Good morning. My name is Jessa and I will be your conference operator today. At this time, I would like to welcome everyone to the Biogen Third Quarter 2019 Financial Results and Business Update. [Operator Instructions] I would now like to turn the conference over to Mr. Joe Mara, Vice President, Investor Relations. You may begin your conference.

Good morning, everyone and welcome to Biogen’s third quarter 2019 earnings conference call. On today’s call, we will be discussing our Q3 results as well as an update on our Alzheimer’s program aducanumab including our plan to file in the U.S. Before we begin, I encourage everyone to go to the Investors section of biogen.com to find the earnings release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. Our GAAP financials are provided in Tables 1 and 2 and Table 3 includes a reconciliation of our GAAP to non-GAAP financial results. We believe non-GAAP financial results better represent the ongoing economics of our business and reflect how we manage the business internally. We have also posted slides on our website that follow the discussion related to this call. I would like to point out that we will be making forward-looking statements which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties and our actual results may differ materially. I encourage you to consult the Risk Factors discussed in our SEC filings for additional detail. On today’s call, I am joined by our Chief Executive Officer, Michel Vounatsos; Dr. Al Sandrock, EVP, Research and Development and our Chief Medical Officer; Dr. Samantha Budd Haeberlein, Vice President, Late Stage Clinical Development and our CFO, Jeff Capello. Now I will turn the call over to Michel.

Thank you, Joe and good morning everyone. I will start by giving you an outline of this call since we are announcing both Q3 results and news on aducanumab. First, I will review the recent news on aducanumab. Next, I will provide the key highlights of a strong quarter. Al and Samantha will then provide additional details on aducanumab and progress across the rest of our pipeline. Jeff will discuss our financial performance for Q3 and I will close before we open the call for questions. This is an important day as we are announcing that based on discussion with the FDA, we plan to submit a regulatory filing in the U.S. for aducanumab. If approved, aducanumab will become the first therapy to reduce clinical decline in Alzheimer’s disease and the first therapy to show that removing amyloid beta can lead to better clinical outcomes. This is an important milestone providing hope for patients, physicians, caregivers and families around the world. It is also important to highlight that the path taken in the pursuit of discovering and developing breakthrough treatments is not always direct and straightforward. As you know in March, we announced our decision to discontinue the Phase 3 EMERGE and ENGAGE studies for aducanumab in Alzheimer’s disease based on a pre-specified futility analysis. In retrospect the result of our futility analysis was incorrect. Based on what we know now it is clear that the pre-specified futility criteria did not adequately anticipate the effect of all the variables in these trials. So, what happened? First, the decision to stop these trials relied on an earlier and smaller dataset comprised only of patients who had the opportunity to complete 18 months of treatment as of December 26, 2018. At that time, the futility analysis predicted that the trials were unlikely…

Thank you, Michel. Before diving in, let me first take a moment to say how excited I am, about the opportunity to lead the R&D organization here at Biogen. I’m extremely proud of the team for all the hard work that brought us to today’s announcement on aducanumab, and I believe now more than ever, that Biogen is uniquely positioned to bring breakthroughs in neuroscience and transform the lives of patients with neurological disease. As Michel said, we were all surprised when we learned of the potential implications of the new analysis of a larger dataset from the Phase 3 studies of aducanumab. Following discussions with external advisors and the FDA, we have now come to better understand what happened, and even more importantly with the positive implications of the larger dataset may mean for patients, physicians and the broader scientific community. To start, I will briefly summarize our current understanding of the Phase 3 data, before I turn the call over to Samantha, who will describe in more detail, the series of events and analysis that have led us to the current conclusions and status today. First, it is important to understand what the results – that the results you will hear about today, which we have analyzed in consultation with the FDA, are based on a new analysis of a larger dataset, than that which was used for the futility analysis. Our primary learning from these data is that sufficient exposure to high dose aducanumab reduced clinical decline across multiple clinical endpoints. This reduction and clinical decline was statistically significant in EMERGE, and we believe that patients – that the data from patients who achieve sufficient exposure to high dose aducanumab in ENGAGE support the findings of EMERGE. After consultation with the FDA, we believe that the totality…

