Q3 2019 Earnings Call

After the speaker's remarks, there will be a question and answer session. If you'd like to ask a question. During this time simply press Star then the number one on your telephone keypad. Please limit yourself to one question to allow other participants time for questions. If you require any further follow up you May press star one again to rejoin the queue. Thank you I'd now like to turn the conference.

Operator: There will be a question and answer session. If you would like to ask a question during this time, simply press star, then the number one on your telephone keyboard. Please limit yourself to one question to allow other participants time for questions.

Operator: If you require any further follow-up, you may press star 1 again to rejoin the queue. Thank you. I would now like to turn the conference over to Mr. Joe Marra, Vice President, Investor Relations. You may begin your presentation. 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 adecanamab, 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 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.

<unk> Mr., Joe Moore, Vice President Investor Relations you May begin your conference.

Good morning, everyone welcome to Biogens third quarter 2019 earnings conference call on today's call will be discussing our Q3 results as well as an update on our old timers program out of Canada, including our plan to file in the U.S.

Before we begin I encourage everyone to go to investors section a barge and dotcom.

Finally earnings release.

The 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 wanting to and table. Three includes a reconciliation of our GAAP to non-GAAP financial results. We believe non-GAAP financial results better represent the ongoing economic so my business and reflect how we manage the business.

Internally, we've also posted slides on our website that follow the discussion later this call.

Joe Marra: 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 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 FCC filings for additional details.

Joe Marra: I encourage you to consult the risk factors discussed in our SEC filings for additional detail. On today's call, I'm joined by our Chief Executive Officer, Michelle Venazos, Dr. Al Sandrock, EVP, Research and Development, and our Chief Medical Officer, Dr. Samantha Budd Haberlein, Vice President, Late Stage Clinical Development, and our CFO, Jeff Capello. Now I will turn the call over to Michelle. Thank you, Joe, and good morning, everyone.

On today's call I'm joined by our Chief Executive Officer, Michelle, but not sows Dr. out Sandrock E V P research and development and our Chief Medical Officer, Dr., Samantha, but Heberlein Vice President late stage clinical development and our CFO , Jeff Capello now I will turn the call over to Michelle. Thank you Joe.

Hello, and good morning, everyone.

Michelle Venazos: 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 EducandyMap. Next, I will provide the key highlights of a strong quarter. Al and Samantha will then provide additional details on Adukanimab and progress across the rest of our pipeline. Geoff will discuss our financial performance for Q3, and I will close before we open the call for questions.

I will stop by giving you an outline of these calls she's got announcing Bull Q3 results a news on your garden Bob.

First I will review the recent views on that you couldn't you Matt.

Next I will provide the key highlights office trough quarter.

And some myself will then provide additional details on I'd you can I just couldn't mob and progress of course, the rest of all the pipeline.

Jeff will discuss our financial performance for Q3, and I will close before we open the call for questions.

Michelle Venazos: This is an important day as we are announcing that, based on discussions 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.

This is an important day as we are announcing that based on discussions with the FDA. We plan to submit yeah. That's we'll be filing in the U.S. as you can you Bob.

If approved as you can you might want to become the [laughter] therapy to reduce Guinea could decline in as I Miss disease, and the first therapy to show that we moving I mean, we've been talked can lead to better clinical outcomes.

This is an important milestones providing cope patients.

Patients caregivers and families around the world.

He is also important to highlight that the they can interpret shutoff discovering and developing Brexit treatments is not total waste direct and straightforward.

Michelle Venazos: 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 early Alzheimer's disease based on a pre-specified fertility 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 data set comprised only of patients who had the opportunity to complete 18 months of treatment as of December 26, 2018.

As you know in March we announced our decision to discontinue the fifth street emerge and engage studies flood you can you maybe early does I missed disease based on a pre specified for GTT analysis.

In retrospect, the reason I suppose could you be Kennedy's Easter was in correct.

Based on what we know now it's clear that the pre specified for GTT criteria did not adequately UNFI paid the effect of old about your boards in these trials.

So what happened.

First the decision to still be strives relied on in the failure and motivate US said comprised of oney hofh patients who had the opportunity to complete 18 months old treatment as of December 26, 2018.

Michelle Venazos: At that time, the futility analysis predicted that the trials were unlikely to meet their primary endpoint upon completion. Futility analyses are common in lab studies, and they use statistical modeling to attempt to predict the outcome of the studies based on a number of pre-specified assumptions and criteria. There are multiple methodologies that can be used for futility analysis, and the methodology we used was a well-accepted approach.

At that time, <unk> and their disease predicted that the trials were unlikely to meet the primary endpoint upon completion.

[laughter] GTT on their disease, a common in lock studies and they use statistical modeling to attempt to predict the outcome of the studies based on a number of pre specified assumptions and criteria.

Then we keep ordered methodologies that can be useful for TD generated and the middle did you. We used was it well accepted approach.

Michelle Venazos: However, based on what we have learned, we know now that the futility analysis did not adequately account for the effect that the earlier enrollment in N-GAGE had on patients' overall exposure to high-dose aducanumab. Second, in the month following the discontinuation of these studies, our team has continued to analyze the vast set of clinical imaging and biomarker data that the studies generated. In addition to further analysis of the data set which informed the futility analysis, we also gained access to and analyzed additional data, including data on patients who completed treatment after the cut-off date for the futility analysis, as well as data for patients who did not complete the full duration of the study. Once we became aware of the potential implications of this larger dataset, we consulted with external advisors, followed by the FDA at a type C meeting in June, as we began conducting further analysis.

However, based on what we have learned we know now that this <unk> did not adequate he account for the effect that the.

Enrollment in engage hot on patients overboard exposure to Heidi daus educating Bob.

[laughter] chicken.

The month following the discontinuation of the studies our team has continued to analyze the vast set of clinically imaging and biomarker data that the studies have generated.

In addition to for the and that easy something because said Twitch informed if we could be kidney disease. We also gained access to and analyzed additional data, including big though on patients who competed treatment. After the cutoff date for the for TD kidney disease as well as data for patients who did not complete.

The full duration of the study.

Once we became aware of the potential implication of this allowed to dataset, we consulted with external advisors followed by the F.D.. We did type C meeting in June as Weve begun conducting for the analysis.

So.

Michelle Venazos: Third, the new analysis of the larger dataset, which was conducted in consultation with the FDA, showed that aducanumab had a dose-dependent effect on the underlying pathology as measured by amyloid PET imaging and reduced clinical decline in patients with early Alzheimer's disease as measured by the pre-specified primary and secondary endpoints. Based on a second type C meeting held with the FDA just yesterday, we believe these data support irregulatory filing. Beyond aducanumab, we are hopeful about the implications of these results for similar approaches targeting amyloid beta, including BAN2401. Looking forward, we plan to submit a regulatory filing in the U.S. in early 2020 and will continue dialogue with regulatory authorities in international markets, including in Europe and Japan.

The new one not easy something larger deficit, which was conducted <unk> they shouldn't we be XT eight.

Showed that I, just couldn't emad had it dose dependent effect on the underlying but to the G as measured by immediately but imaging and.

Reduce clinical decline in patients with early Alzheimer's disease as measured by the pre specified primary and secondary endpoints.

Based on the Sickens type C meeting held with the if you just yesterday. We believe these day does to bolt yeah. Good luck to refine link.

Beyond the Aducanumab, we are hopeful about the implication of these results for she Milano approaches Bucketing I mean, the we'd been <unk>, including bond 24 or one.

Looking forward, we plan to send me doing literally funding in the U.S. Yoo early 2020 and we continued dialogue with regulatory authorities in international markets, including in Europe and Japan.

Most importantly, we hobby <unk> commitment to the patients community starting with those who participated in our clinical trials.

Michelle Venazos: Most importantly, we have a deep commitment to the patient community, starting with those who participated in our clinical trials. We aim to offer access to aducanumab as soon as possible to eligible patients previously enrolled in the Phase III studies, the long-term extension of the Phase I, Prime B study, and the Phase II, Evolved study. We will work towards this goal with regulatory authorities, principal investigators, and institutional review boards with a sense of urgency. I know this development is unexpected for all our stakeholders, including the many patients involved in our clinical studies and their families, our investigators, our investors, and our employees, and I'm sure you have a lot of questions. We were also surprised when we initially learned about the potential implications of this additional data, but our surprise quickly turned to the hope that we may be in the position to offer Alzheimer's patients the first therapy to reduce clinical decline in this devastating disease.

We this you both of the F.D.

We aim to offer accessed why did you can you Bob I soon I suppose she bought two eligible patients previously enrolled in this phase three studies the long term extension of this phase one prime B study and the face to evolve study.

We will work towards these goals, we just take led to a three keys principal investigators and be institutional review boards, we the sun.

Urgency.

I know these developments he's unexpected for all our stakeholders, including the many patients involved you know a clinical studies and their families. Our investigators Oh investors and I'm pleased.

And I'm sure you'll have a lot of questions.

We will also surprised when we initially learned about the potential implication of these additional data, but I was surprised quickly turn to the hope that we may be the position to offer as I'm, especially since the first therapy to reduce pinnacle decline in these devastating disease.

We are humbled and honored by this opportunity.

Michelle Venazos: We are humbled and honored by this opportunity, and we are committed to following the science and doing the right thing for patients. Now, let me review some financial highlights from the third quarter. Compared to the same period a year ago, Biogen delivered solid top-line and bottom-line growth. Third quarter revenues grew 5% to $3.6 billion. Third quarter GAAP earnings per share grew 17% to $8.39, and non-GAAP EPS grew 24% to $9.17.

And we are committed to following the science and doing the right thing for patients.

Now, let me review some financial highlights from this quarter.

Compared to the same better go to your goal Biogen Deleveraged, Saudi topline and bottom line growth.

So quarterly reviews grew 5% to 3.6 billion dollar third quarter GAAP earnings per share grew 17% to $8 in such a nice sense and non-GAAP , yes, 20%, 24% to nine 2017 cents noted me briefly review progress.

Michelle Venazos: Now, let me briefly review our progress against our strategic business priorities. First, we continue to demonstrate resilience in AMES, and we remain focused on addressing the IP challenge with TechFedera, while also preparing for the expected launch of Umerit. Second, Spinraza revenues grew double digits both year over year and quarter over quarter.

So again, so how did you can business priorities first we continue to demonstrate resiliency in M.S. and we remain focused on addressing the IP challenge, we fix either a well also preparing for the expected launch of the memory T.

Second Spinraza revenues grew double digit both year over year and quarter over quarter.

Michelle Venazos: Third, our biosimilars business continues to grow, led by the recent launch of Imral B. Fourth, we continue to progress our pipeline with a positive readout on Vumerity and the addition of two new clinical programs. And fifth, Biogen has continued to be disciplined and focused on capital allocation. As we have demonstrated, we are committed to maximizing returns for our shareholders while continuing to bring innovative therapies to patients. Something that demands a thoughtful approach to all our investment over both the short-term and the long-term.

Third I would buy you will see me those piece, that's going to integral led by the recent launch of Im hobby.

Well, we continue to progress our pipeline, we depositi readout on humility and the addition of two new clinical programs.

And [laughter] Biogen has continued to be disciplined and focused on therapy center location.

As we have demonstrated we are committed to maximizing returns for our shareholders. While continuing to bring you know about TCEP used to patients something that demand is successful approach towards olo investment over both the short term and the long term.

Before turning the corner over to either.

Michelle Venazos: Before turning the call over to Al, I would like to congratulate him on his new role as the head of R&D at Biogen. I know I speak for the broader Biogen family in expressing my confidence in Al as a scientist, as a clinician, and as a leader. Al is taking the helm at a time when I believe Biogen R&D has never been stronger, and I believe he's well equipped to continue driving Biogen R&D forward.

