Biogen Inc. (BIIB) Earnings Call Transcript & Summary

Good morning, good afternoon, good evening, everybody. Thank you very much for joining us in the first webinar of our series of webinars for 2021. And boy, was the webinar we have was the first one, we have decided this time to tackle one of the most interesting issues in our field and area. We have invited Biogen to present that data on aducanumab. Now I'm going to tell you a little bit more about what we're going to speak about in the second slide and why we called this webinar. So Biogen, as many of you will know, is a multinational biotechnology company based in the U.S., which specializes in therapies for the treatment of neurological diseases. ADI has worked with Biogen for a number of years. They are interested, of course, in the fact that our membership includes the people that would be eventually beneficiary of what they are doing. We will hear from Biogen about the data from the Phase III clinical studies ENGAGE and EMERGE. But let me tell you a bit why we did this. Back in November, Biogen presented aducanumab for approval to the Food and Drug Administration in the U.S. I followed the meeting when this happened. And I was quite surprised by the fact that the committee didn't really seem to analyze in great detail what this aducanumab did. And I felt that if I was confused about this particular piece of result, which I followed very closely, then everybody else in the world would be confused. I was also concerned because of COVID-19, the FDA may be distracted and may not consider how important is the presentation of effectively what's the first possible medication in our area that has come on to the -- could come into the market in decades. So we invited today Dr. Samantha Budd Haeberlein to speak to us. Now Sam and I met the first time in Kyoto in Japan at ADI International Conference 3 years ago. And I -- it was one of the first research that I met Sam, and I was struck by her story and why was she doing these. As many researchers around us, she had a story of Alzheimer's in her family, and she was moved by that to become a researcher and to find a solution. When I heard her story, I thought, my God, with people like this in the background, there is no doubt that one day, with this level of motivation or passion, we will find a solution. And I never thought that, that could be so soon. So 3 years down the line, we can have a possibility. So we need to really make all of our community aware of what is happening, wonder about whether if this is approved. And of course, our 2 experts today, both Sam and Dr. Alireza Atri, who many of you will have heard at our recent conference and who also has been motivated by his personal story to find a solution for Alzheimer's disease. So with Ali and Sam, we'll really explore what it means aducanumab for our community. But also, I want to remind you, we all have a part to play in this. We, as possible beneficiary of this, need to make our nations aware and need to make our communities aware that this may be happening, and there may be some call to action. I will tell you a little bit more about at the end of this webinar, as ever. Now if I could have the next slide, please, Ali. So this is what we are going to have. My introduction is what we are doing. The context from Dr. Atri, who will tell us his experience of this particular medication. Dr. Atri is the Chair of ADI Medical and Scientific Advisory Panel, and then a presentation of data from Dr. Haeberlein from Biogen. Then we'll have a live question-and-answer session and conclusion. So the question and answer will take the last 15 minutes of this meeting. We have had well over 700 people registered. And as I speak to you, the numbers are growing. We already have more than 400 online. So I am going to now talk to you a little bit about ADI's position. But before I do that, can I remind all of you that the slides of this webinar will be available on our YouTube channel as soon as we possibly can do that. Usually, it's within 24 hours. The entire webinar is being recorded and will be available online. Also, please, we invite you to tell us in the chat who you are and where you come from. It's always interesting to see the international composition of our audience. But if you have questions, please put them in the Q&A box, and we will pick them up at the end. So I told you a little bit already about ADI's position. We waited the [ indication's ] optimism for the final FDA findings, which should happen in the next few months. For us, priority must be ensuring that health care systems are prepared, especially tackling the difficult areas of diagnosis. Diagnosis is crucial in order to be able to use this medication, as our speakers will tell you in a moment. And it's also crucial for us to have transparency around taxes and costs. We want governments to be in a position that they adopt this. We will continue to work, of course, with Biogen and other biopharmaceutical company on treatment, breakthroughs on reducing stigma, improving diagnosis, et cetera. This is our commitment, and we will continue to do that. Next slide, please. Before I pass to this slide, I would just want to remind you that ADI is a charity, that everything we do is -- here is free. And we are very happy if people want to make contributions to the organization. So do remember that when dealing with us, everything we do is free, but it does the cost to us. So if you could make a donation, we would much appreciate it. And with that, I give the floor to Dr. Alireza Atri, the Director of the Banner Sun Health Research Institute and with his many, many other hats on. Ali, please tell us about your views on aducanumab. Thank you.

