Biogen Inc. (BIIB) Earnings Call Transcript & Summary

My name is Tim Miller. And on behalf of Merit Cudkowicz and the VALOR Working Group, I am delighted to present today results from the Phase III VALOR study and its open-label extension evaluating the clinical efficacy and safety of tofersen in adults with ALS and confirmed SOD1 mutation. This study was sponsored by Biogen and uses antisense oligonucleotides developed by Ionis Pharmaceuticals, so some relevant disclosures. I serve on an advisory board and received clinical support for -- from Biogen and have a licensing agreement with and consulting for Ionis Pharmaceuticals, and you can see other disclosures there as well. Merit Cudkowicz received compensation from an advisory board for Biogen, and you can see her other disclosures there as well. Mutations in SOD1 cause dominantly inherited ALS. About 10% to 20% of the 10% that's familial or 1% to 2% overall for ALS. And mutant SOD1 protein is prone to misfolding and likely interferes with multiple different cellular processes. The evidence indicates that SOD1 has -- the mutant SOD1 shows a toxic gain of function. And tofersen is an intrathecally administered antisense oligonucleotide that's designed to reduce SOD1 mRNA, and the protein will fall as well and potentially slow disease progression. The VALOR study is for -- was for adults with weakness attributable to ALS and a confirmed SOD1 mutation. Randomization was 2:1 with 108 participants overall randomized to tofersen 100 milligrams or placebo, and the main part of the study took place for 28 weeks. And then there's an open-label extension that followed where everyone received tofersen 100 milligram dose. The primary endpoint is the ALS functional rating scale revised, that total score, the change from baseline. The key secondary endpoints are breathing, the percent predicted of the slow vital capacity strength, which is the handheld dynamometry megascore and then time to death or permanent ventilation and also time to death. Other secondary endpoints included fluid biomarkers, the CSF or cerebrospinal fluid SOD1 protein levels, which we expect to decrease with treatment with tofersen and plasma neurofilament level. And then one key exploratory endpoint that I'll discuss today is the ALS questionnaire. We used a study enrichment, so a fast-progressing population in a slower-progressing cohort. The faster-progressing cohort was defined by having an SOD1 mutation known to be associated with shorter survival and greater than 0.2 points per month progression or another SOD1 mutation with greater than 0.9 points per month progression. Again, this is on the ALS functional rating scale, the slow decline and for both of those groups for vital -- or slow vital capacity of 65% or greater. Also, the slower-progressing cohort also with SOD1 mutations with no requirement in terms of how quickly they are progressing and a slow vital capacity of greater than 50%. There were prespecified subgroups defined based on baseline plasma neurofilament, and I'll show you some of those results. Overall, the groups were relatively well matched in terms of Riluzole and edaravone use. Those are 2 FDA-approved drugs for ALS. Time from symptom onset plasma neurofilament levels, the ALS functional rating scale prerandomization slope, ALS functional rating scale baseline total score and also the percent predicted of the slow vital capacity at baseline. So in each of those measures, these groups were relatively well matched. The effect on clinical function of the ALS functional rating scale was the primary endpoint. The ALS functional rating scale is a 48-point scale. It has 4 subdomains of fine motor, gross motor, bulbar function and breathing. And on this endpoint -- so for each of these slides or multiple slides will show in blue, which is a slower progressing group and in red is the faster-progressing group. The solid lines are those treated with 100 milligrams of tofersen, and the dashed lines are those treated with placebo. In the left is the VALOR study, and then on the right, the VALOR plus the open-label extension. And as you can see in the VALOR study, there was a relatively little difference and no statistical difference between the groups treated with tofersen compared to those treated with placebo. In the VALOR plus the open-label extension, there may be some stabilization of the ALS functional rating scale in this group that have been treated with placebo shown here. In terms of target engagement, this drug is designed to lower levels of SOD1 mRNA, and the protein then falls according to its half-life. And the SOD1 protein levels do fall in the cerebrospinal fluid in those treated with tofersen, again, placebo and the dashed lines, treated group in solid. These 2 groups here, they were on placebo up until the time of the open-label extension, and then their SOD1 protein levels also fall in the cerebrospinal fluid. So it is clear that SOD1 is lowered by tofersen. How about neurofilament? Neurofilament is a nonspecific marker of neuronal degeneration. It's an intermediate filament protein that leaks out of the cells, and it has increased in the setting of ALS as in many other neurodegenerative diseases. With treatment of tofersen, the neurofilament levels fall, that's shown in both the rapid and the slowly progressive group. And in the placebo group, they do not change over time. You can see again in the placebo group that once treated, the neurofilament levels are lowered, though perhaps not to the same extent as those who were treated initially with tofersen. In terms of respiratory function shown here, the rapidly progressive group, there is a trend towards stabilization of the slow vital capacity seen in the dark red line here compared to the dashed line. And there may be some stabilization of breathing or slow vital capacity in the open-label extension seen here in the blue dash line initially treated with placebo and then open-label treated with tofersen. In terms of muscle strength, there -- very little difference between the tofersen treated group and the placebo in the primary VALOR study in the open-label extension, again, there may be some interesting changes here. I should mention that for these previous slides, there's no statistically significant difference between the groups. Looking at a patient-reported outcome, looked at the ALS assessment questionnaire, 5 questions, to look at the patient-reported outcomes. And again, there may be some stabilization in the patient-reported outcomes. I should mention here that worsening would be increasing, and then the dashed line, the placebo, you can see, are getting worse over time. Very little difference in the slowly