I would like to congratulate him on his new role as the head of R&D at Biogen.

I know I speak for the broader Biogen 5 million expressing my confidence in <unk> as a scientist as it commission and as the leader.

He sticking to the head and at the time when I believe Biogen R&D has never been stronger.

And I believe he is well equipped to continue driving Biogen R&D forward.

Geoffrey Christopher Meacham: Thank you, Michelle. 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 Michelle said, we were all surprised when we learned of the potential implications of the new analysis of a larger data set from the Phase III studies of aducanumab. Following discussions with external advisors and the FDA, we have now come to better understand what happened and, even more importantly, what the positive implications of the larger data set 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 analyses that have led us to the current conclusions and status today,

Thank you Michelle.

Before diving and 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 educating your Matt and I believe now more than ever the Biogen is uniquely positioned to bring breakthroughs in neuroscience and transform the lives of patients with neurological disease.

As Michelle said, we were all surprised when we learned of the potential implications of the new analysis of a larger data set from the phase three studies about you Canyon Matt.

Following discussions with external advisors and the F.D.A., we have now come to better understand what happened and even more importantly, what 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 three data before I turn the call over to Samantha we will describe in more detail. The series of events in analyses 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.

Geoffrey Christopher Meacham: First, it is important to understand 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 data set 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 employees. This reduction in clinical decline was statistically significant in eMERGE, and we believe that data from patients who achieve sufficient exposure to high dose aducanumab and engage support the findings of eMERGE. After consultation with the FDA, we believe that the totality of these data support a regulatory filing. Importantly, patients included in the futility analysis were those who had enrolled early in the trials.

Which we have analyzing consultation with the FDA or 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 as you can you mad reduced clinical decline across multiple clinical endpoints.

This reduction in clinical decline was statistically significant and emerge and we believe that patients that that's that data from patients who achieve sufficient exposure to high dose as you can you maybe in engage support the findings of emerge.

After consultation with the FDA, we believed that the totality of these data support a regulatory filing.

Importantly patients included in the futility analysis, where those would enrolled early in the trials and those early enrolling patients had a lower average exposure to add you can imagine in large part due to two protocol amendments that occurred sometime after the started the trials. These two protocol amendments were put in place precisely to enable.

Geoffrey Christopher Meacham: And those early enrolling patients had a lower average exposure to aducanumab, in large part due to two protocol amendments that occurred sometime after the start of the trials. These two protocol amendments were put in place precisely to enable more patients to reach high-dose aducanumab and for a longer duration. As a consequence, the larger data set available after trial cessation included more patients with sufficient exposure to high-dose aducanumab. Moreover, differences between eMERGE and eNGAGE can mostly be accounted for by a greater level of exposure to high-dose aducanumab in eMERGE due to multiple factors, including the fact that eNGAGE started earlier and enrolled earlier than eMERGE, meaning that Taken together, we believe that these data and the associated extensive analysis provide compelling evidence that aducanumab reduces the otherwise devastating and inexorable clinical decline of Alzheimer's disease. To expand further, I will now hand the call over to Samantha.

A more patients to reach high dose Edu Canyon, mad and for a longer duration.

As a consequence, the larger data set available after trial cessation included more patients with sufficient exposure to high dose that you can you Matt.

Moreover, differences between emerge and engaged can mostly be accounted for by a greater level of exposure to high dose edgy Canyon, Matt in emerge due to multiple factors, including the fact that engage started earlier and enrolled earlier than emerge meaning that fewer patients any engage had sufficient exposure to high dose as you can you may.

As well as other factors, including differences in the degree of dose suspension due to ARIA.

Taken together, we believe that these data and the associated extensive analysis provide compelling evidence that adds you can you may have reduces the otherwise devastating and inexorable clinical decline of all simers disease to expand further I will now hand, the call over to Samantha.

Samantha Budd Haberlein: 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 multi-center, 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. At 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, the incidence 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.

Thank you I'll, 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 where phase three multi center randomized double blind placebo controlled parallel group studies designed to evaluate the efficacy and safety of I'd you can imagine in early Alzheimer's disease.

The studies were identical design.

Full enrollment emerge included 1638 patients and engage included 1647 patients.

Based on the data from the phase one be prime study a bunch of Kenyan matter, we believed that higher doses. Aside you can you, Matt maybe associated with improved clinical outcome.

However, as the incidence of amyloid related imaging abnormality ARIA for short the most common adverse event associated with that you can imagine also increased with and you can you map dose and occurred more often in April E. Four carriers. The non carries the phase three studies had a number of.

Samantha Budd Haberlein: The Phase III studies 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 mg per kg for ApoE4 carriers and 6 mg per kg for non-carriers, where as the high dose was initially defined as 6 mg per kg for ApoE4 carriers and 10 mg per kg for non-carriers. Results from the PRIME study for ApoE4 carriers titrated to 10 mg per kilogram became available in August 2016. These data showed that the incidence of ARIA, as well as discontinuations from treatment due to ARIA, in APOE4 carriers receiving aducanumab titrated to 10 mg per kg, appeared to be reduced as compared to the fixed-dose cohorts.

Design elements, such as titration dose levels and management with the enterprise to mitigate and manage the risk of Oreo.

In addition, dosing is that you came up with stratified by April equal carry a status.

The low dose was defined as three milligram per kilogram equally for carriers and six milligram per kilogram for non carriers.

Where's the high dose was initially defined a six milligram per kilogram equally for carriers and 10 milligram per kilogram for non carriers.

Results from the Prime studies equally for carriers titrated to 10 milligram per kilogram became available in August 2016.

These data showed that the incidence of ARIA as well as discontinuations from treatment Jude ARIA and equally for carriers, receiving and you can you Matt Titrated to 10 milligram per kilogram appeared to be reduced as compared to the fixed dose cohort.

Samantha Budd Haberlein: 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 to 10 mg per kilogram. Of note, in each study, approximately two-thirds of enrolled patients were ApoE4 carriers, and the number of carriers was well balanced across each of the arms of both studies. Each dose arm had a titration period such that the maximum number of monthly 10 mg per kg doses that any patient in the high dose group could receive in the 18 month study was 14. Moreover, the original protocol recommended that some patients with ARIA suspend their dosing and then restart and remain at a lower dose. Engage enrolled its first patient in August 2015, and Emerge began enrolling patients approximately one month later in September 2015.

Following this analysis the protocols for the ongoing phase three studies were amended such that the high dose in April E. Four carriers would then be increased from six to 10 milligram per kilogram.

Of note in each study approximately two thirds of enrolled patients were equally for carriers and the number of carriers was well balanced across each of the arms of both studies.

Each dose on how to tie traction period, such that the maximum number of monthly 10 milligram per kilogram doses that any patient in the high dose group could receive in the 18 months study was 14.

Moreover, the original protocol recommended that some patients with ARIA suspend the dosing and then restart and remain at a lower dose.

Engage enrolled its first patient in August 2015, and emerge began enrolling approximately one month later in September 2015.

Samantha Budd Haberlein: Two key amendments were made to the protocols during the conduct of the study. In July of 2016, we amended the protocol to allow patients with ARIA who suspended dosing to resume aducanumab treatment at the originally assigned dose. And then, in March of 2017, as I mentioned, the protocol was amended to increase the high dose for ApoE4 carriers from 6 to 10 mg per kg after titration.

Two key amendments made to the protocols during this conduct of the study.

In July of 2016, we amended the protocol to allow patients with ARIA who suspended dosing to resume as you can imagine treatment at the originally assigned dose.

And then in March of 2017, as I mentioned, the protocol was amended to increase the high dose I, probably four carriers from six to 10 milligram per kilogram off to tie traction.

Samantha Budd Haberlein: Taken together, these protocol amendments had the effect of allowing more patients to receive their target dose. Since enrollment in ENGAGE had begun and remained ahead of eMERGE, overall, more patients in eMERGE were impacted by the protocol amendments and received the 10 milligrams per kilogram dose of aducanumab. On March 21, 2019, we announced the termination of Emerge and Engage following the outcome of a pre-specified fut

Taken together these protocol amendments had the effect of allowing more patients to receive that target does.

Since enrollment in engage had begun and remained ahead of emerge overall more patients in emerge were impacted by the perch called amendments and received the 10 milligram per kilogram dosing of educating map.

On March 21, 2019, we announced the termination of emerge and engage following the outcome of a pre specified futility analysis.

Samantha Budd Haberlein: The futility analysis was based on efficacy data for all patients in the two trials who had enrolled early enough to have had the opportunity to have completed the 18-month study period by December 26, 2018. Futility criteria, which were pre-specified in the statistical analysis plan, would be met if both arms of both trials were predicted to have had less than 20% probability of being positive at the end of the study. This probability used pooled data from the two trials to predict the future behavior of the remaining patients. This is a well-accepted statistical methodology for two trials that are identical in design, such as eMERGE and ENGAGE. However, this pooling methodology assumes no large heterogeneity between the studies.

The futility analysis was based on efficacy data on older patients in the two trials, who had enrolled early enough to have had the opportunity to have completed the 18 months study period by December 26, 2006 2018.

Futility criteria, which were pre specified in the statistical analysis plan would be met if both arms of both trials. We are predicted to have had less than 20% probability of being positive on the primary endpoint at the end of the study.

This probability used to cool data from the two trials to predict the future behavior of the remaining patients.

This is a well accepted statistical methodology for two trials that are identical in design such as emerge and engage however, this pooling methodology assumes no large heterogeneity between the studies.

At the time of the futility analysis and merge was trending positive while engage was note.

Samantha Budd Haberlein: At the time of the futility analysis, Emerge was trending positive, while Engage was not. We did not understand the drivers of these different results. While we did know that the protocol amendments could have had differential effects on the two studies due to the relative timing of enrollment, we did not anticipate the magnitude of the effect this would have on the data. Following the discontinuation of EMERGE and ENGAGE, additional data from these studies became available, namely the 2,066 patients who had the opportunity to complete the full 18-month study period by March 20th, as well as all 3,285 patients who had enrolled Importantly, once we had applied the pre-specified statistical analyses to the larger dataset, we were excited to see that eMERGE met its primary endpoint on CDR-Summer boxes or CDR-SB.

We did not understand the drivers of these different results.

While we did note that the protocol amendments could have had differential effects on the two studies due to the relative timing of enrollment we did not anticipate the magnitude of the effect. This would have on the data.

Following the discontinuation of emerge and engage additional data from these studies became available, namely the 2066 patients who had the opportunity to complete the full 18 months study period by March 20, as well as all 3295 patients who had.

Enrolled in the trials in what's known as the intent to treat all righty T. population.

Importantly, once we had applied the pre specified statistical analyses to the larger dataset. We were excited to see the emerge met its primary endpoint on CD or some of boxes or CD RSP.

Samantha Budd Haberlein: CDRS-B scores are obtained through clinician interviews of patients and caregivers and assess three domains of cognition and function, namely memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care. Specifically, in the intent-to-treat population, patients from the high-dose aducanumab group showed a 23% reduction in clinical decline from baseline in CDRS-B scores at 78 weeks, with a The corresponding result in the Opportunity to Complete or OTC dataset was also 23%, with a nominal p-value of 0.03. The low-dose group also had less decline on the CDRS-B than placebo. However, the differences were smaller than in the high-dose group and did not attain statistical significance.

C. D. RSP schools are obtained through clinician into views of patients and caregivers and assess three domains each of cognition and function, namely memory orientation judgment and problem solving community affairs, Herman hobbies and personal care.