Thank you, Paola. Thank you, ADI, Sam, Samantha Budd Haeberlein. First of all, I'm a cognitive behavioral neurologist. I take care of patients and families with cognitive and behavioral disorders, many of them with Alzheimer's disease. And as Paola mentioned, I've been motivated for many, many years to do better for our patients and families because really, when we think about this, this is a collective problem. It's not going to be solved by just biotech, by pharma, by governments. We have a collective state in this -- stake in this as patients, families, advocates. And the line is very, very thin. All of us will experience this and -- in our lives at some point. And as Paola knows, when I was in graduate school, I took care of my aunt who was like a mother to me. She lived with us. And I was 19 years old. I couldn't take care of her anymore, and my mom was away. And that's when she went into a nursing home. And I was a specialist already in Boston when my dad came down with this. This is from -- and we took care of him at home for 10 years. And so for almost 20 years now, I -- this is all I do. I take care of patients and families. I'm involved with research. And I think the -- and I'll give you full disclosure. I'm a consultant to Biogen. I have seen the data. I've worked on the data to think about it and -- as I am with many, many other companies and organizations. So the aducanumab data is way too important for our field not to understand it properly and put it into context. No matter what happens, we need to bring a collective wisdom to this to understand it better, considering the dire need that we have for more effective treatments. The treatments that we have currently, they are not nothing. They have value and meaningfulness, but we want more effective treatments. And it's been almost, well, 17 years since we had something approved in the U.S. And this idea that we're going to find this magic bullet that suddenly is going to have this huge effect that is going to take a process that has happened that started in the brain, usually 15, 20, 25 years before individuals show symptoms, that we're going to give a drug and within months, we're going to revert things and take symptoms. That -- honestly, even though I have [ cure AD ] behind me, and that's our goal, that is not something that is going to happen over the next few years. It won't happen with aducanumab, and it's not likely to happen with the drugs in that class in the same way. We probably will need multiple approaches at different times and going earlier because what we understand is that by the time individuals in their 70s and 80s, there's a number of brain diseases that act together. And so if aducanumab and drugs like it affect one pathway, do you have this expectation that suddenly things are going to be cured. I think that's a false hope. But it does not mean that it doesn't have value and meaningfulness. And I think that's really, really important. Dr. Budd Haeberlein is going to talk to you about the data. It's complex. It's nuanced because of the clinical trial. When you look at it, don't look at it from the viewpoint, again, of whether this drug is going to take me and put me back to 5 years. No. It's something -- think about the cholesterol story. 50, 60 years ago when there were arguments, many years of arguments between clinicians and scientists, is cholesterol good for you, bad for you? What kind? Should we decrease it? How much? It took years and years. And the first-generation drugs came along, and they did so much. And then now we have other drugs. And our expectation wasn't that you were going to take cholesterol and going to give the drug and you're going to stop atherosclerosis and heart failure. It takes years for that to occur. We understand that. In the same way that with cancer therapies, it's taken us a long time, the field a long time to get to the point where you understand there's many kinds and you have to think, in many ways, long term, not just short term. So I look at it in that viewpoint. I look at it as, can we have incremental benefits for something like aducanumab, which would be the first in its class? It would be the tip of the spear. And no doubt, the -- as -- if -- as drugs like this come along, years from now, we're going to improve and understand how to use it, who do use it, who benefits more. And I think that's really, really important. And to my eye, it's always important to think about safety, not to hurt people. And can we have guardrails? Can we have monitoring for a drug? Do we understand the side effects and the adverse events? And can we allow patients and families to understand this to make their own choices? Because that autonomy is very, very important. Because when we talk about meaningfulness, the patient's and family's voice needs to be heard also. It shouldn't be just statisticians arguing about things. But it really comes from the viewpoint of, could there be guardrails enough? Do we understand the safety to explain to people? Are you willing to take this drug and giving them the choice? I'll let Dr. Haeberlein present, but a few points that I think are not disputable. Of the 2 studies, 302, you'll hear, was a positive study. We can't argue about that. That was a positive study. And now do we need -- how much more do we need? Do we need another positive study? Is this enough to go along with all the things that have happened in the field and other data that's there to weigh the balance? What's acceptable? Those are questions for the field. I think we're going to talk about that for a while. So I'll stop there because we're going to have a fair bit of Q&A after this. So I'll pass it along to Dr. Budd Haeberlein.

Thank you very much, Ali. I'm really sorry, I'm trying to unmute myself. And so, Samantha, the floor is yours. We really need to see now in detail what this data is. And please, throughout the webinar, Sam will speak uninterruptedly. But please do send your Q&A because I'll start putting those together. Somebody just asked online whether Biogen has filed in Japan. They filed with the EMA in Europe and, as far as I know, also in Japan. So Samantha, I think you can confirm that. So yes, the Japan filing has happened. So we are talking already of something that globally is of relevance and interest to us all. Sam, the floor is yours.

Thank you very much, Paola. And thank you, Dr. Atri, for such a great introduction. Paola, I just would like to mention to Annie that I'm trying to share my slides, but it says that that's been disabled. So maybe, Annie, you could share slides from your desktop?

So Annie, I'm sure, has the slight deck. So probably she'd be able to do that. Annie, could you make yourself visible and let us know rather than leave us in suspense at this point? That would be really helpful.

Sorry. Samantha, you should be able to share your slides now.

So thank you. Let's see if you can do that. Thank you, Sam.

All right. Thank you. So I'm sharing slides on my desktop. Can you confirm that you can see them?

We can see them.

