the 1st generation of anti O beta antibodies, it's highly selective for toxic aggregated forms of amyloid beta And has low nonbinding lowbinding to nontoxic monomers.
Aducanumab binds specifically to the aggregated forms of amyloid beta in the aggregation pathway, which includes the insoluble fibrils That we measure with amyloid PET imaging. Aducanumab also binds to the soluble aggregates such as oligomers, One of the highly toxic forms of amyloid beta. Biophysical data have also shown that aducanumab Uniquely also blocks a step called secondary nucleation and thereby also reduces the formation of toxic oligomers. In EMERGE, ENGAGE and PRIME clinical studies, labeled in the slide as Studies 1, 23, respectively. Aducanumab reduced amyloid beta plaque in a dose And time dependent manner compared with placebo.
Amyloid beta plaque was reduced in the high dose arms at 18 months By 71% in EMERGE, Study 1 and 59% in ENGAGE, Study 2, Which is a reduction from baseline to 24.5 and 36.8 centilloids, respectively, at 18 months. In each of the clinical studies, a continued decrease in brain amyloid beta plaque levels Was observed during the long term extension treatment periods. In PRIME Study 3, amyloid beta plaque levels In the brain continued to decline in a time and dose dependent manner in the long term extension period through week 222 as shown here. EMERGE and ENGAGE were terminated prior to their planned completion. The study endpoints were analyzed based on the pre specified statistical analysis plan where the primary efficacy endpoint Was the change from baseline on the CDR summer boxes at week 78?
In EMERGE, treatment with aducanumab high dose Demonstrated reduced clinical decline as evidenced by a statistically significant treatment effect On change from baseline in CDR summer boxes compared to placebo. Also in EMERGE, Statistically significant differences from placebo were observed in the aducanumab high dose group on all Secondary efficacy endpoints evaluated. In ENGAGE, no statistically significant differences We're observed between the aducanumab treated and placebo treated patients on the primary efficacy endpoint. In prime, the clinical assessments were exploratory. The results for the clinical assessments, CDR Summer Boxes And MMSE were directionally aligned with the findings from EMERGE.
Exposure response analyses for IMerge and Engage demonstrated that higher exposures to aducanumab We're associated with greater reduction in clinical decline on CDR summer boxes, ADAS COG13 and ADCS ADL MCI. In addition, higher exposures to aducanumab were associated with greater reduction In amyloid beta plaque in EMERGE and ENGAGE, an association between reduction in amyloid beta plaque And clinical decline on CDR summer boxes was also observed, as is shown in the chart on this slide. We recently presented at AAIC that the association between amyloid beta plaque reduction and Clinical decline can also be seen by assessing clinical decline in patients whose amyloid Plaque levels were below an SUVR of 1.1 at the end of the study. An SUVR of 1.1 corresponds To the threshold for amyloid beta pathology, positive and negative. As Table 1 shows and colored in green, A numerically smaller magnitude of decline across key clinical measures in all three studies was Served in patients in whom amyloid beta plaque levels were lowered to amyloid negative, I.
E, an SUVR of below Or equal to 1.1. Relative to those who did not reach this threshold, so an SUV are greater than 1.1. The green denotes a lower mean or median progression. The safety of aducanumab has been evaluated in 3,078 patients who received at least one dose of aducanumab. Adverse reactions that were reported in at least 2% of patients treated with aducanumab and at least 2% more frequently Then in patients on placebo are shown in this table.
The immunogenicity of Aduhelm has been evaluated. In up to 41 months of treatment in EMERGE and ENGAGE, less than 1% of patients receiving Aduhelm Once monthly, developed anti aducanumab antibodies. ARIA E was The most common adverse reaction reported. ARIA E can be observed on MRI as brain edema or sulcular fusions. And ARIA H, which includes micro hemorrhage and superficial sclerosis.
In EMERGE and ENGAGE, ARIA E and or H was observed in 41% of patients treated with aducanumab with a planned dose of 10 milligram per kilogram Compared to 10% of patients on placebo, RAE was observed in 35% of patients Treated with aducanumab 10 milligram per kilogram compared to 3% of patients on placebo. The incidence of RAE was higher in APOE4 carriers than in non carriers. Clinical symptoms were Present in 24% of patients treated with aducanumab, 10 milligram per kilogram, who had an observation of ARIA Compared to 5% of patients on placebo, I. E, 76% of patients who experienced ARIA Did not report symptoms. The majority of ARIA E radiographic events occurred early in treatment Within the first eight doses, although ARIA can occur at any time.
MRI scans prior to and during treatment with aducanumab are required to monitor for ARIA. Regarding the next steps for aducanumab, multiple elements will provide continued generation of data on efficacy And real world effectiveness. We are currently working diligently to design the confirmatory trial, And our aim is to complete this ahead of the reported deadlines and we're making good progress with the protocol. Elements of this study are based on insights from operational and clinical feasibility assessments, New analyses pertinent to the study design, engagements with regulatory agencies and other aducanumab program objectives. The goal of this study is to verify the clinical benefit of aducanumab and to do so expeditiously.
We're dedicating considerable resources to support our aim of completing the trial ahead of the required schedule. Embark, our open label, multicenter safety study of aducanumab in subjects Previously in the aducanumab studies is now fully recruited with more than 1700 patients enrolled. EMBARK will evaluate the long term safety and tolerability of aducanumab. We plan to present the EMBARK baseline data At an upcoming medical meeting, which should yield important insights on the effects of treatment interruption. We have also initiated EyeCare AD, a prospective real world observational study Of aducanumab in patients with Alzheimer's disease in the U.
S. This study will recruit 6 1,000 patients and we'll evaluate long term clinical and quality of life outcomes in Alzheimer's disease patients. We'll also provide insight into the health care resource utilization of Alzheimer's disease patients And the burden placed on informants and care partners. And it will assess the long term safety of aducanumab. For aducanumab, we also continue with global regulatory reviews and submissions and we have a subcutaneous formulation under development.
Now I will share highlights of our Tau portfolio, specifically on VIVATEI, an antisense oligonucleotide Developed in collaboration with Ionis. As Dominic mentioned in his presentation, the pathological species of tau are not clear, And so reducing all forms of tau is expected to prevent the formation of all toxic species. BIIB080 reduces de novo production of all 6 human splice isoforms of tau and therefore should reduce All post translationally modified forms of tau, including aggregates and other toxic species. Sure. Ablation of tau does not alter microtubule stability or axonal transport.
This is likely due to redundancy with Other microtubule associated proteins such as MAP1B. And as Sally John presented, Tau loss of function mutations detected in over 40 individuals in the U. K. Biobank suggests that loss of tau function Is well tolerated. BIIB080 targets intracellular tau directly and reduces both intracellular and Since tau dysfunction is key to several neurodegenerative disorders And so reduction of tau protein by BIV80 can be applicable to multiple diseases.
The placebo controlled portion of the Phase 1 study, a multiple ascending dose study in patients with mild Alzheimer's disease, is complete. And in the next slide, I will show the results we recently presented at AAIC. In the Phase 1, BIIB080 showed time and dose dependent reduction in the concentration of CSF total tau And phospho tau, which is the first clinical demonstration of antisense mediated suppression of CSF tau protein In patients with Alzheimer's disease. Four cohorts assessed a low, medium and a high dose Administered via intrathecal bolus q4 weeks and a dose q12 weeks. The results Four CSF measures of phospho tau and total tau are shown below.
Mild and moderate AEs were reported in the study. Based on the Phase 1 efficacy and safety, BIIB080 will be evaluated in Phase 2 for Alzheimer's disease. As discussed earlier, Alzheimer's disease is underpinned by 2 major pathologies And other mechanisms are triggered and involved in disease progression. These pathologies Maybe separated in time, at least for a period, but are then coexisting. Optimal treatment of Alzheimer's These may then be achieved by addressing more than one of these pathways.
With our portfolio of approaches, We have the opportunity to further inhibit disease pathology by having more than one treatment at a time, And we are actively exploring this approach. I would now like to hand over to Lynn Kramer from Eisai to present lucanumab.
Thank you, Samantha. Let me now turn to lecanumab or BAN2401, Which was recently granted Breakthrough Therapy Designation by the U. S. FDA. The first three slides are going to focus on recent data presented at the AAIC.
In the graph on the left, you can see the time course of amyloid plaque clearance based on PET imaging from our Phase 2 trial, Study 201 and its open label extension. The blue line represents those treated With placebo in the core and the red line represents those treated with 10 milligrams Per kilogram biweekly in the core. During the core phase of Study 201, Lecanumab 10 milligrams per kilogram biweekly converted over 80% of subjects from amyloid positive To amyloid negative after 18 months of treatment. During the gap period, During which there was no treatment, amyloid plaque was stable in both groups With small 1% to 2% increases per year. Of note, in the response Of amyloid clearance in the open label extension in patients not previously treated with leucanumab, the blue line, They had substantial plaque clearance at 3 6 months of treatment and by 12 months of therapy, this group Also had over 80% of subjects converting to amyloid negative.
In the box on the right hand side of the slide, You can see that the rate of Area E occurrence was 9.9% for subjects treated with leucanumab 10 milligram per kilogram biweekly in the core phase and 8.9% In the open label extension phase for subjects newly treated with leucanumab 10 milligrams per kilogram biweekly. The combination of this large Phase 2 study and the completely enrolled Phase 3 study, CLARITY AD, Provides a safety database that already fulfills the ICH guidelines from a regulatory perspective. Next, let me review the plasma biomarker data from lecanumab Study 201 and its And it's open label extension, which evaluated longitudinal plasma A beta 42:forty ratio And the relationship to longitudinal amyloid PET and clinical endpoints. As you can see in this graph, when compared with the previous slide graph, plasmaabeta42:forty ratio Tracked very well with pet SUV are changes, although directionally opposite across the core phase on the left, The off treatment gap period in the middle and the open label extension phase On the right, during the GAAP period, the plasma abeta42:forty ratio Started to decline again, as you can see in the middle part of this graph, which we believe is an early indicator Of the disease pathology starting to rebound.
Retreatment with lecanumab in the open label extension phase, As you can see on the right, drives plasma A beta 42:forty ratio to increase again, Which is likely associated with leucanumab clearing newly generated amyloid, including protofibrils, Even after amyloid plaque removal, this data suggests we need additional information to inform us Optimally on the treatment duration. This first of its kind data Suggest that we are fast moving into a new era with the possibility of being able to use plasma biomarkers To track disease progression and monitor drug effects in individual patients. In the graphs on this slide, you can see when subjects treated with placebo or 10 milligram per kilogram biweekly in the core phase are compared. These groups maintained parallel course After treatment was discontinued, the subjects who initiated treatment for the first Time in the open label extension, therefore, later in their course, do not catch up clinically. This suggests a potential disease modifying effect of lecanumab.
In graph 2 on the right, We trace the same subjects from the core phase of the off treatment gap period to the OLE phase, Totaling about 5 years on average. The red line represents subjects Who received leucanumab 10 milligrams per kilogram biweekly, both during the core phase And the open label extension phase. And the blue line represents subjects who received placebo During the core phase and then were treated for the first time with leucanumab 10 milligram per kilogram biweekly During the open label extension phase, as you can see in the open label extension phase, both the red line And the blue line showed a shallower slope relative to the yellow line. The yellow line represents disease progression seen in a similar population from the ADNI study. In addition, the red line stayed below the blue line the entire time, even after the blue line cohort Started to receive lecanumab in the open label extension phase.