Specifically in the intent to treat population patients from the high dose educating about group showed a 23% reduction in clinical decline from baseline in CDR recipe schools at 78 weeks with a P value of 0.01.

The corresponding result in the opportunity to complete or LTC dataset was also 23% with a nominal P value of 0.03.

The low dose group also had less decline on the CD RSP than placebo. However, the difference is was smaller than in the high dose group and did not attain statistical significance.

Samantha Budd Haberlein: In eMERGE, patients on high-dose aducanumab also showed a reduction in clinical decline as measured by MMSE, with a p-value of 0.06, a 27% reduction in clinical decline as measured by ADASCOG 13 with a p-value of 0.01, and a 40% reduction in clinical decline as measured by ADCS-ADL-MCI with a p-value of 0.001. A small numeric advantage for low dose over placebo was observed in all endpoints except for MMSE. MMSE and ADAS-CoG are measures of cognitive performance in domains relevant to Alzheimer's disease, such as memory, orientation, and language. ADCS ADL MCI, on the other hand, is a caregiver-rated assessment of activities of daily living, including conducting personal finances, performing household chores such as cleaning, shopping, and doing laundry, and independently traveling out of the home.

In emerge patients on high dose educating <unk> also showed a reduction in clinical decline as measured by the pre specified secondary endpoints.

Specifically, we saw a 15% reduction in clinical decline as measured by and the messy with a P value of 0.06, a 27% reduction in clinical decline as measured by eight us coax 13, with a P value of 0.01.

And a 40% reduction in clinical decline as measured by 80 C. S. HDL MCR <unk> with a P value of 0.001.

A small numeric advantage for low dose over placebo was observed on all endpoints except for in the messy.

And then Missy and Adas cog images of cognitive performance in domains relevant to Alzheimer's disease, such as memory orientation and language.

80 C S 80 out and see I on the other hand is a can't give a rated assessment of activities of daily living including conducting personal finances, performing household chores, such as cleaning shopping and doing laundry an independently traveling out of the home.

In engage the primary endpoint was not match.

Samantha Budd Haberlein: In ENGAGE, the primary endpoint was not met, though the low dose showed results similar to the low dose of the merge. Results of the ITT and OTC analyses of the secondary endpoints in ENGAGE showed no statistically significant differences in decline on MMSE, ADAS-CoG-13, or ADCS-ADL-MCI compared with placebo. However, small numeric advantages for the low dose over placebo were observed on these endpoint

Though the low dose.

Results similar to the low dose the message.

Results of the I.T.T. and OTI see analyses of the secondary endpoints in engage showed no statistically significant differences in decline on M. A C. Eight us Coke 13, or 80 C S HDL and siani compared with placebo, however, small numeric advantages.

For the low dose of a placebo were observed on these endpoints.

In addition to the clinical data, we observed supporting data from multiple Biomarkers imaging of amyloid plaques de position in both studies demonstrated that treatment without you can imagine resulted in a dose and time dependent reduction in amyloid plaques bowden compared to placebo with P values left.

Samantha Budd Haberlein: In addition to the clinical data, we observed supporting data from multiple biomarkers. Imaging of amyloid plaque deposition in both studies demonstrated that treatment with aducanumab resulted in a dose and time-dependent reduction in amyloid plaque burden compared to placebo, with p-values less than 0.001. The magnitude of the reduction in the high doses is similar to that seen in the Phase 1B study. Adjikanyimab also demonstrated an impact on CSF biomarkers of tau pathology. A statistically significant reduction in CSF phospho-tau levels was observed in Emerge and Engage, with a dose-proportional response in Emerge.

And 0.001.

The magnitude of production in the high doses is similar to that seen in the phase one be study.

I'd you can imagine also demonstrated an impact on CSF biomarkers of tower pathology.

A statistically significant reduction on CSF Foster hotel levels was observed in emerge and engage with a dose proportional response in a much.

Samantha Budd Haberlein: Aducanumab produced a numeric reduction in CSF total tau levels in eMERGE and ENGAGE, with a dose proportional response in eMERGE. Although the primary and secondary endpoints were not met in ENGAGE, in post-hoc analyses, the subset of patients who received sufficient exposure to 10 mg per kg aducanumab, in this case at least 10 doses of 10 mg per kg, showed similar results to the comparable population from eMERGE in terms of both amyloid plaque reduction and reduced clinical decline on CDRS-B. The safety and tolerability profile of aducanumab in eMERGE and ENGAGE was consistent with previous studies of aducanumab, with the most commonly reported adverse event being Aria E and headaches. Although the underlying cause of ARIA-E is not well understood, it is likely that the MRI signal of ARIA-E is due to increased extracellular fluid. The majority of patients with ARIA-E did not experience symptoms during the ARIA-E episode, and ARIA-E episodes generally resolved within 4 to 16 weeks, typically without long-term clinical sequelae.

As you can you imagine produced and numeric reduction in CSF total account levels in emerge and engage with a dose proportional response in emerge.

Although the primary and secondary endpoints would not met in engage in post talk analysis, the subset of patients who receive sufficient exposure to 10 milligram per kilogram as you can imagine in this case at least 10 doses of 10 milligram per kilogram per kilogram showed similar results.

To the comparable population from emerge in terms of both amyloid plant production and reduce clinical decline on CD RFP.

[noise] safety and Tolerability profile of educating them in emerging engage with consistent with previous studies of educating them with the most commonly reported adverse event being ARIA E and headache.

Although the underlying cause of ARIA is not well understood. It is likely that the M or I signal of already is due to increased AXT extra cellular fluid.

The majority of patients with our <unk> did not experience symptoms during the ARIA episode and our E episodes generally resolved within four to 16 weeks typically without long term clinical sequentially.

Samantha Budd Haberlein: We plan to present further details on the new analysis of the larger dataset from Adjikanimat at the CTAD meeting in December, which we plan to webcast. But, first, across multiple clinical endpoints, the larger aducanumab dataset demonstrated a statistically significant reduction of clinical decline in early Alzheimer's disease patients in eMERGE, and we believe that data from a subset of ENGAGE support these findings. Second, exposure to high-dose aducanumab was important for efficacy, and differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies. Finally, following consultation with the FDA, we believe it is reasonable to submit a regulatory filing for aducanumab based on these data.

We plan to present further details on the new analysis of the larger dataset from educating but at the Sicad meeting in December which we plan to webcast.

So to summarize fast across multiple clinical endpoints. The larger I'd you came up dataset demonstrated a statistically significant reduction of clinical decline in early Alzheimer's disease patients and emerge and we believe that data from a subset of engage support these findings.

Second exposure to high dose educating Matt was important for efficacy and differences and exposure to high dose and you can imagine largely explained the different result.

Futility analysis and the new analysis of this larger dataset as well as the different results between the two studies.

Finally, following consultation with the FDA, we believe it is reasonable to submit a regulatory filings as you can you map based on these data.

Samantha Budd Haberlein: As Michelle and Al mentioned, the path that brought us to today was long and complex. We will be working with our investigators to re-dose eligible patients who had previously participated in the aducanumab clinical trial, and we look forward to working with the FDA as well as regulators around the world to find a path to make the drug available to patients. Most importantly, we envisage a future where physicians may finally have an option to offer patients to help reduce clinical decline in Alzheimer's disease. I'll now turn it back over to Al.

As Michelle and Al mentioned, the past that brought us to today was long and complex, we will be working with our investigators to reduce eligible patients who had previously participated in the I'd. You can you met clinical trial, and we look forward to working with the F.D.A. as well as regulators around the world to file.

<unk> to make the drug available to patients.

Most importantly, we envisage a future where physicians may finally have an option to offer patients to help reduce clinical decline in Alzheimer's disease.

I'll now turn it back over to out thank you Samantha.

Geoffrey Christopher Meacham: 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 that 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 III study in early Alzheimer's disease in collaboration with ACI.

We believe that these positive results for educating you may represent a turning point for patients caregivers physicians and scientists in the fight against all Simers disease more broadly. We believe these results represent an inflection point in neuroscience drug development and validate our core strategy.

By demonstrating that removal of aggregated forms of amyloid beta can result in improved clinical outcomes. We believe these results have positive implications for band to 401, a distinct antibody that also targets aggregated amyloid beta that we're currently evaluating into phase three study in early all saying.

This disease in collaboration with a site.

Geoffrey Christopher Meacham: More generally, we believe these data may have positive implications for additional assets in our portfolio that target the causal pathobiology of neurodegenerative disease, particularly those validated by human genetics. These include our tau-directed aspects for Alzheimer's disease and primary tauopathies, our alpha-synuclein antibody for Parkinson's disease, and our SOD1 and C9-ORF-targeting antisense oligonucleotides for Given our depth of expertise, and 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.

More generally we believe these data may have positive implications for additional assets in our portfolio a target the causal Paso biology of neuro degenerative disease, particularly those validated by human genetics.

These include our tile directed assets for Alzheimer's disease, and primary Taiwan, but these are alpha synuclein antibody for Parkinsons disease, and our Esso de won and see nine or targeting a antisense oligonucleotides for L.S.A.O.L.S.

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 M.S.

Geoffrey Christopher Meacham: This quarter, we announced positive top-line results from EVOLVE-MS-2, a Phase III study of Vumerity, or Deroximal Fumarate, a novel oral fumarate for relapsing-remitting multiple sclerosis, compared to Tecfidera. Vumerity was statistically superior to Tecfidera on the study's pre-specified primary endpoint, the individual The proportion of patients who discontinued due to GI adverse events during the five-week treatment period was 0.8% for Vumeriti and 4.8% for Tecfidera. Of note, this continuation rate for Tecfidera is similar to that observed in the Phase III studies of Tecfidera, in which 4% of patients discontinued due to GI events. Earlier this month, Alkermes received tentative approval from the FDA for Brumerity. We are working with Alkermes and the agency to secure final approval as quickly as possible. Moving to Tysabri.

This quarter, we announced positive top line results from evolved M.S. to a phase three study of America or the rock similar Fumarate and novel oral Fumarate for relapsing remitting multiple sclerosis compared to tech for Dara Meritor was statistically superior to tech for dairy under studies pre specified primary endpoint IC.

As you all gastrointestinal symptom and impact scale with a P value of 0.0003.

The proportion of patients who discontinued due to G.I. adverse events during the five week treatment period was 0.8% for Mary and 4.8% for Tech for Dara of note. This continuation rate for Tech Proterra is similar to that observed in the phase three studies of text idera in which 4% patience.

When you do to G.I. events.

Earlier this month Alkermes received a tentative approval from the F.D.A. for Blue Meredith, we are working without alkermes and the agency to secure final approval as quickly as possible.

Moving to Tysabri previous analysis of real World data from the U.S. touch registry demonstrated that extended interval dosing of tysabri reduced the risk of PML by between 78 and 99% in this population however, whether extended interval dosing preserves the efficacy profile profile.

Geoffrey Christopher Meacham: Previous analysis of real-world data from the U.S. Touch Registry demonstrated that extended interval dosing of Tysabri reduced the risk of PML by between 78 and 99 percent in this population. However, whether extended interval dosing preserves the efficacy profile of Tysabri remains an open question. To this end, at last month's ECTRIMS meeting, we presented data on the efficacy of extended interval dosing with Tysabri using data from the Tysabri observational program. After propensity score matching, the results indicated that there was no significant difference in annualized relapse rate or risk of relapse between the two groups.

Tysabri remains an open question do this and at last month's ECTRIMS meeting, we presented data on the efficacy of extended interval dosing with Tysabri using data from the Tysabri observation on program.