Wonderful. Thank you. So good morning, good afternoon and good evening, everybody around the world. I would like to start by thanking Alzheimer's Disease International for inviting us to share a presentation on aducanumab, which is an investigational compound for Alzheimer's disease. So if I put these in slide show, does that work for everybody? Okay, very good. Thank you. We are grateful to be able to present some of our data and to respond to questions from the community, which I look forward to at the end of this presentation. As we just heard and I'll confirm that aducanumab is under regulatory review in the U.S., in the EU and in Japan. We press released that we had submitted for approval in Japan in December of last year. As many of you are aware, and it has been mentioned, that part of the U.S. review is that there was an Advisory Committee at the end of last year and which is hosted by the FDA. As is customary to those sessions, they are open to the public. But we did subsequently learn that due to capacity issues that many people who were interested to listen into the presentations were unable to. So we are very pleased to be able to accept the invitation today to present some of the data from that Advisory Committee. So thank you, Paola, and to your team for that opportunity. This is a slide that I need to share to make the statement that in this presentation, I potentially may be making forward-looking statements and a reminder that aducanumab is an investigational drug. It is currently under regulatory review, and it is not approved in any country for use at this time. Finally, and before I start and present the data from these trials, I really want to thank the countless patients, caregivers and patient advocates who have contributed to the many scientific advancements in Alzheimer's disease research and also to the research conducted on the aducanumab clinical trials by participating in those studies all over the world. Here, you see the countries that participated in our Phase IIIs. It's because of you that I'm able to be here and to share the data from these trials. So deeply and sincerely, thank you for that commitment. A brief note on the FDA Advisory Committee. We do stand behind the analyses and the results of aducanumab that we presented. The core joint briefing book that was part of the materials for that meeting was the first ever such joint briefing book from the neurology division. And it's the totality of data, so the whole data taken together that I'll discuss, that provides the substantial evidence of clinical effectiveness or efficacy of aducanumab, as demonstrated by Study 302, which is also called EMERGE; and supported by the Study 103, which has the name PRIME, some of you may know. Biogen and the FDA concluded that the partially discordant results of the second Phase III Study 301 called ENGAGE did not meaningfully detract from the persuasiveness of the positive Study 302. We have applied the highest scientific rigor and integrity in the analyses that we submitted, and indeed, we collaborated with the FDA on those. But we do recognize that this is a complex data set, and we do recognize the challenges associated with the first-ever positive Phase III study in Alzheimer's disease. Let me start with something that is so important. Alzheimer's disease remains a significant unmet medical need. As Dr. Atri said, there are treatments that are available. These are helpful, but they don't stop or slow or alter the course of the disease. And today, around the world, we are about 50 million people who are living with dementia worldwide. And we know that Alzheimer's is the predominant diagnosis of individuals with dementia. Alzheimer's is a progressive neurological disorder. Now it results in memory loss, but there's also behavioral symptoms, and together, a loss of ability to perform the activities of daily life. And sadly, in advanced stages of dementia, patients become completely dependent. And so this is a disease that affects the individual, affects the families and affects society. And so we must do something for it. If I now go deep into the pathology, the cause of the disease, which is what we need to do when we want to address the disease to bring forward new treatments for any disease. In Alzheimer's disease, there are 2 pathologies. We call them hallmarks or characteristics. Another way of saying it is you always have these. In Alzheimer's disease, there are 2 proteins that form pathologies and that are the cause of what goes wrong in the brain. There's amyloid, which is a peptide, which is generated by brain cells, neurons, and is released from those neurons. And then in Alzheimer's disease, it aggregates from the single unit called monomers into bigger groups called oligomers and fibrils and ultimately deposits in the brain as amyloid beta plaques or plaques for short. These are what we now can visualize, we can see in the brains of patients with Alzheimer's disease by certain brain imaging techniques. Amyloid propagates the dysregulation and the pathology of the second protein I mentioned, which is the dysregulation and aggregation of tau inside of neurons. This then triggers a cascade of brain cell dysfunction, neuro-inflammation and neuronal death, the loss of the functional brain cells. Aducanumab then, in this cascade, binds very specifically to the oligomeric and fibrillar forms of amyloid, including the plaques that we can see. And this leads to the clearance of the plaques, the reduction in downstream pathology and the preservation of neurons. Now this type of approach, in contrast to existing treatments, is expected to reduce the progression and change the course of disease. Aducanumab is not the first such anti-amyloid approach, and Dr. Atri mentioned, there have been a number of approaches. But aducanumab has benefited from the learnings from the very first generation molecules and does differ from them in several important ways. As a molecule, aducanumab is very specific for the toxic forms, the aggregated forms of a beta. And the clinical trials implemented elements that were specifically designed to improve the ability to assess the efficacy of Alzheimer's disease. And as such, importantly, aducanumab was the first of this generation that we have today of anti-Abeta antibodies to demonstrate proof of concept before initiating Phase III. And proof of concept means to impact clinical decline before we started the Phase III studies. And so subsequently, being first, aducanumab then is the only program at this time to have read out with positive results in Phase III trials, which are the final trials before regulatory submission. Here's an overview of the overall aducanumab clinical development program, which are 8 clinical studies over a period of now 9-plus years. Paola mentioned that it seems rather quick that we came with aducanumab since her first learning about the program. But indeed, these programs do take a significant period of time to fully conduct and investigate a new treatment in Alzheimer's disease. These 8 studies then enrolled more than 3,600 patients with Alzheimer's disease. And some patients have been exposed to aducanumab for more than 6.5 years through this program. The first study I mentioned called PRIME or Study 103 was the first efficacy study and the so-called proof-of-concept study. We then have the 2 studies that I'm going to present mostly on today, which are Study 301, Study 302, the Phase III studies that started in 2015. What we have ongoing today is Study 304. 304 is a study where patients from all of these preceding studies, if eligible, can continue to be dosed with aducanumab, and it's where we continue to follow the long-term safety of aducanumab. First then, let's just reflect on the Phase Ib. I'm just going to share one slide of the results from that study. Back in 2014, 7 years ago, when this data first became available, it really was a big deal and very surprising to the community. Aducanumab was really the first molecule that showed the breakthrough of both significant large reduction in those amyloid plaques and an effect on the clinical outcome measures. The study enrolled patients with early Alzheimer's disease, and you're going to hear me refer to that a number of times in the Phase III, and also was one of the first studies to ensure that patients did have pathology, so by doing the PET brain imaging as part of the start of the studies. So here then are some of the results from that study. On the left, these are the brain images. The leftmost are individuals who were on placebo through the 1 year of the trial. And this is measuring levels of that brain pathology, amyloid plaque. And the red is an indication of higher levels of amyloid, and blue is lower levels. On the right-hand side, these are the aducanumab-treated patients, and the dose is 3, 6 and 10 at 1 year. And you can see that there is subsequently decreasing levels of amyloid at the higher doses. And this was, again, a robust reduction in amyloid in that study. Moreover, it was accompanied by a reduction in the clinical measures. Here, I'm showing just 1 of the 2, which is the CDR sum of boxes. And so although this was a small study, at the highest doses, here, 10 milligram per kilogram, this was a significant reduction at 1 year in the progression of the disease in these individuals. And so aducanumab was the first molecule to show this proof of concept. And so then it's the first to have gone into Phase III with this information. So let me turn to the Phase III studies then. And this is a little bit similar to the chart I showed earlier. The 2 Phase III studies were identically designed studies, and they were 18 months in