Biogen Inc. (BIIB) Earnings Call Transcript & Summary

We're at the top of the hour, and I'm hoping that my video and sound is working. If something's not working, I hope the AAN folks will tell me. Welcome, everyone who's online. It's pretty exciting to be at the academy. It always is for the emerging science. I can't pretend that it's not more exciting to be sitting cheek to jowl in a room. But it's pretty exciting to be sitting here listening to the abstracts. There's a lot of very cool stuff. I'll remind you that these abstracts scored at the absolute top. This is what peers thought was really great science. So it's just going to be a fantastic collection of presentations. I'm Peter Goadsby. I'm a neurologist at UCLA and at King's in London. I don't have to read the usual sorts of things. You don't have to mute because everyone's turned off. You probably ought not smoke. But I guess it's your house, so whatever you want to do. We don't advise Amazon Shopping or any -- or -- and I guess if you want to ride a bike or something like that, that's not a bad thing. I want to put my disclosures up. My area of interest is in migraine. So it's important that I say that I've consulted for the people involved in the exome study, the people involved -- Lilly, the, galcanezumab study that will get presented, along with other companies involved in the migraine space. I just want to make that disclosure very clear. I want to welcome Dr. Castrillo-Viguera, who's going to present EMERGE and ENGAGE, top line results, Phase III studies, aducanumab in early Alzheimer's disease. Doctor?

I'm going to present the top line results from EMERGE and ENGAGE, 2 Phase III studies to evaluate aducanumab in patients with early Alzheimer's disease. Aducanumab is an investigational compound and is not yet approved in any country. The aducanumab Phase III studies, EMERGE and ENGAGE, were 2 18-month, randomized, double-blind, placebo-controlled Phase III studies. They randomized 3,285 patients at 348 sites. Patients had either MCI due to Alzheimer's disease or mild Alzheimer's disease. There were 2 dosing regimens, low and high dose, which were randomized 1:1:1 with placebo. The primary endpoint was CDR sum of boxes at 18 months. Each of the dosing regimens was stratified by APoE4. The low dose in APoE4 carriers were titrated to 3 milligram per kilogram, and APoE4 noncarriers were titrated to 6 milligram per kilogram. At the beginning of the study, APoE4 carriers were titrated to 6 milligram per kilogram in the high-dose regimen, and APoE4 noncarriers were titrated to the target dose of 10 milligram per kilogram. Halfway through the study, we amended the protocol to Protocol Version 4, where both APoE4 carriers and noncarriers were titrated to 10 milligram per kilogram in the high-dosing regimen. By week 78 in the high-dosing regimen, the target number of doses was 14. The baseline demographics was well balanced across arms and across studies, and the baseline disease characteristics were also well balanced across arms and across studies and was consistent with the inclusion criteria. The primary and secondary endpoints were met in EMERGE and had a difference versus placebo of between 18% to 40% and always statistically significant at the high dose. In the low dose, there was a numerical difference versus placebo, although this was not statistically significant. In the amyloid PET subgroup, there was a statistically significant dose- and time-dependent reduction versus placebo in both low and high dose. In the CSF sub-study, there was a statistically significant, dose-dependent reduction in phosphate tau and a numerical difference versus placebo in the total tau. In ENGAGE, the primary and secondary endpoints were not met. There was a numerical difference versus placebo in the low-dose group. In the PET sub-study, there was a dose- and time-dependent reduction versus placebo which was statistically significant. However, this -- and the high dose was lower than that, which was seen in EMERGE. And we also understand that the median cumulative dose was lower in the ENGAGE subgroup, 126 milligram per kilogram, versus the EMERGE subgroup at 140 milligram per kilogram. To understand the difference between the studies and the impact of changing the protocol, we defined the population by a randomized cohort who had the opportunity for all 14 doses of 10 milligram per kilogram, and this was termed the post-Protocol Version 4 or PV4 population. If we compare the ITT population with the post-PV4 population, we can see that the post-PV4 population in ENGAGE is consistent with the overall ITT population in EMERGE. A small tau PET sub-study was also conducted, and this -- these results are pulled from both studies as they were all in the post-PV4 population. In the 3 prespecified regions, we can see a dose-dependent, statistically significant reduction in the medial temporal composite, and in the high dose, a statistically significant reduction versus placebo in the temporal and frontal composite. Shown here are the adverse events, which were well balanced across arms and studies and which were consistent with the patient population with the exception of RAE. For patients who experienced an event of RAE, the majority were asymptomatic. And those who did report symptoms, symptoms included headache, dizziness, visual disturbances, nausea and vomiting. RAE episodes were generally resolved within 4 to 16 weeks. And the majority of patients were able to continue their investigational treatment. In summary, following study termination, analysis of a larger dataset showed that EMERGE high dose reduced clinical decline and in sub-studies showed an effect on disease-related biomarkers. ENGAGE did not reduce clinical decline. However, in a post-hoc analysis, data from a subset of patients did support the positive findings of EMERGE. The most common AEs were RAE and headache. And a re-dosing study is currently offering aducanumab to eligible patients who were actively enrolled in the aducanumab clinical studies.