After propensity score matching the results indicated that there was no significant difference and annualize relapse rate or risk of relapse between the two groups.

And we recently completed enrollment for the phase three be Nova study of Tysabri at two year randomized prospective trial that will directly compare the effectiveness of every six week dosing versus the approved every four week dosing regimen. After at least one year of standard dosing.

Geoffrey Christopher Meacham: And we recently completed enrollment for the Phase 3B NOVA study of Tysabri, a two-year randomized prospective trial that will directly compare the effectiveness of every six-week doses versus the approved every four-week dosing regimen after at least one year of standard dosing. Also this quarter, the EMA updated the labels of Avonex and Pelagridi to remove pregnancy contraindications and, where clinically needed, to allow use during pregnancy and breastfeeding in women with relapsing MS. With these updates, interferon beta therapies are the only MS treatments in Europe that can be considered for use in MS patients throughout the full course of pregnancy. This is important given that women are diagnosed with MS at least 2-3 times more frequently than men, and women are often affected during their childbearing years.

Also this quarter the yeah may updated the labels of Avonex and PLEGRIDY to remove pregnancy, contra indications and where clinically needed to allow used during pregnancy and breast feeding in women with relapsing a mess with these updates interferon beta therapies are the only M.S. therapies in Europe , there can be considered for.

Use in M.S. patients throughout the full course of pregnancy.

This is important given that women are diagnosed with M.S. at least two to three times more frequently than men and women are often affected during their childbearing years.

Geoffrey Christopher Meacham: Turning to our progress in neuromuscular disorders, at last month's Congress of the European Pediatric Neurological Society, we presented new interim data from the open-label SHINE extension study of Spinraza in children with later-onset SMA. Now, including data on patients up to 15 years of age, followed for up to six years, this analysis demonstrated that, in stark contrast to the natural history of SMA, patients with type 2 SMA treated with Spinraza demonstrated improvements in motor function, as assessed by the Hammersmith function on the motor scale expanded, and patients with type 3 SMA treated with Spinraza demonstrated stable Hammersmith scores and improvement in distance walked. No participants discontinued treatment due to adverse events, and no new safety concerns were identified.

Turning to our progress in neuromuscular disorders at last month's Congress of the European Pediatric Neurological Society, we presented new interim data from the open label Shine extension study of Spinraza in children with later onset SDMA.

Now, including data on patients up to 15 years of age followed for up to six years. This analysis demonstrated that in Stark contrast to the natural history of SMS patients with type two estimate treated with Spinraza demonstrated improvements in motor function as assessed by the Hammersmith function on motor skill expanded.

And patients with type three estimate treated with Spinraza demonstrated stable Hammersmith scores and improvement in distance walked.

No participants discontinued treatment due to adverse events and no new safety concerns were identified.

Geoffrey Christopher Meacham: Taken together, these data again underscore the robust, durable efficacy and well-established longer-term safety profile of Spinraza across a broad range of SMA patients. Also this quarter, we published data from the NURTURE study of Spinraza in pre-symptomatic infants in the journal Neuromuscular Disorders. Data from the NURTURE study showed that all patients treated with Spinraza were alive and achieved the ability to sit without support, none required permanent ventilation, 92% achieved walking with assistance, and 88% achieved walking independently.

Taken taken together these data again underscore the robust durable efficacy and well established longer term safety profile of spinraza across a broad range of estimate patients.

Also this quarter, we published data from the nurture study of Spinraza in Presymptomatic infants in the journal neuromuscular disorders.

Data from the nurture study showed that all patients treated with Spinraza, we're alive and achieve the ability to sit without support non required permanent ventilation, 92% achieve walking with assistance and 88% achieved walking independently.

Given spin rod as Spinraza as well characterized safety profile, we recently announced the phase two three the vote study to evaluate whether higher doses of Spinraza can provide even greater efficacy and the currently approved dose.

Geoffrey Christopher Meacham: Given Spinraza's well-characterized safety profile, we recently announced a Phase II-III DEVOTE study to evaluate whether higher doses of Spinraza can provide even greater efficacy than the currently approved dose. Our review of PK-PD data suggests that individuals with higher CSF concentrations of Spinraza achieve greater improvements in CHOP intent and motor milestones. As with any therapy that is developed to address high-end MET needs, companies who lead need to continually explore ways to optimize their treatment.

Our review of PK PD data suggested individuals with higher CSF concentrations of Spinraza achieved greater improvements in chop intend and motor milestones as with any therapy that is deval that has developed to address high unmet need companies, who lead need to continue its continuing to explore ways to.

Optimize their treatment.

Building on the success of Spinraza, we aim to build a broader neuromuscular franchise, including HLS.

Geoffrey Christopher Meacham: Building on the success of Spinraza, we aim to build a broader neuromuscular franchise, including ALS. At the meeting of the Northeast ALS Consortium held earlier this month, we presented new data on neurofilament levels assessed in the Phase I-II Multiple Ascending Dose Study of tefersin, our antisense oligonucleotide targeting SOD1 in patients with SOD1 ALS. As a reminder, previous data from this study showed that treatment with 100 mg of tefersin was associated with a statistically significant reduction in CSF-SOD1 protein levels and trends towards slowing of clinical decline as assessed by three independent measures relative to placebo. This new analysis of the same population showed that baseline neurofilament levels in both the plasma and CSF were correlated with baseline disease activity, and treatment with 100 mg of tefersin reduced levels of neurofilament in both plasma and CSF.

At the meeting of the northeast less consortiums held earlier. This month, we presented new data on their phone that levels assessed in the phase one to multiple ascending dose study up to first since our antisense oligonucleotides targeting so the one in patients with Esso do you want a less.

As a reminder of previous data from this study showed that treatment with 100 milligrams of to person was associated with a statistically significant reduction in CSF. So do you want protein levels and trends towards slowing up clinical decline as assessed by three independent measures relative to placebo.

This new analysis of the same population showed the baseline are filling that levels in both the plasma and CSF, we're correlated with baseline disease activity.

And treatment with 100 milligrams of to first and reduced levels of neuro filament in both plasma and CSF.

These data further highlight the concordance across data sets generated in this study, including target engagement clinical and nerve filament data and thus illustrate the potential for an antisense oligonucleotides to target genetic drivers of neuro degenerative disease.

Geoffrey Christopher Meacham: These data further highlight the concordance across datasets generated in this study, including target engagement, clinical, and neurofilament data, and thus illustrate the potential for antisense oligonucleotides to target genetic drivers of neurodegenerative disease. In movement disorders, we continue to advance the Phase II study of Vib92 or Gosiranumab, an antibody targeting extracellular tau, NPSP, with data expected by the end of the If this Phase II study is positive, we believe we would be in a position to file for regulatory approval.

In movement disorders, we continue to advance the phase two study of did 92 or go Serrana map and antibody targeting extra cellular tout in P.S.P. with data expected by the end of the year in this phase two if this phase two study is positive we believe we would be in a position to file for regulatory.

Ruble.

In Parkinson's disease, we continue to progress the phase two study of bid this before an antibody targeting extra cellular alpha Synuclein, we expect data from the one year placebo controlled period of this study, including data on safety as well as neuro imaging based assessment of straddle dopaminergic transporter density in.

Geoffrey Christopher Meacham: In Parkinson's disease, we continue to progress the Phase 2 study of BIV-54, an antibody targeting extracellular alpha-synuclein. We expect data from the one-year placebo-controlled period of the study, including data on safety as well as neuroimaging-based assessment of striatal dopaminergic transporter density in the second half of next year. Also this quarter, as we work to build further depth in movement disorders, we dosed the first patient in the Phase 1 study of BIV-94, an antisense oligonucleotide targeting leucine-rich repeat kinase 2, or LRK2, in Parkinson's disease. Toxic gain-of-function mutations in LRRK2 constitute the most common genetic cause of Parkinson's disease, representing approximately 5% of In addition to LRK2's role in familial Parkinson's disease, data from the literature suggest that LRK2 gain-of-function may also contribute to the pathogenesis of sporadic Parkinson's disease. As a result, this Phase I study will include Parkinson's disease patients with or without verified mutations in LRK2. Importantly, BIP-94 leverages the same RNase H-mediated degradation mechanism utilized by Telfers.

The second half of next year.

Also this quarter as we work to build further depth and movement disorders, we dose the first patient in the phase one study a bid nine before and antisense oligonucleotides targeting Lucy enrich repeat kinase too or look to in Parkinson's disease.

Toxic gain a function mutations and look to constitute the most common genetic cause that Parkinson's disease, representing approximately 5% of all Parkinson's disease cases.

In addition to Lrtwos role and familiar Parkinson's disease data from the literature suggests that work to gain a function may also contribute to the pathogenic this of sporadic Parkinson's disease. As a result. This phase one study will include Parkinson's disease patients with or without verified mutations and look to.

Importantly bid 94 Leverages. The same are nice h. immediate degradation mechanism utilized by to first soon.

With the addition of did 94 to our pipeline. We are now advancing episodes targeting the most common genetic cause of Parkinson's disease to genetic causes are they allow us and tell pathology, which underpin several primary and secondary tail off at these including all Simers disease, and we aim to build further depth across our air so.

Geoffrey Christopher Meacham: With the addition of BIP-94 to our pipeline, we are now advancing ASOs targeting the most common genetic cause of Parkinson's disease, two genetic causes of ALS, and tau pathology, which underpins several primary and secondary tauopathies, including Alzheimer's disease. And we aim to build further depth across our ASO pipeline as we continue to emphasize our focus on genetically validated targets and defined patient populations. In acute neurology, we continue to advance the Phase III study of BID-93 or IV glabenclamide for cerebral edema caused by large hemispheric infarction, or LHI. As a reminder, BIP-93 blocks SIR-1-TRIP-M4 channels that are hypothesized to mediate brain edema following LHI. Given that these channels are also hypothesized to mediate expansion of hematoma and perihematoma edema associated with brain contusion, this month, we dosed the first patient in a Phase 2 study of BIP-93 for brain contusion. Approximately 280,000 patients are hospitalized due to head trauma annually in the United States, and we estimate that brain contusions occur in approximately 25 to 35 percent of these patients. There are no pharmaceutical agents approved to mitigate contusion expansion, which is associated with worsened clinical outcomes.

Pipeline as we continue to emphasize our focus on genetically validated targets and defined patient populations.

In acute neurology, we continue to advance the phase three study a bid 93 or Ivig live bank when my for cerebral edema caused by large how mix, how many large habits merrick infarction or L. HR.

As a reminder, bid 93 block SER, one trip and four channels that are hypothesize to mediate brain edema following l. HR.

Given that these channels are also also hypothesize to mediate expansion of hematoma, and Perry hematoma redeem associated with brain contusion. This month, we dosed the first patient in a phase two study a bid 93 for brand contusion.

Okay. Approximately 280000 patients are hospitalized due to head trauma annually in the United States and we estimate the contusions occur and approximately 25% to 35% of these patients.

There are no pharmaceutical agents approved to mitigate contusion expansion, which is associated with worsens clinical outcomes.

The primary objective of this new study of did 93, we'll evaluate the proportion of patients with brain contusion, who exhibit in an expansion in contusion volume over the course of in 96 hour infusion of did 93 versus placebo.

Geoffrey Christopher Meacham: The primary objective of this new study of BIP-93 will evaluate the proportion of patients with brain contusion who exhibited an expansion in contusion volume over the course of a 96-hour infusion of BIP-93 versus placebo. Importantly, we believe that the shared pathophysiologic features of LHI and brain contusion exemplify the interconnectivity of neuroscience that we are leveraging as we continue to increase the depth and breadth of our This also highlights our strategy to pursue multiple indications for a given asset, particularly once we believe safety has been adequately established.

