Biogen Inc. (BIIB) Earnings Call Transcript & Summary

Good morning, good afternoon, good evening. My name is Carmen Castrillo, and I'm here to present the EMBARK study design. These are the disclosures [ of the efforts ], our forward-looking statements and our legal disclaimer. I want to start by presenting the aducanumab program overview, which encompasses 7 studies, as you can see above: Phase I studies, including the Phase Ib PRIME study with its long-term extension; Phase II study EVOLVE that was started in 2018; and 2 Phase III studies, ENGAGE and EMERGE. As you all know, too, on March 2019, Biogen declared futility on the Phase III studies. And that decision and declaration impacted all ongoing studies, the 4 studies that you can see here and all studies came to a complete stop. After analysis of a larger dataset then that of the futility analysis, Biogen found that there were positive results in EMERGE. And that prompted the company to commit to restart aducanumab dosing in the patients that were impacted. What is the rationale for EMBARK? The EMBARK study really is based on the findings of EMERGE, which the treatment with high-dose arm of that study showed a significant -- that significantly reduce the clinical decline versus placebo in the prespecified primary and secondary analysis and was also supported by biomarker results. The ENGAGE study was a negative study. However, we found an analysis done after futility that patients that had similar high-dose exposure to aducanumab had similar results to EMERGE. Again, EMBARK is trying to address 2 fundamental questions: what is the long-term safety of and efficacy of aducanumab at high doses and for a long uninterrupted period as well as what are the changes that happen in patients that have been in -- stopped the treatment and what happens during the treatment gap with the clinical and biomarker results? EMBARK then, it's a longitudinal, single-arm, open-label Phase IIIb study in patients with Alzheimer's disease previously participating in other aducanumab studies. They were -- there are really some eligibility and inclusion/exclusion criteria that we'll see next. We are studying a single dose, 10 milligrams per kilogram IV every 4 weeks with a titration period that is similar to that of the Phase III studies. The duration is planned for 24 months. We calculate a sample size of 2,400 patients approximately. And again, primary objective is safety and tolerability of 10 milligrams per kilo of aducanumab after a treatment gap either in patients that have been exposed or in patients that have been -- that are naive to treatment. And there are exploratory endpoints for efficacy and biomarkers. Inclusion/exclusion criteria, you can see here the high-level list. Mainly, the inclusion is very, very short. The list is short. We need participants -- active participants of the feeder studies that have a care partner that are able to understand and consent for the study and also are able to comply with the study test and procedures. For the exclusion criteria, you see here the list. The majority is the usual exclusion criteria, major systemic disorders that impair studying like stroke, psychiatric illness, new onset seizures, unstable cardiovascular, et cetera. We also need patients who have been able to have -- undergo frequent MRIs. Here are the objectives. And we will go with each one of them, primarily for safety and the 3 main exploratory. The safety analysis, we'll look at the endpoints are incidence of adverse events, serious adverse events with an immunogenicity and ARIA, are the most specific ones that we are going to look for in the long term. Again, the parameters that we are going to look at is incidence and also classification for AEs that lead to discontinuation of study or drug as well as serious adverse events, the characterization of ARIA, ARIA-E and ARIA-H as well as anti-aducanumab antibodies in serum. Here, on the bottom line, you can see the MRIs. The monitoring schedule, that is exactly as it was in the Phase III studies with 5 MRIs in the first year and 3 in the second year. Here, we are going to see the efficacy endpoints. We will look at the changes in cognition, neuropsychiatric status, function and quality of life with the tests that you see here listed. I don't need to give them. They are basically the same that we would be studying in the long-term extension of the Phase III studies with an addition of the Clinician Global Impression of Change. As you can see in the bottom line cartoon, those assessments, psychological assessments are done every 6 months, together with the quality of life. Some are more sparse. The biomarker endpoints, we are going to study with 3 sub-studies that are optional: amyloid PET sub-study, the tau PET sub-study and the CSF sub-study. All these are in sites that opt in for these sub-studies. And we are aiming to increase the number of tau PET that we collect with aducanumab since tau PET was one of the sub-studies that was more impacted by futility. We continue longitudinal analysis of people that participated in the former amyloid PET and CSF PET. And we will do also volumetric MRI in everybody. You can see here in the cartoon the timings of these optional sub-studies. And here, you can see everything together from cognition, MRI monitoring and biomarkers. The statistical analysis is very simple. We look at incidence and also changes from baseline. And we will look for characterization of ARIA, both radiological and via the symptomatology. And the safety populations are the general safety population that entitles everybody that is receiving at least one dose of aducanumab. And the MRI population for purposes of ARIA is not only having the drug but also being able to receive at least one at post baseline MRI. For exploratory analysis, we are aiming to look at 2 main questions. Again, what is the effects of a treatment gap in patients treated with a potentially disease-modifying therapy? So we look at changes of the end scores of the feeder study to the baseline score in the EMBARK study for clinical and amyloid PET and the longitudinal study of the changes in EMBARK itself with changes from baseline on EMBARK to the 24 months endpoints for all amyloid, tau PET, CSF and clinical and pharmacoeconomic. For the population, it's everybody that receives at least one dose of the study treatment and for the sub-studies, those who have one dose of the study to remain in at least one of the procedures. For analysis of efficacy, we'll have to stratify patients by prior exposure to aducanumab, mainly the length of exposure as well as dose. And also, we'll probably need to take into account length of washout as well as the demographic characteristics. And this is characteristics at entrance. EMBARK is expected to be one of the largest clinical trials in Alzheimer of the contemporaneous type, as I said, with around 2,400 patients. We have 20 countries, 312 sites selected. And as of the 21st of September, we have screened 880 patients with 531 randomized. Short -- in short, I would like to highlight what we expect to learn from EMBARK study. We are hoping to get a deeper understanding of ARIA, both in patients pretreated and patients naive. We are also trying to learn what happens when there's a treatment interruption with amyloid therapies and maybe have more light -- shed more light on the durability of effects. We will also learn what is the treatment effect on patients that are a little more advanced in the disease course by looking at patients that are treatment-naive from the feeder studies. And late -- and last but not least, we plan a large sub-study of imaging and fluid biomarkers that provides an understanding also of the durability and modification of the disease course with aducanumab. So in summary, I'm not going to say anything new. But EMBARK is our global open-label, single-arm study of aducanumab long term with the dose of 10 milligrams per kilogram every 4 weeks. The primary endpoint is long-term safety and tolerability. We are currently enrolling patients in many countries. And we estimate and hope to enroll the target participants that you see here. And this is our intent to learn really and characterize more of the benefit-risk of aducanumab in the population of Alzheimer -- early Alzheimer. We want to acknowledge and thank the community, the patients and the caregivers, in particular, but also the investigators, all the staff and our collaborators to be able to achieve this task. Thank you.