These findings support the 2 concepts. One, that lecanumab therapy maintains a disease modification effect with continued treatment when patients are Still in the early stage of Alzheimer's disease and 2, that initiating therapy early And maintaining treatment provides greater benefit long term. Work is ongoing to determine the best treatment regimen To do this, let me now summarize the status and upcoming milestones for lucanumab. Firstly, our Phase 3 CLARITY AD study completed enrollment of 795 early Alzheimer's patients in March of this year. The patients had confirmed amyloid positive status and we're stratified by APOE4 status, meaning APOE carriers or non carriers, Clinical staging and concurrent Alzheimer's disease medication use.
They were randomized to placebo Orlucanumab 10 milligram per kilogram biweekly. The primary endpoint is CDR sum of boxes. Secondly, under the breakthrough therapy designation, we have initiated communication with the FDA To seek the most optimal and expedited regulatory pathway forward for lecanumab. Thirdly, as reported at the AEIC, initial experience with our Phase 3 study named AHEAD-three 4.5 suggest it is feasible to identify participants across the continuum of preclinical Alzheimer's disease. We have so far activated almost 80 clinical trial sites globally and randomized over 100 subjects.
Lastly, a subcutaneous formulation is under development to be administered in a specialized device With the goal of enhancing patient convenience, we plan to initiate a Phase 1 study to evaluate the pharmacokinetics And bioavailability of this formulation within the calendar year. Thank you very much for your kind attention. Back to you, Samantha.
Thank you, Lynn. In conclusion, our 2 anti A beta antibodies, aducanumab and lekanumab reduced amyloid beta plaque significantly by 18 months. Their reduction in amyloid beta plaque is associated with a reduction in clinical decline. The lekanamab off treatment data Show that the subjects who initiated treatment for the first time in the open label extension, therefore, later in their disease course, Do not catch up clinically. Amyloid beta plaque was stable for approximately 2 years off treatment, Although that's not the whole picture, as the plasma biomarkers suggest that the disease biology starts to rebound After stopping treatment after 18 months.
Additional data is needed to inform optimal duration of treatment. In regards to tau mechanisms, BIIB080 has shown the first clinical demonstration of antisense mediated Suppression of CSF tau protein in patients with Alzheimer's disease and will progress to Phase 2. Thank you for your attention. I would now like to turn it over to Mona, who will discuss the exciting work we are doing to address neuropsychiatric diseases.
Thank you, Samantha. My name is Mona Kotecha and I lead the neuropsychiatry and pain drug development team at Biogen. I'm very pleased to be here today with Jim Doherty, the Chief Research for Sage Therapeutics to share with you some exciting developments in the Biogen Neuropsychiatry portfolio. Earlier, Al Sandrok spoke about the continued significant unmet needs of patients affected by disorders of the nervous system. Over the years, Biogen has addressed these needs in multiple sclerosis, spinal muscular atrophy and Alzheimer's disease.
However, we've also expanded our existing investment in neuropsychiatry to address mental disorders which have a tremendous impact on functioning and quality of life. Within the field of psychiatry, the focus of our discussions today will be depression and schizophrenia, which affect 284,000,000 people worldwide. Existing standard of care drugs for both disorders leave patients and their providers wanting. In major depressive disorder, there has been only scattered meaningful innovation in treatment since the introduction of SSRIs, which Still serve as a pillar in the treatment of depression. The current antidepressants have key limitations, including a delayed onset of effect, Requiring 6, even 8 weeks of therapy and limited efficacy with approximately a third of patients being considered Treatment resistant.
Similar holds true for schizophrenia. With 1% of the U. S. Population affected, Traditional antipsychotics may address some symptoms we might commonly associate with the disease, psychosis and hallucinations, But negative symptoms and impaired cognition have no effective treatments. The significant impact of mental illness, the dramatic rise in incidence and prevalence triggered by the pandemic And continued unmet need are reasons enough to develop new treatments for psychiatric diseases.
But there is another key strategic driver For Biogen's expansion in this space, the area of neuropsychiatry is a logical extension and natural complement To Biogen's core development franchises. Specifically, psychiatric manifestations of neurologic diseases are common. Examples of the overlap between psychiatry and our other areas of focus are highlighted on this slide. Depression is a very common comorbidity for patients and caregivers in multiple core areas. And Parkinson's disease may manifest And substantial psychiatric symptoms, including psychosis.
Agitation is a common feature of Alzheimer's disease. Customer focus is a Biogen core principle and this principle motivates us to address the whole patient, taking into account Overlapping comorbidities in our disease areas. Leveraging synergies across our disease areas Is one way we can progress our aim to treat customers holistically and efficiently. Our near term objectives focus on the late stage drugs in our pipeline. 1st, together with Sage, We will execute on the development of zuranolone, which has positive pivotal data in both major depressive disorder and postpartum depression.
We believe that zuranolone with its novel mechanism of action has the potential to shift the paradigm for depression treatment And could be administered on an episodic as needed basis. But MDD and PPD are just The beginning for zuranolone as it may have applications in other mental illnesses. In fact, we're actively assessing opportunities for future in new indications, while simultaneously seeking to expand the potential global footprint for the molecule. Additionally, we continue to progress BIIB104, an investigational drug currently under study in Phase 2 For the treatment of cognitive impairment associated with schizophrenia or CIAS. I'll share more details about BIIB-one hundred and four later in my presentation.
So what is in our future? Building on the anchors of our current late stage compounds, we hope to expand our footprint in neuropsychiatry to build a neuropsychiatry innovation engine. We're very excited to be working with our colleagues at Sage to develop psuranolone. I'll now turn it over to Jim Doherty to provide more details on that development program.
Thanks, Mona, and good morning, everyone. I am Chief Research Officer and Head of Clinical Development at Sage Therapeutics, a biopharmaceutical company dedicated Our collaboration with Biogen for the development of Xiranlone and SAGE-three twenty four Continues to be very productive, and we're pleased to have them as partners in these efforts. I'll be speaking today about zuranolone, the lead program in our depression franchise. We believe that zuranolone represents an opportunity, if we're successful, to change the treatment paradigm in depression And to provide relief to millions of patients in need. Just a reminder that I'll be making forward looking statements in this presentation, and as always, I encourage everyone to read the Risk Factors section of our SEC filings.
Zoranolone was discovered and developed at Sage and is a great example of our approach to brain health R and D. Our key principles can be summarized as follow the science and lead with human data, and that's what we've done with Xiranli. It's important to understand that the target profile for zuranolone is fundamentally different from existing standard of care antidepressants in several important ways. 1st, zuranolone has a truly novel mechanism of action and is intended as a 2 week, As needed course of treatment. This is an innovative approach as current antidepressants are typically prescribed For at least 6 months following a first depressive episode and chronically following subsequent episodes.
2nd, the onset of efficacy that we have seen in our clinical trials has consistently been rapid with ceramalone as soon as after the second dose. Again, with current antidepressants, it typically takes 4 to 6 weeks to see an effect. Importantly, although the duration of treatment has been short, the response we have seen in our trials has not been, as we have seen a maintained response in the ziranolone group that has lasted throughout the duration of the follow-up period in our clinical trials. And 3rd, zuranolone has been well tolerated in clinical trials to date, and we believe that zuranolone has the potential Based on the results that we've generated to date, We believe that ziranolone has the potential to be a treatment that can be administered as needed, meaning a short 2 week course of once daily dosing that produces rapid relief from symptoms within days. Given the efficacy and safety data from our completed clinical trials, We believe that if we're successful, ziranolone could be an appropriate choice for a wide range of patients with depression.
Xoralone is a neurosteroid neuroactive steroid based positive allosteric modulator of GABA A receptors, which is a truly novel mechanism of action. Importantly, zuranolone interacts with both the receptors in the brain, a fundamentally different way of engagement with the GABA system than other GABA modulators like Benzene A Azipines. We believe that interacting with both synaptic and extrasynaptic receptors is important to the clinical profile of ziranolone. To that point, we have extensively characterized ziranolone preclinically. As this figure shows, ziranolone is a potent potentiator functionally, Enhancing inhibitory GABA A receptor currents of both synaptic, seen in blue, and extrasynaptic receptors, seen in orange.
Here you can see a summary of the ziranolone clinical development program. The program is comprised of multiple trials that were each If you look at the color coding, you can also see the alignment of specific trials With the 3 parallel and independent potential paths to a first regulatory filing, including monotherapy, Postpartum depression and co initiation with a current standard of care antidepressant. And what you'll see in the subsequent slides are that the findings we've generated in this program to date are quite consistent across the entire program with respect to both efficacy and tolerability findings. With this overview in mind, I'd now like to walk through the high level results from the completed trials in the program with an emphasis on the key questions we were looking to answer with each trial. I'll begin with our first pivotal trial, MDD-two zero one B in major depressive disorder, a trial designed to demonstrate repetitive effect with a 2 week course of treatment.
The trial measured relief of depressive symptoms as measured by the HAM D17, a validated depressive scale. We saw statistically significant and clinically meaningful reductions in the HAM D in the ziranlim group at day 15, The primary endpoint, providing evidence for rapid relief of symptoms. In addition to a statistically significant improvement in as measured by the HAM D17, we also saw a statistically significant reduction in depressive symptoms as measured by MADRS as well as in anxiety symptoms as measured by the HAMA. Importantly, ziranalone was well tolerated in the study, And I'll summarize the tolerability profile of ziranalone across the entire development program to date later in the talk. Results from the MDD-two zero oneb trial led us to the question, would we see the same type of effect in a postpartum depression population?
On the next slide, you'll see results from the ROBIN trial in postpartum depression, where the answer is clearly yes. We did see the same rapid and robust improvements in depressive symptoms for the ziranolin group in this study, with durable effects maintained out throughout the treatment period. A very similar profile And again, we saw statistically significant effects beginning at day 3 And continuing out to the primary endpoint at day 15. Now you'll see results from the recent pivotal waterfall study in MDD, Showing statistically significant improvement in depressive symptoms at day 15 in the ziranlin group compared to placebo as assessed by the AMD-seven team. We're seeing the same pattern of improvement that's very consistent with the other completed trials in the landscape and NEST program with significant improvements beginning at day 3 and continuing out to the primary endpoint at day 15.
And again, We see adorable response throughout the completion of the follow-up trial follow-up period of the trial. Turning to the earlier MOUNTAIN study in MDD, which had a similar design to the trials I've already discussed. Although we did not achieve statistical significance at The primary endpoint, Day 15, we did see a very consistent profile with Ziran alone that we believe is quite supportive of the overall landscape and NASH programs. The graph on the left shows the full analysis set where you can see the Same rapid and robust improvements in depressive symptoms beginning after just 2 doses with a statistically significant effect at day 3, Day 8 and Day 12. Given the outcome of the study, as shown on the right side of the slide, We did an ad hoc analysis of subjects with baseline HamD-seventeen scores of greater than or equal to 24, Which is actually a majority of the population.
As you can see in this ad hoc analysis, there was significant improvement in depressive symptoms At all measured time points out to and including the primary endpoint. In addition To the placebo controlled studies and given that this is a novel 2 week course of treatment, we asked ourselves how will this be used by physicians and how can we provide the appropriate Real world data to help them understand how this drug could be delivered in the real world. The SHORELINE study in MDD, The largest naturalistic study that we're aware of in the depression space was designed to answer these questions. For context, The SHORELINE study includes a 2 week initial course of treatment and responders are able to continue in the study for up to 1 year with additional treatment as needed. What we saw in the data from the 30 milligram cohort is again a rapid and robust improvement in HAM D17 scores With 42.9% of initial responders requiring no additional treatments through 1 year after the initial single 2 week treatment And approximately 70% of the subjects with positive responses to the initial 2 week courses around 11 30 milligrams required either just that initial treatment or at most one additional course of treatment during the 12 month study.
