Biogen Inc. (BIIB) Earnings Call Transcript & Summary

All right. Good afternoon, everybody. I'm Marc Goodman with SVB Leerink. Thanks for joining us for our next session in our third annual CNS Forum, and we're lucky enough to have a company called Biogen join us here. And we have Chris Henderson, the Head of Research at Biogen. And Chris has been in this role a little over a year now, right? But you've been with the company probably 7-ish years.

Yes.

And so thanks again for joining us. And so we're going to cover a couple of areas probably in a little more detail than most people are probably familiar with it.

I want to start with ALS.

Sure.

Hot areas. Many potential agents in development that we go after protein aggregation, complements its regulation, plays a role in neuroinflammation. I mean the -- broadly, I guess, what are your thoughts on these different approaches? And, obviously, Biogen has several approaches and let's kind of talk through those approaches and why you have so many different approaches?

Yes. And I'm glad you're starting with this. I think ALS is one of the most glaring unmet needs there are in neurology. And it's really Biogen's ambition to change lives for patients and their caregivers in this disease. And we're looking at both. As you know, there are both genetic forms, which make up about 10% of the total and sporadic forms with no genetically identified courses that make up about 90%. So you're asking about several of these biologies, which may underlie the sporadic form the disease. And of course, getting the answers right there is going to be really important because -- this is a disease which we can't really model in preclinical models. And by definition, there is no preclinical model of sporadic disorder. So we have to really increase our chances of getting it right in the clinic. And so what our focus is further enriching our source for human data and focusing on specific targets rather than just biologies. And we want to know those targets whose modulation will have the strongest effect. And to test those, we're going to have to have cheaper, shorter proof-of-concept trials in ALS so that we can take early decisions on whether it -- to advance or terminate the program. And it's because of confidence in target being central in the way we look at ALS that we first started working on the familial or genetic forms of the disease. And with the goal, which we're already realizing of expanding to drugs that may target the broader population. And I think it's quite interesting you are asking about biologies. But the first of these genetic targets, SOD1, which we'll talk about more, we've known that gene for 30 years. And yet, we still don't know really the biology that it's affecting to cause disease. So knowing that target is really important and here we have the target. So I think as well as the target, just going into the genetic forms first is a way of really ushering in a new era of ALS clinical trials. In the past, we haven't been able to have what we have now, which is better targets, better preclinical data, biomarkers, better stratified patient populations, new outcome measures and really an understanding of the disease. And so we're gaining that from these trials in the genetic forms of the disease and without learning, even as we await the readouts of the first genetic trials, we're taking those into trials for this form.

So let's talk through some of these. Let's talk -- it's been the first. SOD1 ASO, maybe what's the hook to the product. It's an ASO. Give us the kind of the lay of the land of this product?

Yes. And it's on the SOD1 tofersen. We have the most details. So maybe also to put it, first of all, in the sort of overview of the pipeline. And then we can come and chat more about some of the details about the Phase III trial and other things going on around SOD1. But our lead program is antisense oligonucleotide in partnership with Ionis tofersen, and it's targeted against superoxide dismutase 1, SOD1, which is an enzyme that is expressed all over. But when mutated, it can misfold and interfere in multiple set of the processes. And there's a lot of evidence to say that these are gain of function mutations. So our therapeutic hypothesis is that if we reduce the levels of SOD1, we'll be able to slow disease progression. And so as you know well, Marc, we had a Phase I/II study data being published in the New England Journal. And one of the first parts of that I mentioned now on this overview is that we saw that using this ASO at the highest dose of 100 milligrams over a 3-month period, we could get a 36% reduction from baseline in the concentrations of SOD1 in the CSF, whereas in the placebo group, that reduction was only at 3%. So this shows us engaging the target. And as I said, maybe we'll go down to some of the other programs first and then we'll come back to more details about the clinical readouts in SOD1.

Okay. Okay.