Thank you, Al. Let me now describe in more detail how we got here. It’s important to first understand the design of the studies and how that evolved over time. EMERGE and ENGAGE were Phase 3 multicenter, randomized, double-blind, placebo-controlled parallel group studies, designed to evaluate the efficacy and safety of aducanumab in early Alzheimer’s disease. The studies were identical in design. A full enrollment EMERGE included 1,638 patients and ENGAGE included 1,647 patients. Based on the data from the Phase 1b PRIME study of aducanumab, we believed that higher doses of aducanumab may be associated with improved clinical outcomes. However, as the incidents of amyloid related imaging abnormality or ARIA for short, the most common adverse event associated with aducanumab, also increased with aducanumab dose and occurred more often in ApoE4 carriers than non-carriers. The Phase 3 study had a number of design elements, such as titration, dose levels and management with MRI to mitigate and manage the risk of ARIA. In addition, dosing of aducanumab was stratified by ApoE4 carrier status. The low dose was defined as 3 milligram per kilogram for ApoE4 carriers and 6 milligram per kilogram for non-carriers, whereas the high dose was initially defined as 6 milligram per kilogram for ApoE4 carriers and 10 milligram per kilogram for non-carriers. Results from the PRIME study for ApoE4 carriers titrated to 10 milligram per kilogram became available in August 2016. This data showed that the incidence of ARIA as well as discontinuations from treatment due to ARIA in ApoE4 carriers receiving aducanumab titrated to 10 milligram per kilogram appeared to be reduced as compared to the fixed dose cohort. Following this analysis, the protocols for the ongoing Phase 3 studies were amended such that the high dose in ApoE4 carriers would then be increased from 6…

Thank you, Samantha. We believe that these positive results for aducanumab represent a turning point for patients, caregivers, physicians and scientists in the fight against Alzheimer’s disease. More broadly, we believe these results represent an inflection point in neuroscience drug development and validate our core strategy, by demonstrating the removal of aggregated forms of amyloid beta can result in improved clinical outcomes, we believe these results have positive implications for BAN2401, a distinct antibody that also targets aggregated amyloid beta that we are currently evaluating in a Phase 3 study in early Alzheimer’s disease in collaboration with Eisai. More generally, we believe these data may have positive implications for additional assets in our portfolio that target the casual pathobiology of neurodegenerative disease, particularly those validated by human genetics. These include our Tau directed assets for Alzheimer’s disease and primary tauopathies, our alpha-synuclein antibody for Parkinson’s disease and our SOD1 and C9ORF targeting antisense oligonucleotides for ALS. Given our depth of expertise, our deep and interconnected neuroscience pipeline including nine additional readouts expected by the end of next year, we believe that Biogen is uniquely positioned to capture the opportunity in neuroscience, and potentially deliver a suite of breakthrough therapies for diseases of the nervous system. With that in mind, let me now review the highlights across the rest of our pipeline in the third quarter. Starting with MS, this quarter we announced positive top line results from EVOLVE-MS-2, a Phase 3 study of VUMERITY or diroximel fumarate, a novel oral fumarate for relapsing remitting multiple sclerosis compared to TECFIDERA. The remedy was statistically superior to TECFIDERA on the studies pre-specified primary endpoint, the individual gastrointestinal symptom an impact scale with a p-value of 0.0003. The proportion of patients who discontinued due to GI adverse events during the five-week treatment period…

