Allow me to welcome everyone to this very important presentation by our colleagues from Biogen. This is John Dwyer, president of the Global Alzheimer's Platform Foundation. This was initially intended as a discussion of the science and clinical aspects of Biogen's drug, aducanumab. We've broadened it to the public, which I think is terrific. Let me just say a word about who GAP is for those of you on this call that don't know us. The Global Alzheimer's Platform Foundation's mission is to reduce the duration and cost and improve the quality of Alzheimer's disease clinical therapeutic studies. Not a trivial mission, to say the least. Over the last six years, we have combined with our network of over 80 truly leading clinical trial sites in North America to try and accelerate and improve clinical trials for a variety of different Alzheimer's therapies. We're proud to say one of those was Biogen's. It is with that background that we have in our audience all of our sites, I hope, their PIs and staff who have worked so hard to bring aducanumab to the place where it is and other very important therapies to meet our singular goal of trying to accelerate a therapy for this scourge known as Alzheimer's. With that in mind, let me just mention the foundation's conflicts, such as they are. We have been the proud recipient of grants over the last six years from Biogen, as well as having worked with them on a clinical trial in a fee-for-service capacity. The only other conflict worth mentioning is that both my chairman, George Vradenburg, and myself have testified before the FDA in support of the Biogen application, recognizing that there is no disease-modifying therapy for either mild cognitive impairment or mild AD. Just a word about this particular endeavor. We are so keen to have Biogen particularly, as represented by Samantha, to take on the opportunity to really tell us what Biogen sees as their data, as their clinical benefit to patients, and say the things in a clear, unbroken way that might not have been available to us during the ad com. The passage of time has also allowed them to learn a bit more, I suspect. There will be questions. We asked our PIs and colleagues to provide questions. Those questions have been provided to Samantha in advance. That is to reflect the unique regulatory circumstances we operate in, and it was the only prudent thing to do. I will be asking a set of questions that came from our PIs, and she will answer them. With that, and without further ado, let me introduce Samantha Budd Haeberlein, a woman who has been living with this particular application for quite some time, the Head of the Neurological Disease Group at Biogen. Samantha, thank you very much for coming. I look forward to your remarks. Thank you very much, John, for your very kind introduction. Thank you to John and Cindy and the GAP Foundation for inviting us to present our data today. As you mentioned, there are a number of questions. There were many questions submitted from the GAP organization. Thank you, everyone. It really showed a great deal of interest in this work, and I look forward to answering as many of those as possible. We've got a lot lined up to answer at the end of the presentation. Let me share my screen and see if I succeed in that. Can you now see the presentation? Yes. Wonderful. You can still see it? Yes. Okay, very good. Thank you. Without further ado, I'll jump in. This slide is a necessary slide just to ensure it's clear that I may be making forward-looking statements through this presentation. As a reminder, let me just minimize that. As a reminder, aducanumab is an investigational drug, and it is currently under regulatory review here in the U.S., but also in the EU and in Japan, and it's not approved for use in any country at this time. Just want to start by outlining the main data that I'll be speaking to today comes from the phase III trials that recruited 3,285 patients at 348 sites in 20 countries. As John just mentioned, a number of those sites in the United States are part of the Global Alzheimer's Platform. Really it is because of the patients. Their families, the patient advocacy such as GAP, and the clinical trial sites. Because of their efforts that we're able to actually report this data. I'd like to start by thanking everybody for their commitment and for advancing the research in Alzheimer's disease. As John mentioned, there was an advisory committee. As part of the FDA review of aducanumab last year, there was an FDA advisory committee, and this is held or hosted by the FDA. I just want to really make sure it's clear that we do stand behind the analyses and the results of aducanumab that were presented at that advisory committee, and I will be presenting many of those here. It was an unusual advisory committee. There was a core joint briefing book that was the first ever joint briefing book issued by the neurology division from the FDA. The way to look at the data that we have submitted for regulatory approval is that it's the totality of data that provides substantial evidence of clinical effectiveness of aducanumab. This is demonstrated by Study 302, study also called EMERGE, and is supported by Study 103, which is also referred to as PRIME. Biogen and the FDA did conclude jointly that the partially discordant results from Study 301, or ENGAGE, do not meaningfully detract from the persuasiveness of Study 302. We have applied the highest scientific rigor and integrity in the analyses that we've submitted. Many of the analyses to understand the differences between the studies was conducted in collaboration with the FDA. We do, however, recognize the complexity of this data set and the challenges associated with the first positive Phase III study in Alzheimer's disease. This audience really almost doesn't need this slide, but for me, it's always important to realize and recognize what we're up against. Alzheimer's disease is a significant unmet medical need, not only to the patients, but to their families and society as a whole. As of 2018, we know the numbers. There are about 50 million people living with dementia, with Alzheimer's as the predominant diagnosis among those individuals. Alzheimer's is a progressive neurological disorder, results in memory loss, but also behavioral symptoms and a loss of ability to perform daily activities. In advanced stages, that actually means that these patients become completely dependent on care from families or from society. Alzheimer's disease is ultimately fatal. There's no treatment today that alters the course of the disease. That's where we have been putting our efforts for quite some time. In order to bring forward new treatments that address the underlying pathology of disease, you have to understand the disease. What we know about Alzheimer's is that there are two main pathological hallmarks. One is amyloid or beta-amyloid, which is a peptide formed inside of neurons, which is then released from neurons. In Alzheimer's disease, there's