So yes, the next in the list is the most frequent genetic course of ALS, which is C9orf72. And there, again, we have an ASO which specifically targets transcripts from that gene but contain an hexanucleotide repeat, which all evidence suggest is causal in the disease by different mechanisms. And so we hope that by reducing the levels of that, we'll be able to, once again, influence the course of the disease. These patients are about 5% to 10% of all ALS, and that includes some places that used to be called sporadic until this genetic defect can be diagnosed. So that's in currently in Phase I, and we're eagerly awaiting the readout of that. But I talked earlier about bridging from the genetic forms to the more sporadic forms. And I think really the archetype of that is what we're doing with another target, ataxin-2, ATXN2. And the reason for that is that there is genetic evidence for its involvement in ALS but also evidence that suggests that a therapeutic targeting ataxin-2 may be applicable to the broad set of patients, and this is sort of model we're using in multiple places. If we talk about Parkinson's, where I'm sure we'll talk about LRRK2, and it's a very similar sort of model. So in the case of ataxin-2, we know that a set of patients with a moderate-sized repeat -- poly repeat have a higher risk of getting ALS. And we recently published actually that those patients tend to progress faster than the average ALS patients. So those are clearly targets for the ataxin-2 drug. But there were 2 real reasons to think it might be more broadly applicable. The first is there's a lot of evidence suggesting that ataxin-2 is upstream of TDP-43 aggregates of which have seen in more than 95% of all patients. And so may be impinging on what we think is maybe a central mechanism in all ALS or nearly all ALS? And secondly, if you look in post-mortem pathology of nearly all ALS patients, and you look specifically ataxin-2, even in nonmutation carriers, you can see that this protein is mislocalized within the cell. So we really believe it's at the heart of a mechanism that could be acted in both ataxin-2 mutant and general ALS carriers. And so here, too, we have an ASO targeting the knockdown of ataxin-2, and that too is in Phase I now. And the particular interest of this is that showing some of the links we can create now we've got this broader neuroscience portfolio. Ataxin 2 is the causal gene in another quite distinct disease, spinocerebellar ataxia type 2 or SCA2. And so obviously, we're going to be interested as soon as we have evidence for the functionality of this ASO in looking into an indication like SCA2.

Interesting. Interesting. And what about BIIB100? Did we cut...

Yes, BIIB100. I don't have many updates on that because the trial -- the trials are ongoing, but that's an example of where we took a biology, which is nucleocytoplasmic transport, which is biology that none of us suspected we'll be working on as ALS specialists, but we're just a wide range of data in model systems and correlating data in human suggest that perturbations to the way that proteins and molecules shuffle between the nucleus and the cytoplasm and back could be underlying the disease. And so this is a small molecule that targets Exportin 1, XP01. And there are many proteins involved in this transport, but some of our precure data strongly support the idea that modulating XP01 could be efficacious, at least in those models. And so we're looking forward to the results from the trials. But as I say, that's ongoing, and I don't really have a fresh update.

And since you have different approaches here, does it even make sense as you move into later trials to even try combination?

So I think it's common sense from what we've learned across disease areas that combinations will have their role to play in neurological neurodegenerative diseases. I think we feel it's really important not to just place on -- our hope in a cocktail, but understanding the biology behind each. And so I think that's something we can look forward to. But our major goal now is to show an effect with each of these targets singly and that knowing what happens in the patients will allow us to construct a much more targeted combination therapy.

Yes. So let's come back to the SOD1 tofersen just for a second since that's short stage. And let's talk about the study that's running right now. How -- what should we be expecting when the data comes out, what are we looking for? What do you find when the data comes out? What's meaningful to you, that will be important. We can file this thing, it works. How does it compare to the Phase II work that you've done, that you talked about that's been published?

Yes. So maybe for the people listening, and I'll just sort of briefly review what was so promising about the Phase I/II, which was because I think that's implied in your question. This was a MAD study. And I already mentioned that actually we saw a reduction in SOD1 in the CSF, which we believe and hope corresponds to reduction in tissues. And the data that we had in a very small population at the time for 3 months was that there was a slowing in the approved ALSFRS-R clinical score, which measures overall functional status. We show slow -- we showed a reduction in the loss of slow vital capacity and also got signals from handheld dynamometry, which is limb muscle strength. And to go with -- and it's because we got concordance across these end points, even with those -- with a smallish group that we and obviously, general thought that, that was really worthy of interest. And the key point, I think, was that we were able to show that neurofilament in the plasma or CSF which we are taking, exploring as a measure of ongoing neurodegeneration, those levels were also reduced to the high dose group. So this was a case it won't be appropriate for all but in these rare diseases where we've got the right doses, the right number of patients to create the proof of concept, we feel it's right to move straight to the pivotal Phase III study, and that's what we're doing now. So the VALOR study is what it's called. It's a fixed-dose study. And its primary endpoint is once again this change of base from baseline in the ALSFRS total score. And we're looking now at week 28, and this will be placebo-controlled. And this will be a longer period in that Phase I/II trial. And so this should increase our chances of detecting meaningful clinical changes in a wide range of SOD1 patients. But of course, we'll also be looking at CS levels of SOD1 as well as the other clinical endpoints and overall survival. So what we should be looking for, yes, it's a significant change, hopefully, convergently in the same way as we saw in Phase I/II of multiple endpoints. And that should be breaking out later this year.