This means that treatment with ziranolone 30 milligrams in this study enabled approximately 70% of patients To receive only 2 or 4 weeks of treatment to maintain a treatment response over the course of a year. That's very different than the current standard of care for depression. We expect to report a Top line data cut from the 50 milligram 1 year cohort in SHORELINE in late 2021. We are also continuing to enroll patients in the study Following our announcement earlier this year that we've expanded the target enrollment to 500 patients and we are offering patients from the CORAL study The ability to roll over into the SHORELINE study following completion of the CORAL study. To summarize, the landscape And NEST programs are an integrated set of studies that we believe tell the stories of RanLune through measures of that are widely accepted as valid measures of depressive symptoms.
These measures include both investigator reported and patient reported outcomes. I've walked you through today what we believe is the promising efficacy for Xiranalone. Another key feature of the Xiranalone data we've generated to date It is that it has been very well tolerated. On this slide, you can see the consistent tolerability profile for Xiranlone from our clinical trials to date. Adverse events seen have been largely associated with the mechanism of action, Somnolence, dizziness, sedation, but rates across the program have been generally tolerable.
What we don't see with Xiranlone are the adverse events frequently associated with current antidepressant therapies. In fact, The symptoms that are typically the cause of treatment discontinuation with standard of care antidepressant drugs, weight gain, Sexual dysfunction, euphoria, GI upset and sleep disruption have not been seen to date with XERANLA. On this slide, you can see a first look at integrated data of patients experienced to date with Xiranalone in trials from our landscape and NEST programs From a tolerability point of view, shown as number needed to harm or NNH, NNH is a metric often used To characterize tolerability as compliance to medication and as a standardized measure of discontinuation from a clinical trial for any adverse event. Starting on the left, you can see discontinuation rates across studies in the program, which are quite low and generally comparable to placebo rates And what you see on the right is a meta analysis of standard of care antidepressants With an NNH of between 743, whereas with ziranolone, you see a score of 98, We just differentiated from the reference data on standard antidepressants and speaks to the fact that ziranolone has been generally well tolerated in our clinical trials.
And lastly, we believe that if we're successful, Ziran alone has the potential to impact millions of lives. We think not only is there a near term opportunity in postpartum depression and major depressive disorder, But we also believe that there are additional opportunities to explore in treatment resistant depression, bipolar depression, Generalized anxiety disorder and a variety of other mood disorders. And so with that, thank you for your attention and back to you, Mona.
Thank you, Jim. Biogen looks forward to continuing to collaborate with you on the development of zuranolone. Now I'll talk a bit about schizophrenia. Schizophrenia is characterized by 2 or more persistent symptoms in the context of reduced functioning. These symptoms may include disorganized speech, positive symptoms such as delusions and hallucinations And negative symptoms such as apathy and flat affect.
Importantly, cognitive deficits are common. These include deficits in memory, attention, visual and verbal learning and comprehension. Pharmacologic treatment for schizophrenia is essential in preventing serious outcomes like hospitalizations, Which can grossly disrupt the life of a schizophrenia patient and can even proceed a suicide attempt. Now while there are approved treatments for schizophrenia, There are primarily antipsychotic medications that address positive symptoms and there are no approved therapies for cognitive impairment, A feature highly correlated with functional outcome and disability. This slide shows the importance to psychiatrists Of treating cognitive impairment.
In a survey conducted in approximately 3,000 psychiatrists, improving cognition, Social functioning and negative symptoms were important in treating stabilized schizophrenics. The proportion of doctors rating these goals in the top 3 is shown on the left. Shown on the right, a study done across the Middle East and Africa affirmed that The potential to improve cognition is one of the most important factors to psychiatrists when selecting a drug therapy to improve a Patient's social functioning. So I'd like to tell you a bit more about BIIB104 now. BIIB-one hundred and four is being developed as a potential treatment for CIAS based on the hypothesis that hypofunction may underlie CIAS.
NMDA and AMPA receptors on the postsynaptic membrane Regulate glutamate transmission, the brain's main excitatory neurotransmitter and are postulated to play a role in regulating synaptic and function, which in turn is believed to be important for cognitive processes such as forming memories. BIIB104 is a high impact potentiator of the AMPA receptor. By potentiating Activity of AMPA BIIB104 may also enhance NMDA receptor function and activity and could potentially improve CIAS. A Phase 1b study was conducted to evaluate multiple doses of BIIB104 administered to patients with stable schizophrenia Receiving antipsychotic medication. In this randomized double blind placebo controlled trial, FIB-one hundred and four was administered for 14 days and the study explored 104's impact on cognitive behavioral endpoints.
These exploratory efficacy analyses demonstrated a statistically significant improvement in the matrix Consensus cognitive battery working memory domain at the highest dose evaluated and a dose response relationship was demonstrated. Working memory is the ability to mentally hold and manipulate information about the present in order to act on the future. And so these results are particularly exciting as working memory is a cognitive domain in schizophrenia with among the highest correlations with functional outcomes. These results and the potential for BIIB104 to serve patients with CAAS motivated Biogen to move into a longer And larger Phase 2b study called TALI and that's currently ongoing. The TALI study will enroll up to 2 19 patients And is a randomized double blind study looking at 2 doses of BIIB104 versus placebo.
The dosing period is 12 weeks And the primary endpoint is the change from baseline in the MCCB working memory score. We're actively recruiting this study and we look forward to results next year. Schizophrenia is a serious mental illness With a diverse set of symptoms ranging from hallucinations to a loss of pleasure, but that importantly impedes cognition in the vast majority of Patience. In turn, this cognitive impairment affects day to day functioning, the ability to hold a job, Live independently and have healthy social interactions. Major depressive disorder impacts some of these same functional outcomes in a different way.
Available treatments leave unmet needs for both diseases. Cognitive impairment for schizophrenia is not addressed with any current treatments. Standard of care antidepressants, which largely work through the monoaminergic system, have multiple limitations and so a new mechanism of action is particularly We look forward to working with Sage to continue to progress sironolone globally, And we also look forward to the results of BIB-one hundred and four in cognitive impairment and schizophrenia next year. Together, These offer hope that we might change the reality of people living with mental illness. Thank you for your time.
We'll now take a short break before Toby reviews Biogen's ALS pipeline.
Thank you for the opportunity to speak today about our ongoing ALS programs at Pfizer. My name is Toby Ferguson, and I lead the Neuromuscular Development Group. As with other neurologic diseases, there is tremendous unmet need in ALLL. However, given our understanding of the disease and The possibility to modify underlying causes of disease, we feel that progress is possible for this deadly disease. Biogen has a long standing investment in ALS.
Today, I look forward to highlighting not only our current effort, but the lessons we have learned from past efforts as we seek to develop therapies and ALS. Here you can see our broader neuromuscular pipeline. We're developing a pipeline of programs with support for human genetics and pathobiology Starting at muscle disease, spinal muscular atrophy and ALS. Today, our focus is ALS. We have a broad and growing ALS pipeline across genetic forms of the disease and more recently for the broader form of ALS.
This includes Tafersen in pivotal studies for possible treatment of SOD1 ALS, BIIB78 in early phase studies for the possible treatment of ALS caused by SINNARF72 mutation and BIN105 for the possible treatment of broader ALS. We also have a number of preclinical programs. We look forward to a readout from Tilfersen this fall, followed by initial data on BIIB078 next year. In addition, We're optimistic about the potential to develop therapies for the much larger opportunity of broad ALS in the future. ALS is a devastating, progressive neurodegenerative disease characterized by the loss of motor neurons in the brain and spinal cord.
The early manifestations of ALS typically begin with weakness in the muscles, the arms or legs, or those muscles supporting breathing, speech or swallowing. ALS is uniformly fatal and the average survival following diagnosis is 3 to 5 years. The most common cause of death is respiratory failure. ALS is an orphan disease affecting approximately 168,000 individuals globally, including approximately 14,000 It's genetic ALS caused by mutations in SOD1 or SOD1. Relative to its prevalence, the incidence of ALS is significant With approximately 15,000 newly diagnosed cases each year across the G7.
The relatively low prevalence reflects The low life expectancy for the disease. Dallas places a tremendous emotional and physical burden on patients, For families and our caregivers, as well as substantial financial burden on both families and the healthcare system. At present, Grizoal and Gerobone are the only approved treatments for ALS in the U. S. And neither markedly slows or halt progression of the disease.
As a former neuromuscular neurologist, I can confirm there is an urgent need for effective disease modifying therapies for ALF. Unfortunately, over 50 randomized controlled clinical studies in ALS have failed to demonstrate efficacy. A notable example was our own Phase 3 EMPOWUR study, which evaluated Dexzepromepexel in broad ALS. Despite a lack of clear mechanistic rationale, dexpromopexol demonstrated encouraging early clinical results. However, The Phase 3 study in EMPOWUR failed to demonstrate differentiation from placebo on any of the prespecified efficacy endpoints, including the AOS Functional rating scale as shown here.
Provided, this result represented an inflection point and the learnings from this rich data set reshaped our approach, clinical development in ALA. Specifically, in contrast to dexamapaxel And to increase the probability of success across our ALS pipeline, we initially focus on targets supported by human genetics. In the case of the first one, BIIB078, the underlying genetic positive ALS were understood. For other programs such as BIIB105, A program designed to determine the attacks in 2 reduction may be an effective therapy in broad ALS population. Data generated using Empower helped to suggest that it takes into expansions, increase the risk of ALS and contribute to a more quickly progressive form of the disease.
We also learned from EMPOWUR that is crucial that the totality of the disease be captured, that the appropriate biomarkers of disease activity And possibly treatment response are included throughout development. Overall, our belief is that key learnings from each of our ALS programs We'll continue to inform the subsequent programs, enable successful development therapies for all people with ALS. Across our ALS portfolio, we are deploying rigorous experimental medicine method, including biomarkers of target engagement, Disease activity, help de risk early stage clinical program. Neurofilament is one potential pool I would like to spend a few moments on. Neurofilament is a structural component of Axon and in neurodegenerative diseases such as ALS.
Ordered onto the spinal cord and brain, Shown here in orange, shed neurofilaments into the spinal fluid in the blood when they degenerate. The filaments can then be measured in the spinal fluid And more importantly, good luck. In ALS, levels of neurofilament are approximately 10 times greater In our own EMPOWUR study, we found that patients with more rapid disease decline At higher levels of norethilament in the blood. This observation has been replicated by many others. Similar to ALS, Aerofilament levels are also elevated in SMA.
Importantly, following treatment with SPINRAZA, Aerofilament levels Dramatically and quickly reduced. Together, these data suggest that measurement of neuro filament could be a meaningful marker of treatment response in ALS And an important tool in ALS drug development. As I've noted, about 10% of ALS patients have known genetic cause of ALS. However, despite an underlying assumption that a family history of ALS is an appropriate indicator to drive genetic testing, We recently estimated that about 72% of all patients eventually diagnosed with genetic ALS and about 61% of patients Eventually diagnosed with SOD1 ALS do not have a known family history of ALS. Family history thus does not appear to be an appropriate driver of genetic testing.