an imbalance in the production and clearance of this peptide Aβ, such that it is then able to aggregate from the small monomers into oligomers, fibrils, and then into amyloid beta plaques. These are the clumps of beta-amyloid that we can visualize in the brains of Alzheimer's patients using amyloid PET imaging. Amyloid beta is responsible for initiating the dysfunction of the second pathology, the hyperphosphorylation and aggregation of tau protein, which is found inside of neurons. Together, the tau fibrils, tangles, and amyloid beta plaques lead to synaptic dysfunction, inflammation, and neuronal death. There is a great deal of extracellular activity with microglia, dying neurons, which is also occurring at the same time. aducanumab, as a mechanism of action, targets directly the pathology by binding to oligomers, fibrils, and the amyloid plaques that are deposited in the brains of individuals with Alzheimer's disease. Thereby reduces the progression of Alzheimer's disease and is different from treating the symptoms of Alzheimer's disease and is aimed to stop or slow the progression of the disease, so-called disease modification. aducanumab is not the only, not even the first such approach to remove and reduce the degree of amyloid in the brain in Alzheimer's disease, but it is different from those that have gone before. It benefited from a great deal of learning from the first generation of anti-amyloid approaches. For example, at the molecular level, Aducanumab specifically binds to the neurotoxic aggregated forms of Aβ and retains effector function, which actually enables the microglial-mediated clearance of the aggregated Aβ. In the clinical trials, there were a number of elements that were implemented and that you're well familiar with that are now considered important to enable the ability to see the efficacy of an approach such as Aducanumab. For example, ensuring patients did have biomarker-confirmed Alzheimer's disease. Enrolling patients much earlier in their disease progression. Aducanumab was the first of the current generation of antibodies to demonstrate proof of concept before initiating the phase III trials, and I'll recap on what that is from the PRIME study. Accordingly, it's therefore, having completed the phase III, is the only program at this time to have read out with a positive result in the phase III trials. We know there are other programs that are now also showing reduction in amyloid and association with reduced clinical decline. Aducanumab is now among others that have shown this effect. Here's an overview of the clinical development program, and for this audience, you can very much appreciate the long timeframes of a clinical development program. A big deal of this is how we are able to recruit and enroll patients into these clinical trials. Starting in 2011 and then with the phase III trials having read out in 2019, having read out early in fact. There were eight clinical trials, and the first efficacy trial was Study 103 or the PRIME study, and then the bulk of this presentation will be on Study 301 and 302, which were initiated in 2015. Happening today is Study 304, and this is a redosing study. All patients who were previously in an aducanumab clinical trial, those who are eligible are able to come back to Study 304, which is an open label extension study where all patients it is possible to receive aducanumab. There's no placebo arm in that study. Just to recap then on the phase I-B study or Study 103. At the time this data read out, which was 2014, it was really quite remarkable data. On the left here, I'm showing the brain imaging, the amyloid PET imaging results from that study where patients who were treated with aducanumab, and you can see here the doses on the right, three, six, or 10 milligram per kilogram. You saw a dose dependent and statistically significant reduction in amyloid plaque at the one-year time point. This was quite a robust reduction in amyloid compared to programs that had previously attempted this approach. What was also remarkable was that even in this small study, there was also an effect on the two clinical endpoints. I'm showing here the CDR sum of boxes, and here you can also see the dose dependency of the reduction in clinical progression on CDR sum of boxes at one year. You can see in the high dose, 10 mg per kilogram and titration to 10 mg per kilogram, this was statistically significant even in this small study. The clinical endpoints were exploratory. I would say somewhat unexpected given that the study was designed to be able to test the effect on the reduction of amyloid plaque in the phase I-B. With these strong but surprising results, we were able to design the phase IIIs, which I'll spend the rest of this presentation on. Moving into the phase III studies then. I'll build this slide out. The phase IIIs were two identically designed studies. They were 18 months in duration. They were randomized, double-blind, and placebo-controlled. As I mentioned, they recruited 3,285 patients. The patients were early Alzheimer's disease, which was the same population or similar to that in the phase I-B, including patients with MCI due to Alzheimer's disease and mild Alzheimer's disease, and with an MMSE range of between 24-30. Two doses were tested in this study, the primary endpoint was CDR-SB change from baseline at 18 months. There were other clinical endpoints, including the secondaries MMSE, ADAS-Cog 13, and ADCS-ADL-MCI. We had sub-studies for a number of key biomarkers, I'll share the results from those as well. The phase III study was 18 months in duration, which was longer than the phase I. The phase I was 12 months in duration. One of the reasons for that longer duration was because we made changes to the dosing regimen in phase III to mitigate for the incidence of amyloid-related imaging abnormalities or ARIA. ARIA was detected in the phase I study and as I mentioned, it is an imaging abnormality, so it is found on MRI. It's believed to be due to an increased permeability in the cerebral vasculature due to antibodies binding to amyloid and removing it. It's found with aducanumab and with some other anti-Aβ antibodies. We made two changes to the dosing regimen to mitigate for ARIA. One was a 24-week titration to reduce the instance of ARIA, and you can see on this schema, the steps through doses one, three, and six before reaching the target dose of 10 mg/kg. Then in the study, the target dose was 14 doses of 10 milligram per kilogram. We also had a second impact from ARIA in that we had differential dosing by APOE4 carrier status. This is because ARIA is found to be both dose-dependent but also has a greater incidence in APOE4 carriers. On this next slide then, these are the two dosing regimens that we had in phase III. The top two lines represent the low dose group, which was 3 milligram per kilogram for APOE4 carriers and 6 milligram per kilogram for APOE4 non-carriers. In the high dosing regimen, the two joint lines at the bottom here, at