duration, so longer than the Phase I. 3,285 patients were recruited across 20 countries in 348 clinical trial sites. The patients in the study were early Alzheimer's disease, both individuals with MCI due to Alzheimer's disease and also those with mild Alzheimer's disease. There were 2 doses that were assessed for efficacy and safety, and they were randomized 1:1:1 with placebo. There were a number of clinical endpoints. The primary endpoint was the CDR, or Clinical Dementia Rating scale sum of boxes, and there were other clinical endpoints assessing the symptoms in Alzheimer's disease. The target dose, based on that Phase I study, was 10 milligram per kilogram. Now in the Phase I, we did also detect ARIA. ARIA is an imaging finding that is detected on MRI, so structural brain images, and in the Phase I was shown to be -- shown to occur in a dose-dependent manner and to be more frequent in APOE4 gene carriers. ARIA findings on MRI are thought to result from increased cerebrovascular permeability as a consequence of antibody binding to amyloid in the brain. And it's a finding that has been reported for a number of anti-Abeta antibodies. So the consequence for our trials, what we selected to do was prior to the doses at 10 milligram per kilogram, we had a titration. And you can see the steps on this chart of successively increasing doses for the first 6 months of the studies. The second thing we did was also to have a lower dose for APOE4 gene carriers in each of the dosing categories. And these 2 steps were made to reduce the incidence of ARIA in the studies. So in Phase III, here are dosing regimens. The low dose then was either 3 or 6, depending if you were a noncarrier or carrier of APOE4. And in the high dose, the doses were 10 or 6 if you were a carrier -- if a noncarrier or a carrier. And that was at the beginning of the study. Partway through the study, we received more data from Study 103 that showed that it was safe to take both carriers and noncarriers to the top dose of 10 milligram per kilogram. And so partway through the study, we amended the protocol such that all individuals in the high dose would be titrated to 10 milligram per kilogram. APOE4 gene carriers are actually the majority of patients with Alzheimer's disease, about 70% in our trials and other trials. And so changing that dose did have an appreciable effect on the average dose across the high-dose arm, taking -- you see the numbers on the right here from 116 milligrams cumulative dose at the beginning of the study to 153 after we changed that protocol. And that has turned out to be quite important for the difference in results, both from the start of the study to the end of the study, but also between the 2 studies. About 4 years into the study, so we fully recruited the 3,285 patients over a 35-month period. But then in 2019, about a year before the end of the study, the studies were assessed by in what's called a futility analysis, i.e., a prediction to see if the studies would be positive at the end of the study. The analysis used a certain methodology and assessed the first half of the data from the trials. The methodology we used was called conditional power, and that's a probability that the efficacy endpoint would be statistically significant at the final analysis. Unfortunately, 2 key assumptions in this analysis did not hold up. And the futility analysis did not accurately predict the future results. The 2 assumptions are listed here: one was that the identically designed studies would lead to similar study results; and the second one, that the treatment effect would remain consistent over time through the studies. However, at the time of the futility analysis, Study 302 was trending positive, whereas Study 301 was not. And so the identical design did not have similar study results. Given the prediction, though, of the futility analysis, the studies were stopped in March of 2019. And at that time, all of the data was then brought in and analyzed for efficacy and safety of aducanumab. And the remainder of this presentation is on the results that we had from the full data set from Studies 302 and 301. If I start with Study 301 and reflect on what are the clinical endpoints that we measure in Alzheimer's disease. Alzheimer's disease is frequently referred to simply as a disease where memory declines. And certainly, that is one component. But it is multifactoral. There are a number of symptoms that are involved in the loss of cognitive function. Indeed, there are also behavioral symptoms that are impacted. And each also impacts the ability for patients to continue to conduct their normal activities of daily living: Their hobbies, their social interactions, their job, driving and so on. So in Alzheimer's disease clinical trials, we use a number of clinical rating scales, and there were 5 used in the studies that I'm going to talk about. Their names are listed on the right here, the acronyms for each of those, and I'll take you through them a little bit. Each of these are validated and have been widely used in Alzheimer's disease. As I mentioned, they cover the full scope of symptoms that are experienced by patients with Alzheimer's disease. And they're also collected in different ways. So there are a number of paradigms. Some of them are based on expert clinical judgment, so the clinician talking to the patient and talking to the caregiver also provides their own expert judgment. There are also caregiver and patient reports. And then there are direct cognitive performance tests that the patients need to conduct. These 5 scales cover a range of important symptoms. And as shown on this schematic, there's little overlap between what they measure. The primary outcome was the CDR sum of boxes and which is an integrated scale that measures both memory and activities of daily living. So we'll start with that primary score then. And this first graph shows you in Study 302 that the high dose, the green bar, met the primary objective of a difference versus those on placebo of 22% at the end of the study. The low-dose group had an intermediate effect of 15%. Now CDR sum of boxes comprises 6 different domains, 6 domains of measuring both cognition and function in Alzheimer's disease, and those domains are listed on the left here. And their names are pretty self-evident: orientation, community affairs, personal care. And these gray bars represent those domains in the placebo arm. So patients on placebo in this study all continued to decline across all domains measured by the CDR sum of boxes. In the high-dose arm, in the green bars here, we can see that aducanumab treatment had a reduction in decline in each of these elements in the CDR sum of boxes and supporting the overall score I showed on the previous slide. On the other clinical endpoints then, and I'm showing those here, we have MMSE and ADAS-Cog that are covering tests of memory. And we have the ADCS-ADL, which is assessing activities of daily living. Again, each of the green bars, the high dose shows a positive effect of treatment with aducanumab, which has a difference from placebo between 18% to 40%. And the low dose is intermediate on each of these. We also included an additional scale, the neuropsychiatric inventory, which is a scale that measures behavioral symptoms such as anxiety, agitation, aggression and depression. And here, the high dose showed an 87% reduction in the clinical decline on these scores and a 33% reduction at the low dose. This scale also asks the caregiver about their burden on these particular behaviors from patients because we understand that not only are these behavioral symptoms difficult for patients, they are very challenging for their caregiver as well. And caregivers of patients in the high dose reported an 84% less burden compared to caregivers of patients who received placebo on this scale. As with Study 103, we measured that brain pathology using amyloid PET imaging. So this is a graph, whereas previously, I showed you brain images. And with both low dose and high dose by the 18-month time point, we see a dose-dependent and statistically significant reduction in that brain pathology. And at the high dose, this degree of reduction is quite significant, quite robust and very similar to what was seen in the 10 milligram per kilogram dose in Study 103. We also assessed biomarkers of the downstream pathology, the second pathology that I referred to, both tau -- phospho-tau, a marker of dysfunction in Alzheimer's disease, and also total tau levels. Both of these were assessed in the spinal fluid of a subset of patients in Study 302. And you can see again that the green bar and the blue bar show a reduction. And you see the numbers on the left here, the minus versus the group treated with placebo. We also assessed in a small subgroup using a very new imaging tool, the MK6240 tau pathology by brain imaging. And in the 3 plots that you see here, these are 3 regions of the brain where we expect to see tau pathology. And indeed, the gray bar, those are individuals in the placebo arm. And you can see that at the time point assessed at the end of the study that the individuals on placebo, tau pathology had increased in that group. Whereas in the low- and high-dosing arms, there was a reduction in tau pathology, as measured by this new imaging modality. So we had both CSF fluid and brain imaging of tau pathology showing that aducanumab's effects are not just on amyloid, but they do also impact the downstream effects in Alzheimer's disease. At the individual patient level, we were interested to know whether there's a correlation between the reduction in amyloid pathology, represented by the bubble in orange on the left here, and the impact