progressive group, very little progression on the scale in the slowly progressive group. Looking at the time-to-event analysis. The median time to death and time to death or permanent ventilation were not able to be estimated due to the low number of events. And so we completed a post-hoc analysis for -- that also included the withdrawal due to disease progression. And you can see that in those -- with the early start of tofersen, there were fewer events, in particular, the withdrawal due to disease progression. And that's shown here, again, the blue, the slowly progressive; red, more rapidly progressive group. We next looked at enrichment markers. So if you look first at the ALS functional rating scale change, so the slope from baseline to day 197 and then look at how does that compare to the prerandomization ALS functional ratings slope. Could we tell from this prerandomization slope who was going to be rapid progressive, who was going to be slowly progressive? And there's a relatively weak correlation there. If you use the same Y axis, the ALS functional rating scale change from baseline. And then look at that implied it, compared to the baseline plasma neurofilament, there's a better correlation here. So the plasma neurofilament level was better able to determine the progression during the course of the study. So now looking at the same measures that I showed you already, but now looking with groups that are above or below the median neurofilament level. The faster-progressing group above the median neurofilament group shown in red. The more slowly progressing group below the median neurofilament level shown in blue, again, solid lines treatment; dashed lines, placebo with the open-label extension. And this was the effect on the ALS functional rating scale. If you then look at breathing function measured in the similar way, there seems to be some stabilization or a trend to some stabilization of breathing, the slow vital capacity, again, not statistically significant, and here are the changes in the open-label extension. Muscle strength, as measured by handheld dynamometry megascore, showed relatively little difference between the groups, perhaps some stabilization in the treated group in the rapidly progressive form, and here's the data in the open-label extension. If you -- again, looking at the patient-reported outcome, this is the ALS assessment questionnaire. There is a trend towards stabilization of this questionnaire. Worsening is increasing, less worsening in the tofersen-treated group. There was relatively little change in the slowly progressive group in either the tofersen-treated or placebo. We looked at the similar time-to-event analysis, again, with a post-hoc analysis of the withdrawal due to disease progression in the groups in blue, the more slowly progressive; and in red, the more rapidly progressive group. Again, there were fewer events in the tofersen-related groups -- the tofersen-treated groups. About 50% of the SOD1 mutations in the United States are secondary to mutations in the -- mutations at A4V, also known as A5V new nomenclature. And this mutation has a well-known rapid progressive course. And if you look at the median disease duration from these multiple studies, the median disease duration is about 1.2 years. There are 2 reports of people living for longer than 3 years with the A4V mutation, and this is time since onset of disease. So one natural question to ask is how do the participants in this trial do on tofersen. And you can see the 1.2-year mark here. I should note that there are 4 participants that are ongoing in the study and the open-label extension shown here in the dashed to 3.2 years, 2.4 years and at 1.4 and 1.4 years here. So they are still in the open-label extension. And you can see that there are -- that overall, there may be an increase in survival with 1.5 years as the median for time of onset symptoms -- symptoms to death, withdrawal or the data cutoff here in July of 2021. In terms of safety, nearly all of the subjects had at least 1 treatment-emergent adverse event. Most of the events were mild to moderate in severity. Many of the AEs were consistent with ALS disease progression, for example, falls or the lumbar puncture procedure, for example, procedure pain, headache or back pain. The safety profile in the open label was comparable to the VALOR study. There were several participants treated with tofersen, who had serious adverse events involving the central nervous system. There were no similar events in the placebo group, and these are shown here. The myelitis with the sensory motor deficits was clinically monitorable and was reversible. And there were many in the tofersen group that had treatment-emergent CSF abnormalities. Most of these were not reported as adverse events. And there were some changes in the cerebrospinal fluid in the placebo group as well, which is shown here, though a greater number of changes in tofersen. The changes included a shift to high leucocytes and also a shift to high protein. And these are events that we will continue to monitor closely. So in summary, VALOR did not achieve statistical significance on its primary endpoint of the ALS functional rating scale at 6 months. However, there were consistent effects seen across key secondary and exploratory clinical outcome measures. These effects became more apparent with longer-term follow-up in the extension. As earlier initiation of tofersen led to a slowing of decline in faster-progressing participants and an apparent stabilization of clinical function in the slower-progressing participants. Tofersen administration led to sustained reductions in the total CSF SOD1 protein, demonstrating a clear target engagement. And there were also lowering of plasma neurofilament levels that's suggestive of a slowing in neuronal degeneration. Most of the adverse events were mild to moderate in severity and many were consistent with ALS disease progression or LP-related events. There were some serious neurologic events, including myelitis, that were seen in the tofersen-treated participants. Thank you to the study participants and their caregivers and families, the VALOR and open-label extension steering committee, the investigators and site staff and the entire community without whom these important studies could not have been conducted. The study steering committee consists of myself, Merit Cudkowicz, Angela Genge, Pam Shaw and Gen Sobue. The principal investigators are listed here. And there are multiple groups that have supported this program from the beginning, and these groups are listed here. And I thank you for your attention, and I look forward to answering some questions. Thank you.