the beginning of the study, APOE4 non-carriers were titrated to 10 milligram per kilogram, but APOE4 carriers were titrated only to 6 milligram per kilogram. Partway through the recruitment for these studies, we received data from the 103 study that showed that it was safe to titrate patients' APOE4 carriers also to the 10 milligram per kilogram dose. Partway through, we amended the protocols such that for the high dose regimen, both APOE4 carriers and non-carriers could be titrated to 10 milligram per kilogram. APOE4 carriers are, in fact, the majority of the population. Two-thirds of patients with Alzheimer's disease are APOE4 carriers, and so this had an appreciable effect on the dose in the high dose arm. At the beginning of the study, so before protocol version four, as you see the acronym here, pre PV4, the average dose was 116 milligram per kilogram, whereas in patients recruited after protocol version four, the median cumulative dose was 153 milligram per kilogram. You can see that had a significant impact on the dose. This actually turns out to be quite important for differences that we saw in the results between the two studies. I mentioned that the study started in 2015. It, in fact, took 35 months to recruit the full patients in both studies. In 2019, so well into the study and about a year before the end of the studies, we terminated the two trials following a futility analysis. That futility analysis was later determined to be inaccurate, and let me just describe that a little bit. The futility analysis is a prediction, and it used a methodology called conditional power, and that's the probability that the primary efficacy endpoint analysis, what would occur in the future, would be statistically significant at final analysis. Using this calculation on approximately half of the study data, the futility analysis predicted that the studies would not be positive at the end of the trials. However, when we brought in the full data after the futility analysis, we learned that two key assumptions in the prediction did not hold, the futility analysis did not accurately predict those future results. Those assumptions were, one, that identically designed studies would lead to similar results. Therefore, the methodology that was used, pooled conditional power, is appropriate. That turned out to be incorrect because we had different results for the two studies. The second assumption, that a treatment effect would remain consistent over time, while with the protocol changes and the dosing changes, that also turned out not to hold. At the time we conducted the futility analysis in March of 2019, the results did already indicate that Study 302 was trending positive, whereas Study 301 was not. However, the upshot of this is, given the futility prediction, we terminated the trials in March of 2019. As the studies were almost complete, we then brought in the remainder of the data, and we conducted the analyses according to the pre-specified statistical analysis plan. It's with that larger data set that we determined that, one, the futility analysis was incorrect, and two, that we actually had efficacy in Study 302. The remainder of this presentation is based on the larger data set. First, just to reflect on the clinical endpoints that are used in these trials. It's very simple and straightforward to say that Alzheimer's is characterized by a loss of memory. There are a number of important and distinct symptoms that characterize Alzheimer's disease. We, as do others, used multiple clinical rating scales in the phase III trials. The scales that we use are listed on the right here, and these are validated and widely used in the early Alzheimer's disease population that we recruited. They do cover the full scope of symptoms experienced by patients with Alzheimer's disease. In addition to the different symptoms, they include a range of paradigms, including the clinical judgment-based assessment of patients and caregiver input, also patient and caregiver direct reporting and cognitive performance tests, the one thing that people think of most frequently in regards to Alzheimer's disease. These capture a range of paradigms and a range of symptoms. The scales are also quite distinct in the dimensions that they measure, and there's quite minimal overlap between them. It's between only 5%-25% overlap in questions or items in one scale that is measuring something similar in another scale. Let's start with Study 302 then. Here is the primary objective of CDR Sum of Boxes at week 78. In the green bar, the high dose shows a 22% reduction compared with placebo, and this is statistically significant. In the low dose, we see a 15% reduction. This is not statistically significant, but is numerically in the direction of aducanumab. CDR Sum of Boxes as an endpoint actually has 6 domains. Three each are covering aspects of cognition and function, those domains are listed on the left here, orientation, community affairs, home and hobbies, judgment and problem-solving, memory, and personal care. The gray bars that I'm showing here are the individuals in the placebo arm of Study 302, and you can see that on each of the domains in the CDR Sum of Boxes, there is progression from baseline to week 78. For patients in the high-dose arm, the green bars here, you can see that there is a reduction in progression at each and every one of the domains measured by the CDR Sum of Boxes, and so therefore supporting that the overall result is not driven by any one domain in this particular scale. As I mentioned, other endpoints were measured. Here are the secondaries in the rank order of MMSE, ADAS-Cog, and the ADCS-ADL, where the high dose is statistically significant and has reductions between 18%-40% compared to placebo. In the low dose, we also see more clearly for ADAS-Cog and ADCS, an intermediate effect also for aducanumab, although these are not statistically significant. Among the tertiary endpoints, we had one additional clinical efficacy endpoint, was the Neuropsychiatric Inventory version 10, which assesses behaviors such as aggression, agitation, anxiety. In this endpoint, we also see in Study 302 a statistically significant effect, an 87% difference versus placebo in the high dose, and again, an effect but not statistically significant in the low dose in this particular endpoint. The NPI also captures caregiver input on their distress. There's a separate score that is conducted in regards to how the caregiver feels about these types of symptoms. The caregivers of patients who received high dose reported an 84% less burden compared to the caregivers of patients who received placebo, which is a very important data point as we do understand that these symptoms in particular are not just important to patients, but they are some of the most distressing for the families and caregivers. As in Study 103, we did also assess the reduction in amyloid plaque pathology. Here, instead of showing pictures of the brain, this is a quantification, looking