And with a positive study, I have to assume one study is enough here to kind of file, right? I mean this is a high unmet need.

We can't really go into discussions with the regulators. As you know, but this is the trial that's been planned as a pivotal trial.

Yes. Exactly.

And one thing that maybe just still talking about SOD1. So we learned a lot -- we very much believe that Biogen in learning from one program and moving to the other. So we don't jump from area to area. We try and go by adjacency. And you, Marc, can probably decipher on the call now it's been right, the SMA drive quite well. And what's been so striking with that data is that as we go earlier and treat the presymptomatic genetically diagnosed children, the effects become even stronger. And so it's become a theoretical possibility to look at carriers of SOD1 mutations who have a high chance of later on developing SOD1 ALS. And so we have launched a study called the ATLAS study that's going to evaluate the benefit of tofersen in these carriers. And we'll be looking to see if it delays the total onset or -- and/or slows the disease progression. And we hope that by initiating prior to clinical symptom onset, we may have even bigger effects. So very pleased to announce the first participant has enrolled in this study. And that doesn't actually mean dose because there's a whole run-in period, but that's really ongoing. And so it will be an important complement to VALOR in our plans.

Let's flip gears to tau. What are your current thoughts on tau?

So maybe I'll just say a couple of things about Aduhelm, an accelerated approval of Aduhelm because that's -- I'm not going to go into a detailed review of it, as you may imagine. But it sort of sets the scene for what we want to keep on doing because we want to remain a leader in Alzheimer's disease for the long term. And so we believe that this accelerated approval is going to open a new era of Alzheimer's drug development. And that includes multiple things, including lecanemab, BAN2401, an amyloid targeting antibody that we have in Phase III with Isis and recently awarded a breakthrough designation. But really importantly, because I think this sometimes got hidden behind the aducanumab shadow, we have a deep preclinical Alzheimer's pipeline. And that's diversified both in terms of approaches, our molecular targets, and we've really built up an operations to drive that. And obviously, really, the next stop on that train is tau. It's really considered a really important target in Alzheimer's but still more evidence is needed. So we need to understand this biology. And as I think most people on the call are familiar with, one of the potential interests of tau is that the accumulation of tau, once amyloid starts many, many years before the onset of symptoms in most patients and the onset of tau accumulation really parallels the loss of cognitive endpoints. And therefore, we hope we are able to target later projects. So maybe I could talk about the 2 main efforts that we have in tau at the moment. So I mean the most recent news was disappointing news about gosuranemab, which was an antibody that we in-licensed against the internal region of tau. And that, like other trials for tau antibodies, was really testing the hypothesis that tau during the course of the disease and in alignment with the broad stages can spread from one cell to another in one brain region to another. And so I mean the BIIB92 or gosuranemab, it did the job we wanted it to do as far as we can work out, a large internal tau on the CSF, and that was consistent with prior studies but it didn't meet the primary endpoint, which was a change from baseline on the CDR summit boxes. And we're still analyzing that data set and plan to present more complete results in the future. Our other program I think that I've always said this for all the readouts, is an ASO to tau. And we believe that is a more general hypothesis -- a general thrust of the tower hypothesis. With the antibody, we are saying we think this form of tau may be doing this thing, data really supporting testing that in the clinic. It's hard to fully interpret any negative outcome. But if we can just reduce the level of the tau safely in many centers across the brain, then we can ask what the role of tau is in disease progression. And that's intracellular and extracellular tau because we're targeting the messenger RNA. And so once again, in collaboration with Ionis, we have BIIB080, a tower ASO and really exciting Phase Ib MAD study. This was done in mild Alzheimer's patients, and it showed that the drug must get administered. IT was generally well tolerated and really strikingly resulted in a dose dependent and a time independent reduction in CSF of total tau and possible tau and with a striking durability of effect. So we are planning to present those results at the upcoming AAIC meeting next month, and we're currently finalizing plans to advance debate into a Phase II study in Alzheimer's.