Importantly, we we believe that the shared pathophysiological features of L.A. try and brain contusion exemplify the interconnectivity of neuroscience that we are leveraging as we continue to increase the depth and breadth of our pipeline.

This also highlights our strategy to produce to pursue multiple indications for given asset, particularly once we believe safety has been adequately established.

And finally in our all samaras disease portfolio. This quarter, we completed enrollment in the phase two study of go Serrana Mab in early all samaras disease, and we continue to advance the phase one studies have been 76, a distinct anti tau antibody and bid 80 and air so aimed at reducing the expression is.

Geoffrey Christopher Meacham: And finally, in our Alzheimer's disease portfolio. This quarter, we completed enrollment in the phase two study of Gosaranumab in early Alzheimer's disease. And we continue to advance the phase one studies of BIB-76, a distinct anti-tau antibody, and BIB-80, an ASO aimed at reducing the expression of tau in the central nervous system. Taken together with the positive results of aducanumab, we believe that no other company is better positioned to deliver breakthrough therapies for Alzheimer's. Overall, this was a historic quarter for Biogen and for the patients, caregivers, physicians, and scientists around the world who have been waiting decades for a therapy that can reduce the clinical decline of Alzheimer's disease. With that, I will turn the call over to Geoff.

In the central nervous system.

Taken together with the positive results of that you can you map, we believe that no. Other company is better positioned to deliver breakthrough therapies for all samaras disease.

Overall this was a historic quarter for Biogen and for the patients caregivers physicians and scientists around the world who had been waiting decades for therapy that can reduce the clinical decline of all samaras disease.

With that I will turn the call over to Jeff. Thanks. So.

Geoff Meacham: Thanks, Val. Good morning, everyone. I'll now review our financial performance for the third quarter of 2019. As Michelle mentioned earlier, we had a strong financial performance in Q3. Total revenues for the third quarter grew 5% year-over-year to approximately $3.6 billion. All GAAP earnings per share increased 17% and non-GAAP earnings per share increased 24%, both compared to the prior year.

Good morning, everyone I'll now review, our financial performance for the third quarter 2019.

As Michelle 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% gold compared to the per year.

Overall, our emmis business delivered revenues of approximately 2.3 billion in the third quarter of this year, including Opus royalties for approximately a 180 million growing 2% versus the prior year.

Geoff Meacham: Overall, our MS business delivered revenues of approximately $2.3 billion in the third quarter of this year, including Ocrevus royalties of approximately $188 million, growing 2% versus the prior year. Global MS revenues in Q3 2019 were stable versus the prior year without Ocropus 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 2018 were impacted by a decrease in channel inventory of approximately $30 million. Unknown Executive, Ami Fadia, Adam Keeney, Chris Schott, Biogen Inc. Global third quarter, TACFIDERA revenues increased 3% versus prior year, as TACFIDERA delivered strong global patient growth of approximately 8% year over year. In the U.S., Tecfidera revenues were flat year-over-year as Tecfidera's share of total prescriptions remained relatively stable compared to the last couple of quarters. Outside the US, TechBidder 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.

Global Emmis revenues in Q3, 2019 were stable versus the prior year with brokers royalties and the total number of patients on our emmis products globally continue to grow in the low single digits versus the prior year.

You SMS revenues in Q3 2018 were impacted by a decrease in channel inventory of approximately 30 million compared to a decrease of approximately 5 million in Q3 2018.

Decrease of approximately 30 million in Q2 2019.

Global third quarter Tech for their revenues increased 3% versus prior year.

Separator delivered strong global patient growth of approximately 8% year over year.

In the U.S. Secretary revenues were flat year over year as secretary share total prescriptions remained relatively stable compared to the last couple of quarters.

Outside the U.S. separator 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 and several European countries.

Q3, global interferon revenues, including both Avenue supplied where do you decreased 10% versus Q3 2018 due to continued shift from an injectable platforms.

Geoff Meacham: Q3 Global Interference Revenues, including both Abenix and Plagarity, decreased 10% versus Q3 2018 due to the continued shift from injectable platforms to oral or high-efficacy therapies. Fabry Worldwide revenues increased 3% versus the 3rd quarter of 2018. We were pleased with this growth in SABR revenues as it continued to perform well in the high-efficacy segment. In the U.S., we grew salary revenues 4% year over year as we continue to maintain stable salary share of total prescriptions compared to the last couple of quarters. Outside the U.S., we grew to 72%, driven by volume growth in several markets and Favorable Tidings Shipments, somewhat offset by pricing pressure. Overall, we were pleased with the execution of our MS franchise and the continued strong performance of our MS business in the third quarter, and remain focused on maintaining resilience and being MS market leaders. Let me now move on to Spinraza.

For high efficacy therapies.

Sorry worldwide revenues increased 3% versus the third quarter 2018.

We were pleased with this growth into Saudi revenues as it continues to perform well in the higher efficacy segment.

The U.S., we grew savi revenues, 4% year over year as we continue to maintain stable to several share of total prescriptions compared to last couple of quarters.

Outside the U.S., we grew to 72% driven by volume growth in several markets.

A couple times shipments somewhat offset by pricing pressures.

Overall, we were pleased with the execution of our Emmis franchise and the continued strong performance of our EMS business in the third quarter.

We remain focused on maintaining resilience and emmis market leadership.

Let me now move on to Spinraza.

Global third quarter spin revenue revenues increased 17% versus prior year and 12% versus the prior quarter to 547.

Geoff Meacham: Global third quarter spend revenue revenues increased 17% versus the prior year and 12% versus the prior quarter to $547 million. In the third quarter, Fenrise achieved year-over-year and quarter-over-year revenue growth both in the U.S. and outside the U.S., driven by continued patient growth across both mature and new markets. And, we now have approximately 9,300 patients on Spina Raza, including the Expanded Access Program and clinical

In the third quarter Spinraza achieved through year end quarter over revenue growth both in the U.S. and outside the U.S driven by continued patient growth across for sure and new markets.

And we now have approximately 9300 patients on spinraza, including the expanded access program and clinical trials.

In the U.S. revenues increased 6% versus Q3, 2018, and 3% versus Q2 2019.

Geoff Meacham: In the U.S., revenues increased 6% versus Q3 2018 and 3% versus Q2 2019. Additionally, the number of patients on therapy in the U.S. increased 3% as compared to the end of the second quarter of 2019. And importantly, we continue to make strong progress with adults, the largest patient segment, with the number of adults on Spenraza growing 8% compared to the prior quarter, which is the third quarter in a row with higher single-digit growth. As a reminder, SOGENSEMA is competing in a limited portion of the market, specifically the approximately 5% of estimated patients who are under 2 years old.

The number of patients on therapy in the U.S. increased 3% as compared to the end of the second quarter 2019.

And importantly, we continue to make strong progress with adults the largest patient segment with a number of adults on spinraza growing 8% compared the prior quarter, which is a third quarter in a row with upper single digit growth.

As a reminder, so adjustment is competing in a limited portion of the market specifically the approximately 5% of estimate patients were under two years old.

Within that segment, we have begun to see some impact on Spinraza performance.

Geoff Meacham: Within that segment, we have begun to see some impact on SpinRiser performance. Outside the US, revenues increased 27% versus Q3 2018 and 21% versus last quarter, driven by strong performance in established markets such as the EU and Japan, as well as key markets in both Latin America and Asia Pacific. We were pleased to see double-digit patient growth versus the prior quarter outside the U.S., and we are now approved in over 50 countries. Additionally, we recently dosed the first Spinarazda patients in China.

Outside the U.S. revenues increased 27% versus Q2, 2018, and 21% versus last quarter driven by strong performance in established markets such as you in Japan as well as key markets and both Latin Americas and Asia Pacific.

We were pleased to see double digit patient growth versus prior quarter outside the U.S and we're now proven over 50 countries. Additionally, we recently dose the first spinraza patients in China.

Overall, we were pleased to see continued patient growth across the larger mature markets and continued rapid uptake for more recently launch markets.

Geoff Meacham: Overall, we were pleased to see continued patient growth across the larger mature market and Continued Rapid Uptake for More Recently Launched Markets. Given our expected continued patient growth and execution across many global markets. Due to our established product profile and the significant market opportunity, we remain optimistic about our SMA business. In our biosimilars business, we generated $184 million this quarter, growing 36% versus the prior year, driven by emeralds. We estimate that we now have approximately 180,000 patients on Biosumers in Europe.

Given our expected continued patient growth.

And execution across many global markets are established product profile and the significant market opportunity, we remain optimistic about our SMB business.

And our Biosimilar its business, we generated 184 million this quarter growing 36% versus prior year driven by Emerald.

We estimate that we now have approximately a 180000 patients Abbas summers in Europe .

Total ANSI anti CD 20 revenues in the third quarter increased 16% versus the prior year, primarily driven by opus royalties.

Geoff Meacham: Total anti-CD20 revenues in the third quarter increased 16% versus the prior year, primarily driven by Ocrupus royalties. Q3 Ocravis royalties benefited by approximately $10 million due to an adjustment related to prior periods. We continue to expect Rituxan revenues to be impacted by the entry of Biosilver in the U.S. beginning next month. Total other revenues in the third quarter decreased 26% versus the prior year, driven by the decline in our manufacturing services revenues due to our divestiture of the Hillerod plant.

Q3, Oelkers royalties benefited by approximately 10 million due to adjustment related to prior periods.

We continue to expect retraction DRAM revenues to be impacted by the entry about summers in us beginning next month.

Total other revenues in the third quarter decreased 26% versus prior year driven by the decline in our manufacturing services revenues due to our divestiture of the Hiller on plant.

Importantly, we continue to see geographic diversification of our revenue base driven by growth in MSR revenues outside the us the continued market expansion of Spinraza and our growing by customers business.

Geoff Meacham: Importantly, we continue to see geographic diversification of our revenue base driven by growth in MS revenues outside the U.S. Continued market expansion of Sprint Rasa and our Growing Biosoners Business. In the third quarter, approximately 41% of our product revenues came from outside the U.S., versus approximately 37% in Q3 2018 and 32% in Q3 2017. We aim to continue capitalizing on global growth opportunities for both our current commercial portfolio and our pipeline of products. Let me now turn to the expense lines on the P&L. Q3 2019 Gross Margin was 88%, an improvement versus both prior year and prior quarter, which were both 87%. Due to favorable cost of goods sold, product mix, and higher margin contract manufacturing, Q3 GAAP and non-GAAP RD expense were both 15% of revenue. R&D expense included approximately $58 million in trial closure costs for both Ellevestonstat and BG11. 233 GAAP and non-GAAP SG&A expense for both 15% of revenue. Q3 GAAP other expense was $27 million, and non-GAAP other expense was $23 million. In the third quarter, our GAAP tax rate was approximately 12%, and our non-GAAP tax rate was approximately 16%.

In the third quarter, approximately 41% of our product revenues came from outside the us versus approximately 37% in Q3, 2018 and 32% in Q3 2017.

Aimed to continue capitalizing in global growth opportunities, both their current commercial portfolio and our pipeline of products.

Let me now turn to the expense lines on the piano.

Q3, 2019, gross margin was 88% and improvement versus both prior year in prior quarter, which are both 87% due to favorable cost of goods sold product mix and higher margin contract manufacturing.

Q3, GAAP and non-GAAP R&D expense for both 15% of revenue.

R&D expense included approximately 50 million in trial close their costs for both elevates the stat and BG 11.

Q3, GAAP and non-GAAP vesting expense were both 15% of revenue.