at SUVR. You can see that there is a dose and time-dependent reduction, which is statistically significant. The absolute value of 0.278 in the high dose at week 78 is very similar to what was seen with 14 doses of 10 milligram per kilogram in the phase I study. A robust reduction in amyloid pathology. In this study, we had sub-studies assessing disease-specific tau pathophysiology and neurodegeneration biomarkers. On the left is CSF phospho-tau. While this is a small subgroup, we had not very large uptake of CSF in the subgroups. We nonetheless see a dose-dependent and statistically significant reduction compared with placebo in phospho-tau. Over on the right, we see a similar pattern with the biomarker of total tau. We did also implement towards the end of the study across both studies, a small tau PET imaging substudy to assess using a novel tau PET ligand, MK-6240, the effect of aducanumab on the reduction of tau pathophysiology directly using imaging. Here I'm showing three different composite regions of the brain in which one would expect tau deposition to occur in this patient population, and indeed to be increasing over the period of this clinical trial. The gray boxes are the placebo arm, so the individuals in the placebo arm. You can see by the increase from baseline in each of these composite regions that that's indeed occurring in the patients who do not have aducanumab. There is an increase in tau neurofibrillary tangles. Whereas in the low and high dose, we see a reduction compared to placebo in each of these regions. With both CSF and imaging biomarkers, which are independent methodologies, we can see that aducanumab is not only affecting amyloid pathology, but it's also having an impact on the downstream pathophysiology. We were interested to understand at the individual patient level, whether there is a correlation between the reduction in amyloid and the consequent impact to the clinical outcomes. That's shown in this schematic here, the orange representing the reduction in amyloid. On the four primary and secondary endpoints that we assessed, we can see a statistically significant correlation with the clinical outcomes at the individual level. There's also a strong correlation between the reduction in amyloid and the reduction in phospho-tau as measured in the CSF. That's what the 0.52 stands for here. There is also a relationship between the reduction in phospho-tau and the clinical outcomes on the four clinical outcomes measured, and you can see that two of those even achieve statistical significance, as shown on the right here. Moving to Study 301, we have a different picture with partially discordant results. Here in this slide, similar to one I showed before, is the primary endpoint and the secondary endpoints for Study 301. The green bar again is the high dose and directly you see on CDR-SB with the 2% in the wrong direction. Study 301 is a negative study. We have some reduction in ADAS-Cog and ADCS-ADL, but none of these changes reach the level of a p-value of less than 0.05. Interestingly, the low dose, the blue bars, has an intermediate effect. This intermediate effect, which is all in the direction of aducanumab, is very similar to the magnitude that we also saw with the low dose in Study 302, and which is the reason that we refer to these results as partially discordant. This picture is also repeated in the biomarkers. For example, on the left here is the amyloid plaque reduction in Study 301. It looks very similar. You see the time and dose dependency. You even see statistical significance. In fact, the high dose is at 0.235, 16.5% smaller than in the high dose of Study 302, whereas the low dose is very similar to that in Study 302. What we learned later is that, and here in this PET subgroup, the cumulative dose in this group is 10.4% smaller than that in Study 302. We see a similar effect in the CSF biomarkers, and I'm just showing one of them here in that we do have a reduction compared with placebo. None of these reach statistical significance or a p-value of less than 0.5. The low dose is again numerically very similar to the low dose in Study 302, and the high dose is not. It's in fact very similar to the low dose. We have this blunted effect occurring in the high dose in the biomarkers. Here in the CSF subgroup, the treatment effect is only 51% in Study 301 high dose. One way to try and put the three studies together and try and understand the relationship between the reduction in amyloid and the clinical effect is to plot, as we've done here, the amyloid PET SUVR on the x-axis and then the treatment effect on CDR Sum of Boxes on the y-axis. The pink dots, these are the dosing arms from the PRIME Study 103, one, three, six and 10. Then you also have the titration group, which has an average dose of 5.3. You can see how they're small dots. They relate to the size of the population, but nonetheless are quite clearly falling along a line of association between amyloid plaque reduction and reduction in clinical decline. Adding in the doses low and high from both of the phase III, we see that the 301 and 302 low doses fall into a very similar place in terms of degree of reduction of amyloid plaque, and they fall between the three and six milligrams from the phase I-B, as one might expect. The Study 302 high-dose arm falls in a region quite similar to that from Study 103, 10 milligram per kilogram arm. It's the 301 high-dose arm which is falling outside of this correlation analysis. We refer to the results as partially discordant. The low dose are similar in both clinical and biomarker endpoints. The high doses are not similar in biomarker or clinical endpoints, but the exposure-response relationship when we assess patients on the basis of their exposure is concordant. Here's another way of looking at that degree of consistency, here using the data from the three studies, looking at the common endpoints. The dark green color here is filling in the squares where each of the results has a p-value of less than 0.05 favoring aducanumab. We can see that all of the measurements in Study 103 are in dark green, as are the high-dose arm in Study 302. The light green, these are the cells where the results are numerically supporting aducanumab but do not achieve that p-value. You can see that in the high doses Study 301, here is where we have the two cells that are no longer supporting directionally and is inconsistent with the rest of the dataset. Why are the two results different? We spent an extensive period of time trying to understand the differences between the studies, given that there were so many consistencies. We conducted this work together with the FDA. We concluded from that work that the demographics, the disease characteristics, as well as the frequency, severity, and management of ARIA were in fact all similar between the studies. The underlying pharmacology of aducanumab is similar in both studies, and this is quite critical, i.e., if a patient has received