Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Great. Thanks so much, everybody. It's my pleasure to be hosting this panel with Frank Bennett, an R&D leader at Ionis, and also one of the experts in neuroscience and neurology drug development. And he's been kind enough to join this conference every year. So I really appreciate it, Frank, for you coming today. On that note, I was maybe just kind of hoping you could start, Frank, and give an overview of the various clinical-stage assets that Ionis has in development for CNS. And then naturally, we can get into Q&A and more of a discussion. So thanks again.

Well, my pleasure, and thank you for inviting me to participate. Yes, so we have a rich and growing pipeline of CNS drugs. To date, we have 2 approved drugs with -- and 9 drugs currently in clinical development, and a rich pipeline of preclinical drugs. Now just focusing on intrathecal-administered drugs. SPINRAZA is obviously a marketed product. It's a standard of care for SMA patients. And our partner, Biogen, is currently doing 2 additional studies for the drug that should further enhance the profile. First off, they're looking at higher doses of the drug in SMA patients. And they're also looking in patients who aren't responding adequately for gene therapy and adding SPINRAZA on top of their gene therapy dose. We have, I guess, a couple of other highlights is tofersen, which we'll probably get into a little bit later, which is completing Phase III trials this year. And then we'll talk about MAPT, which is our drug targeting the tau protein that has just completed its Phase I/II study, and we'll release some of the data later this year from that study. And then there's a number of other projects that are currently in early clinical trials, including additional ALS drugs, a drug for Parkinson's disease and then a drug that could be used for both Parkinson's as well as multiple system atrophy there.

Great. Yes. I get to pick and choose which I'll ask about now.

Yes. A very exciting pipeline of drugs. And we also have a couple of drugs that should be entering clinical trials this year.

I think Alexander's disease and stuff like that. So that's great. Maybe to set the stage, on the SMA franchise, how much work are you guys continuing to do there? And as that space gets more competitive, are there any next-gen projects or dosing interval extensions that you can do to kind of bolster your foothold?

Yes. So the -- as I mentioned, Biogen is conducting a study called a BOAT that's examining a higher dose of the drug in patients. And there's 2 things that will come out of that. One is looking for enhanced efficacy of the drug by using higher doses. And then also, with higher doses that should support less frequent dosing intervals in the patients. We also have a follow-on compound that we've been working on that, again, should support both an enhanced potency as well as a longer duration of effect. And based on data that we've seen, we believe that we can support it every 9 months to every year dosing with that drug, based on preclinical data. So it's very encouraging for the patient population that we'll have additional therapeutic opportunities for the patients.

Great. Awesome. All right. Very good. Well, I wanted to ask one other kind of platform thematic question as we think about the probability of success in different diseases. And I guess, if we think about the 2 most mature CNS programs, right, you've got SPINRAZA, which is a major success and tominersen, which didn't work out, and there's a lot of differences between those assets. But one of the most obvious is the degree to which Huntington's is a whole brain disease and involves deep brain structures, whereas SMA is perhaps more accessible from an intrathecally administered drug. As we kind of look across the other indications from these 2 experiences, what do you think the read-through is? And do you think the setback in Huntington's, is that all cautious for some of these full brain diseases that might not be as easy to access via IT delivery?

Yes. First off, I'd just like to comment that we're very disappointed for the community. We had a lot of hopes on this drug. And unfortunately, with Roche stopping the Phase III study, it's very disappointing to the community. And so we owe to the community to really understand what's going on with the drug. And I think it's -- we're really early in the process of understanding the data and analyzing the data. So I think it would be a disservice to both the community and to the drug. To reach any conclusions at this point. We just need to be patient, keep an open mind and drill down on a variety of different hypothesis that may be driving the outcome that was observed. So that's sort of a background that I need to put out there. And the honest answer is we don't know enough to know what the read-through is on other programs. We're very encouraged by the SPINRAZA data. It really had a very robust effect on patients. And we believe that by being on target, that we can translate to other programs and other diseases, but we're still early enough that we have to prove that today.

Yes. Okay. Fair enough. I realize that the Huntington's asset, there's still a lot that's TBD, but figured it's too topical not to at least ask.

No, I understand.

All good. Maybe let's talk a little bit about ALS because I -- we had Al Sandrock from Biogen on yesterday, pretty interesting discussion with him about SOD1 and C9 orphan. So maybe we can drill down a little bit more specifically with you, Frank. And I guess you've got this early positive signal with SOD1 that shown a pretty big effect size and you've got genetic validation of that target. Maybe review some of that data. And as you think about kind of going to a bigger sample of patients in ALS, what would you see as kind of the biggest risk to application, if there is anything kind of obvious there that you would point to?