Good morning. Well, I guess for those of you watching the U.S. election, we're not sure if it's a good morning yet. But I'm very honored to get a chance to moderate the Q&A from the first 3 talks this morning. So I think we'll just jump right into it. So the first question is for you, Dr. O'Gorman. And it's whether the justification for selecting bupropion as an experimental arm and was memantine considered as an experimental arm.

Thank you, Reisa, for the question. Bupropion is a component of AXS-05. And so it was included to demonstrate that AXS-05 is having a therapeutic benefit that is greater than that which you would get by giving bupropion alone. And this is exactly what the study showed. And for the purpose of this study, no, memantine was not considered as an experiment.

Okay. Thank you. I'll take the next question because I think it's for the AHEAD 3-45 study. And the question is have regulators agreed to using the PACC5 as the single primary outcome for A45? And yes, we have met already with the FDA and put this forward as the single primary outcome and are proceeding. We certainly will be looking for supporting evidence from others as well. But in this preclinical AD with the new FDA guidance, we have people in stage 1 and 2 and we'll be using a single primary outcome of the PACC5. All right. And the next question is for Dr. Castrillo. And I'll start with the first one, which is will patients need to stay on aducanumab for life.

Well, Imagining the person asking the question is meaning what is the durability of the effect of aducanumab and then or if there is any sign of reaching nonresponse to the drug. And at this point, we don't have this information. We hope with the EMBARK, we will learn more about the long-term effects of aducanumab. And of course, if the drug gets to be approved, more information will come from real world. But at this point, this is to be determined.

Okay. All right. One of the next questions is for me for the AHEAD study, which is asking whether subcutaneous administration will become available as an option versus IV. This is definitely something that we are working on and, of course, is trying to get accelerated in this setting of the COVID situation. Right now, we will be in IV and we'll be offering home infusions as well but certainly working towards subcutaneous. The next question is back for Dr. Castrillo. It's a nice presentation, a comment to you. And for EMBARK, mentioned the patients randomized as of September 21 and asks isn't this an open-label study.

Yes. It is an open-label study. I'm as not sure what is the question. That was like a cut for being able to say how it was, the enrollment, at the time of doing the recording. But yes, it's an open-label study and a first patient in -- was in March of this year in the U.S. And that was a snapshot.

Okay. Great. There is a question for you, Dr. O'Gorman. I apologize if you addressed this already. But will there be a second study of AXS-05 for Alz agitation? And if so, when is that anticipated to start?

We will continue to development of AXS-05 for AD agitation. There will be a second study. We're designing that now. And once the design is finalized, that will also be declared. So very much pushing on with the development based on the positive results of the first pivotal studies.

Okay. Terrific. All right. These are not quite in order, but there were -- how they're popping up on my screen. So I'll take the next one, which I think is -- says, Dr. Sperling, do you expect the incidence of ARIA to be lower in people with less amyloid? Excellent question. We don't fully know answer. We are -- that's why we are doing titration in the study just in case. But yes, there is evidence from other antibodies that the amount of amyloid at the time of treatment does influence the likelihood of ARIA-E. This is old data from bapineuzumab. So if that's correct, then we would expect lower incidence in A 3-45. This is -- I'm going to move this question over because it's a bit of a question, I think, for everyone on the panel. Do we know the amount of antibody in the brain for any passive immunotherapy? How much will get into the brain? So let me let Dr. Castrillo and Dr. O'Gorman answer this and then I can weigh in if needed. Dr. Castrillo, do you want to take that first? Yes.

So I can speak for aducanumab. And we know that the blood-brain barrier pass or the CSF to serum ratio is 0.1%. So -- and that is very average for antibodies or monoclonal antibodies, IgG1.