sufficient dosing and exposure of aducanumab, even in Study 301 high dose, the response has the same relationship as in Study 302. What we determined the differences were largely driven by was in Study 301 overall, a lower exposure to 10 milligram per kilogram dosing, and an imbalance in a small number and distribution of rapidly progressing Alzheimer's disease patients. Actually, a very small number. What we did conclude from that work was that even in Study 301, patients who were randomized to have the full opportunity for 10 milligram per kilogram did have results similar to Study 302. This is one way of looking at that type of data. You have Study 301 at the top here and Study 302 at the bottom. If we include the subgroups who had the opportunity for 10 milligram per kilogram, i.e., not including those APOE4 carriers at the beginning of the study who were only titrated to 6 milligram per kilogram, in both studies, the weighted means of these groups on CDR Sum of Boxes gives a 23% reduction versus placebo. That is consistent for both studies. Moving to look at the top-line safety data from the phase III trials. ARIA, as I mentioned earlier, was a safety finding of interest. It does refer specifically to radiographic abnormalities observed with aducanumab and other anti-Aβ antibodies. There are two types of ARIA that are defined and reported. One is ARIA-E or ARIA edema, and this is vasogenic edema or sulcal effusion, fluid movements in the brain. The other is ARIA hemorrhage, which are either brain microhemorrhages or localized superficial siderosis. As I mentioned, we believe that these may result from increased permeability as a consequence of antibody binding. Here are the most common adverse events associated with aducanumab in the placebo and the high dose, 10 milligram per kilogram. We can see that ARIA-E is the most common, followed by headache and then ARIA-H, falls, and then ARIA-H superficial siderosis. Serious hypersensitivity reactions were in fact rare, with an incidence of less than 0.1%. Compared to placebo, aducanumab was not associated with other abnormalities in vital signs. Taking a bit of a closer look at the clinical and MRI characteristics of ARIA-E, given that these are identified by MRI imaging, it's important to understand that actually the majority of these, 74% of them in the high-dose arm, are not associated with symptoms. Patients are unaware that they have this radiographic finding. 26% did report symptoms. The most common symptoms were headache, confusion, dizziness, and nausea. Most symptoms reported were mild or moderate in severity. Further, the MRI findings of ARIA-E were typically mild or moderate in severity and transient. We had 98% of them resolving. The characteristics of ARIA-E in these trials is very similar to what we and others have reported previously. I think I'll skip over this scale. In closing, we believe that these three trials establish the safety and efficacy of aducanumab. Study 302 is a positive study with robust and internally consistent results across a number of clinical and biomarker endpoints. Study 103 is an independent and second study that provides supportive evidence. While Study 301 is a failed study formally, we believe that we understand the reasons for the differences between the studies, and we find in post-hoc subgroups support for Study 302 and 103 in this study. In summary, we believe 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. I'll end there. Thank you very much for listening. Thank you, Samantha. That was great. I would, in the interest of time and our audience, jump right into the questions. The first group is about the specifics around the aducanumab studies 301 and 302. Question one, the FDA has a guideline and criteria for substantial evidence of efficacy. Does aducanumab satisfy those criteria? Thank you, John. The answer is yes. We believe that the data we have on aducanumab does achieve the threshold for substantial evidence of effectiveness. That is for the FDA to decide, and that's obviously deliberations that are ongoing. If we look back at the guidelines for substantial evidence of effectiveness, I don't know if you guys are hearing my little dog barking at the door. Just to refer to the guidances, there's a draft guidance at the moment for substantial evidence of effectiveness, 2019. Fundamentally, the threshold for evidence of effectiveness has not changed since 1998 at the FDA. In that guidance, it does support that the FDA does have regulatory flexibility. There is the ability to approve data on the basis of one robust single trial with corroborating data, there are different ways that data can corroborate. We do believe that 302 is a large, robust clinical trial with internally consistent results and supported not just by multiple clinical endpoints but also by biomarkers. Study 221AD103 could fulfill the criteria for a supportive study in the context of that guidance. I hope that's helpful. All right. Question two, the placebo decline in Study 221AD302 was substantially larger than the placebo decline in Study 221AD301. Couldn't this difference account for the apparent drug placebo difference in the 302 study? Thanks for the question. I know there's a lot of interest around this one. Right at week 78, CDR Sum of Boxes in Study 301 is slightly lower than Study 302. We don't believe that the difference in placebo between the two studies is driving the effect. Let me outline, there's a number of points that we don't believe that this is the case. First, we actually planned for a placebo decline of 2.0 units throughout the 18 months of these trials. In fact, both trials have a lower placebo decline than was programmed, making it more difficult for either of the trials to have shown efficacy. The degree of placebo decline was lower, but it's nonetheless quite consistent with contemporary clinical trials in this patient population. The results that we have through the 18 months, if you look at the placebo at every 200 patients, is also actually, there's no systemic difference between the two studies. Another thing to point out is while that's a focus on CDR Sum of Boxes, if people look closely at the data, the MMSE actually is in the other direction. In fact, the placebo decline in MMSE on 302 is less than on Study 301. You still see an effect of aducanumab in the high dose in Study 302. That goes against the idea that it's placebo that's driving it. Last but not least, both studies have a fairly consistent numerical difference on the low dose. Irrespective of the placebo decline, you have a consistency of effective aducanumab in the low dose. Had the placebo been driving the effect, it would have also squashed that low dose in 301, and that's not what we see happening. On closer inspection, placebo is really important. You have to have decline to be able to see a difference. We don't believe that placebo decline is driving that difference between the two studies. Another question of interest is, are there lessons