on the clinical outcomes. And these numbers here, for each of these 4 clinical scales that we assessed, all show the appropriate direction. So positive CDR and ADAS, negative MMSE and ADCS, that there is a correlation between the degree of reduction of amyloid and the clinical outcomes. There was a strong association also between the degree of reduction of amyloid and the degree of reduction in those individuals who we also assessed tau in the spinal fluid. That's what that 0.52 number means. And consequently, there is a relationship between the degree of reduction of tau and the clinical outcomes. So in Study 302, as Dr. Atri mentioned, this is a robustly positive study with each of the measures that we assessed, clinical and biomarker, being statistically significant for the high dose and an intermediate effect at the low dose. Turning to Study 301, however, the results were partially discordant. I'm showing the 4 primary and secondary clinical endpoints on this slide, where you can see the green bars do not consistently show an effect and none of these met the statistical significance needed for effect in the high dose. Interestingly, the low dose, the blue bars, are of a level that is intermediate and similar to the low dose in Study 302. And this is why we refer to these as partially discordant. On the biomarkers, we see a very similar picture. In the amyloid PET that I'm showing you here, we do see a dose-dependent reduction in the low dose and the high dose at month 18. And that low dose value is very similar to the low dose in Study 302. But the high dose is smaller. It's, in fact, 16.5% smaller than the level that was achieved in Study 302. Similarly, with the CSF markers, here, I'm showing you phospho-tau. There is an effect at low dose. There is a difference, I would say, numerical difference from placebo, that is similar to that which was observed in Study 302. But at high dose, it is the same as low dose. And so this pattern is somewhat reproduced. And in fact, it's 51% smaller than that which is seen in Study 302. This plot here puts together the results from the 3 studies that I've just referred to: the association between amyloid reduction, which is along the X-axis; and the clinical effect on the Y-axis. The smaller pink dots are from Study 103, and the size of the dots relates to the size of the number of patients in each of those dots. And looking at the doses, the 1, 3, 6 and 10, you can see quite clearly that they fall along the line of a consistent association between the amount of reduction of plaque and the slowing of clinical decline. When you put in the Phase III studies, the bigger studies, you see that the 301 and 302 low doses fall along this line. And the 302 high dose also falls along this line and is very similar to the 10-milligram from the Phase I 103 Study. And it's the 301 high dose that does not follow an otherwise consistent association between the plaque and clinical effect. So in summary, across those 2 Phase III studies then, we have partially discordant results. The results were very similar for the low dose in both clinical and biomarker measures. And the discordant results really come with the 301 high dose, both for clinical and biomarker effects. Here's another way of looking at the 3 studies. In this table, we are including the clinical and amyloid plaque measures that were assessed across all 3 studies. And so this provides a useful summary of those efficacy and biomarker results. In dark green, what we have are the results that have a p-value of less than 0.05. So these are statistically significant and favor aducanumab. And you can see that in Study 103, all 3 measures are dark green. And in Study 302 high dose, all measures are dark green. What we have in the light green, these are results that aren't numerically supporting aducanumab. And you can see that the low dose has a great deal of consistency that are also directionally supportive of aducanumab. So why wasn't the high dose the same? And this, of course, has been a key question and has been the basis of a great deal of investigation that we conducted together with the FDA in the preceding time since we had these results. What we concluded from our investigations in collaboration with the FDA was that the demographics and disease characteristics, meaning the basis of the patients in the study, but also the frequency and severity and management of ARIA that I mentioned were all similar between the 2 studies. That's not what was different. The underlying pharmacology of aducanumab, meaning that for a given exposure in both studies, we saw a given reduction in amyloid plaque and a given clinical outcome. And that was similar in both Studies 301 and 302. What we did determine was different and what was largely driving the difference between the study was that in Study 301, that high dose had a lower exposure to that 10-milligram per kilogram target dose. And there was also an imbalance in a very small number, 5, in fact, of rapidly progressing Alzheimer's disease patients. In fact, when we look in Study 301, and we only look at patients who were randomized to groups who could have the opportunity for dosing at 10-milligram per kilogram. Those patients had results similar to Study 302. And this is one way of looking at that particular data. At the top here is Study 301 and those patients who could get 10-milligram per kilogram and the similar groups in Study 302. And if you average those together, the weighted mean, which is in gray in this particular graph, you have an effect of 23% in Study 301, which is also 23% in Study 302. So on the clinical endpoint, and this is CDR sum of boxes, that if patients did have the opportunity for 10, they did have an effect on CDR sum of boxes. And this helps us understand the difference between the 2 studies. Turning to safety then for these 2 studies. As I mentioned, the overall safety for both Study 301 and 302 was similar. I mentioned earlier ARIA, which stands for amyloid-related imaging abnormalities. And I mentioned that this was detected on MRI, so it refers to radiographic abnormalities observed with aducanumab and with some other anti-Abeta antibodies. And there are 2 types that we report. One is called ARIA-E or ARIA-Edema, which is a swelling or fluid shift in the brain; and ARIA-H or ARIA-Hemorrhage, which includes microhemorrhages or localized superficial cirrhosis in the brain. And as I mentioned, these, we believe, today result from potentially increased cerebrovascular permeability as the antibody binds and removes amyloid. Here are the most common adverse events reported with aducanumab in both of those studies comparing placebo with the high dose arm, the 10-milligram per kilogram arm. As you can see, ARIA-E here is the top of this list as most common adverse events with aducanumab followed by headache. And then we also see in this list ARIA-H brain microhemorrhage and ARIA-H superficial siderosis, which are also those radiographically detected findings. Serious hypersensitivity reactions to aducanumab were rare and had a very low incidence of less than 0.1%. And there were no other treatment-related abnormalities in vital signs or clinical labs or ECGs. Looking a bit more closely at ARIA then because the fact that we detected on MRI, what is the consequence of ARIA? Well, largely, and as shown here, 74% of patients where we detected ARIA have no symptoms associated with ARIA and only approximately 1/3, 26% do report symptoms in association. The most common symptoms that they did report were headache or confusion or dizziness and nausea. And most of those symptoms, as reported by their clinician, were mild or moderate in severity. And equally, on MRI, most of the ARIA-E findings were mild or moderate and transient, with the vast majority resolving within a few months of appearing. Just to come back to the clinical scales that we have used to assess the efficacy in Alzheimer's disease. And I'll just reiterate, there's no one symptom that is readily representative of saying we have an effect in Alzheimer's disease. And it's important to view the totality, all of these results. Over on the left here, we have CDR sum of boxes, where in Study 302 we have that 22% effect. And on pure cognition or cognitive function, we have MMSE and ADAS-Cog with 18% and 27% effect at 18 months. And then on activities of daily living, which are closely associated with independence of patients in Alzheimer's disease. In the context of this trial, there was a 40% effect, which is -- so over an 18-month period, that means somebody could be independent for 7 months of that 18-month period, whereas they wouldn't have in the placebo arm. And on the exploratory endpoint on behavior, a 87% reduction in those symptoms relative to placebo. In summary then, we believe that these 3 studies establish the safety and efficacy of aducanumab. Study 302 is a clearly positive study. It has robust and internally consistent results consistent across all endpoints. Study 103 was an earlier, independent and second study that also provides supportive evidence to Study 302. And Study 301 failed. But we have studied this, and we understand the reasons for the difference between these results. And in post hoc subgroups, we find that there are patients in Study 301 who are supportive of the results in Study 302 and 103. In summary, we conclude that consistent exposure to 10-milligram per kilogram aducanumab is effective at reducing the clinical decline in patients with early symptomatic Alzheimer's disease and has a favorable benefit/risk profile. And I think I'll conclude the presentation with that slide. Thank you very much for the opportunity to present this data again.