Okay. So now I think we should take the time to hand the remaining time over to Dr. Miller and to talk about the results of his clinical trial.

Yes. And if we are ready, Dr. Miller, we did receive several questions for you. And to get started, we had -- can we...

Can I jump in just with 2 things real quick, [ Sabrina ], before we get going?

Absolutely. Go ahead.

So first, I wanted to extend broader the thank-yous. I wanted to mention at UCSD Richard Smith, Don Cleveland; at Biogen, Toby Ferguson and [ Steph Rodet ]; and Ionis colleagues, Holly Kordasiewicz, Tracy Cole, Eric Swayze, Roger Lane and Frank Bennett. So that's the first thing I wanted to mention. And then second, I'm several hundred meetings in, in the virtual space and haven't had this happened yet, but I had one of those oh-nos. I recorded a version, -- another version that we didn't play the latest version today. So the reason to record another version, and this is -- I want to make sure I get this exactly right, the safety data you saw slightly overstated the numbers of serious neurologic events. For the correct slides, please see the presentation available through Biogen's website. So I wanted to -- and then the other reason that I'm disappointed we didn't show the second version because I thought I did a better job with it. And I'm just going to highlight 1 or 2 things I thought we did better, Sabrina, before -- and then I'll take all your questions. So when you sit with the data for a while -- I mean I think you noticed the strength of the SOD1 knockdown and the really impressive effect on neurofilament. But when you sit with the data while and look at the OLE, a couple of things stand out. One, in the slow progressors that are treated initially with tofersen, they don't seem to progress. They're slow. We don't know whether that was the natural history of that group or not. We don't know. In those initially treated with placebo in the OLE, as you look at that, you see them, they decline slowing. And about 12 weeks in, right, when you'd expect SOD1 to be coming down, they also appear to stop progressing. They're slow. So it's -- again, it's hard to know. Then the other point to make that I did better on the second version than the first is that if you look at the OLE in each of the measures, you see a greater separation of tofersen and placebo as you look out for that longer time frame. So you see the effects on multiple different secondary endpoints. Anyway, I wanted to just comment on that. And the slides are available on Biogen's website. So you can now dissect these data. It went by quickly. It's a lot of data to digest in the 20-minute talk. You can also digest all of these data yourself. Okay. Let's jump in.

No. Absolutely, Tim. And I'm so happy that the recording and the slides will be publicly available. I think many of us who work in ALS trials will definitely look at those closely and keep digesting the data. So in terms of target engagement, your data clearly indicated a strong target engagement, as evidenced by reduction of SOD1 in the CSF as well as the neurofilament light chain data. So a few questions about this. So the first question is, do you think that we would need a stronger level of SOD1 knockdown for clinical efficacy?

I don't think we need a stronger level of SOD1 knockdown. I think that the lowering that we show is substantial. I think that the effect on neurofilament also shows, in my opinion, that we're having an effect on neurodegeneration on the disease process. So -- and then the other point to make is that the levels of lowering in the CSF are predicted to be much more substantial lowering in the spinal cord and brain stem. So those levels that we see, there's much greater knockdown in the spinal cord and brain stem. So I think that the lowering was very good in the study, and I don't think that we need to go for more lowering.