Thanks, Al. Good morning, everyone. I will now review our financial performance for the third quarter of 2019. As Michel mentioned earlier, we had a strong financial performance in Q3 2019. Total revenues for the third quarter grew 5% year-over-year to approximately $3.6 billion, while GAAP earnings per share increased 17% and non-GAAP earnings per share increased 24%, both compared to the prior year. Overall, our MS business delivered revenues were approximately $2.3 billion in the third quarter of this year, including OCREVUS royalties for approximately $188 million, growing 2% versus the prior year. Global MS revenues in Q3, 2019 were stable versus the prior year with OCREVUS royalties and the total number of patients on our MS products globally continued to grow in the low single-digits versus the prior year. U.S. MS revenues in Q3, 2019 were impacted by a decrease in channel inventory of approximately $30 million compared to a decrease of approximately $5 million in Q3, 2018 and a decrease of approximately $30 million in Q2 2019. Global third quarter TECFIDERA revenues increased 3% versus prior year, as TECFIDERA delivered strong global patient growth of approximately 8% year-over-year. In the U.S., TECFIDERA revenues were flat year-over-year as TECFIDERA share of total prescriptions remained relatively stable compared to the last couple of quarters. Outside the U.S. TECFIDERA performed very well again in Q3 2019 with continued volume increases across all large European markets and Japan versus the prior year, somewhat offset by pricing pressure in several European countries. Q3 global Interferon revenues including both AVONEX and PLEGRIDY decreased 10% versus Q3 2018, due to the continued shift from the injectable platforms to oral or high efficacy therapies. TYSABRI worldwide revenues increased 3% versus the third quarter of 2018. We were pleased with this growth into TYSABRI revenues as…

Thank you, Jeff. To summarize, first, the positive clinical results for aducanumab position Biogen to potentially lead the fight against Alzheimer’s disease. Second, these data validates Biogen strategy to focus on an interconnected neuroscience pipeline and productization of target supported by human genetics. Third, our base business continued to deliver solid performance in Q3 2019, driven by strong execution against our strategic priorities. Between now and the end of 2020, we expect continued progress as we aim to build a multi-franchise portfolio including nine additional mid to late stage data readouts, the expected launch of VUMERITY in the U.S. and submitting the regulatory filing for aducanumab in the U.S. while continuing dialog with regulatory authorities in international markets, including in Europe and in Japan. I am proud of the Biogen team for not being deterred by history of disappointment in the pursuit of Alzheimer’s therapies and more so for continuing their work of analyzing the clinical trial data with unprecedented focus and intensity even in light of an apparent futility results. This work reflects Biogen’s steadfast determination to follow the science, tackle the biggest challenges and do always the right thing for the patients. Finally, what is most important today is that in consultation with the FDA, we are excited to be moving ahead and preparing for regulatory filing for aducanumab on the ground of positive clinical results. And we will be redosing eligible patients from our Alzheimer’s trials as quickly as possible. This is a major step in the fight against Alzheimer’s disease and an important inflection point for Biogen’s neuroscience mission. We believe now more than ever that our core focus on neuroscience will enable us to maximize the value for all our stakeholders. First and foremost, for the patients as well as for our shareholders as the leader in neuroscience, we believe that no other company is better positioned to continue to deliver breakthrough therapies for diseases of the nervous system. We will continue to execute on our cost strategy to build a multi franchise portfolio across our core and emerging growth areas. We are inspired by the progress we have made in tackling Alzheimer’s disease and the broader scientific implications of the positive clinical results for aducanumab. I would like to thank all the Biogen employees in particular, those who have been working tirelessly on the aducanumab program and the many more who will contribute to this critical priority over time. I am incredibly grateful for all the patients, physicians and caregivers who have dedicated so much time and efforts to our Alzheimer’s clinical studies and advancing our understanding of this very complex disease. I would like to thank the FDA for their guidance, and independent scientific expertise throughout this process. We will now open up the call for questions.

Thank you. [Operator Instructions] Your first question comes from the line of Umer Raffat from Evercore ISI. Please go ahead.