And I think you have one other. You have tau map, right, don't you?

There's also -- so I didn't talk about that. We also have BIIB76, which is another tau map. And so where I don't have any updates on the development of that. Obviously, the gosuranemab results will affect our consideration of it.

Yes. That's why I was getting ready to ask you whether maybe the map approach here is not the right approach. I don't know.

It's too early to say that, but it's quite logical to raise the -- in the way you do.

Yes, yes.

But honestly, it's too early to say because we still don't know one, I don't mean Biogen, no one knows what the toxic speech spreading species of tau is, if there is one. And we certainly don't know whether the antibodies out there are appropriately targeting that. So I'm not saying that the spreading hypothesis is eliminated or the other antibodies, including BIIB076 couldn't have an effect but it becomes yet more important to understand, as I said, all we do here to understand the mechanism and focus on really what we're aiming for with each drug.

Let's switch gears to stroke, quite an overlooked area for Biogen's pipeline. I don't get a lot of questions from investors about it. But as I look there, I'm like, wow, you've got 2 approaches. One, you made an announcement earlier this year that you're moving forward. So I mean which store, do you need new drugs for stroke, so tell...

Yes. And I know it's sort of considered a graveyard for drug development. But I think that's rather unjust actually leaving aside Biogen's efforts. I mean it is the fifth leading cause of death. But when you look back over the past decade, treatment has really significantly improved prospects for patients. But still a long way to go. And so that's really why we're excited about timely readouts from TMS-007, which I'll talk about, and the ongoing study with BIIB093 for large hemispheric infarction. So one of the clinical developments that's changed in prognosis in stroke is endovascular thrombectomy, EVT. And of course, that's not a drug-based approach. But I think it's provided potentially a new broader window of intervention of small molecule drugs because the data from that show that if you can remove the clot even 24 hours after the onset of stroke, you still get benefit. So -- but going back to more and more classical drug modalities, it's actually more than 20 years since the last drug to stroke, tPAs, tissue Plasminogen Activator, was approved for acute ischemic stroke. And of course, it's had a lot of impact but its use is limited to the window between 3 and 4.5 hours after the onset of stroke. And that means that many individuals are just not eligible for this treatment. So TMS-007 sort of goes after the same general mechanism, but we call it BIIB131 now, by the way. I discovered that for this call. It's -- because the major blood clotting event is plasminogen being activated for plasmin, which will then own degrade fibrin, and so rather than putting in the activator tPA itself, TMS-007 is a small molecule which binds the plasminogen, changes its confirmation, we believe, and then increases its binding to fibrin. And so that means you're activating it at the site of the clot, if this mechanism is true, and endogenous tissue Plasminogen Activator can come in and do the job. So I think that's one real interest about the mechanism. Another is that -- there's evidence that it can have anti-inflammatory effects. It works -- it inhibits the system called soluble epoxide hydrolase. And we know that the inflammation is involved downstream of reperfusion. So that adds additional potential rationale. So when the data readout earlier this year, yes, really encouraging. And there are different elements to that. So the first is -- and these are aligned with the end points that we defined for the study. So the American Heart Association says that the most feared complication of current tPA treatments is symptomatic intracranial hemorrhage. And we saw no incidence of this with the BIIB131 treatment, so extremely encouraging. But of course, function is important as well as safety. And BIIB131 showed positive impacts on blood vessel reopening using MR and geography and patient recovery. And I think you know these are often measured due to the Rankin Scale, which is a measure the degree of disability and dependence. And in the BIIB131-treated patients, 40% of patients achieved scores of 0, 1, which is a significant increase over 18% among the placebo group. And scores of 0 to 1 really indicate and there's either no residual symptoms or no significant disability. So very encouraging for a Phase 2.0 study. And what's really important, going back to the rationale I gave at the beginning and some of the limitations of tPA is all of these patients were dosed beyond the time window of approved thrombolytics and including up to 12 hours of the onset of stroke and on average around 9 hours in. So we plan to present the full results of the medical meeting. That's not yet decided, and we are planning the next steps of the 131 program, but you can understand that we are very enthusiastic.