Thank you so much, Sam. I think I have never seen our trunk line being so quiet. And that is testament to the fact that, I think, everybody has been transfixed by the clarity and the authoritativeness of your presentation. Your brief was to make something very complex be understood by an audience whose background is very diverse, and I think you have perfectly accomplished that. That is also justified by the level of the questions that we have received. Now we have about 15 minutes for the questions. We may be able to go over about 5 minutes. We'll see how it goes. But I know that our audience will also have other engagement and may drop off. Now I'll ask both you and Ali to answer the question as emphatically as possible so we can take as many as possible. Just so that the audience knows, we ask the participant to prefile some questions and some people did.

And with that in mind, I'm going to start with one of those questions that were prefiled. So I'd like Sam to answer this first and then Ali. Will regular imaging need to take place? And if so, with continued use, is it safe for the clients? Sam first and then Ali, please, concise.

Thank you. We do believe that some imaging will be useful to continue to monitor treatment with aducanumab, hopefully, if approved. And the discussion of just how much imaging will be appropriate is the conversation we are having with regulators. Thank you.

Thanks so much. Ali?

Yes. So again, full disclosure, I actually was an investigator in the trial. And so if you were in the trial, you knew that this was an incredibly well-monitored group, very conservative protocols in place. Many imaging was done. I do believe that it is important to have these guardrails afterwards. That you have to choose the patients appropriately and monitor them appropriately. So afterwards, I think it's going to be very, very important to teach the clinicians how to do this, the radiologist how to look at the scans, who to give the drug to, how to monitor it. And I think the data shows the side effects, the potential side effects were acceptable, but they do need monitoring. And some patients will choose to take it and some people won't. The way I explain ARIA to folks is that, you have this -- you have basically amyloid tau inflammation, et cetera. And amyloid is like this toxic kindling that starts 20, 25 years before in the brain, accumulated. Ultimately, when tau and phospho-tau and the tangles start, that's like a fire that starts in the brain, along with inflammation, which is another fire. And then you have the vascular system, the blood vessels. And as Dr. Budd Haeberlein said, in Alzheimer's disease, the blood vessels are lined with amyloid. They become both stiff and leaky. And what is ARIA? The way I explain ARIA is that these small blood vessels, as they're moving things along, even without having aducanumab, individuals with Alzheimer's disease will leak. So we see these microhemorrhages and things like that. So ARIA is almost like a bruise. So you can see the inflammation a little bit and you can see a little bit of -- just like in your hand when you bruise something, it may become inflamed or you may have a little bit of leakage from the capillaries, right? And this could happen in the brain, but the important fact is that most of ARIA, it doesn't show symptoms. People don't know about it. We catch it on imaging. And when it does occur, it's generally mild and transient and can be reversed. It's important to continue to understand how to manage it. We know how to do it in clinical trials. But it's really important to know that it doesn't change the course. So the individuals who had it versus the ones who didn't, their course was not any different. And there were no catastrophic things that happened during the trial. So in a monitored environment, that's important for people to know and to be transparent that you have a drug that is removing amyloid from the brain, has modest efficacy and may have these side effects. And then you work with patients and families to go along with that. But I do agree that there needs to be monitoring.

Thanks so much, Ali. This answer also the question around ARIA that had been asked in pre element. But Sam, can I ask you to answer one bit of that question that we did not. Some people are asking, is this drug trial looking at removal of amyloid from the brain or an alternative approach? And with that, having looked at the questions coming in, can you please let us know what happens to the plaque? Is it removed for good? Do we need continuous treatment? What happens?

Thank you very much, Paola. So aducanumab binds to those plaques. It attracts to the antibody, microglia, which have been referred to as the gardeners of the brain that clean up all sorts of debris. So the microglia do exactly that. And aducanumab stimulates the microglia to clear the plaques from the brain. Aducanumab does have another role in that it also binds to the soluble oligomers that are floating around as well. And those oligomers are toxic to neurons. So we can see the removal of the plaque. We do believe, based on another antibody's data, that removal of the plaque can be sustained for some time once it has been cleared. But we also have that additional biology that's happening in the oligomers also being continuously bound by aducanumab and removing them. So in summary, Paola, today, we know that we need to continue to treat with aducanumab to remove the plaque. We don't yet have enough information to understand how long to treat for. We know that we start to have those clinical results at 18 months. So this is a chronic treatment. And we do need to continue to learn and try and understand, is there a point at which you've removed the plaque and is treatment different after that point in time? These are things we need to continue to learn.