Hello. If I may, I only have a question on aducanumab but it’s got three parts, and given the significance of the news today, I would really appreciate if you could bear with us on it. So my three parts are as follows: first, I’m not attempting to correlate the two but Michael Ehlers departure ahead of this data announcement, just wanted to hear are those two things are related in anyway or not. Second, the implication in the data is that the high with insufficient exposure at the high dose, the second trial worked as well. But when we look at CDR Sum of the Boxes low dose actually looks more consistent than the high dose and also for patients that did not make it to the large opportunity to complete dataset, those patients actually especially in MMSE more consistent than the patients that did have a sufficient exposure. So I guess I’m just trying to understand how spot on is that finding on patients that had a sufficient exposure and those are the ones that drove efficacy. Thank you so much.

Thank you, Umer. This is Michel. Mike decided to leave the company on his own and I can cannot thank him enough for his many contributions over the past three and half years to Biogen. So, thanks, Mike. And at the same time I’m extremely confident in Al’s leadership as a clinician too, as a scientist to take the helm at the time where the R&D portfolio never been as stronger, the team also and the capabilities.

Umar, this is Al Sandrock, and I will turn it over to Samantha later for follow-up. But look, your point is well taken, the low dose is consistent across ENGAGE and EMERGE, and that’s because the particularly the second protocol amendment, really affected the high dose arm of – in the carriers. So in the low dose arm or in the protocol amendments had less of an effect and I think that’s one of the main reasons for the consistency in the results across the two studies. I’ll turn it over to Samantha for a follow-up.

Yes, that’s correct. Umar you’ll also see that in the high dose for ENGAGE that we do have a partial response on ADAS-Cog13, and the ADCS-ADL-MCI. And so the potential read that you have there on CDR-Sum of Boxes and MMSC is that these are potentially less sensitive as endpoints. So what Al said is that in the high-dose group we know that we have less doses than we – at the high dose than we had in EMERGE, and we also know that the studies were to some degree impacted by dose suspensions due to ARIA, so dosing is a complex combination of duration, magnitude and no interruptions.

Thank you very much.

Your next question comes from the line of Phil Nadeau from Cowen and Company. Please go ahead.

Good morning. Thanks for taking my question. It’s also, as you might imagine on aducanumab. I guess in two parts. First, if you pull the data from ENGAGE and EMERGE, would the pooled results still be positive on the primary endpoint and kind of related to that, could you give us some sense of what the differences between ENGAGE and EMERGE were in exposures at those high doses. It seems like the trials didn’t start far apart, there’s just a month, so kind of in response to the last question, you mentioned exposures rely on dose suspensions and whatnot. Can you give us some sense quantitatively of how different the patient populations at that high dose were in ENGAGE and EMERGE in terms of their exposure? Thank you.

Certainly. So the first part that if we pulled the outcomes on ENGAGE and EMERGE at the high dose essentially you’ll get an intermediate effect, not much more complicated than that. But we are looking at these stand-alone studies as two independently identically designed studies. The second part of the question, which I had forgotten actually,

Differences in ENGAGE and EMERGE,

Yes, so they started one month difference between the two studies, as I mentioned and they remained different throughout the entirety of the studies and that initial one month at certain periods of the studies in particularly through the protocol amendments was greater in the middle of the studies and more details around this will come at the presentation in CTAD.

Your next question comes from the line of Terence Flynn from Goldman Sachs. Please go ahead.

Hi, thanks for taking the question. Maybe two parts for me as well. Just wondering if you can share any additional commentary on the second Type C Meeting, did FDA agree that a single positive trial could be sufficient for approval or is that likely a review question? And then can you give us the rates of ARIA in the high dose arms of the two trials? Thanks.

Yes, hi, this is Al. It’s generally our policy not to comment too much on the content of regulatory interactions. I will say though that they thought it was reasonable for us to submit an application to – for approval. So that’s the main, that was the upside of the meeting.

And the second part of the question was on ARIA and high dose and that was consistent in incidence for the studies that we have previously reported, and we’ll give more details on that at CTAD.

Your next question comes from the line of Geoff Porges from Leerink. Please go ahead.