Looking at this in more detail, we found that only 50% of patients with a family history of ALS, 20% without a family history are ever tested for genetic ALS. These data suggest multiple reasons for lack of testing and that substantial numbers of patients with genetic ALS will likely not be detected, Genetic testing is not performed more routinely across all populations of ALS patients. To reemphasize my prior point, As we enter a world where genetically driven ALS therapies may emerge, increasing awareness of both the genetic forms of ALS and access to genetic testing It will be crucial for identification of patients with genetic forms of the disease. To that end, Biogen has partnered With the genetic testing company Invitae to offer a no charge genetic testing program called ALS identified. This program provides access to genetic testing for a panel of ALSGs, including SOD1 and SINNOORF 72.
The program has been launched in the U. S. An additional geographic expansion is under assessment. In addition, the identified data will be shared with ClinVar. ClinVar is a public access database It serves as a repository of human genetic variation and disease phenotype.
These data will help us better understand the underlying genotype, phenotype correlations of ALS And this effort will help address and drive broader genetic testing across all ALS populations. Now I would like to highlight in more detail some of our work in SOD1 ALS. On some of the dominant mutations in the SOD1 gene We're first identified as a cause of ALS in the early 1990s by Bob Brown. The SOD1 gene encodes a ubiquitously expressed enzyme that when mutated is prone to misfolding. The mutated misfolded forms of SOD1 likely play a key role in motor neuron death The exact downstream mechanisms of toxicity are poorly understood despite many years of research.
Importantly though, Multiple lines of evidence indicate that the toxicity of mutant SOD1 is derived from a toxic gain of function mechanism. We therefore hypothesize that reducing the levels of SOD1 will slow disease progression. In collaboration with Ionis, our experience and success with SPINRAZA and SMA demonstrated that potential of antisense oligonucleotides To safely and effectively modulate splicing of SMN to pre investigator RNA to increase production of full length SMN protein. However, the therapeutic goal in many diseases is to reduce the levels of a toxic protein. To address this need, as in the case of SOD1, ILYSS has developed a distinct ASO chemistry that allows for the efficient recruitment of the enzyme ribonuclease H For RNSH, the degradation of the target messenger RNA bound by the ASO.
Following Cleavage of the messenger RNA, RSH releases the attack ASO and thereby allows a single ASO molecule to catalyze the degradation of many messenger RNA transcripts. Importantly, this RNase Hb mediated mechanism is shared by other ASOs in our portfolio for BIIB080, Which targets xenonore for ALS and VIBONA V, which targets ATAXA II for ALS. In light of the strong underlying genetic rationale and the ability to potentially modulate SOD1 with an ASO, We initiated a randomized placebo controlled Phase III study to evaluate Tafersen, an ASO designed to grade SOD1 messenger RNA And individuals with SOD1 ALS. The primary outcome measures of this study were safety, tolerability and pharmacokinetic. CSF SOD1 protein levels were assessed as a biomarker of target engagement and were a key secondary.
One key exposure outcome was measurement of neurofilament in the plasma and CSF. In this study, A person who is generally well tolerated at doses up to and including 100 milligram. Most adverse events were mild or moderate in severity We include headache, procedural pain and post lumbar puncture syndrome. CSF exposure of Traverse and SOD1 target engagement Greatest in the 100 milligram treatment arm. Compared to placebo, treatment with 100 milligrams each person Resulted in a reduction of CSF SOD1 levels by an average of 36% on day 85.
In addition, Treatment with Tafersen was associated with a trend toward lowering plasma neurofilament in both the overall population and more quickly progressing patients. These neurofilament data are the first data to suggest that neurofilament may be an appropriate marker for treatment response in ALS, but do need to be confirmed. To examine whether you observed lowering in CSF SOD1 levels, the highest dose was associated with a possible slowing of clinical decline. Patients were evaluated across 3 exploratory clinical measures. Treatment with 100 milligram Tuphersen resulted in a slowing of functional decline As assessed by the ALS function rating scale, the slowing of decline in respiratory function as assessed by sylobalic capacity and slowing of decline in muscle strength As assessed by handheld dynamics, these trends were generally consistent across groups of patient care guides By race of disease progression and along with evidence of target engagement and possible biomarker based treatment response with neurofilament reduction Support of the initiation of pivotal trial, the SOD1 ALS or to first.
VALOR is a continuation of the Phase onetwo single And multiple ascending dose study, Twersen, and has a plan to be up this fall. The primary endpoint of the study, Analysis based on the ALSFRS score. Key additional endpoints include measures of CSF SOD1, neurofilament, strength, Respiratory function and patient report outcome. One key theme that recurs throughout efforts to develop meaningful therapies For neurodegenerative disease, the timing of treatment may be crucial. The evolution of neuro filament as a marker of disease activity, The pioneering work done by some ALS colleagues, Michael Vanatar has suggested that presidmatic treatment Obsenetic forms ALS may be possible.
On the left diagram, you see outlined a pre symptomatic and symptomatic phases of the disease. In the presymptomatic portion of the disease, no definite signs or symptoms of ALS are present. At some point, these signs and symptoms are detectable And the patient develops clinically manifest ALS. Doctor. Benatar and his collaborators followed for many years people who carry SOD1 mutations, But did not yet have signs or symptoms of ALS.
Their key insight was that neurofilament appears to gradually rise Prior to the conversion to clinically manifest ALF, you can see this diagram on the left is a gradual elevation of neuro filament In the presymptomatic phase of the disease. On the right, you can see data developed in collaboration with Doctor. Benatar. It demonstrates that we're rapidly progressing in SODRAN ALS patients. Neurofilament levels rise about 20 months prior to conversion to active disease.
These data suggest that it may be possible to design a clinical trial in which trial participants are enrolled and treated When the neuro filament exceeds a certain threshold, they are followed for conversion or lack thereof to manifest ALS. Given the possible importance of early treatment of SOD1 ALS, we have recently announced the opening of enrollment in Atlas. Atlas is designed to determine initiation of presymptomatic treatment of SOD1 ALS with the person and delay the emergence of clinically manifest ALS. The key endpoint will be emergence of clinical disease within 12 months. The key features of this study are outlined here.
In particular, when patients initially enroll in the study in Part A, they have both normal neurofilament levels, no evidence of clinical manifestations of ALF. Once their serum neurofilament light levels meet or exceed 44 picograms per ml, they're enrolled in Part B and randomized to either a person with 100 milligrams or placebo I followed until the emergence of clinically manifest ALS. After emergence of ALS, all participants will be transitioned to Versa Part C. Though we understand it to be less likely, Part D would capture participants with emergence of clinical ALS prior to infection of an elevation of peripheral. It is our hope that this trial will better inform the importance of early treatment with trofersen We pioneer biomarker based presymptomatic treatment, which is NatCat.
Let me now take a deeper look at our CNOORF72 program. Hexanucleotide repeat expansions in a non coding region of the xenonor-seventy two gs represent the most common cause genetic cause of ALF. These expansions occur between exons 1a and 1b as shown in the upper left. Like mutations in SOD1, Expansions in cnorf are hypothesized to be for a toxic gain of function. Specifically, mutant cnorf toxicity is thought to Results in production of repeat containing RNA transcript.
These could be detrimental in either or both two way. They can form RNA Foci, sequester RNA binding protein and they can also undergo repeat associated non ATG or Ran translation We produce aggregation prone dipeptide repeat proteins or GPRs that are postulated to be toxic. Potentially mitigate synodal mediated toxicity, we are developing an RSH ASO, potentially decrease the production of toxic group RNA And consequently of DPRs. 578, our lead ASO targeting CNOOR. This ASO binds to the sequence upstream of the hex nucleotide repeat expansion.
Only a minority of transcripts from the synov gene contain these repeats. So this approach allows for selective lowering of the disease associated transcripts, while preserving the majority of Synodoropharm A. This selectivity may be important as homozygous deletion of XenoRx has been shown to reduce immune related pathology in preclinical model. We are currently advancing BIIB078, the Phase 1 multiple ascending dose study in ALS patients The study is ongoing in the primary and secondary outcome measures for safety Consistent with our aim to mitigate risk across our portfolio And offer early insights to potential efficacy. We have built the biomarker of synodulf target engagement within the central nervous system.
In this respect, We'll measure the DPR's GA and GP in CSF during the course of the trial. Importantly, preclinical data shown on the right suggests The BIIB078 can effectively reduce tissue levels of GA and GP. In addition, we will incorporate downstream markers of possible treatment response such as neurofilament. Data from this study is expected in 2022. We aim to build on our work in ZENIC ALS, We've seen novel, scientifically driven drug targets with a much larger opportunity in broad ALS.
The central feature of ALS pathology, The accumulation of aggregated TDP-forty three in the neurocytoplasm as shown on the left image of Ortech. Aggregated TDP-forty three is found in most ALS patients. Their presence is correlated with motor neuron death. The mutations in TP43 can cause rare genetic forms of ALS. For these reasons, dissimilar TP3-forty three biology It'd be possible to drive ALS in a broad population.
The central therapeutic hypothesis in ALS is that cytoplasmic accumulation TDP-forty three, due to a toxic gain of function or loss of TDP-forty three from the nucleus may also contribute to disease pathology. These data strongly suggest that modulation of TDP-forty three or related biology may be crucial to developing disease modifying therapies In the broad ALS population. To potentially address the toxic gain of TDP-forty three function, we have collaborated with Ionis to develop FIB-one hundred and five. 5.05 is an intrathecal ASO investigated, possibly treat the broad ALS population. Overall, we introduced ataxin-two, which we hypothesized will decrease aggregated TP43 and approved TP43 related toxicity.
Our potential targets to modify T-forty three, TEXX gives a large amount of evidence to support its role in human error. It was first discovered by Aaron Gittler as a modifier of T42 toxicity in yeast. He and others then quickly demonstrated that modulation of Ataxin-two Also modified disease phenotypes in fly and mouse models. We confirmed that knockdown of attacks in 2 modified survival and function in mouse model of TDP-forty three ALF. Perhaps most important, expansion repeats in the ATAXA2 gene in human beings are found to increase the risk of ALS by 7 fold And are associated with a more quickly progressive phenotype.
Our BIIB105 study is ongoing and in the early stages of clinical development. We thus have multiple clinical programs to target the main genetic positive ALS as well as others focused on human biology That could be relevant to all ALS patients. We also recognize that ALS biology is complex and see further to address the needs of patients with broad ALS by advancing additional partners. There's no single gene responsible for broad ALS. We have therefore invested to understand the underlying biology.
The field has advanced over the past 5 years with evident from many potential targets, Including those related to EB-forty three, PACSIN-two, stress pathways and EPO cytoplasmic transport. To increase the chances of finding successful molecules for BLADE ALS, we've established a high throughput in vivo target validation core We identify agents based on targets and pathways derisked with genetic validation and relevant gene biology. For example, We understand that drug targets supported by Human Genetics have a higher probability of success. However, so far Genetics has mostly focused on identifying targets linked to the risk of human disease, much less so on disease progression, which is the focus of most drug development effort. Biogen, we have therefore generated genetic data in a large number of clinically characterized ALS patients, including participants from our own EMPOWUR trial, We generated an overall cohort of 1600 patients that have been well clinically profile.
These analyses hint at multiple targets that may affect disease progression. Our genetic efforts are also complemented by target discovery, rooted in human biology and pathology, With a broad goal, detecting and advancing novel targets for broad ALS. To summarize, Our goal is to be the leader in ALS. Rooted in recent significant advances in human genetic disease pathophysiology, We've been taking a rigorous approach to ALS, working with the patient and academic communities with the goal of creating a new standard for investigational trials. We are focused on targets with strong validation from immunogenetics, modernizing and accelerating clinical trial design, The use of novel biomarkers, focusing on patient populations most likely to benefit from a given treatment.