Thank you. For some reason, the muting and unmuting is flipping on and off. Must be the most common thing that's said in the English language these days, unmute. Thank you for the presentation. It's very clear. We have a question on the board, which I'll take because I think if we've got audience questions. We really ought to take them. And then I'll ask you some really silly questions because they're from someone who's not in your field. So the questioner, who's anonymous -- normally, we wouldn't do that at the academy. But in the context, I think, of what we're doing, we're just going to be -- we're going to go with flexible.

Sure.

And I appreciate your flexibility. So what is the real-world impact of the approximate 0.5 MMSE difference between placebo and active drug decline at the end of the trial?

So that is a very loaded question. We all know the MMSE scale is a very blunt scale and it goes from 0 to 30 and 0.5 as a group-level difference compared to placebo in a very early on population. I think we need to, first of all, anchor it to global scales of assessment of patient status. And unfortunately, we did not have those anchors in our Phase III trials. So I think in general, for the public, we know that the MMSE can be advancing. But over 1 year or 1.5 years in this early population, it's very, very variable. It's one of the bluntest scales, although it was included as a secondary because of the broad use. So I think we're working on this. We're trying to get also the field and the subject matter experts' opinion on all this, the meaningfulness, which is one of the most difficult things to prove after proving your statistical significance in a new drug, in a new class. And we're working towards this.

Yes. It's not easy, I guess, for neurologists to use to the Mini-Mental State. So it's a fair question if not, as you say, a little bit...

It is very complicated for a quick answer.

Yes. Well, it's the science meeting, so we're allowed to get into the weeds. And let me get into the weeds a little bit. I'm looking at this from the outside, and I see one primary endpoint that was positive and I see one primary endpoint that was negative. I see the PET data change in both.

Yes.

And I wonder, if you're standing from the outside and I'm standing from the outside, this might sound really silly, but is your antibody changing amyloid? And is it -- does that mean that it's a good treatment of that but that the Alzheimer's probably is more complex than that and that's why you don't have the same sort of fidelity with the clinical endpoint?

So for sure, Alzheimer is very complex, and it's not only a matter of amyloid. So our monoclonal antibody is targeting one of the hallmarks of the neuropathology of Alzheimer. And as in the field, we talk about this amyloid cascade hypothesis as a hypothesis that amyloid is causing some downstream changes that then include tau abnormal aggregation and then, therefore, neuronal loss and toxicity. Said that, we have seen in both trials changes in the amyloid plaque burden by the amyloid PET. And we have 2 doses, so the low-dose arm and the high-dose arm. And what is clear in both studies is that our low-dose arms behave very similarly both in the tau -- sorry, in the amyloid plaque reduction by PET as well as in the clinical results. So on that sense, our low arm -- low-dose arms are consistent between the 2 trials, where we have had this very surprising and complex situation of completely divergent results in the high-dose arms with one study positive and the other with an evidence of decrease of the amyloid burden also by PET, although it is smaller, as we pointed out in the presentation. So the effect size in reduction in the high-dose arm on ENGAGE is smaller than in 302. And as we also explained very briefly and, of course, very high level in this presentation, we have found a very different level of dose exposure in high-dose arm.

Yes. Can I -- you did say all of that, and I'm just pointing out the fact that there's a bit of a disconnect. I do want to get -- I wanted to interrupt you, I'm sorry, but it's the nature of this medium without the body in which -- there's one other question on the thing, and I think people who bothered to ask questions should have them. So it's a straightforward question. What is the longest a person has been on aducanumab?