Q3, GAAP other expense was what was 27 million and non-GAAP other expense was 23 million.

In the third quarter, our GAAP tax rate was approximately 12% and our non-GAAP tax rate was approximately 16%.

Compared to Q3 2018, our Q3 2019 GAAP tax rate benefited from the remaining amount realized from us corporate tax reform the change in our tax profile in Q2 2019.

And recently enacted tax reform in Switzerland.

In the third quarter, we repurchased repurchase approximately 3.1 million shares at an average price of $233 per total value for approximately $718 million.

Geoff Meacham: Compared to Q3 2018, are Q3 2019 GAAP tax rates benefited from the remaining amount realized from U.S. corporate tax reform? A change in our tax profile in Q2 2019, and recently enacted tax reform in Switzerland. In the third quarter, we repurchased approximately 3.1 million shares at an average price of $233 for a total value of approximately $718 million. As of September 30th, 2019, we had approximately $3.4 billion remaining under our 2019 share repurchase authorization. Which now brings us to our diluting earnings per share. In the third quarter, we booked GAAP EPS of $8.39, an increase of 17% versus the prior year, and non-GAAP earnings per share of $9.17. A 24% increase was the priority. We generated approximately $1.7 billion in net cash flows from operations in Q3. We ended the quarter with approximately $6.3 billion in cash and marketable security.

As of September 32019.

We had approximately $3.4 billion remaining on our 2019 share repurchase authorization.

Which now brings us to or diluted earnings per share in the third quarter. We book GAAP EPS of $8.39, an increase of 17% versus the prior year and non-GAAP earnings per share of $9 in 17 cents, a 24% increase versus the prior year.

We generated approximately 1.7 billion a net cash flows from operations in Q3.

We ended the quarter with approximately 6.3 billion and cash marketable securities and $6 billion and debt.

Now I'll turn the call back over from shell for his closing comments.

Thank you Jess.

To summarize first the positive clinical results for as you can be mab position biogen to potentially lead the fight against Alzheimer's disease.

Second.

This data dates biogen strategy to focus on an interconnected neuroscience pipeline.

And probably physician of targets supported by human genetics.

Third our base business continued to deliver solid performance in Q3, 2019, driven by strong execution again, so as strategic priorities.

Between now and the end of 2020 .

We expect continued progress as we aim to be a multi franchise portfolio, including.

Michelle Venazos: $6 billion in debt. I now turn the call back over to Michel for his closing comments. Thank you, Geoff. To summarize, first, the positive clinical results for aducanumab, which is positioned by Ogen to potentially lead the fight against Alzheimer's disease. Second, this data validates Biogen's strategy to focus on an interconnected neuroscience pipeline and prioritization of targets supported by human genetics. Third, our base business continues to deliver solid performance in Q3 2019, driven by strong execution against our strategic priorities.

Nine additional meet its too late stage data read outs.

The expected launch of the memory T in the us.

And submitting the regulatory filing for I'd you can you maybe in the U.S., while continuing dialogue with regulatory authorities in international markets, including in Europe and in Japan.

I am proud of the Biogen team for not being deterred by a story of disappointment in the pursuit of ideas I Miss therapies and more so for continuing their work off another using the clinical trial data with unprecedented focus and intensity.

Michelle Venazos: Between now and the end of 2020, we expect continued progress as we aim to build a multi-franchise portfolio, including... 9 additional mid- to late-stage data readouts, the expected launch of Umeriti in the U.S., and submitting the regulatory filing for Adukanumab in the U.S. while continuing dialogue with regulatory authorities in international markets, including in Europe and in Japan. I am proud of the Biogen team for not being deterred by a 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 result. This work reflects Biogen's steadfast determination to follow the science, tackle the biggest challenges, and always do the right thing for the patient.

Even in light of an apparent for GTT results.

This work reflex Biogen steps cause determination to follow the science that because the biggest challenges and do always the writing for the patients.

Finally, what she is most important today is that in consultation with the FDA. We are excited to be moving to head and preparing for regulatory filing for educating mab on the ground of positive clinical results.

And we will be reducing eligible patients promo enzymes trials as quickly as possible.

DCC major step in the fight against that as I am as disease, and an important inflection point for Biogen suicide in submission.

Michelle Venazos: 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 basis of positive clinical results, and we will be re-dosing 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 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 core strategy to build a multi-franchise portfolio across our core and emerging growth areas.

We believe now more than ever that that would call for cusano science will enable us to maximize value for all our stakeholders.

And for most for the patients as well as for our shareholders.

As the leader in science, we believe that no other companies, but to position to continue to did you have a breakthrough therapies for diseases of the never see stem.

We will continue to execute on our cost fatigue to beat emergency franchise portfolio across our core and emerging growth areas.

We are inspired by the progress we have made instantly as I'm as disease and the broader centipede implications of the positive clinical results for I'd you came up.

I would like to thank all the Biogen employees in particular, those who have been working tirelessly on the educating my pull comment and many more who will contribute to this critical priority kill the time.

Operator: 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 Adjukanima program, and the many more who will contribute to this critical priority of the time. I am incredibly grateful for all the patients, physicians, and caregivers who have dedicated so much time and effort to our Alzheimer's clinical studies and advancing our understanding of this very complex disease. I would like to thank the FDA for its guidance and independent scientific expertise throughout this process. We will now open up the call for questions. Thank you. If you would like to ask a question, please press star, then 1 on your telephone keypad. As a reminder, please limit yourself to one question. If you require any further follow-up, you may press star 1 again to rejoin the queue. Your first question comes from the line of Umer Raffat from Evercore ISI.

I am incredibly grateful for all the patients physicians and caregivers, who have dedicated so much time and efforts to our ads I Miss clinical studies and advancing our understanding of this very complex disease.

I would like to thank the FDA, well take guidance and independent scintific expertise throughout this process.

We will now open up the core for questions.

Thank you he would like to ask a question. Please press Star then one on your telephone keypad as a reminder, please limit yourself to one question. If you acquire any further follow up you May press star one again to rejoin the queue. Your first question comes from the line of Omar Saad from Evercore ISI. Please go ahead.

Oh, if I may I only have a question on AD you came out but it's got three part and given the significance. The news today I would really appreciate if you could bear with us on it. So Mike My three parts are as follows first and I'm not attempting to correlate the too, but Michael Ehlers his departure.

You are ahead of this data announcement.

Umer Raffat: Please go ahead. Well, if I may, I only have a question on Educandumat, but it's got three parts. And given the significance of the news today, I would really appreciate it if you could bear with us on it. So my three parts are as follows. First, I'm, and I'm not attempting to correlate the two, but Michael Ehlers' departure ahead of this data announcement, just wanted to hear if those two things are related in any way or not. Second, the implication in the data is that how spot on is that finding on patients that had a sufficient exposure, and those are the ones that drove efficacy.

Just wanted to hear.

Those two things related in any way or not.

Second.

The implication that data is that the high if within sufficient exposure at the high dose the second trial work as well, but when we look at CDR. Some of the boxes lodos actually looks more consistent than the high dose and also for patients that did not make it to the the large opportunity complete data.

Those patients actually especially on met the more consistent then the patient that did have a sufficient exposure. So I guess I'm just trying to understand.

How 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 Omar this is Michelle Mike decided to leave the company awnings on and I can cannot seem to think came enough for his many contributions over the past when how she has to biogen. So thanks, Mike and the same time I'm extremely confident in IADS leadership.

Michelle Venazos: Thank you so much. Thank you, Umer. This is Michel. Mike decided to leave the company on his own, and I cannot thank him enough for his many contributions over the past three and a half years at 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 a time when the R&D portfolio had never been as strong, the team, also, and the capabilities.

As a clinician to as a scientist to take the head and at the time with the R&D portfolio never been a stronger the team also and the capabilities.

Our this is al sandrock in it I will turn it over to sum up the later for.

Geoffrey Christopher Meacham: Umer, this is Al Sandrock, and I'll 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 second protocol amendment really affected the high dose arm of the treatment in the carriers. So in the low dose arm, 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 follow-up.

Follow up but.

Look you your point as well uptake in the low doses consistent across engage in emerge and that's because the particularly the second protocol amendment really affected the high dose arm of of.

In the carriers so in a low dose arm. 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.

In it over to some at the for all of them, Yes, that's correct.

So see the in the high dose for engage that we do have a partial response on Adas Cog 13, and the 80, CS audio and see I and so the potential rate that you have there on CDR seven boxes and MSC is that these are potentially less sensitive as endpoints, so what I'll say.

Samantha Budd Haberlein: Yeah, that's correct, Al. Umer, you'll also see that at the high dose for ENGAGE, we do have a partial response on ADAS-CoG-13 and the ADCS-ADL-MCI. And so the potential read that you have there on CDR-7 boxes and MMSE is that these are potentially less sensitive as endpoints. So what Al said is that in that high dose group, we know that we have given less doses than we had 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. Dosing is a complex combination of duration, magnitude, and no interruptions.

Ed is that in the high dose group, we know that we have less doses than we had 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 our yet so dosing is a complex AG 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.

Operator: Thank you very much. Your next question comes from the line of Phil Nadeau from Cowan and Company. Please go ahead. Good morning.

Good morning, Thanks for taking my question. It's also as somebody mentioned on how to check them out.

Phil Nadeau: Thanks for taking my question. It's also, as you might imagine, on Hadar Ketamab. I will answer in two parts. First, if you pooled 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 all that far apart. They're just a month or so old. In response to the last question, you mentioned that 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.

I guess in two parts first if you pull the data from engage in 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 of what the differences between engage in emerge were.

In exposures at those high doses it seems like the trials Didnt start all that far apart. There just just a month so I'm kind of Wouldnt in response to the last question you mentioned.

Exposures rely on dose suspensions and whatnot can you 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 the first part that if we pulled the outcomes on engage in emerging high does essentially you'll get an intermediate effect not not much.

Samantha Budd Haberlein: Certainly, so the first part that if we pooled the outcomes of 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 as stand-alone studies as two independently, identically designed studies. There's a second part of the question which I've forgotten.

Allocated than that.

But we are looking at these as Standalone studies as to independently identically designed studies.

The second part of the question, which I forgot nationally differences and engage them are different so yes. So they started one months 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 and particularly through the protocol of men.

Samantha Budd Haberlein: Differences in Engaged and Emerged. Yeah, so they started with a one month difference between the two studies, as I mentioned.

Samantha Budd Haberlein: and they remained different throughout the entirety of the studies, and that initial one month at certain periods of the studies and 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.

Since I was greater in the middle of the studies and more details around this will come at the presentation and see Todd.

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

Operator: Your next question comes from the line of Karen Flynn from Goldman Sachs. Please go ahead. Hi, thanks for taking the question. Maybe two parts for me as well.

Hi, Thanks for taking the question maybe two parts for me as well I'm. Just wondering if you can share any additional commentary on the second type C meeting.

Karen Flynn: I'm 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.

FDIC 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 trial. Thanks.

Hi, this is out.

Geoffrey Christopher Meacham: 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 for approval, so that was the upshot of the meeting.

It's generally our policy not to comment too much on on the.

You know 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 would the upshot of the meeting.

Samantha Budd Haberlein: And the second part of the question was on ARIA and high dose, and that was consistent in incidence per the studies that we have previously reported, and we'll give more details on that at CTAD.

And the second part of the question was on ARIA and high dose and that was consistent in incidents pad. The studies that we have previously reported and we'll give more details on the at Sicad.

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

Operator: Your next question comes from the line of Geoff Porges from Lerink. Please go ahead. Thank you very much, and thanks for having Samantha on the call. It's very helpful.