Yes, very interesting. Okay.

So BIIB093 -- sorry, go ahead.

No, I was going to say BIIB093.

So this is focused on large hemispheric infarctions. These are about 15%, overall of our ischemic stroke and the most often associated with occlusion of the large mid-cerebral artery but can have other causes. And in this case, you get severe edema of the brain that compromises arterial inflow particularly. And the edema that results can lead to the compression of the brain within the skull and can result in brain herniation, which is a life-threatening event. So BIIB093 is actually an IV formulation of an existing drug, glibenclamide. It's a member of the sulfonylurea class of treatments for diabetes. And it's been used in its oral form for over 30 years. So its safety profile is well understood. And so we're now in Phase III for the prevention and treatment of severe cerebral edema in patients with LHI. In terms of other treatments available for these patients where the mortalities from 40% to 80% and an elevated risk of long-term disability, one thing that does happen is decompressive craniotomy. And this is a very invasive, obviously, a surgical procedure, which -- when you remove a section of the skull and you relieve the pressure within the cranium and you attempt to reverse or stave off significant herniation. So there have been clinical studies and this does result in a reduction in mortality, but the effects on disability are clearly more modest, appear to be more modest and suggest there's still a very high unmet meet. So maybe I went -- the mechanism of action of BIIB093 is well described. It acts at the level of ATP sensor and TRPM4 Ion channel and one of -- gaining out of this. And so we believe that provides strong potential rationale for this treatment. I mean the good news about this trial is that although the COVID pandemic really impacted stroke treating in the acute care setting, we continue to enroll patients in the trial.

So this is a Phase II trial. Is that?

Phase III.

Phase III. Got it. And when did it get started?

I will have to ask.

Is it last year? It was in the past year?

Slightly before that, I believe, but I'm going to -- that's public knowledge. I just don't have the...

Yes, yes, yes. That's fine. I just wasn't sure if it was over a year ago or whatever. That's fine. So...

Yes. I mean, yes, because before COVID and, of course, like these trials are going in the -- more strongly affected than other things.

Yes, yes. Let's switch gears to Parkinson's. You talked about your innovative approaches to Parkinson's. You have a CK1 inhibitor, which is BIIB118. You have BIIB094 from Ionis, 122, which is part of the Denali deal. And then I think you have another ASO, I believe, for MSA, which I kind of think about with Parkinson's is similar, but I know they're different. So what do you think about these different approaches in Parkinson's? Like what...