Thank you very much and thanks for having Samantha on the call. It’s very helpful. First, could you answer whether the analysis that you presented and presented to the agency has been independently verified. What confirmation of both the statistics and the results do you have? Secondly, do you have any intention or plans for a confirmatory pivotal trial to supplement these two trials? And then I hate to sort of push on the issue of the type, the FDA meeting but did the FDIC, the full analysis or did the FDA just here the company summary of the analysis? Thanks.

Let me with the last question and I’ll let Samantha answer the first couple. First of all, the FDA did see the full analysis of both studies and I would also say that the only study we have planned right now is the redosing study and any further study, we’ll update you as soon as we plan one.

Thanks, Al. Going to your first question, Geoff. Have we had independent review. As we mentioned, one of the first steps that we undertook was to engage external advisors to help us review this data and that did include independent statistical experts, but the data that we did take to the FDA as Al says was a full dataset, which was an analysis of the blinded data conducted using the same statistical analysis plan as we had originally planned for the end of the study. And the validity of the dataset was the first thing that we analyzed together with the FDA. To your second question on whether we are conducting another study. As we’ve mentioned, our next steps are twofold, one is the FDA indicated to us that it is reasonable for us to file these two studies, and for us to go ahead and put together a re-dosing study for the patients who were in previously enrolled studies of aducanumab.

Your next question comes from the line of Michael Yee from Jefferies. Please go ahead.

Thanks. Thanks for the question. Appreciate it. Al or Samantha, I guess, just wanted to understand, ENGAGE a little bit more specifically in the high dose you appropriately say that there was a slightly negative trend overall in the high dose. But in the subgroup of exposure patients, which as you think about a third of it, they had a nice benefit. I guess the question is how do you think about the patients you did not have enough exposure, did they drive a strong negative trend? Are those patients at harm? How do you think about that since that’s a huge majority of the patients and how is that explainable given the difference in EMERGE? Thanks.

Thanks, Michael. I’ll start. Look, I don’t think – first of all there is a slight negative. I would say that that was just basically no effect. And then those who did not have the high dose, I would not say that they had a negative effect, in fact, in many ways, there was either neutral or positive effect. But I would point out this, you remember the 6 milligram per kilogram dose arm in PRIME, that everybody was wondering about. You always ask me questions about it. I remember, Michael, and we thought that was an outlier. Well, maybe that wasn’t the outlier. Maybe that was true in that the 3 milligram per kilogram that looked like it was trending was the outlier. So in other words, what I’m saying is that there is a very sort of sharp dose response, if you will, you have to get to high dose of aducanumab and intermediate dosing at least in an 18-month trial is not enough.

Okay. Thanks.

Your next question comes from the line of Cory Kasimov from JPMorgan. Please go ahead.

Hey, good morning guys. Thanks for taking my question. I guess first just to ask Phil’s question more directly, can you tell us yet how many patients got the 14 doses of 10 mg per kg in each study in the full dataset? And then as a follow-up, did you see any difference in ApoE4 carriers versus non-carriers, especially in the patients who completed after the futility cohort and would have had more exposure to the higher dose? Thanks.

Yes. So the first thing I want to mention is, in terms of the numbers of subjects who had the particular dataset that you’re referring to more dose, more than 10 doses of 10 milligram per kilogram, there’s more than a 10% difference between the two studies, but that’s not the only parameter of difference that is important for dose. As I’ve mentioned, you need to achieve high dose for long enough, but also have no interruptions, and so that’s a more complex calculation between the two studies.

ApoE4 versus non.

So your question regarding ApoE4 carriers versus non-carriers, the analysis that we’ve conducted to date has been on the entire studies. And as we’ve mentioned for EMERGE, we have a positive but we met the primary endpoint for the entire patient population and details of subgroups is something that will come to later. And we’ll have details at CTAD.

Okay, thank you.

Your next question comes from the line of Geoff Meacham from Bank of America. Please go ahead.