Aurelia's journey has taken us from the data set generated by Empower, with initial focus on monogenetic conditions such as SOD1, CDNOLF72 And now, transition to targets that focus on biologies we believe are relevant to the broader population. We further believe that the experience we have gained will allow us to take a rational, systematic approach to a broad ALS and maximize our public success It's difficult endeavor to see. Thanks for your attention. I'd now like to hand it over to Josh.
Toby, thanks so much and good morning. I'm really pleased to introduce and review Biogen's entrance into stroke. My name is Josh Bell, and I'm the Medical Director and the Clinical Development Lead For multiple neurovascular programs here at Biogen, I'm a clinician scientist with expertise in stroke, brain trauma And neuroprotection. Stroke is a common disorder and has profound impacts on patients and their families. Despite this fact, it's been many years since there was any significant innovation in medical treatment of stroke.
Biogen accepts The challenge and the responsibility to reshape the standard of care in the treatment of acute stroke, and we're addressing significant unmet needs through 3 opportunities: 1st is expanding the treatment window 2nd and third, taking advantage of a greater understanding of 2 secondary mechanisms of injury: Edema formation and neuroinflammation. Our programs fit well in the context of the growing use of endovascular thrombectomy for the treatment of acute ischemic stroke. Today, we're going to discuss 2 programs that represent significant innovative advances that will position Biogen competitively in the stroke landscape. Biogen is entering with 2 really exciting innovations. First, BIB-one hundred and thirty one or TMS-seven.
Going forward, I'll refer to this as BIB-1 hundred and thirty one. This is a recently acquired small molecule following our positive Phase 2 study And a potential best in class thrombolytic. 2nd asset, BIIB093 or glbencomide, It's a novel approach to treat edema following large hemispheric infarction. It's one of the most severe forms of ischemic stroke and it's being studied in the Phase III CHARM trial. BIIB093 is also being studied as a potential treatment for brain contusion following head trauma in the Phase II ASTRAL study.
Stroke occurs when blood supply to a brain is compromised or interrupted, usually by a combination of Atherosclerotic buildup and acute clot formation. When brain cells are deprived of oxygen nutrients, injury and death can occur within minutes. However, we've recently learned that when acute stroke presents, substantial portions of the brain at risk Our potentially rescuable, timely intervention to address clot formation and edema. As depicted here, 85% of strokes present as an acute ischemic stroke. Its effects, On average, about 1 in 6 individuals at an average age of 65.
Critical subset of AIS, large hemispheric comprises about 10% to 15% of AIS. On average, it affects a younger age group. Large hemispheric Farchen is also likely to be complicated by malignant edema formation, leading to severe disability and death. Unfortunately, younger patients are more susceptible to this, owing a less volume in the skull for a swelling brain to expand. This underscores a high unmet need.
Subiogen's 2 assets will address the spectrum of AIS as depicted here. The approved treatment landscape for AIS includes TPA and endovascular thrombectomy or EBT. Depicted here on the vertical axis on the left is the elapsed time from stroke onset. The bar on the left provides percentage Stroke patients who arrive in certain time windows. For instance, only 27% of patients arrive and start their care within 4.5 hours since they were last in normal health.
What this means is that only a minority of patients may even be eligible to receive tPA from a timing perspective. The short time window is also meant to address symptomatic hemorrhages, which can be the most concerning adverse event associated with tPA and increase in incidence As tPA is given later in its time window. So in the end, very few patients actually receive tPA with estimates of only about 6%. The BIIB131 clinical development plan is designed to address this treatment shortfall by extending the time window out to 24 hours, This is shown in yellow, while maintaining efficacy and an appropriate safety profile. Inovascular thrombectomy, which is a significant innovation for the treatment of acute ischemic stroke and involves mechanically retrieving and removing the clot It's being studied out to 24 hours and it can be used in combination with thrombolytic agents.
Finally, BIIB093, which is in development to treat brain edema, is being studied with a dosing window that starts within 10 hours last known normal. So now I'm going to introduce BIIB131, and we'll review the Phase 2 study. So BIP-one hundred and thirty one is a potential best in class thrombolytic and was recently acquired following a successful Phase 2. BIB-one hundred and thirty one is thought to have a dual mechanism of action, first as a thrombolytic and second as an anti inflammatory. Firstly, and unlike tPA, which causes systemic plasminogen activation, BIV131 causes a conformational change In plasma imaging that increases its affinity towards fibrin.
By enhanced fibrin binding, BIIB131 is thought to cause local clot directed thrombolysis. Secondly, an anti inflammatory mechanism has been identified with this compound, inhibition of molecule called soluble Metabolites of arachidonic acid, epoxide fatty acids depicted here as EET, Have anti inflammatory and vasodilatory actions? Preclinical stroke models support a role for inhibition of soluble epoxide hydrolase as being neuroprotective. So these two positive mechanisms led to the Phase 2 study with our extended time window that I'm now going to describe. The recent systemic administration of tPA is limited to 4.5 hours has to do with increasing risk of hemorrhage over time.
To test the hypothesis that BIIB131 might be administered safely at later time windows, the study was designed with safety as the primary objective. Acute stroke patients not eligible for tPA or endovascular thrombectomy were randomized to receive either BIIB131 or placebo out to 12 hours after last known normal, progressively increasing doses were administered in 3 cohorts. In addition to safety as a primary objective, 2 key secondary outcomes supported evaluation of potential efficacy: Modified rank and scale and recanalization is determined by MRA and geography. Let's take a look at the results. 1 patient of 38 in the placebo group experienced symptomatic hemorrhage.
But of the 52 patients who received BIIB131, Not a single one experienced symptomatic hemorrhage. This was despite the fact that there was an extended treatment window. On average, patients receive BIVV-one hundred and thirty one at 9.5 hours or placebo at 9.3 hours. This was after the onset of their stroke symptoms. Let's Take a look at 2 key secondary outcomes that support the potential efficacy.
So John Rankin first developed this functional outcome scale in 1957. This was modified in the 1980s. And the range of functional outcomes spans from no symptoms, which is a 0, mild symptoms with no functional limitations or a 1 to severe bedridden and death or a 5 or a 6. In the study, modified Rankin Scale scores demonstrated that patients who received BIIB131 were more than twice as likely as placebo patients To achieve 0 or 1 on the scale, which signifies functional independence of day 90, so it's 40.4% versus 18% for placebo group. Let's take a look at the recanalization data.
So this is an illustrative case that demonstrates reperfusion following treatment with BIP-one hundred and thirty So 78 year old man who presented with an occlusion of a main branch of his middle cerebral artery, he had an NIHSS of 9, which indicated he had moderate disability. He was treated with drug 8.5 hours after stroke onset. On the left, The red arrow, what you can see is only one main artery with a white signal showing blood flow. However, on the 24 hour reperfusion scan on the right, Additional vessels are now visible due to clot breakdown. Incredibly, the 78 year old not only tolerated the treatment safely at 8.5 hours, But he also emerged with 90 day MRS score of 1.
This means he was able to perform all his significant activities with no significant disability. The next slide I'm going to show quantifies observed blood vessel recanalization in those who had visible vessel occlusions on angiography. So 15 placebo in 24 BIIB131 patients had identifiable visible vessel occlusions. Patients receiving BIIB131 were more than 4 times as likely to recanalize at 24 hours. So to summarize, 52 patients who received BIIB131 up to 12 hours of stroke onset and none had symptomatic cerebral hemorrhages.
The average time to treatment was 9.5 hours and 9.3 hours for our placebo group. The recanalization rate was also greater in the BIIB131 group and you were shown a demonstrative case of a participant who received BIIB131, We canalized the main branch of his middle cerebral artery and he's now functioning independently with mild neurologic deficits. At day 90, modified rank and scale scores demonstrated that patients receiving BIB-1 hundred and thirty one Much more likely to be assigned 0 or 1 indicating functional independence. So our team is actively designing further clinical studies to confirm these results. I'd now like to introduce BIIB093 Urglobanklomide.
This is a small molecule designed to treat one of the key secondary mechanisms of injury following stroke, Edema or brain swelling. Research over the past few years has demonstrated that The SER-1TRPM4 ion channel is a key regulator of cerebral edema and potentially hemorrhage formation following CNS injury. And thus, this might be a potential therapeutic target for stroke and brain contusion. The channel is blocked BIIB093, which is an IV cell phondylurea. In order to test the hypothesis That BIIB093 might treat cerebral edema, a Phase 2 study was undertaken in patients with large hemispheric infarction or LHI.
Among the most severe strokes, Patients are very high risk of malignant brain edema in LHI. And I'll now detail results of the Phase 2 study. These were highly compelling and they informed a large global Phase III study, the TARM trial.
This
is now recruiting patients with LHI. And we've also initiated a Phase 2 study in brain contusion, the AASTRAL study.
Let's take a
look at the Phase 2 LHI study results. So large hemispheric infarction is defined by a minimum core stroke volume of ADCCs. This is about onethree of a cup Or an ASPECT score of 5 or less. This is a disease in which malignant edema could potentially be reduced with BIIB093. So in this Phase 2 study, 41 patients were randomized to BIIB093 and 36 to placebo.
The primary endpoint of the Phase II trial was an MRS 0 to 4 without the need for a decompressive craniectomy, which is a common procedure used when intracranial pressure is dangerously high, often due to cerebral edema. Although the study missed the primary endpoint, this was influenced by inconsistent application of guidelines for surgical intervention from select sites. Notably, the study demonstrated that the pre specified cohort of patients not receiving a decompressive craniectomy And who were treated with BIIB093 were more likely to have an MRS of 4 or less than those receiving placebo. There were also significant effects of BIIB093 on several secondary and tertiary endpoints, which included mortality and reduction of brain midline shift At 72 to 96 hours, the latter of which is a radiologic indication of cerebral edema and was highly supportive of proof of concept. With respect to safety, hypoglycemia was a known potential adverse reaction, but was proved to be manageable with proper clinical oversight.
So the CHARM study, which is now enrolling, is a double blind placebo controlled Phase 3 study in which approximately 768 patients with LHI, as defined by one of several brain imaging modalities, We'll be randomized to placebo or BIV93 within 10 hours of stroke onset. Primary outcome is the Day 90 modified Rankin Scale Score. Key secondary endpoints include survival, other functional outcome analyses and midline shift. Study design permits all forms of standard of care, which includes endovascular thrombectomy. There's also a special protocol assessment agreement with the FDA And orphan drug and fast track status have been obtained.
So to summarize, Neurovascular disorders remain a significant cause of disability and mortality. Biogen has potentially transformative compounds And Frankly has the expertise and the desire to enter the neurovascular space with these novel compounds designed to complement existing therapies. This includes endovascular thrombectomy. Our portfolio addresses not only blood clot formation with potential best in class thrombolytic, But also key causes of secondary injury, including brain edema and neuro inflammation. BIIB093 and BIIB131 will anchor Biogen's And through this portfolio, Biogen accepts the challenge and responsibility of reshaping the standard of care and stroke.
Thanks very much. I'd now like to hand things over to Natalie.
Thank you, Kirsten. Good afternoon. My name is Nathalie Franchemond, and I lead Development in Immunology and Multiple Rose at Biogen. It's a great pleasure for me to share with you our progress in immunology. What I would like to do with you today Is first remind you briefly about our journey in immunology from the early days of Biogen to today.
2nd, review our 2 lead assets in Phase 3 and discuss the exciting signs supporting their development And last, discuss the growth perspective of our portfolio. From Biogen's foundation, we have leveraged a Strong scientific know all in immunology. We had for many years an immunology franchise and a neurology franchise. It is at the intersection of the immunology and neurology franchise that our multiple sclerosis pipeline was born. From these early days, we brought 5 immunomodulator agents to patients suffering from MS.