Thank you so much, Sam. [Operator Instructions] Another question…

Can I add to that? So it kind of goes back to my opening statements about cholesterol again, right? so when the first generation drugs came along, they didn't know how much, how long, how do you lower it. And you can see over 20 years, 30 years, we have improvements in drugs. We have improvements in goals and targets, that the LDL should be lowered to a certain amount, that there are other risk factors and other conditions that can interact with that. And so the idea that you would lower cholesterol, give a drug today, and suddenly the plaque that's built up in your blood vessels, for example, for hardening of the arteries, is going to completely go away, right? That seems preposterous now, right? So we're in the same way. So you don't wait until people have multiple heart attacks and heart failure now to say, oh, I'm going to start reducing cholesterol now. I mean we know that it's better to do it earlier. And these are the kinds of things that we're learning from aducanumab and the drugs like it.

Thanks so much. The element of comparing it to cholesterol is particularly helpful, I think, to all of us that are maybe confused about this particular element. This does make it much clearer. And many of the audience will be familiar with that particular issue. Now can I ask you to answer one of the questions that seem to have a lot of seconders from Dr. Anna Rodrigues in the Q&A from Wake Forest University in the U.S.A. Sam, could you let her know what isoforms of phospho-related tau were measured?

That is a very specific question. I'm trying to remember the answer. Anna, maybe I need to get that one to you offline. So the question is, there are many phosphorylation sites on tau. And actually, there are upwards of 35 sites that can be detected in the test tube. About 20 of these are detected in patients with Alzheimer's disease. And then a handful of them, 3 or 4 of them, assays have been made that are robust enough and validated enough to be able to be applied to these very specific clinical trial settings. So we have used one that is publicly available and validated. I just don't want to make a mistake exactly which one it is, Anna. But you'll recognize it, and I'll get that information to you.

Thank you very much. Many people are asking me when the presentation will be available online. It will be on YouTube immediately after this. Now there is a question from Diane Blackwell. When ARIA was identified, was the drug discontinued or not during the period where most resolved or was it due to the drug being discontinued? Yes.

Thank you for the question. ARIA was originally identified in 2006 or '07 with another antibody to Abeta. So this is a phenomena that we have learned about for many years prior to these trials. So when we started these trials, we put in place different ways of managing ARIA. In the beginning, as Dr. Atri was mentioning, we were very conservative in regards to if somebody experienced ARIA in the Phase I, we would stop dosing with aducanumab until that ARIA finding had resolved on MRI or no symptoms were present. We gradually learned more that we could, in fact, continue to dose patients with small ARIA, and those ARIA would still naturally resolve even while on treatment. So ultimately, by the end of the study, we had learned to be able to manage patients who had experienced ARIA and changed the rules in regards to whether patients could continue treatment or, in some cases, we still decided to suspend treatment and then to resume treatment after the ARIA had resolved. I hope that answered your question.

Thank you so much, Sam. You tried your best. Some of the questions are very specific. Now there is a number of questions that go back to one of the question that we had at the beginning. If the FDA approved, plus due to the cost, are we in danger of poorer countries and people being left behind? Now let me answer this one. Yes, we are, obviously. In so many constituency, it will be years before any possible benefit will be seen. And one of the people asking questions is one of our Board member from India who is asking rightly, have you got any intention doing clinical trials in India? I think that a lot of other people in this call are wondering whether there'll be any clinical trials that include my country. And the fact is, however, that this potential therapeutic treatment has not been approved anywhere. So to the person asking, where can he find it in his pharmacy, well, you can't. And also the administration of this may be a little bit more complex and also act and source that may be complexity also in the diagnosis of that would be necessary in order to be able even to administer this. Many of members of ADI live in countries where not only PET imaging or CSF may not be available, especially if doctors may not be available. There may be no neurologists, no dietitians, no psychiatrists. So for all of you listening, remember, in order to even be enabled to take advantage of something like that, a certain groundwork needs to be in place. And this is why we are having this webinar. We are making you all aware that this one may be around the corner, but it will not be around the corner for everyone. Also, please be aware that this costly, obviously, possibilities will come to clash with what is currently happening with COVID-19 and the general financial crisis that will follow. And so we at ADI have been advocating now for 1 year for increasing the level of alertness globally, that our movement may be having a moment of rest, even at the same time, some therapeutics may come on the market. And this is very dangerous because it means that we may not progress the way that we should be progressing. So this is also to make you all aware that your governments need alerting to the fact that certain basics need to be in place in order for everybody to take advantage of the fantastic work that companies like Biogen but not just Biogen, are doing at this moment, although Biogen is, by far, the most advanced in that respect. So…

Paola, I have an answer on the…

Yes.

I have an answer to Anna Rodrigues in regards to the phospho-tau that was requested. So phospho-tau 181 was the epitope in that CSF assay.

Perfect. Thank you very much. So that's fully answered. Ali, do you want to say something else about availability in lower-income countries.

Me?

Yes. Is there anything else you wanted to add? No. Okay. No problem.

Yes. We have a lot of question.

No problem at all. So let's talk about, some of the questions are about the FDA approval. When is the Biogen, Sam, expecting to hear from the FDA or for that matter from the other agencies that you have filed with?

Thank you. So each agency has specific time lines in relation to their own processes and procedures. In regards to the FDA, we have something which is called a PDUFA date. And so they are to provide us with a decision on or before the date, which is the 7th of March of 2021.

Thank you so much. And following that, how will Biogen handle aducanumab supply/demand? Are there multiple manufacturing sites?

Yes. Biogen will be ready to be able to bring aducanumab to patients through their own manufacturing, which involve more than one manufacturing site globally. Yes.

Thank you. A question from Justin Schneider. CDR depends on clinician assessment. Can you confirm that the raters were blind to study allocation?

Each site only ran one study. And the raters for each study, so each patient, required 3 raters. You had somebody who was involved in the treatment and care and ARIA management of a patient. And then CDR sum of boxes was applied by an independent rater who did not rate any of the other scales and was blinded from the safety and ARIA outcomes of the patient. So not only was the CDR rater blinded, we then had a separate rater for the secondaries who applied those secondary measurements, and they were also blinded from the treatment and management of the patients.

Thank you very much, Sam. Another couple of questions whilst we have another few minutes left. Do you have any hypothesis for why the effect on MMSE was relatively small and by extension, where the cognitive effect sizes could be improved?