It sounds like you could give my talk, Marc. But so yes, absolutely on the layout for all of those. So obviously, vital despite the existence of effective modality is really reducing symptomatically the lows of Parkinson's. We still don't have a disease-modifying therapy. And so we are focusing on what the science tells us, and we're trying to choose the best modality we can. And where possible and where we think that the target is sufficiently important, we are very determined to go in with multiple modalities until we can learn what's best for the patients, what most affects some of the biomarkers and endpoints we're looking at. So maybe I'll start actually with LRRK2, which is this kinase target. And I mentioned this earlier on when I was talking about ataxin-2. I think it's really another example of something where there are a set of patients with mutations who have a much higher risk of getting Parkinson's disease, and it's probably almost certainly through change this lysosome function. But there's enough literature to suggest that these changes are common across Parkinson's disease to make us think and others think that it's testing LRRK2 therapies in the broader Parkinson's population is also very important. And this is -- we talked about -- you started the conversation by talking about biologies. I would say that lysosome biology and Parkinson's is one of the ones that's most validated by multiple sources of evidence, both human and animal. And of course, the well-known one is the GBA mutations that lead to Parkinson's and because they lower the GK activity. So the -- and so LRRK2, it is elevated even in the sporadic idiopathic patients. And so we are with -- both our programs aim to look at these different populations. So I'll go first to BIIB122, which is the collaboration with Denali. That's been I'm sure you're very familiar with. This is a small molecule inhibitor of the kinase activity of the molecule. We got the catalytic role of it. And Denali just announced the results from the Phase Ib study and said that DNL151, which we call BIIB122, achieved both its target and its pathway engagement goals. And the target was about reducing LRRK2 levels, phosphate LRRK2 levels in whole blood, and this was achieved at the low dose. Similarly, for pathway engagement, this is looking at pathways downstream of LRRK2 that were notably affected by LRRK2, and therefore, should be changed if we're hitting the target. And so phosphate 10 was also changed the -- greater than 50% reduction in the low dose and lysosomal function, we can measure in different ways but through a reduction in phosphate. And LRRK2 was a 25% reduction in the low dose and 50% in the high dose. So this means that we got achieved -- Denali achieved the target engagement goal. And so we're really planning to initiate 2 late-stage studies by the end of this year, 2021. And as I said, one of them will be in patients with confirmed LRRK2 mutations. And the other will be in idiopathic onshore PD. BIIB122 does target one absolutely central aspect of LRRK2, which is its catalytic activity. But the reason we like having a second program, which is BIIB094, which is the ASO with Ionis, is targets degradation of the messenger RNA like many of the other ASOs I talked about today although not SPINRAZA, the ones that act through lowering levels. And that means that we -- all functions have liked to, and they may well be others targeted. It also means that by going into the CNS, we have -- we expect to affect the levels of CNS like to more strongly than the periphery. And it will be interesting to look at the comparison between those 2. So I think it's just, LRRK2 it's just a really good example of how we are about following the biology and the genetics, and these studies will, first of all, just allow us to understand the role of LRRK2 and hopefully, with the target engagement we're seeing, provide some important benefit for patients. The other maybe -- I'll go maybe next to the other Parkinson's drug, then briefly to the MSA one sort of the order you gave them in. So quite different is BIIB118, and this is a small molecule. It's aimed at modulating -- regulating circadian rhythm, and it's an inhibitor of casing kinase01, CK1. And the hope is to address some of the behavioral symptoms across various diseases, but we're focusing first on Parkinson's and on something whose abbreviation I can't pronounce. I'll say the full words which is a rigorously wake rhythm disorder. And these are really important problems patients, both insomnia and sleepiness during the day, and there is no current approved treatment. So the hypothesis is that daily inhibition of CK1 can really compensate the loss of rhythm that you see in these patients. And that's in the Phase Ib study. So it could be highly complementary in Parkinson's and potentially in the future in other diseases to some of the disease-modifying therapies we're bringing forward. Lastly, and this goes into -- really into the area of synuclein as a target, which is maybe one we want to talk about more generally. But the ASO that you mentioned, BIIB101 for MSA is one that reduces the levels of alpha-synuclein. And so the -- that because MSA, although not genetically linked to alpha-synuclein has strong deposits of alpha-synuclein in -- across the brain and in different cell types, sometimes from Parkinson's. But I agree with you. It's a very similar movement disorder in that way. And it will first be tested in MSA. And we'll see later on what happens about extending ASOs to Parkinson's...

We only have another minute or 2, Chris, but I'm trying to understand alpha-synuclein, We've had a little bit of setback kind of in alpha-synuclein, maybe but how is that still kind of moving forward here?

Yes, you win some and you lose some. First of all, I'd say, I think of all the targets for large indications, synuclein is the one with the most complete evidence. So genetic -- monogenetic causes in patients and so on. So -- it will take a lot to make us disciplined in synuclein as a target. But it's true, our cinpanemab antibody did not reach its efficacy goals. And I'd say the discussion here is very similar to what we were discussing just a bit earlier for gosuranemab in the tau antibodies. Does that remove the hypothesis of spreading for synuclein? No. But does it make it even more important to go after the -- that in a very targeted way. So that's why we think that having an ASR approach here very parallel to what we're doing for tau has a chance of showing increased efficacy and could be more viable. And certainly, we'll provide -- about the role of alpha-syn in Parkinson's.

Yes good. Thank you. Thank you. Well, we're kind of out of time. I wish we could because there's so many other products to talk to, but I tried to focus on a few that we normally don't talk about as much, at least...

Yes.

We don't. I know you do all day, but thank you for joining us, Chris. Take care.

Thank you. We're really excited about that. Thanks. Goodbye.

Thank you.