Hey, guys. Thanks for the question and all the detail on aducanumab. Al, I just have a couple of regulatory type of questions all related. If half of the EMERGE achieved significance at the high dose and none of ENGAGE achieved it, is it you guys expectations that the PRIME study could count as one of the two pivotals? Second one is, does a conditional approval, pending another successful Phase 3 did that come up in the FDA discussion? And then third, have you had any discussions with the European regulators on the data? Thank you.

Let me start with the last question first. So we have just started to contact the European regulators that we haven’t had any substantive discussions as of yet. In terms of the EMERGE and ENGAGE, I – we looked at – we look at ENGAGE in totality as a positive study that stands on its own. And remember, as Samantha said we use pre-specified primary and secondary outcomes, we didn’t look at a subset. We looked at all the patients and based on that, we believe the study met its primary endpoint and the secondary endpoints as well. I think that whether or not a single trial can be approved, there are circumstances where an FDA can approve a drug based on a single study, it’s up to them to determine what those circumstances are, and so I’ll just leave it at that and then I would say that ENGAGE, we believe, we showed the data for example in those who achieve sufficient exposure to 10 milligrams per kilogram. We do see evidence of efficacy. So I would say that EMERGE stands on its own, ENGAGE has supportive evidence, and I would also say that PRIME is supportive, it’s a well controlled Phase 1b, some may call it Phase 2 trial, and we’ll submit all the data.

Just to add there, Al, EMERGE is the study that met its primary endpoints. I think you said ENGAGE.

Did I say anything wrong?

Yes.

Yes. I get confused in times.

Your next question comes from the line of Brian Abrahams from RBC Capital Markets. Please go ahead.

Hi there. Thanks for taking my questions. So a question, just a little more clarity on the ENGAGE study, for the subgroups of patients I guess for both ENGAGE and EMERGE with 10 interrupted – receiving 10 uninterrupted high doses. Can you talk about the baseline characteristics for the aducanumab verse placebo arms across both studies and how well balanced those were? And then, can you maybe help us understand how feasible was it for patients? I guess, once the protocol – was protocols, were amended to remain on 10 uninterrupted doses or is the lesson here that if you do need to temporarily discontinue for ARIA or whatever reason you’re probably best off not restarting the drug? Thanks.

So, thanks. Thank you for the question. I want to point out that the analysis that we conducted in close consultation with the FDA around determining who in ENGAGE did have a response were exploratory analysis. And any time that you look at a subset of patients who you have very important questions in regards to whether they are balance for the baseline characteristics. The studies overall, were very well balanced for all baseline characteristics and as I mentioned, ApoE4 status. But those subgroups are exploratory in nature and they help us understand that dosing is important for efficacy. And in the context of an 18-month trial, one does tend to see that you need a certain number of doses for clinical benefit of aducanumab. However, that’s not the same as one would anticipate in a real world situation where an individual is taking aducanumab for an extended period of time, for a dose interruption would likely be of less significance.

Yes, I agree with Samantha. I think that dose suspension in the context of an 18-month study was – it could be problematic, because they didn’t achieve enough of the high dose. But in clinical practice, we don’t do 18 month treatment periods. We’re going to treat patients for longer periods of time. And in that situation I think dose suspension may be acceptable in some patients.

Your next question comes from the line of Matthew Harrison from Morgan Stanley. Please go ahead.

Great, thanks for taking the question. I guess a follow-up and sort of second question from me. So first one is, you’ve been talking about exposure and dose a lot. Could you just broadly comment on how many of these patients actually achieved all the factors that you were looking for and how easily you think that will be the case in clinical practice. And I guess, the related question to that is, dose exposure curve that you’re sort of talking about Al. I mean, what were their characteristics that were different were the kinetics of the amyloid plaque reduction different in these subgroup of patients with the achievement of tau or amyloid reductions were they significantly different. I’m wondering what you think is sort of biologically happen to account for this steep dose exposure curve [indiscernible]?