Thank you very much and thanks for having some math or on the call very helpful.

First could you answer whether.

Geoff Meacham: First, could you answer whether the analysis that you've 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 of FDA meeting, but did the FDA see the full analysis, or did the FDA just hear the company's summary of the analysis? Thanks.

The analysis that you presented and presents the agency has been independently verified.

What confirmation of both the statistics.

The results to have secondly.

You have any intention or plans for a confirmatory.

Pivotal trial to supplement the phase two trials.

Then I hate to sort of push on the issue of the TARP.

The FDA meeting but.

Did the FDIC the full analysis or that the FDA just hit the company's summary of the analysis. Thanks, Let me let me start with the last question and I'll, let some at the answer the first couple first of all.

Geoffrey Christopher Meacham: Let me start with the last question and let Samantha answer the first couple. First of all, the FDA did the full analysis of both studies. And I would also say that the only study we have planned right now is the re-dosing study, and any further study we'll update you as soon as we plan one.

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 reducing study and any further study will update you as soon as we see we plan one.

Yes, a good thanks, our current your first question, Jeff I'm 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 expense, but the data that we did take to the FDA as al says.

Samantha Budd Haberlein: Thanks Al. Going to your first question, Geoff, have we had an 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 data set 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 data set 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 patients who were in previously enrolled studies of aducanumab.

As a full dataset, which was an analysis of the blinded data.

Conducted in using the same statistical analysis plan. We had originally planned for the end of the study and the validity of the dataset was the first thing that we analyze 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 education.

Yep.

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

Operator: 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 a appropriately say that there will change slightly negative trend overall in the high dose, but in the subgroup of exposure patients, which as you think.

Michael J. Yee: Thanks, thanks for the question; I appreciate it. Al or Samantha, I guess I 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 is I think about a third of it, they had a nice benefit. I guess the question is, how do you think about the patients who did not have enough exposure? Did they drive a strong negative trend? Are those patients at risk? 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.

A third of that they had a nice benefit I guess the question is.

How do you think about the patient you did not have enough exposure. They drive a strong negative trend are those patients at harm how do you think about that since that's a huge majority to patients and how is that explainable given the difference in the March thanks.

Thanks, Michael I'll start look I don't think you know.

Samantha Budd Haberlein: Thanks, Michael. I'll start.

Geoffrey Christopher Meacham: Look, I don't think, you know... First of all, there's a slight negative effect. 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 a neutral or a positive effect.

First of all the the there's a slight negative I would say that that was just basically no effect.

And then in the <unk> those who did not have the high dose I would not say that they had a negative effect in fact in many ways.

It was either neutral or positive effect, but I would point out. This you remember the six milligram per kilogram dose arm in prime that everybody was wondering about you always asked me questions about it I remember Michael.

Operator: But I would point out this. Do you remember the 6 milligrams per kilogram dose arm in Prime that everybody was wondering about? You always ask me questions about it. I remember, Michael. And you thought that was an outlier. Well, maybe that wasn't the outlier. Maybe that was true in that the 3 milligrams per kilogram that looked like it was trending was the outlier. So in other words, what I'm saying is that there's a very sort of sharp dose response, if you will. You have to get to high doses of aducanumab. An intermediate dose thing, at least in an 18-month trial, is not enough. Okay.

And and we thought that was an outlier well, maybe maybe that wasn't the outlier maybe that was true and that the three milligram per kilogram that looked like it was trending with the outlier. So in other words, what I'm, saying is that there's a very sort of sharp dose response. If you will you have to get to high dose as you can imagine intermediate dosing.

At least in an 18 month trial is not enough.

Okay.

Thanks.

Your next question comes from line of Cory Kasimov from JP Morgan. Please go ahead.

Corey Casamob: Your next question comes from the line of Corey Casamob from J.P. Morgan. 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 a 14 doses of 10 makes for cake in each study and the full data set and then as a follow up did you see any difference in April you for carriers versus non carriers, especially in the.

Samantha Budd Haberlein: Hey, good morning guys. Thanks for taking my question. I guess first, just to ask Phil's question directly, can you tell us yet how many patients got the 14 doses of 10 mg per kg in each study in the full data set? 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?

Patients, who completed after the futility cohort and would've had more exposure to the higher dose. Thanks.

Yes. So first thing I went to mention is in terms of the numbers of subjects, who had the particular dataset that you're referring to more dose at 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.

Samantha Budd Haberlein: If you had more exposure to the higher dose, thanks.

Operator: So the first thing I want to mention is, in terms of the numbers of subjects who had the particular data set that you're referring to, more than 10 doses of 10 mg per kg, 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 a high dose for long enough but also have no interruptions. And so that's a more complex calculation between the two studies.

Achieve high dose for long enough, but also have no interruptions and so thats a more complex calculation between the two studies.

Second in April versus not.

So your question regarding April carry especially is known carriers. The analyses that we've conducted to date has been on the entire studies and as we've mentioned for emerge we have a positive we met the primary endpoint for the entire patient population and details of subgroups is something that will come to later.

Geoff Meacham: Neighborhood vs. non-neighborhood

Geoffrey Christopher Meacham: So, your question regarding APOE carriers versus non-carriers, the analyses that we've conducted to date have been on the whole studies, and as we've mentioned for eMERGE, we have a positive result, we met the primary endpoint for the entire patient population, and details of subgroups is something that we'll come to later, and we'll have details at CTAD.

And we'll have details at Sicad, 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 education you map.

I'll just have a couple of regulatory type of questions all related.

If half of emerge achieve Nick significance at the high dose and none of engage achieved it is you guys expectations that the prime study could count as one of the two pivotals.

Samantha Budd Haberlein: Okay, thank you. Your next question comes from the line of Geoff Meacham from Bank of America. Please go ahead.

Operator: Hey guys, thanks for the question and all the details on EducanyMab.

Second one is does a conditional approval pending another successful phase three did that come up in the FDA discussion and then third have you had any discussion with European regulators on the data. Thank you.

Brian Abrahams: I'll just have a couple of regulatory type questions, all related.

Geoffrey Christopher Meacham: If half of Emerge achieved significance at the high dose and none of Engage achieved it, is it your guys' expectation that the prime study could count as one of the two pivotals? The second question is, does conditional approval pending another successful phase 3, did that come up in the FDA discussion? And then third,

Let me start with the last question for so we have just started to contact the European regulators that we haven't had any substantive discussion yes.

Samantha Budd Haberlein: Have you had any discussions with European regulators?

And.

Geoffrey Christopher Meacham: Thank you. Let me start with the last question first. So, we have just started to contact European regulators, and we haven't had any substantive discussions yet.

In terms of the merchant engage I, we looked at we look at engage in totality as a positive study that stands on its own.

And remember as some analysts said, we use pre specified primary and secondary outcomes. We didn't look at a subset we looked at all the patients and and based on that we believe this study met its primary endpoint and the secondary endpoints as well I think that whether or not a single trial.

Operator: In terms of the eMERGE and ENGAGE studies, we look at ENGAGE in totality as a positive study that stands on its own. And remember, as Samantha said, we used pre-specified primary and secondary outcomes. We didn't look at a subset.

Matthew Harrison: 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 might call it phase 2 trial.

Can be approved there are circumstances, where it sta 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.

And those who achieve sufficient exposure to 10 milligrams per kilogram, we do see evidence of efficacy. So I would say that emerged stands on its own engage has supportive evidence and the and I would also say that prime is supportive and say well controlled.

You know phase one piece of mind called Phase two trial and we'll submit all the data.

Just to add their al emerge is the study that met its primary.

Right, Yeah confusing times.

Your next question comes from the line of Brian Abrahams from RBC capital markets. Please go ahead.

Geoffrey Christopher Meacham: Just to add there, EMERGE is the study that met its primary end. Did I get it wrong? Yeah. I get confused sometimes.

Thanks for taking my questions. So the question just a little more clarity on the engage study for the subgroups of patients.

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

Yes for both engaging emerge with 10 interrupted receiving 10 interrupted uninterrupted high doses can you talk about the baseline characteristics offer the added kind of members 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.

Operator: Hi there, thanks for taking my questions. So the question is, just a little more clarity on the ENGAGE study. For the subgroups of patients, I guess for both ENGAGE and eMERGE, with 10 interruptions, receiving 10 uninterrupted high doses, can you talk about the baseline characteristics for the added kanamab versus placebo arms across both studies and how well-balanced those were? And then can you maybe help us understand how feasible it was for patients, I guess once the 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.

To remain on 10 uninterrupted doses or is the lesson here that if you do need to temporarily discontinue Ferrari 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 analyses that we conducted in close consultation with the FDA around determining who engage did have a response, where exploratory analyses and any time that you look at a subset of patients you have very important questions.

In regards to whether they are balance for the baseline characteristics. The studies overall, we're very well balanced baseline characteristics and as I mentioned equally for status on but those sub groups are exploratory in nature and they help us understand that dosing is important for efficacy.

Ronnie Gao: Thank you for the question. I want to point out that the analyses that we conducted in close consultation with the FDA around determining who in ENGAGE did have a response were exploratory analyses. And any time that you look at a subset of patients, you have very important questions in regards to whether they are balanced for their baseline characteristics. And in the context of an 18-month trial, one does tend to see that you need a certain number of doses for the 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, where a dose interruption would likely be of less significance.

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 as you can imagine however, that's not the same as one would anticipate in a real world situation, where an individual is taking out you can you meant for an extended period of time.

Those interruption would would likely be of less significant.

Yeah, I agree with cement I think that a dose suspension in the context of in 18 months study.

Geoffrey Christopher Meacham: Yeah, I agree with Samantha. I think that those suspensions in the context of an 18-month study Unknown Executive, Ami Fadia, Adam Keeney, Chris Schott, Biogen Inc.

What could be problematic because they didnt achieve enough of the high dose, but in clinical practice, we don't do 18 month treatment periods were going to treat patients for longer periods of time and in that situation I think dose suspension may be acceptable in some patients.

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

Operator: Thanks for taking the question. I guess I'll follow up with a sort of second question for me. So the first one is, you know, you've been talking

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

Great. Thanks for taking my question I guess, a follow up in a sort of a second question for me. So first one is you've been talking about exposure in dose a lot.

Jay Olson: I know we've been talking about exposure and dose a lot.

Geoffrey Christopher Meacham: Could you just broadly comment on that?

You just broadly comment on.

Samantha Budd Haberlein: Transcription by Transcription Outsourcing, LLC.

You know how many of these patients actually achieved all the factors that youre looking for and how easily you think that that will be the case in clinical practice and I get the related question about is that.

Operator: practice. And I guess the related question to that is this.

Paul Matteis: This is a dose exposure curve that you're sort of talking about, Al. I mean, were there characteristics that were different? Were the kinetics of the amyloid plaque reduction different?

Dose exposure curb you're sort of talking about al I mean, where there were there characteristics that were different where the kinetic said.

I'm like plaque reduction different in these subgroup of patients the achievement of.

Geoffrey Christopher Meacham: U.S. Department of Health and Human Services, U.S. Department of Health and Human Services,

Power or amyloid reductions are they significantly different I'm wondering what you think is.

Samantha Budd Haberlein: Transcribed by https://otter.ai

<unk> biologically happened to account for the.

Operator: Unknown executive, Ami Fadia, Adam Keeney, and Chris Schott, Biogen Inc.

Deep dense exposure occur.

Operator: Deep Dose Exposure Therapy These are good questions, Matthew, and we're still learning as we look at the data, but I would say this: even an 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 aducanumab and BAN2-401 is that 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's a lag between the two.

These are good questions Matthew and we're still learning as we look at the data, but I would say this the.