Yes. In terms of the neurofilament light chain levels, there was also a general question about how this compares to changes in neurofilament levels seen in natural history studies or in other clinical trials. Would you consider the changes that you saw sort of strong evidence of target engagement in this particular trial?

When I think about target engagement, I think specifically about SOD1. And when I think about neurofilament as a biomarker of neurodegeneration, nonspecific marker. In terms of how it changes -- the natural history of neurofilament in ALS is that it goes up and then stays up and tends not to change very much over time. Multiple groups have shown that. I don't -- I'm not aware that it ever comes back down. I mean maybe somebody has measured the very end stage and -- but I think that it doesn't come back down. And so I'm impressed by the lowering of 60% in the rapid progressors. I think that's a large amount. And in terms of other studies, and again, Dr. [ Pagano ], you could perhaps comment on this as well, I'm not aware of other studies that have shown a major change in neurofilament in ALS. Maybe those are small enough that I'm not aware of, but I'm not aware of any.

Yes. Me either. So there was a question -- not surprisingly, people will be asking about the next steps. So all the questions that we received, there was a specific question about plans for filing. Is there a plan to file with the FDA for the A4V group?

Right. So this is a super important question, and it's one that everybody wants to know, and I think it's something that we need to get out there to families with ALS, to people who have ALS now with these SOD1 mutations. So it's absolutely an important question. Unfortunately, in this setting and at this time, I'm not able to comment on the regulatory or those next steps but just recognizing that it's hugely important and an important task going forward and that, of course, Biogen is now focused on this, and I'll defer to them.

Absolutely. Those are the questions we have. I think we have maybe another couple of minutes. I don't know if, [ Brian ], you have any other questions.

Yes. Tim, thank you so much for that marvelous presentation, marvelous data. One thing that caught my eye was that when you were looking at the crossover patients, the patients who were initially treated with placebo and then crossed over to actual active treatment, the effect was there, but it wasn't -- the magnitude of that effect wasn't as great as for those who were treated earlier. And I'm wondering, and maybe you could speak to this, does this hint at the idea that we have to treat early. And that the earlier we treat, the more effect we're likely to see. And I suppose the knock-on question to that is how long did these patients have -- were they sick before you instituted treatment? What was the sort of average length of their disease?

Right. So both good questions. And I anticipated this question from you, Brian, because you brought this up thing to talk about earlier treatments, so I think we knew that maybe this was coming from you. So in general, you see that either earlier or longer, that's what the open-label extension shows us, both are true of the people that are treated earlier, has a greater effect on the clinical function. I think almost everyone -- or everyone believes that earlier treatment is better. And you'd see some of that in the open-label that especially in the slow progressors where they do decline, and perhaps they stabilize to some extent, but you've lost motor neurons by that point. And this therapy is not going to bring back motor neurons. The idea is that it would stabilize. So wherever you are when you start, you're not going to get back to motor neurons, and so earlier is always going to be better. And you asked about the timing of treatment. That's something we're going back and looking at very carefully, how soon since the onset of the disease? And then does that help us understand the response? It's going to be complicated to understand that because of the onset -- defining that can be challenging, as you know, and then some of the early parts may be not as linear. So I think that we need to, yes, treat earlier, and of course, we'll try to do that.

Yes.

Tim, I -- you may have shown this, but I didn't hear it or maybe it went by too quickly. Was there any difference between males and females in terms of response?

Yes. So the top-level comment to say to that is that we are digging in with this sort of responder analysis, which is really fun to do. I don't have any responder sort of data to present to you today. And I don't have even the response by male/female. So we will look at that and look at other types of responders. Are there people who did well? And is there anything that we can pull out to understand how they might have done better than others? That's a fun part of the data analysis. If I didn't highlight or make clear, this is a new data set. We haven't been sitting with this for very long. We don't have all the analyses done. The goal was to present the top line data as soon as we had it and wanted to be able to present it in this forum, at the ANA meeting, and I'm absolutely thrilled to be able to do so and to make that time line to get it into this meeting, but we don't have all the analysis. But we will continue to look at the data. And of course, I hope to get it into print so that everybody can look at all the details.

Great. Brian, I think we are at the end.

We are, indeed. Thank you very much for -- actually, all of the speakers for their exciting presentations and their marvelous talks and, of course, also to the audience for their insightful questions. So I think with that, I will say goodbye, and thank you all again.