From 2015 to today, we have leveraged our immunology expertise to approach Other neurological disease and continuing developing 2 lead assets in lupus. This brings To us to our portfolio today, which is illustrated on the next slide. Biogen's lupus portfolio has multiple Phase III The first one, dapirolizumab peccol, is developed in collaboration with UCB for systemic lupus Or SLE. The second one, BAP 59, was fully developed from research to development in a host at Biogen And he's in Phase III in SLE. We are also planning to develop it for cutaneous lupus or CLE.
Finally, we are planning to develop small molecules in lupus as a follow-up to our antibody for SLE. This work is at the preclinical stage. Today, our goal is to execute on the development of our 2 lead assets, Pierre Louis, Lizumab, Paykel and BIP 59. These two lead assets are anchored on a long internal History. And we will review together how over time, we have attempted to derisk their biology By genetic evidence and human validation in early phases of development.
We will leverage our development experience To execute on the Phase III program. Doing so, we are aiming to demonstrate Biogen's value in establishing health equity And positively influencing the health ecosystem of the underserved. We have also to maximize our presence in lupus by developing additional molecule, leveraging our deep In the biology of plasmacytoid dendritic cells, PDC and type 1 anti France that we have acquired via BIIP 59 And these cells that we have continuously tapped into for our MS franchise. Finally, We will use genetic, artificial intelligence and again, our biomarker toolbox in an effort to derisk The life cycle management opportunities for BIIB059 in other autoimmune disease of high unmet need. Just a few words on systemic lupus and cutaneous lupus.
Starting on the right, SLE is the prototype autoimmune disease that can affect multiple organs in the body And it's associated potentially with severe organ damage and morbidity, especially among non Caucasian patient. The disease is not rare, affecting 4,000,000 people worldwide and mostly young women of childbearing age. Lupus pathogenesis is thought to be multifactorial and contribution of both genetic and The factor has been described. While the majority of SLE patients will experience Some skin manifestation one day during their disease, cutaneous lupus is a skin based autoimmune disease that can exist In the absence of systemic manifestation, in fact, most of the CLE patient presenting with subacute or chronic CLE may never develop systemic manifestation. Chronic CLE is associated with severe damage, Especially in its discoid form or DLE.
Discoid lupus can be devastating for these young women, Which may experience scarring and dyspigmentation as illustrated in the picture as well as alopecia. These clinical manifestations are associated with impaired quality of life. There is no biologic approved, Especially for CLE. Thus, there is a very significant unmet need for patients with CLE. So what are our latest therapeutic options for systemic lupus patient?
There remains an unmet need for new therapies in SLE as well. Indeed, in the last decades, 2 biologics have been approved for SLE. The first one approved was belimumab in 2011, 10 years ago, and the second one was anifrolumab approved this summer. As a reminder, belimumab targets a growth factor of bliss that is necessary for the maturation of B cells. Anifrolumab is a monoclonal antibody direct against the interferon alpha receptor 1.
Voclosporin, a calcinorin inhibitor small molecule, has been recently approved for lupus nephritis. Our 2 molecules have distinct mechanism of action from the approved therapies. Dapirolizumab PECO inhibits CD40 ligand And is a polyethylene glycol PEG conjugated anti binding Fab fragment lacking a functional Fc domain. Evidence suggests that CD40 ligands provides costimulatory signal via CD40 that are essential for T cell activation, T cell proliferation, generation of antigen specific T cell response as well as B cell maturation and the production Of high affinity antibody. The CD4xCD4x40 ligand pathway is also needed for dendritic cell stimulation And maturation into fully competent antigen presenting cells.
This is, therefore, an important co stimulatory pathway In Adaptive Immunity. Our scientific interest in the CD4D, CD4D ligand pathway started more than 20 years ago. And today, together with UCB, we are developing the pyrrolizumab pickle for patients with SLE. BIP-fifty nine is a monoclonal antibody fully developed in house. It is targeting plasmacy to dendritic cells, And its mechanism of action is further described in the next slide.
VIP59 is a humanized monoclonal antibody against BDC A2, a protein uniquely expressed on the surface of Plasmacytoid dendritic cells, or PDC. PDCs are innate immune cells capable of producing rapidly High amount of type 1 interferon as well as other cytokines and chemokine in response to immune complex in lupus. PVCs are known to be decreasing the blood in patients with lupus and accumulate in target organs such as the skin, the kidney and the joints. It is their presence in the skin that allow us to consider an event specific approach in Phase 1, And we will discuss this together later in this presentation. BIP 59 binds to BDCA 2 And leads to BDCAD to internalization and inhibition of all type 1 interferon, but also interferon lambda, cytokines such as IL-six and TNF alpha and chemokines that are implicated in SLE and healy pathogenesis.
BIIB059 inhibits PDC derived type 1 interferon at the site of the disease, while preserving The protected Type 1 response to virus in all other cells. So this is different from anifrolumab, which antagonized The type 1 interferon alpha receptor 1 on various cells that express it. There is an abundance of evidence linking Type 1 interferon to disease activity in lupus. Genetic polymorphism leading to Type 1 interphone signaling are associated with an increased susceptibility to SLE. RF5, a nuclear factor leading to Type 1 interferon production, is the top non HLA Risking for lupus.
Still, what gave us additional confidence in VEP 59 Was the human validation experiments we conducted in Phase 1. We took advantage of the internal and external knowledge That PBC were present in the skin of SLE and CLE patient to interrogate the effect of BIIB059 On PDC and type 1 Interfront in Phase 1. More specifically in Phase 1, we studied the impact of BIIB059 On type 1 interferon response in a small SLE cohort of 12 patients who had active skin lesion. Four patients were randomized to a single dose IV of placebo and 8 to a single dose IV of BIP-fifty 9 at Skin biopsies were analyzed from samples collected at baseline and at week 4 From active lesion in 11 out of the 12 SLE patients. Sample were evaluated for interferon regulated Proteins, including MXA using immunohistochemistry.
The graph in the middle column Shows that normalization of MXC expression occurred in 5 of 6 the 6 patients with high MXC expression At baseline, upon treatment with BEGFIFYANNA WIG 4, 3 of the 4 patients in the placebo boot had Elevated baseline MXC expression in the skin and did not show any normalization at week 4. An example of this analysis also illustrate in the top panel for Subject 5 and shows that BIP 59 decreases MXC expression to healthy volunteer level. In parallel, reduced cellular infiltration was Serve after treatment, WESP 59. So to determine if this biomarker could be Indicative of a clinical outcome, we conducted a correlation analysis between changes in MXN biopsies at week 4 And changes in Classe A at week 4. Classe A or cutaneous mucuserapematosus disease area And severity index activity is a CLE disease activity endpoint we had collect as an exploratory endpoint in Phase 1.
So we show that improvement in CLAZIA score correlated with reduction in MXA expression in skin lesion. The result of Phase 1 are summarized here also on the left. And on the right, what you can see is another illustration of the Phase 1 data We just discussed. It shows a subject level analysis of MXA in skin biopsy As well as the response of each patient in clasier as defined by a reduction of at least 4 points Inclasi A from baseline at week 4 and or at week 12 in the placebo group in the top panel And BIIP 59 in the lower panel. So altogether, we could demonstrate proof of biology in the skin, a target organ of lupus, And link this proof of biology with early proof of concept.
We confirm that the molecule achieved proof of concept in Phase 2, And data are shown in the next slide. The Phase II study had 2 parts. Part 8, annual SLE patient with active joint and skin manifestation, while Part B Included CLE patient with or without systemic manifestation. In Part B, we study Only one dose of BIP59, while in Part B, we tested a dose response. Consistent with our observation in Phase 1, we showed a greater reduction in percent in change in Class EA With the 3 dose of PIP59 as compared to placebo in patient with CLE in Part B.
The study met its primary endpoint, demonstrating a dose response relationship with the P inferior To 0.001, using the multiple comparison procedure, modeling analysis of percent and change in Class A. The bottom right figure shows the effect of the 3 doses of BEP59, 50 milligrams in red, 150 milligrams in green, 450 milligrams in blue, administer every 4 weeks subcutaneously with a loading dose at week 2 as compared to placebo, and this is on the percentage change of Klasi from baseline Over time, up to week 16. As PDC were known to Present in joint, we studied the effect of BIIB059 on active joint counts in Part A of the study. The primary endpoint was the changes in total active joint coins, which was defined as the sum Of the tender joint cone and the swollen joint cone. As you can see in the left graph at week 24, There was a significant difference in the least square mean absolute change in total active join con from baseline Between placebo and BIIB059415 milligrams groups with a greater decrease observed in the BIIB059 group With a least square mean difference of minus 3.4 and a p value of 0.037.
Importantly, the safety profile of BIP59 was acceptable in both Part A And the Part B of the Phase II study. I also wanted to share with you one additional result Over secondary endpoint in Part A of the Phase II study in SLE patient. These figures illustrate the proportion of patient Achieving a systemic lupus erythematosus responder index response of 4 or greater, SRI 4, A composite endpoint assessing SLE disease activity. We were pleased to see that the higher percentage of participant with SLE, Achievus ORI 4 response was BEP59 at 4 50 milligrams versus placebo At week 24, with the lead square means difference from placebo of about 26%. So where are we today and what's next for BIIB059?
We are now proceeding to Phase III BIIB059. We enrolled the first patients In TOPAZ I and TOPAZ II, which are global randomized controlled studies assessing The efficacy and safety of 2 doses of BIP-fifty nine versus placebo on top of standard of care in SLE. We are leveraging our result of Phase 2 and are using SRI 4 as our primary endpoint. We are planning for CLE development as well and, in the future, potential life cycle management activities. We are excited about this molecule that was developed fully at Biogen and has demonstrated human validation in our early clinical development program.
The other very interesting molecule we have in Phase III in collaboration with UCB is dapirolizumab pekol. So in the next Few minutes, I would like to give you a brief overview of the apirrolizumab pecan program. As you know, the CD4dCD40 ligand This pathway is a cornerstone of the adaptive immune system, and there is a great amount of evidence that blocking this pathway What results in benefit in autoimmunity? This has been shown in multiple preclinical models and in the clinic. As a reminder, the first anti CD40 ligand monoclonal antibody were tested in the clinic more than 20 years ago And I've shown signal of efficacy in autoimmune disease.
Platelet aggregation and thrombus development Had been observed with previous full length immunoglobulin G IgG monoclonal anti CD40 ligand antibody Containing the Fc region that we have aimed to derisk with zapirolezumab pekol as a Fab conjugated molecule. No evidence of platelet activation in human or rhesus macaque platelets And no evidence of an increased risk of thromboembolic events in the development program have been identified to date. Importantly, we confirm the proof of biology of dapirolizumabpekol on autoantibody in lupus, namely Antidouble stranded DNA in our clinical program, both in Phase I and in Phase II. This figure here illustrates the effect of dapirolizumabpekol on anti double stranded DNA in Phase II. Improvement across all dapirolizumab Paykel groups between 24 versus placebo was observed on the level of autoantibody, Which is consistent with the mechanism of action of dapirolizumabpeco and the critical role of the CD40, CD40 ligand pathway In numerous response to T cell dependent antigen.
Following dapirolizumab pickle withdrawal after the 1st 24 weeks of the trial, anti table stranded DNA generally returned to baseline in the observational period as illustrated On the right of the figure. This slide summarizes the result of the Phase 2 on Vikla At week 24. A treatment period of 24 weeks was followed by an observational period of another 24 weeks. Vicla of British Isle Lupus Assessment Group Disease Activity Index 2,004 It is another composite lupus assessment endpoint that is registrational. The primary analysis for Bikla response was analysis and use multiple comparison procedure modeling MCP methodology To identify the best candidate dose response model.