So MMSE is, I would say, of those scales we used, a quite blunt scale. 30 questions and to not be able to answer a question is a really significant question, like what is the day of the week? Where are we? So to really start to decline on MMSE, you have to have a fairly big shift. Our patient population had -- when they entered the study, an average of an MMSE of 26. And that's patients between 24 and 30. 30 is maximum score, fully functioning. So if you think about it, they have to move quite far to decline. But also, there's only one direction. If you're a 30 when you start the study, you can't go to 31. You cannot improve from 30. You can only get worse. So the scale prevents you from being able to measure improvements, but it's also a quite course scale. Given the mechanism of action of aducanumab, we believe, generally, that this is slowing the progression of disease rather than improving symptoms. That is a general mechanism of action.

And there is a question that I am putting together from various questions. Were the patients representative on the clinical trials of various diverse groups and were various ages represented as well?

So the age group, we included patients from between, the ages between 50 to 85. So we enabled patients across a broad range of ages to be in the study. The average age in the studies was around 70 on average. In terms of demographic representation, our trial, as with many other trials, was predominantly White and Caucasian in its representation. We do have other groups represented but not at the level of the epidemiology and not at the level that we wanted to achieve, and that's an area that we continue to work on in our clinical trials broadly and Alzheimer's in specific.

Thank you very much. The final question for you, Sam, you've been under fire. And then I will pass it over to Ali, who has noted some interesting questions he would like to address in the box. The one for you is, how is aducanumab administered? I realize quite a lot of attendees don't know.

Thank you. This is an IV, so intravenous solution, which is applied over the period of an hour or so. So like with many biologics, a patient would be seated, would have an IV and would relax while the drug was administered over that time period. And that occurs on a once-a-month basis.

Thank you so much, Sam. I think I'll let you go now because there are too many questions to answer. Can I say to everybody that we will try to answer further questions on our YouTube channel so that you will all get an answer. Now Ali, you have spotted quite some few interesting points. Would you like to bring them to us before we conclude?

Sure. I think what I'll do is I'm going to make some statements here that takes some of the questions and sort of puts them together. There are a number of questions about measures and effects. So I think the thing to understand again is that by the rules established before from these 2 studies, there were Phase III, 302 met the endpoints. It was completely positive and that's full stop. And the other questions that come up about the efficacy measures. Was CDR the right one? In this condition, as Dr. Budd Haeberlein mentioned, we measure different things: cognition, aspects of cognition, memory, language, et cetera. That can be done by ADAS-Cog, in a blunt way by MMSE. We look at daily function. We look at behavior. And the important thing about this was that the efficacy outcomes were all convergent. So it's not like one of them just showed something and then that was a blip. They were all going in the same direction, whether it was 20% or 40% or 87%, in the case of behavior. And if you think about percent, over the course of 1.5 years, so if 40% gives you 7 more months of function in that time, if you think about relatively early on, and these benefits continue and you have maybe 10 years of life, could that give you -- sustain your function for many more years? We don't know that, but there's no reason to think that may not happen. So that's one of the things I think that's important to understand. There's no disagreement that there was a clear effect on the target that it removed amyloid from the brain. There was also a link between removing the amyloid and affecting tau, these tangles, the fire in the brain. And again, there was a link between that and the clinical outcomes. This is the first drug that showed that. But as you know, this week, another drug in the class, donanemab, showed that. And they looked at a composite of cognition and function, and they showed about 30%, 32% decrease over 76 weeks. And there are some other drugs in this class that have shown similar types of data. The other part that's important that was in the briefing is that in that first study, over a number of years when they took individuals and they started them earlier versus later, the individuals who started later benefited, but they didn't catch up. I think that's really, again, when you put the totality of this together, is important. And then the question about functional unblinding, it's totally true. I was an investigator. I had nothing to do with the ratings. So we had a rater for the CDR and we had a tester for the other things. They were completely separate. And no matter what you say or do, your biomarkers, your amyloid levels, they don't care whether you know or don't know. Those changed. How you perform on these tests of cognition, they changed, even though the CDR and function, et cetera, they're a bit more subjective. So some of the more objective things absolutely changed, and they slowed down. And then I guess, ultimately, when it comes down to it, I think about autonomy and meaningfulness of value for patients and families, that we have to be transparent with them that this is not a cure. This is something that's modest, that can be managed. And people are going to choose one way or the other. But are we going to be an absolute purist and say, we only need -- we have to have 2 studies that go perfectly and have -- or are we going to look at the totality of evidence and decide that a first-in-line drug could be brought to market and we can learn from it as a first-generation drug. So I'll leave it with that, but I'm really, really happy that you were able to present this data to other folks. And we have many years of learning to come from this drug and this class. So the most important thing I'd say is hope. Don't give up hope because companies are working on it. We're working on it. ADI, Alzheimer's Association, all around the world, we're working on it, and we will do it together bit by bit. We may not have a magic bullet, but we are making advances.

Thank you so much, Ali. Yes, this is the most important call to action. So this is our final slide. The most important call to action is don't give up hope because there are people like Ali and Sam working and being incredibly committed to make this happen. So I just want to focus your mind. There are still hundreds and hundreds of you, even if we have been way beyond our advertised time. So what next? The analysis and the discussion around the approval of new Alzheimer's treatments, including aducanumab, should not be delayed due to COVID-19. Make sure that your MP, government, social media knows about this. Make sure that you raise awareness. The approval of a new Alzheimer's therapy right now is too important to ignore. I know we got big issues, but we must make sure that we still do this. And please, if you are enrolled in a clinical trial, please continue attending your clinic to receive treatment. Don't drop out. Please continue because it's only with you committing to this, as Sam said at the beginning of our presentation, that we have come to this result. So this is so important, and we need to keep hope. My next slide, Annie please, is just to remind you that we are a charity. So please, if you can make a donation, do. But most importantly, follow us, also follow us on our social media, continue to spread the message and please, please, do attend our next webinar. We haven't announced it yet, but it's going to be just as engaging with that, if not more. And more will be revealed soon. Follow our e-mail and social to know more. Thank you so much for being with us today. Thank you. Thank you, Sam. Thank you, Ali. Thanks to the wonderful ADI team that makes these webinars possible at all time. Thank you so much, everyone. Bye-bye.

Bye. Cheers.

Thank you. Bye-bye.