from EMERGE and ENGAGE regarding the use of futility analysis in trials that you might share with us? Another good question. I think there was a bit of a knee-jerk reaction that occurred after our futility analysis and some even had the position of, "Hey, you shouldn't do futility analyses. That's not a good idea." Futility analyses play an important role. If we can assess earlier in a clinical trial that a treatment truly is not effective, then we want to guard against patients staying in a clinical trial where we've determined that there is no efficacy or worse, if there is a safety issue happening. Conduct of futility analyses, they are important to do for the benefit of patients. However, as we have learned, despite incredibly intelligent and diligent work to predefine a futility analysis, I would say that the results educated us that the unexpected can still happen. One needs to certainly not believe that one knows everything going into clinical trials. I think we need to have some humility and we need to take some time to understand results that come out from these types of assessments. I would suggest that we try our very best to design these futility analyses, but we need to ensure that we take time to understand what we are seeing when we conduct them. Thank you, Samantha. I think you've addressed this in your presentation, but it's probably worthy of a bit of repetition. Why should we discount the 301 study and value the 302 study? We hear this question all the time. Both studies had the same protocol and roughly the same completion rate, but 301 showed no drug-related improvements, while 302 showed a small but statistically significant improvements for the high dose. Thanks, John. The first thing is while I hope it doesn't come across that we are discounting Study 221AD301. In fact, we're definitely not doing that. I think the formal language of statistics, at least traditional statistics, one trial positive, one trial negative, gives that impression that we are viewing them very much in those ways. Formally, per pre-specified statistical analyses, those are the outcomes of those studies. You know what? There are thousands of patients in those studies, and we spent a great deal of time trying to understand both studies. We started from the standpoint of which of these trials is the right outcome. Where we have concluded is that 302 is positive. It's very, very unusual to see such consistency of clinical endpoints showing an effect. That we have a positive primary endpoint, that's one thing. We're also seeing the same effect on other types of tests, cognitive performance tests, caregiver input-based tests. Using all of these different paradigms that are not highly correlated at a point in time, so we determine that the result in the high dose in 302 is very unlikely to be a false positive. We also then need to understand, so why wasn't 301 also positive? Again, we don't discount 301. It was, in fact, the low dose that opened our eyes, both the clinical and biomarker data, that suggested something had occurred in the high dose. We really did focus our investigations to try and understand what the differences were between the two studies and what those differences may have caused. The other discipline to statistical analyses is more of a exposure response, a quantitative pharmacological approach. Today, we have the computing power to look at each patient and their exposure and their response on these clinical endpoints. When we look at the data from those perspectives, it's much more of a continuum. Patients having low versus high exposure, and those with the higher exposures having the greater effect on the clinical endpoints. When we look at the data from that perspective, that's how we learn that 301 has the same pharmacological response, but overall had less dosing and had other interruptions as well. We're definitely not discounting Study 221AD301. We've learned a great deal by truly trying to understand Study 221AD301. In light of everything you've seen living with this data, what might Biogen do to move away from the old school CDR Sum of Boxes into more objective approaches for measuring drug efficacy? The holy grail. That's a tricky question. Well, there's a tension for trying to measure something in a patient's progression, and a change from that something in progression. In these very early patients, they are not progressing very far in the time frames that are reasonable to conduct clinical trials. I really share the angst that we're trying to measure something with tools that are frankly quite blunt in that period of time. The tension is that for a treatment to obtain approval, we need to be demonstrating that what we're measuring is meaningful to the patients. Right? It needs to have meaning for the patients, and it needs to be a meaningful difference. I think that in earlier clinical trials, trying to understand is there a signal at all, is where there is space for looking at more sensitive cognitive instruments. In the domain where we're trying to prove efficacy, we're kind of trapped by that tension to show that clinical meaningfulness at the same time. One of the ways I think we are capturing clinical meaningfulness is not just focusing on the primary endpoint, but actually having a number of clinical measures covering, as I mentioned, different domains. Activities of daily living, independence of patients, behavioral symptoms of patients, as well as what we refer to as cognition and function. I think it's actually the combination of the endpoints that is more meaningful. Of course, that in trials that are aiming for regulatory approval, we have this issue with statistical analysis and hierarchy, so we have to be very thoughtful about the selection of endpoints. I think for now, we may need to continue to use CDR Sum of Boxes for this stage of Alzheimer's patients. I think we and others have been happy to see the performance of ADAS-Cog13, and the modified ADL scales in this patient population. Great. Thank you, Samantha. Take a couple of deep breaths. I'm going to move on to an area that is very much of interest to the broader community, which hypothesizes around if aducanumab is approved, what are the ripple effect associated with that approval? Specifically, first question, do patients need to have a positive PET result to be eligible to receive treatment if aducanumab is approved? Okay. Well, we can't speculate what the label might be if we are approved. That's really the domain of the FDA. We do have a position in that we do believe that Alzheimer's disease is characterized by the presence of amyloid. We do think that it is important to ascertain the presence of amyloid pathology before initiating treatment, should we be approved with aducanumab. We used PET imaging exclusively in our trials for aducanumab. We know that others use a combination of either PET or CSF, and there's a great deal of work being done to be able to have other methodologies, CSF predominantly, but maybe