These were good questions Matthew and we’re still learning as we look at the data, but I would say this, the – even in MCI patient, if you look at the amount of amyloid in the brain, it’s tremendous. It took 20 years to build that much up and in the context of an 18 month trial, you have to remove a large amount of amyloid. I think that’s what distinguishes as you aducanumab and BAN2401, is that we can – it’s safe enough to achieve the doses that allow us to remove a large amount of amyloid. And if you don’t remove a large amount, you’re not going to get an effect. Also there is a lag. You remove amyloid, and then there is a little bit of a lag for the clinical effect. We saw that in PRIME for example, where we did have some amyloid lowering of six months, but we saw no difference in the clinical outcomes at six months. It was – it took the 12-month time period to see – to start to see an effect on clinical outcomes. So in addition to a large amount of amyloid removal, I think you need to have a little bit of time for that, for that biological activity to have an effect on clinical outcomes That’s what we see and I would say that if you look at the amyloid-PET results that was on one of the slides and those who had more than 10 doses of 10 milligrams, you can see that the SUVR score is very similar in ENGAGE in that subgroup of patients in ENGAGE to the EMERGE total dataset. So – and so again, what it says is that if you give it enough of the high dose, you can achieve a certain amount of amyloid removal and that certain amount is what’s required to see the reduction in clinical decline in an 18 month study.

Yes, Al just add to that, on the question of numbers. On the graph that you’ve just referred to, you got the end numbers. So they were 147 for EMERGE and 116 for ENGAGE in that CDR-Sum of Boxes analysis. But the question you ask of how many patients have the precise criteria? Well there aren’t precise criteria. Dose response is not binary. And so, given the levels of dose you have a different response and it’s a bit of a sliding scale. So we have that exploratory analysis that we disclosed to explain what it is we learned around the importance of dose, but there is no perfect number of doses that are required, it’s not binary.

Your next question comes from the line of Ronny Gal from Bernstein. Please go ahead.

Hi everybody. And thank you for taking the question. And I’m going to stay with aducanumab here. I’m just kind of struggling with the movement from the Interim Futility Analysis to efficacy with relatively small number of patients. Just looking at the number of completed that you have here in EMERGE, you move from 803 patients in the futility analysis to 980 patients in the treatment. So it’s about 180 more patients. If we assume a third of those were on the high dose, 60 more in your total number of folks that you have amyloid beta that you calls got sufficient exposure is at the end of the trial, 127 I kind of wonder if there is just a very small number of patients that drove the entire movement. If you can discuss a little bit that issue of how many patients actually contribute to the difference between stopping the trial for futility and showing efficacy would be appreciated. And then I’m going to – if you don’t mind going to throw my second one in and it will be different, not to kind of just for the variability. And do you have any way to protecting the highest dose TYSABRI from biosimilars through the first-generation products. If you can discuss that at all, I would appreciate it. Thanks.

Ronny, this is Al. My head is swimming even just with the first question. But, so I think first of all you should remember that in EMERGE even at the time of this utility analysis, that study was trending positive as Samantha said. And then we add those additional patients and it didn’t take that many now to then in the April dataset to see that – they had met its primary endpoint. And then I would also say that we also looked at the patients who had not completed 18 months, all the rest of the patients, which is roughly half the patients because we only looked at the first half, the first half of the enrollees for futility. So it’s a large number of patients that we ended up looking at and I remind you that result that you saw in that slide was all the patients in EMERGE, who had been randomized, the ITT population and it was using the prespecified primary and secondary endpoints. And then I now forgot the second question.

Before you jump into that if you look at the slide that you had Slide 22, the number of patient aducanumab that you have there is the number of patients received enough dose. The questions from some of my peers, was how many patients got exposed and both the numbers that we’re seeing on aducanumab on Slide 22 are the numbers we should be thinking about?

So I just want to recap that Slide 22 was a piece of exploratory analysis, it is not the subset, to be release are supported, it’s just a particular analysis to emphasize the point that there are subjects in ENGAGE, whom if they do have sufficient dosing, do support the outcome of EMERGE.