As none of the pre specified dose response model fit the observed week 24 Bigler responder rates with statistical significance. The primary objective to select a dose response relationship model was not met. The best fitting model, EMAX, Had a p value equal to 0.07. Still, the responder rates were numerically higher In all standard of care dapirolizumabpekol dose group compared to the standard of care placebo group as illustrated in this figure. Dapirolizumab Pecol appear to be well tolerated and had an acceptable safety profile.
So where are we today and what's next for dapirolizumab pekol? The Phase III study of dapirolizumab PECOL has been initiated about a year ago, and it's a global randomized controlled trial testing the efficacy and safety Of dapirolizumabpeco versus placebo. The long term extension has also started. This pathway is also relevant to other autoimmune disease and offers multiple possibility for life cycle management in the future. So in summary, we believe we have a deep expertise in lupus, which allow us to grow our portfolio.
This is based on our long standing knowledge in immunological pathway from MS to autoimmune disease. We have also over 40 years of now in protein based medicine and have access to all other modality to target immune cells. Our 2 lead assets are now in Phase 3 after demonstration of proof of concept and human validation. We have a team of experts in immunology and neuroimmunology with the right scientific and development knowledge to execute The clinical development of our molecule. We can capitalize on biology we know well, like PVCs in lupus or B cells To expand our portfolio of molecule in lupus, we have also the option to conduct life cycle management In order, autoimmune disease was high on mid meat was our lead asset.
And with that, I would like now to turn it back over to Al for closing comments.
Between the presentations you've seen here today As well as those available on demand, I think you've seen many examples of the 4 step drug development methodology in action. I hope that you can appreciate not only how neuroscience is changing, but how Biogen is leveraging breaking science To potentially change the risk profile of drug development in this space. We believe that through our dedicated focus on neuroscience, Exceptionally talented organization and key external collaborations, we are well positioned to continue pioneering in neuroscience To deliver innovative new therapies to patients. We'll now take a short break before returning for Q and A.
Okay. Welcome back, everyone. We're now ready to begin the Q and A session. And the first question we have comes from Mark Goodman at SVB Leerink. His question is that Samantha mentioned that you are actively exploring multiple approaches at the same time to treat Alzheimer's disease.
Can you please elaborate on that comment? Do you have any proof yet that a combination approach is better? If you haven't started clinical work yet, when should we expect a reasonable time frame for a combo study to start?
I'll turn it over to Samantha in a moment. But yes, we have multiple approaches. And one of the reasons why we brought These different assets targeting different mechanisms of action was that we could potentially combine the treatments. And so whereas anti amyloid therapies produce some effect, we believe that combining will actually potentially And our philosophy is that you have to understand something about the drug as monotherapy first, for example, the dose response And the safety. So with that, I'm going to ask Samantha to comment.
Thanks, Al. I would agree very much with what you just said, which is we believe And that there are multiple mechanisms at play in Alzheimer's disease. And absolutely, we are bringing forward mechanisms to treat More than amyloid pathways, we talked about BIV80 today, which is really a very exciting program. And so it is our ambition To be combining these potentially in the clinical space, it's too early to say when. The principles that Al just outlined, which is What is the right dose based on target engagement also plays out in combination.
So this model of how to do drug development Applies to selecting the right molecule, the right dose and then combining them so that the two pathways can hopefully synergize or at least Have an additive effect.
Okay. Thank you, Samantha. And the next question comes from Robin Karnauskas at Truist, and she asks about BIIB104 for schizophrenia. She says BIIB104 For this program, what is a good bar for the Phase 2 study? How is the endpoint viewed clinically?
What is clinically meaningful? How hard are Phase 3 trials to do in this area? And do they have challenges with high placebo rates? Essentially, again, asking about the Phase 2 study, what's the bar, what's clinically meaningful and about feasibility of Phase 3 studies.
Yes, I'll start and then Mona will add. Those are really good questions, Robin. As is often the case, we would potentially be the first to get I've approved for negative symptoms of schizophrenia or even or cognitive deficits in schizophrenia. So the path It's not been well laid out by others, although we see signs of other people approaching this and we'll learn as much as we can from those. And so those are the kinds of challenges we take on when we pioneer neuroscience.
Mona?
Thanks, Al, and thanks for this question. I'm Pleased to talk about the TALI trial in cognitive impairment and schizophrenia. You've brought up a couple of points about the challenges in the space and I'll start there. Certainly, conducting trials in psychiatry is very challenging, particularly with schizophrenia where there are challenges with investigational product Adherence, recruitment, retention in the trial, I think we're using some great strategies to address those in the current And this is a place we'll continue to learn and grow and develop and seek to address those challenges. And I think we're well positioned and have great A lot of talent to address some of these challenges.
So in terms of the endpoint, I'm not prepared to Speak specifically about, specifically about, say, a go no go criteria, but what I can say is that that The trial is looking at working memory as a very important predictor of functional outcomes. And we're also assessing psychiatric symptoms, positive and negative symptoms and functional outcomes as well. I think we'll be looking very closely at the totality of the data to think about next steps in that program. And we continue to see this as a really important unmet need with many of the challenges you outlined that we're ready to bring head to face head on.
Great. Thank you, Mona. The next question comes from Michael Yee at Jefferies. And he asks, given the various approaches you have mentioned today in Alzheimer's, do vaccine approaches have good relevance in Alzheimer's or CNS diseases, Given that you could treat early and in a preventive strategy.
Yes. So Michael, that's a great question. And you'll recall that the first step in immunotherapy for Alzheimer's disease actually started with a vaccine in 1792, which was a vaccine of abeta42. And the problem with that trial There were cases of meningoencephalitis. I think it was about 6%.
And that led to the halting of the trials due to safety concerns. But so that was the first foray into vaccinating as a way of conducting Immunotherapy in Alzheimer's disease. So we'll have to learn from that. Obviously, vaccines lead to antibody production And that could be a way to address the disease, but it has to be the right antibodies directed against The aggregated forms of A beta. And you'd have to avoid the what we think were cell mediated immune effects That led to the meningo encephalitis.
So I think it's a possibility. But right now, it looks like Passive immunotherapy approaches seem to be the best course of action. But again, something that bears watching. And if we could direct the antibody response to the right epitopes and deal with the reducing the cell mediated immune components, Then I think it could be a promising avenue.
Great. Thank you, Al. And the next question, I think is probably for Mike McDonnell. The question is, given the number of opportunities you've highlighted today, how do you think about capital allocation
over the next several years.
Sure. And thanks for the question. So you heard Michelle mention earlier today that we've invested approximately $11,000,000,000 over the last 5 years in R and D. You heard Al talk a lot about the collaborations and M and A transactions that we've done there at 27 over that same time frame. And that's really just the backdrop to the 33 programs that we have ongoing, 12 of which are late stage or filed.
And you will see us continue to invest. We have a balance sheet that's in good shape and we have the wherewithal to continue to invest both And inorganically as well as continuing our return of capital to shareholders through our share repurchase program.
Thank you, Mike. Okay. The next question comes from Cory Kasimov from JPMorgan. And his question is, why isn't genetic testing formed more routinely across ALS patients. And what do you think needs to happen to change that?
That's a really good question, Corey, and I'm going to ask Toby to add his comments. But Having seen ALS patients myself, it's not clear frequently what their parent died from. Even for autosomal dominant highly penetrant mutations like SOD, it's only I think Toby said 60% of the time is there a clear family history. And I think that's because the cause of death is frequently unknown. So and then also, I think the other reason is that there are no good treatments.
Why would anybody want to get diagnosed Long before they have symptoms that they're going to get a deadly disease for which there are no treatments. So I think that The advent of therapies, particularly directed at the genetic subsets, will, I think, increase the Excitement about or and the that patients will undergo genetic testing And the prescribers and the physicians will want to test. Toby?
I'll thank you for that and I certainly agree With that comment, as a former neuromuscular neurologist myself, I highlighted that in discussion today that about 50% of patients with family history get tested for ALS, about 20% of those without a family history get tested for ALS. But we know More broadly, there are many patients within both groups who have genetic forms of the disease. So I think there's a clear need to both We work with physicians to identify and make more aware the genetic forms of the disease. In addition, we think there's clear need to Provide better access to genetic testing, I think and this is sort of one of the reasons we've initiated this program with Invitae, what ALS identified to drive broader access to testing. That being said, I think fundamentally Al makes the correct point that with the potential advent of genetically driven therapies, That really will drive broader use of genetic testing across types of ALS and within all population.
Thank you.
Great. Thank you, Toby. Next question is from Phil Nadeau at Cowen. And his question is, in light of the Stabilization in beta amyloid levels post treatment discontinuation. 1 of Biogen's potential competitors is developing an 18 month Treatment regimen for its beta amyloid antibody.
Would it be reasonable to discontinue aducanumab or lekanumab after 18 months? Does Biogen and or Eisai plan to investigate any finite duration regimens for either molecule?
Yes, I'll start and turn it over to Samantha. But I do think that the data that Lynn Kramer showed today And the lecanumab program are important to consider. What he showed was that although the amyloid plaque levels are relatively stable after stopping treatment during that 17 or 18 month gap period When the patients came back into the open label extension, the amyloid plaque label was level was stable. But the A beta 42 to 40 ratio was rebounding, was the word that Lynn used. And so clearly that indicates that there's some biological change going on in the brain that's not manifest In amyloid plaque burden, but in a blood biomarker of amyloid biology.
So I think that, That is important to consider. And so I think this requires further study. Samantha?
Thanks, Al. So Corey, to your question, are we going to study that? Yes, we are. Almost inadvertently, because we terminated EMERGE and ENGAGE and patients were then taken off of Aduhelm Or aducanumab, and are now coming back into EMERGE. We will have data that shows us how those patients Who were on aducanumab or who were on placebo?
What was their clinical decline during that gap period? And what was Their amyloid status during that period. So inadvertently, we are studying it. And as Al just pointed out, With lakenemab, we already have studied that. The two zero one study did not have an open label Extension study and so patients discontinued after 18 months.
And then Lynn presented today the data when they came back into that So they had an approximately or an average of 2 year gap period. While the amyloid was stable, They did continue to decline clinically. But moreover, the really interesting data is are those plasma biomarkers suggesting that The biology is rebounding. There's another thing to consider that when amyloid is becoming lowered Below those levels that we're talking about, the SUVR of 1.1 or 24 centilloids, That is a measurement of a PET ligand. It doesn't mean 0 amyloid.
There's actually still some amyloid there. And We know from our PRIME study that if you continue to dose with aducanumab for out to 4 years, You get a continued reduction in amyloid plaque. So it remains to be seen. More data will come from multiple programs, and I think this is an important question that yes, we are investigating.
Marta, thank you very much for the clear answer. In the first part of your answer, you mentioned Engage Emerge. You meant probably Embark. The patients are coming back in Embark.
Yes. Thank you, Michelle.
Okay. Thank you, Samantha. Thank you, Michelle. So our next question comes from Brian Abrahams at RBC. His question is about BIB-one hundred and thirty one for stroke.
This is very interesting initial data both on safety and potential activity. Recognizing that the numbers may get small, I'm curious about any signals of dose dependence you may have observed on function in terms of the modified Rankin scale and recanalization and how that may guide future dose selection? And then also, did patients who recanalized tend to do better on modified rank and scale at day 90.