also in the future, blood-based tests for amyloid. We do believe that that is an important step, and we are very invested to try to help innovation in that space as well. Thank you. The opposite question actually, in a way. Several researchers and treating physicians wanted to know what would your guidance be, in terms of how to determine when to stop treatment? Initiating or stopping treatment is really a patient-physician conversation. The data we have at the moment suggests or informs us that patients who have had sufficient doses for a period of time are those individuals who may benefit from treatment with aducanumab. We do not today know the long-term basis of that. How long does one need to continue to treat for? What are the signs, symptoms in regards to no longer treating with aducanumab? The window of benefit is unknown. It's something we need to continue to learn, hopefully, with the community in conducting studies with longer duration. Also, it's a very individual conversation, John, for a given family, for a given patient, and in conversation with the physician in regards to aducanumab slows down the progression of disease. It doesn't stop it. There may be a point, and we don't know at what point that is, that a patient decides that it's no longer the right thing for them to be doing. These are important questions and questions that we need to learn. This is not meant to be a yes/no question, but it just might be. Will the healthcare system be ready for the approval of aducanumab based on your PDUFA date? Oh. Unfortunately, it is a yes/no question, but I want to give it more response than that, John. We don't have this type of paradigm of treatment available today. As we were just discussing, diagnosis with a biomarker is likely to be an important step. That one piece right there is we know definitely an infrastructure that is not ready today. We're talking about patients at earlier stages of disease. We know how difficult it is to achieve those numbers of patients in the clinical trial setting. We know that patients are going undiagnosed at that stage of disease today. We know that the primary care setting isn't yet set up to funnel this particular disease through to specialists or to treatment. Those are a couple of things. There was a report by RAND Corporation a couple of years ago that spoke to actually the number of specialists, the number of neurologists available would be another bottleneck. Treatment-specific factors for anti-Aβ antibodies as a class would be the MRI monitoring, which some may be required to ensure the safe initiation of treatment, as well as these antibodies are given IV, infusion capacity is another place. Sad to give you a multi-part response of there are many areas that would not be ready at the point and time of the PDUFA date, God willing, that we are approved. I do know that there are efforts to work towards this. We know that a lot of work will need to be done. We are right there with you in that work. We agree with you. Another question that matters to many people is for those who have been so giving and willing to participate in the aducanumab clinical trials, are they eligible to continue the treatment? Yes. Thank you, John. We do have a study ongoing. It's called EMBARC. This is an open label study. All patients who've previously been in an aducanumab clinical trial are able to seek being able to join that study. Patients do need to be eligible. There are some minimal criteria. This is the study for us to provide the opportunity for aducanumab treatment for all patients who've previously been in our trials, including individuals who were only ever exposed to placebo. We are very grateful to the large numbers of patients who are in fact coming back to join that study. Yes. We see it in the network. You may have more to add. This question is, how can we ensure identifying patients at the right disease stage to optimally benefit from treatment and to avoid inappropriate prescriptions? I think there's a deep appetite to understand what the drug does and doesn't do and which patients are most likely to benefit. Yes, we share that appetite. It goes back a little bit to the question of what might the label say. We can't speculate there either. That is, again, if we are approved, the FDA will determine what the population is in the label. What we do know is that the patient population we treated, which has an MMSE of 24 through to 30 in the phase III trials or 20 through to 30 in the phase I trials, is that we do see efficacy across that quite broad range of patient population. We also don't see necessarily a diminishment of efficacy in going to patients who are more progressed. We've yet to learn really what the extent of possibility is. Again, that's an area that we need to continue to learn. We set up clinical trials to try to answer a question. We've struggled in Alzheimer's disease, haven't we, tremendously to get success in these clinical trials. We've had to be quite strict in regards to defining the patient population, ensuring pathology and all of these things. That means that the trials that are reading out, They're not narrow, but it's a targeted patient population. It means that we don't yet know about the remainder of Alzheimer's disease. Understandably, patients who have moved into mild or maybe even beyond may really, we share that desire to try and understand if there is efficacy. This should be quick. Can patients continue to take their oral anti-dementia drug while on aducanumab? The answer to that would be yes. Our clinical trials were conducted with patients who, at the time of enrollment, they needed to have been on stable medications, which could have been either the acetylcholinesterase inhibitors or an NMDA antagonist, memantine. That's a yes. Great. A number of questions we got were clustered around this concept. For patients and families of the patients, what kind of monitoring would you recommend or guidance you'd give for the clinicians and families for both sustained treatment effectiveness and, even more important, for side effects, particularly as you were starting to discuss ARIA at the higher doses? I'm not sure I quite understand the question. I hope the question's focused on monitoring during the course of treatment and trying to detect effectiveness and the incidence of ARIA. Yeah. Thanks. If we take the safety side of that, John, again, if we are approved as part of label negotiations, we would have ironed out what type of monitoring is believed to be the best to ensure safety of patients upon initiating and being treated with aducanumab. That would be something that would already be defined for the treating physician. As regards monitoring for efficacy, again, the clinical trials, what they do is give us the answer of, in a population, can we measure the effect? It doesn't give us the tools to say in patient A or B, how is it working for them? How do we measure them? You don't translate directly what you see in a clinical trial