I would also say Ronny that the, PET was done in a subset of patients to – so the numbers that you see on the left side, which is the amyloid-PET are from – the only the subset who got the PET imaging.

And the numbers on the right, that’s still not the complete set, this is just a – some sort of a subset.

That’s correct.

And the second question was around, high dose TYSABRI?

IP protection for TYSABRI.

So what we would say that Ronny it’s Jeff, is obviously what we can see kind of what happens with regard to the Phase 3 trials that are going on with regards to biosimilars and we’re supportive of biosimilars coming into the market. We obviously have biosimilars business. We just have to see how their products do and we’ll deal with it when it comes.

And probably we have time for about two more questions.

Thank you. Your next question comes from the line of Jay Olson from Oppenheimer. Please go ahead.

Well, hi. First off, I want to congratulate you for hanging in there and delivering these aducanumab results today. This is very promising news for Alzheimer’s patients and their families. And second of all, I want to thank you for taking my questions. Can you comment on the clinical meaningfulness of aducanumab’s efficacy profile and how does it line up with your target product profile in terms of improvements in cognition and function. Are there any gaps in the profile as you know it now, and how do you know if you optimize the efficacy at the 10 mg per kick dose or would it make sense to test higher doses? Thank you.

Jay, I’ll start and then Samantha will follow up. We believe it is clinically meaningful, we heard that anything above 20% is clinically meaningful as a neurologist being the first drug of its – of its kind we have no drugs right now that affect the clinical decline in Alzheimer’s disease. This would be the very first. So anything North of 20%, we believe is clinically meaningful and I would also add that – in clinical practice. I think that MCI patients, will be – if approved though enjoy the benefit of living an more independent life for longer periods of time. If you look at that AD, the activities of daily living, It’s a 40% effect and that’s a caregiver assessment of whether or not that the patients can live independently, can do their household chores, etcetera so. That’s all very clinically meaningful results.

There’s a question around the dose to 10 mgs?

Yes. So the question of whether we had achieved the correct dose. I think what we have learned clearly is that dose is very important, but that if individuals do receive 10 milligram per kilogram then they do have an efficacious response. I think the trials unfortunately were hampered by a number of operational and other implications that meant – that not enough patients got 10 milligram per kilogram, so we do believe that would be the correct dose.

Great, thank you.

Your last question comes from the line of Paul Matteis from Stifel. Please go ahead.

Great, thanks for fitting me in. Really appreciate it. Within the high dose arm in the ENGAGE study, can you talk about the magnitude of plaque reductions you observed in patients who titrated all the way up to the highest dose versus patient who ever stopped at 6 mg per kg and I guess, does a differential magnitude of plaque reduction in those patients that I’ll tell the same narrative you’re seeing on the difference in clinical outcomes? And then can you just tell us anything else about other measures of function in the engage subset of patients, who titrated all the way up to 10 mgs per kg? Thanks so much.

Thank you. So, to your first question in amyloid plaque reduction, we do believe that PET measurement of amyloid plaque reduction is a very sensitive tool of dose and you’ve correctly identified that ENGAGE at the high dose is showing a lower reduction than in EMERGE and we do believe that, that is a clear reflection of the lower doses that were achieved in that high dosing group in ENGAGE. And the second question was.

Other measures that function...

Other measures that function. Yes, so the exploratory analysis that we have demonstrated for you, we focused on the primary endpoint, and we do not have the same analysis for the functional endpoints, but you do have those results for the overall study where even in ENGAGE, we do have some response on the functional scores, albeit not statistically significant.

Okay, thank you. And I’ll turn it back to Michel for some closing comments.

So thank you all for attending our Q3 call characterized by the go-to file decision for aducanumab with the US FDA, but also with a solid performance for the quarter. Today is about hope and opportunity for the patients first but also for the shareholders. Have a good day.

Thank you. Ladies and gentlemen, this concludes today’s conference call. Thank you for participating. You may now disconnect.