It's great questions, Brian, and I'm going to turn it over to Josh to answer the question about dose.
Yes, Brian, thanks so much. That's a really great question. And in fact, it's the one we're answering right now. So we're actually right in the middle of an exposure analysis to figure out if higher exposure is correlated with a greater likelihood of recanalization. To answer your question, we did have a relationship between recanalization and 90 day MRS.
Of course, these need to be validated in the next phase of the study, But we're extremely encouraged by what we've seen by the preliminary data.
Great. Thank you, Josh. Okay. Our next question is from Paul Matteis at Stifel. He asks, how does Biogen view the positioning of zuranolone As a first or second line agent in depression.
Great question. And I think that I think it could be used in either situation. The CORAL study, as you know, is looking at whether or not Simultaneously starting both zuranolone and an SSRI gives Patients who start both, an additional benefit over those who start just one. So I think that's so That potentially puts it as a first line treatment, perhaps in conjunction with the standard of care. And I should say that we are doing a lot of market research right now, talking to psychiatrists and showing them the data from zuranolone, And we will continue to do that as we gather more data.
But Mona, maybe you'd like to add some comments.
Thank you, Al. I think that you summarized it beautifully. To come back to what Jim talked about earlier in his Presentation. We can say that we've studied ziranolone in a very large variety of patients and It's we have exposure of greater than 3,500 subjects across the total programs. And based on what we've seen thus far, we think it's going to have the versatility to Treat a variety of people with MDD and PPD, regardless of where they are in their treatment journey.
Importantly, I'll come back To what we think is an important differentiator is that this has the potential to offer a rapid onset of action with potential That's something that current existing standard of care antidepressants don't address. And that really does accentuate its ability and potential to address a large Population. And as Al mentioned, in conjunction with antidepressants or on its own. I'll toss it back to Al.
No further comments. Great. Thanks, Mona.
Okay. Thank you both. Next question comes from Nicole Gabreski, who's on Chris Raymond's team at Piper Sandler. Question is there are currently other players in the Alzheimer's Faes who are targeting abeta oligomers versus your approach targeting plaques. Can you discuss the importance of targeting plaques Over oligomers, has your preclinical work supported or refuted that oligomer targeting could provide another mechanism to target the Alzheimer's disease Cascade.
Yes. So that Nicole, those are great questions. And I'll start and then ask Samantha to continue. But So first of all, I would say that I should remind everybody that aducanumab binds to soluble ligomers as well as insoluble fibrils. And lucanumab also binds to soluble oligomers and insoluble fibrils.
And I would also say that the plaque and We believe that there's a halo around the plaque of oligomers. And so targeting 1 targeting the plaque, We believe will also affect oligomers. And also, I think that there are potentially Different kinds of efficacy that one might see from targeting oligomers versus targeting plaques. Some may be more rapid, for example, and have effects on synaptic transmission That separate from other permanent damage to synapses or nerve fibers. Samantha?
Thanks, Al. I'd agree with you that the data we have from the clinical setting suggests that targeting plaques, Reducing plaques is what has been associated with reduction in clinical decline. And there are 3 antibodies that have got both Clinical and amyloid plaque reduction data, so that's aducanumab, lukanumab that we've presented today, but also denanumab. Dananumab, I don't believe, targets soluble oligomers, whereas lekanumab and aducanumab do target those soluble oligomers. And there may be additional toxic biologies associated with the toxic oligomers.
For example, we've got experiments showing That there's a greater stabilization of calcium dysregulation in the presence of aducanumab, and that's an acute effect. So that's something that's mediated more by the soluble species. So it's there is a difference between the antibodies. It'll be interesting to see how those things play out when we are looking at more clinical studies from those molecules.
Thank you, Samantha. Next question is from Jay Olson at Oppenheimer. And he asks, what are your latest thoughts On the regulatory pathway for Tofersen and ALS and also how should results from Tofersen read across to other ALS programs?
Thanks, Jay. Great question. Well, the primary endpoint and the established endpoint is the ALSFRS Decline. And we have favored the use of that in combination with survival, The so called combined assessment of function and survival endpoint, which we actually introduced that concept years ago when we Conducted the Dax pramipexol trial and used that as the primary endpoint. But I think that the regulators are open to other ways of looking at the disease And it'll be interesting to see how this all plays out for the entire field because as you know, there are other drugs Being that are in the process of interacting with regulators and we'll learn from that as well.
In terms of the readout, and I'm going to turn this over to Toby in a minute, but in terms of read through to other programs, Conceptually, very similar mechanism of action. Both C and I and Orf as well as ATAXIN-two, We are targeting sort of the gain of function toxicity. Now in the case of C9orf, it's a little bit more complicated because we don't know if the gain of function is due to Toxic RNA or toxic protein, our drug would theoretically affect both the RNA and the protein, But there are also some indications that you don't want to have complete absence of C9orf activity. And so we've chosen an ASO to preserve sort of, if you will, wild type C9orf gene product Activity. But yes, in terms of conceptually, both are all three of our ASO programs Employ ASOs to lead to RNase mediated degradation of mRNA.
Toby?
Thank you, Al. I certainly agree. I think I'd first start with a comment on the regulators around the world do accept The ALS functional rating scale as an endpoint, classically, what we've seen is approval based on about a 2.5 point difference, for example, with Adderavone at 6 months. Stephanie said, I think I strongly support Al's point of view that the regulators are open to alternate discussions around other potential ways to show benefit for these participation. I would highlight in terms of read through to our ALS programs, I think I would put it in 3 categories.
As you look at a group of programs, SOD1, CNO Orphanotaxo II, I think there's fair data on target engagement and the utility of an RASO to do that. CNS is quite important and with implications across our programs. I'd also highlight that as we look at a large data set, which has included potentially important biomarkers such as neurofilaments, We'll learn a lot of lessons in this context as well. I think in terms of endpoints, target engagement And a notable emergence of new biomarkers such as neurofilament, we'll learn quite a bit from the Towerson program, we'll have substantial implications for follow on. Thank you.
Okay. Thank you, Toby. Our next question comes from Ting Lu at UBS. And the question is, again, on ALS. So on Tofersen and ALS, does the VALOR trial also enroll those patients with an VC less than 50%?
If so, what is the rationale of enrolling these patients who are traditionally considered as a more aggressive type? And then finally, would there be a pre specified subgroup analysis for Valor in fast progressors versus others?
Toby, why don't you take that?
Thank you, Al. So the in terms of We haven't enrolled patients with lower ESO capacities in this study. At this moment, actually, we're not commenting on the more detailed So group analysis, yes.
Okay. Thanks, Toby.
Hey, Mike, maybe we should Mike, we should remind people that the people who did the prerecorded presentations are also available for Q and A.
AR, yes. So we have a few minutes left. If anyone has a question related to those, feel free to put it in. Okay. Our next question comes from Eddie Hickman at Guggenheim.
And his question is, do you plan to enroll a similar patient population for the BIV-eighty studies. And if so, will patients be allowed to be on Aduhelm concurrently? If not, will it be difficult to enroll the proper
Samantha, do you want to take that?
So by the same patients, perhaps You're asking about the stage of disease. And yes, we're looking at very similar stages of disease as we have Studied with aducanumab, so that's Stage 34 or MCI due to Alzheimer's disease and mild Alzheimer's disease, Those patients are at the earliest of symptoms with Alzheimer's disease. And what we're trying to do is really match The stage, the clinical stage with where is the pathology and we know that there is A certain percentage of individuals who are at that stage of disease, who do already have some tau That has started to spread away from the originating areas in Alzheimer's disease patients. And so the question for us is, do we want to suppress tau before it has started to spread Or after it started to spread. So there are multiple questions that one can conduct within that particular clinical trial.
We recently did a study with BIIB092, the Tango study in over 600 patients, Also in Stage 3 and 4 Alzheimer's disease. And in those patients, we had baseline tau PET imaging in every Single one of the patients in that study. And so we actually have a very good understanding of tau pathology in relation to the clinical staging. And there's quite a Correlation, as we know, of tau pathology and clinical symptoms. So that's one of the things that we'll be looking at.
To the question of whether patients will be on background, Aduhelm during the clinical trial, that's one of the questions we're actually investigating. We do believe it is still possible and will still be possible for some time to conduct clinical trials, not necessarily on the background of Aduhelm as a treatment because there is a great deal of interest to find complementary treatments and to assess the efficacy of, For example, these tau modalities. But it is a really important question. And as we are putting together our approach, Cole, these are the types of things that we are discussing, Both internally and with external experts.
Okay. Our next question comes from Geoff Meacham at Bank of America. His question is the clinical program in lupus is somewhat of Shift for the company given it's more removed from its neuroscience base. Can you see the company focusing on more opportunities outside of neurology where the risk is somewhat lower.
Well, let me start and maybe I'll turn it over to Michelle and Natalie. But I would say that BIIB059 and in some ways the anti CD40 ligand, We're very proud of because a lot of that work actually happened here. We had our CD40 ligand program in lupus 20 years ago. And we also the BIIB059, the anti BDC A2 antibody is homegrown. We unraveled much of the biology right here at Biogen and we discovered the drug.
So we're very proud of that. Lupus in many ways Fits many of our characteristics in terms of unmet need as well as the validated drug targets and the drug development feasibility. And so in terms of the strategic question, I'm going to ask Michelle and then maybe Natalie to add.
If I may add, as discussed during the presentation, the bridge To immunology is MS, and we are very proud to have those 2 Phase IIIs and one of them invented in house. I think that we have the opportunity to continue to invest in that space with the prioritization on Specialized immunology, more to come at a later stage. Nathalie, you want to add something?
Thank you, Michel, and thank you all. Yes, I agree. I think it is the 2 assets that have been really like compelling because of what I'll explain you. The bar was really high in immunology. We needed to Genetic evidence, human validation and these two assets did really meet it.
And then in addition, As what Michel said, there is we are really working at the intersection of immunology and neuroimmunology. And If you listen to Chris Anderson and Joe Romana in my group about the progress we've made on the BTK, this is exactly what I mean about That intersection between neuroimmunology and immunology, so we can do it.
Okay. I think we have one final question from Myles Minter at William Blair. And he asks, Toby mentioned that neurofilament light levels are a great predictor of asymptomatic ALS patients converting to disease progression. Do we have a good sense of if neurofilament light levels are a predicting biomarker of functional improvement in response to treatment? Or is it a lagging indicator?
Seems to be mixed data in adjacent indications. Does your assumption change between asymptomatic
patients enrolling in Atlas
and that of symptomatic patients enrolling in Atlas and that of symptomatic patients in VALOR.
I want to turn that over to Toby.
Thank you, Al, and thank you. It's a great question. What I'd highlight first, frankly, is a bit of uncertainty on either end of this. We do know reiterate that neurothermal level rise during a pre symptomatic phase of the disease. So the patients actually don't have any The real point of Atlas is to try treating patients early when they have that sort of elevation of neurofilament beyond a certain level and see if you can actually stall their Conversion to Frank ALS.
So that's trying to get drug to patients as early as possible To keep them as close to normal as possible. That being said, on the symptomatic side of things, what we've seen in the Phase III data with tepersen is a possible lowering Neurofibilent Light, for example, in the serum and then in adjacent indications such as SMA or MS, you've seen reductions in neurofibilament that do have some Relationship with clinical response. I'll highlight within ALS that we yet don't know the relationship of neurofilament reductions And of course, it's there in quite active interest. If we could define and understand that, it could be quite important for the rest
Great. Thank you, Toby. So that concludes our program for today. Hope that you found the presentations helpful and informative, and thank you again for joining us.