into the physician and patient setting. That really will be for them to have an ongoing dialogue with routine assessments and a conversation as opposed to the type of trial endpoints that we use. I would not recommend that that's what we expect to see happening. I think sometimes we also get the question, John, maybe I'll just spontaneously raise it, of should we be looking at biomarker endpoints? I think that's an interesting one. I would say today we don't know enough. We've shown that we do, even at the individual patient level, there is an association between the degree of reduction of amyloid or tau and the clinical results in a patient. That's, again, not something that is a tool that is monitorable over time. I'm hopeful that that may be the direction that we go in, John. Certainly that would enable us to be more objective about the response to a treatment. Again, lots to learn. Yes. Obviously, a process is in front of us to deal both with patients' and families' concerns and frankly, payers' concerns because this journey is going to have enormous consequences for all of us, right? We've done great. We have about three minutes left, and we're in the if-time-allows questions. You've been a real trooper, Samantha. I'm going to pick, this is really one that many people ask. Do you believe, and you've lived the dream, that you've effectively responded in your further submissions to the FDA to all the questions posed by the advisory committee on November 6th, which you did not have an opportunity to answer at that time because of the time and format issues? Do I believe we have sufficiently responded to those questions? I can't really speculate in regards to our ongoing dialogue with the FDA. I think it is fair to say that we have continued to respond to the questions that the FDA have put to us after the advisory committee. We believe that we have fully responded to those. I'm sure you've done your level best. Two more quick ones. Given your experience and looking at the data, what would you say about your experiences with recruitment of underrepresented minority populations into ENGAGE and EMERGE, and what might you think about the lessons learned for future trials? Clearly an area of great interest to the field as we move forward. Yeah. Thanks, John. The learning is that we don't have enough. We simply do not have a population in these clinical trials, in any of our clinical trials that we, as an industry, are conducting that is representative of the patient population. We miss out on not having that. We miss out on not understanding how this disease is potentially treated in representative patients. I think we have to do a lot more in that direction, John. Biogen has undertaken across clinical trials initiatives in order to address this. It's a complicated challenge, and it requires intervention at multiple levels. One of the things that we are thinking about, John, this should be particularly interesting to GAP, which is we select our clinical trial sites. As the GAaP network well knows, we need those clinical trial sites to have a certain level of acumen and technology and access to other services. This means that we end up in these really skilled, high-end clinical trial sites, and actually takes us away from the areas of the underrepresented. Not just minority populations, but takes us away from geographic areas, for example. We've done that. That's something we can turn around. We can invest in trial sites who would address that question and who are centered in those populations or run by those populations. This is something that we really do need to be actively addressing, John. It's certainly an area that in 2021, GAP is hugely working on and making our own substantial investments in. For another day. Let's leave. This is one, though, that is also very timely. Last question, let me before I give you the last question, thank you so much. Your presentation was exactly as advertised, very helpful, very clear, and I know the audience appreciated you soldiering on for an hour and a half. Given your experience with EMERGE and ENGAGE, what biomarkers, given this is more in your control, would you think about including in future trials to sort of inform both trial design as well as clinical practice? All of them and more. Great. That's an easy one for me. What you might not know is we do include, so for example, serum or blood draws are things we take. We take it with an eye to pre-specify, which is name a biomarker before the trial. Also so that we have samples, often not enough, but samples available. These trials took five years end to end, John, and the science has progressed massively in that period of time. Yes. We need to not just include as many biomarkers as we can, but also to future-proof that we can assess things that didn't exist when we started. We have done, to some degree, that, and we continue to explore novel biomarkers that emerged. Let's take NfL, for example, emerged during the time of these clinical trials as potentially an important marker of neurodegeneration. It's incredibly important. I think having the pieces of the puzzle substantiated by objective biomarkers' effects on multiple components of disease has been very important to our understanding of what this data set is. I'm a big advocate for biomarkers. I am sensitive to patient burden. We need to work so that we are doing this in a smart way. Yes. Very sensitive to it. I am very disappointed that we didn't get more CSF in our clinical trial. I've only myself to blame. Is there a position to correct it? I try. I am, John. Actually, it's the PIs that I want to talk to about CSF or the clinical trial site personnel of the value of those biomarkers has been incredible to us, and I know that those are among the more challenging things to ask patients to give. This is not just me, John. This is a collaboration to get these types of things. We promised our more than 200 remaining listeners we'd wrap up. You've been terrific, Samantha. I do want to take literally 30 seconds and say, obviously, we're hopeful for a positive result on aducanumab. For all of you listening, and on behalf of GAP and my fellow GAP collegial and connected enterprises, UsAgainstAlzheimer's, I just want to say how much we approve of the way the FDA has conducted this process. I think we need more collaboration, more communication, more iteration. I've been doing this a long time and I'm no expert, but this is the only way to expedite to either negative or positive answers. The second best thing to an approval is a quick no, so we can just move on and learn and go on. I just want to say those few words in favor of the way the FDA has conducted this process, and we would not associate ourselves with some of the criticism that has been floating. With that, thank you everyone, and especially, thank you, Samantha and Biogen for your time today. Thank you, John, and thank you to the whole GAP platform. Much appreciated. Goodbye, everybody. Thank you. Bye-bye.