Even in M.C. I'd patient if you look at the amount of amyloid in the brain. Its tremendous took 20 years to build that much up and in the context of an 18 trial you have to remove a large amount of amyloid I think thats what distinguishes as you Canyon mab embedded to for a one 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.

Not going to get an effect also theres 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 some amyloid lowering its six month, but we saw no difference in the clinical outcomes at six months. It was it took the 12 month time period to see starts to start to see an effect.

Geoffrey Christopher Meacham: You remove amyloid, and then there's a little bit of a lag for the clinical effect. We saw that in PRIME, for example, where we did have some amyloid lowering at six months, but we saw no difference in the clinical outcomes at six months. It took the 12-month time period to start to see an effect on clinical outcomes. In addition to a large amount of amyloid removal, I think you need to have a little bit of time 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 were on one of the slides, in 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 data set. And so, again, what it says is that if you give enough of the high dose, you can achieve a certain amount of amyloid removal, and that amount is what's required to see a reduction in clinical decline in an 18-month study.

On clinical outcome. So in addition to a large amount of amyloid reimbursable.

I think you need to have a little bit of time for that for the 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 Su VR score is very.

Similar in engage.

And that subgroup of patients and engaged 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.

A certain amount of analog removal and that certain a mountain is what is required to see the reduction in clinical decline in an 18 month study.

Samantha Budd Haberlein: Yeah, Al, just to add to that on the question of numbers, on the graph that you've just referred to, you've got the N numbers, so they were 147 for eMERGE and 116 for ENGAGE in that CDR Summer 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'll have a different response, and it's a bit of a sliding scale, so we have that exploratory analysis that we've disclosed to explain what it is we learned around the importance of dose, but there's no perfect number of doses that are required. It's not binary.

Yeah, I'll 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 city Arsema boxes analysis on but the question you ask of how many patients have the precise criteria whether on precise criteria dose risk.

Bonds is not binary and so.

Given the levels of dose you'll have a different response and it's a bit of a sliding scale. So we we have that exploratory analysis that we closed to explain what it is we learn to round the importance of dose, but there's 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.

Everybody I think about a quest to that could have taken a question and I'm going to stay with that kind of up here.

Im just kind of struggling with the movement from the interim futility analysis to efficacy with relatively small number of patients just looking at the.

Operator: Your next question comes from the line of Ronnie Gao from Bernstein. Please go ahead.

Number of completed that you have here and I mean emerge.

Operator: Hi, everybody. Thank you for taking the question, and I'm going to

From 803 patients futility analysis to 980 patients.

In the treatment. So it's about 180 more patients if we assume a third of those who are on the high dose 60 more in your total number of folks that you have amyloid debate that you called got sufficient exposure.

Ronnie Gao: I'm going to stay with Adhokanamab here. I'm just kind of struggling with the movement from interim futility analysis to efficacy with relatively small numbers of patients. Just looking at the number of completers that you have here in eMERGE.

Is is at the end of the trial.

127, I kind of wonder if if theres just a very small number of patients that drove the entire movement. If you can discuss a little bit that issue of off.

Geoffrey Christopher Meacham: You moved from 803 patient futility analysis to 980 patients.

How many patients actually contribute to the difference between stopping the trial for futility and showing efficacy would be appreciated and then when you don't mind I want to throw my second one and it will be different not another kind of just too for the variability.

Operator: [inaudible]

Operator: Would be appreciated, and then I'm going to...

Operator: If you don't mind, I'm going to throw my second one in, and it will be different, not in Adhukanama, just for the variability. Do you have any way of protecting the high-dose Tysabri from biosimilars to the first-generation products? If you can discuss that at all, we'd appreciate it.

And you have any way to protecting the highest dose stay sabri off from by a similar to the first generation product.

You can discuss that at all would appreciate it thanks.

Randy This is out of my head to swimming, Oh, even just with the first question, but so I think first of all you should.

Geoffrey Christopher Meacham: Ronnie, this is Al. My head is swimming, even just with the first question. So I think first of all, you should remember that in eMERGE, even at the time of the futility 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 data set, to see that the gene 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 on that slide was all the patients in eMERGE. And then I will now forget the second question.

Remember that in emerge even at the time of the futility analysis that study was trending positive as some emphasizing and then we add those additional patients and it didnt take that many now to then in the April dataset to see that cheap.

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 the futility. So so it's a large number of patients that we ended up looking at and I remind you.

That.

That you saw on that slide was all the patients and emerge who had been randomize. The ITC population and it was using the pre specified primary and secondary endpoints and then not forget the second question.

Samantha Budd Haberlein: So before you jump into that, if you look at the slide that you had, slide 22, the number of patients on aducanumab that you have there is the number of patients who received enough dose. The questions from some of my peers were how many patients got exposed. Are those the numbers that we're seeing on aducanumab on slide 22 that are the numbers we should be thinking about?

Yeah. This before jumping into that if you look at the slide that you had slide 22, the number of patients out of kind of not that you have there is the number of patients who received enough dose that the questions from some of my peers was how many fishing at expose those numbers that we're seeing on how to kind of mob on slide 22 that are the numbers, we should be thinking about.

Samantha Budd Haberlein: So I just want to recap that slide 22 was a piece of exploratory analysis. It is not the subset who we believe are supported. It's just a particular analysis to emphasize the point that there are subjects in ENGAGE who, if they do have sufficient dosing, do support the outcome of eMERGE.

So I just want to recap at slide 20.

Hey piece of exploratory analysis it is not the subset.

These are supportive in just a particular analysis to emphasize the point that there are subjects engage them. If they do have sufficient dosing do support the outcome of emerge.

Geoffrey Christopher Meacham: I would also say, Ronnie, that the PET was done in a subset of patients, too. So the numbers that you see on the left side, which is the amyloid PET, are from only the subset who got the PET imaging, and the numbers on the right are still not the complete set.

I would also say Ronnie that the pet was done in a subset of patients too. So the numbers that you see on the left side, which is the amyloid, but all right.

The only the subset who got the pet imaging.

And the numbers on the right I'm still not the complete set this is just some sort of a subset that's correct.

Operator: This is just some sort of a subset.

Operator: That's correct.

Operator: I think the second question was around high-dose Tysabri and the IP protection virus.

I think the second question was around Hydro's Tysabri.

IP protection Vitesse etcetera.

Operator: That's all right now. So, what we would say to that, Ryan and Geoff, is obviously, we'll wait and see kind of what happens with regard to the phase 3 trials that are going on with regard to biosimilars, and we're supportive of biosimilars coming into the market. We obviously have a biosimilars business. We'll just have to see how their products do, and we'll deal with it when it comes. We probably have time for about two more questions. Thank you. Your next question comes from the line of Jay Olson from Oppenheimer. Please go ahead. Oh, hi.

So what we say that rise Jeff.

As obviously.

What we'll wait and see kind of what happens with regard to the phase three trials are going on with regard to bio similars and we're supportive of milestones coming into the market. We obviously have a files homeowners business, we'll just have to see other products do and we'll do it when it comes.

All right probably have time for about two more questions.

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

Oh, Hi, first off I want to congratulate you for hanging in there and delivering these that academy results. Today. This is very promising news for Alzheimer's patients and their families and second of all.

Operator: First off, I want to congratulate you for hanging in there and delivering these adecanumab 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 adecanumab's efficacy profile and how it lines 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've optimized the efficacy at the 10 mg per kick dose, or would it make sense to test higher doses? Thank you.

I want to thank you for taking my questions.

Can you comment on the clinical meaningfulness added kinda minutes efficacy profile and how does it lineup with your target product profile in terms of improvements in cognition in function are there any gaps in the profile as you know it now and how do you know if you optimize the efficacy of to 10 megs per kick dose or would it make sense.

To test higher doses. Thank you.

Jay I'll start and then some at that will follow.

Jay Olson: Jay, I'll start, and then Samantha will follow. We believe it is clinically meaningful. We've heard that anything above 20% is clinically meaningful. As a neurologist, being the first drug of its kind, we have no drugs right now that affect the clinical decline in Alzheimer's disease. This would be the very first.

We believe it is clinically meaningful.

We've 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.

Geoffrey Christopher Meacham: 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, will enjoy the benefit of living a more independent life for longer periods of time. If you look at the activities of daily living, it's a 40% effect. And that's a caregiver assessment of whether or not the patients can live independently, can do their household chores, et cetera. So that's all very clinically meaningful results.

ER in clinical practice, I think that MCR patients.

We'll be.

If approved.

So enjoy the benefit of living and more independent life for longer periods of time, if you look at that age the the activities of daily living it's a 40% effect and that's a caregiver assessment of whether or not the patients can live independently can do their household chores et cetera. So that's all very clinically meaningful.

For results.

Samantha Budd Haberlein: There's a question around the dose, 10 mg.

As a question around that there was the 10 megs, yes. So the question of whether we had achieved the correct. Those I think what we have learned clearly is that dose is very important but that if individuals' do receive 10 milligram can they do have an efficacious response I think the trials. Unfortunately were hampered by a number.

Samantha Budd Haberlein: 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 if individuals do receive 10 mg per kg, then they do have an efficacious response. I think the trials were unfortunately hampered by a number of operational and other issues that meant that not enough patients got 10 mg per kg, so we do believe that to be the correct dose.

Operational and other implications that men, but not enough patients got 10 milligram per kilogram. So we do believe that feed the correct.

Great. Thank you.

Operator: Great, thank you. Your last question comes from the line of Paul Matteis.

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

Paul Matteis: Great, thanks for fitting me in. I really appreciate it. Within the high dose arm of 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 patients who were stopped at six mix per keg, and I guess, does the differential magnitude of plaque reduction in those patients at all tell the same narrative you're seeing on the difference in clinical outcomes? And then, can you tell us anything else about other measures of function in the ENGAGE subset of patients who titrated all the way up to 10 mixes per keg? Thanks so much.

Great. Thanks for fitting me I 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 patients who were stopped at six makes for kagan I guess does that does a differential magnitude of plaque reduction in those patients that I'll tell the same narrative you're seeing on the day.

France and clinical outcomes and then can you tell us anything else about other measures of function in the engage a subset of patients to titrate. It all the way up to 10 makes for kick back so much.

Thank you. So your first question in amyloid plaques production, we do believe that Pat measurement of amyloid plaques production is a very sensitive to of dose and you've correctly identified to 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.

Samantha Budd Haberlein: Thank you. So your first question about amyloid plaque reduction: we do believe that PET measurement of amyloid plaque reduction is a very sensitive tool for 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...

That were achieved in that high dosing group a in engage.

And the second question was other Baggers a function other measures a function yesterday exploratory analysis that we've demonstrated for you we focused on the primary endpoint and we do not have the same analyses for the functional endpoints, but you do have those results for the overall study where even in engage a week.

Samantha Budd Haberlein: and other measures of function.

Samantha Budd Haberlein: Other measures of function. Yeah, so the exploratory analysis that we've demonstrated for you, we focused on the primary endpoint, and we do not have the same analyses 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.

You 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 are flattening out what Q3 called characterized by the go to file decision. Fred you can you maybe the U.S. have d., but also we this solid performance for the quarter today is about hope and opportunity for the pace.

Michelle Venazos: Thank you. I'm going to turn it back to Michel for some closing comments.

Operator: So thank you all for attending our Q3 call, which was characterized by the go-to-file decision for Adjukanimab with the US FDA, but also with a solid performance for the quarter. Today is about hope and opportunity, for patients first, but also for shareholders. Have a good day. Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect. (inaudible)

Yes, 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.

Operator: transcript Emily Beynon

BF-WATCH TV 2021