Yes. So we currently have 3 drugs in development with Biogen for treating ALS, and then we have a fourth drug that's not ready to start clinical studies that's targeting a genetic variant that Ionis is developing. The most advanced is tofersen, which is an antisense drug that targets SOD1 in patients with a mutation SOD1. So ALS, about 20% of the cases have a genetic cause for their disease, with SOD1 being one of those causes. It's the second most common genetic cause of ALS. And the mutations in the SOD1 protein cause a gain of function in the protein. So it becomes toxic to cells. And there's over 100 -- I forget the exact number, 130 different mutations in the SOD1 protein, which is amazing because the protein is only about 130 amino acids long. So almost any amino acid substitution, causes this gain of function toxicity to occur. There's a good genotype to phenotype correlation. So if you have a specific mutation, by and large, you can predict the clinical outcome. So there are some mutations that have a very prolonged disease course years to decades. There's other mutations that, unfortunately, for the patients, have a very aggressive form of the disease where you can succumb to your disease within a year of symptom onset. And so that's sort of a background for interpreting the early Phase I study. And so the early Phase I study was a dose escalation, safety tolerability study, where patients were only administered the drug for 3 months. So they receive 4 doses of the drug over a 3-month period of time. And then we monitored our colleagues by age and monitored the patients. And what was observed was a dose-dependent reduction of SOD1. I should mention that the safety tolerability profile of the drug was good. And so there was no-show stoppers there. And we were able to demonstrate a dose pen reduction of once we are engaging the target and to document that we were on target, the drug is doing what it should be doing. And surprisingly, what we observed is that in the high dose group, where Biogen added enough subjects to be able to do these kinds of analysis, that in the fast progressing patients that have the fast progressing mutations, there was essentially stabilization of their disease that's measured by ALSFRS. That was -- I said it was surprising because we expected that patient population to be the most difficult to treat. But fortunately, or in the placebo group, there was enough change in their ALS FRS over that 3-month period of time that we could differentiate from the treated group from the placebo. So it's not to say that the drug won't work in the slower progressing patients, it's just that in a 3-month period of time, there isn't enough disease progression to really see a meaningful change in their disease to detect the difference. So based on that data, Biogen started a Phase III study. It's a robust study. It's in, I believe, 99 patients. And that study will read out later this year. And we're -- based on the preclinical data or the early clinical data, we're very hopeful that it will replicate in a much larger patient population.

Yes. Okay. Interesting. So have you enriched it for these sicker patients in Phase III? Or is that not necessary, given the duration of the trial?

There is some enrichment in -- I have to be a little careful because I don't remember all the details that's public. But I think it's safe to say there's some enrichment.

Okay. And so those data are later this year, is that right, Frank?

Correct.

Okay. Okay. Great. I want to talk a little bit about C9ORF because I think the discussion there is equally interesting. And for investors consideration, right? There's, I think, 4x as many patients, a big market opportunity. The interesting thing that Dr. Sandrock said yesterday on the lunchtime panel was that there's a good mechanistic rationale for knocking down C9ORF, but the biology is a bit more equivocal, and there's some debate surrounding adenine function and loss of function and that kind of jog my memory for a gene therapy company I met at one point, that I think was looking at a knockdown and replaced the gene approach. And so maybe you can kind of give folks listening in a background on your C9ORF asset, think about the biological rationale there versus SOD1, which S seems like it's really prime for a knockdown therapy, and there's not much to it.

Yes, C9ORF, absolutely, it's a more complicated disease. The mutation, if you will, is a hexanucleotide repeat. So 6 nucleotides that are repeated. In a normal individual, this repeat is occurring, I should comment, in a noncoding part of the gene. So it's not -- it's in an intronic sequence that doesn't quote for the protein. And so this hexanucleotide in unaffected individual may repeat 10 to 20x. Whereas in patients with the disease that repeat -- can repeat up to several thousand times. And so it's a dramatic expansion of the DNA in that region. That has consequences. One of the consequences is that it suppresses the production of an alternate transcript form, which happens to be one of the major transcript variants. So you get a decrease in the amount of C9ORF 72 protein. In addition, that hexanucleotide expansion causes the RNA to become toxic. It sequesters RNA binding proteins and depletes them from the cell. And so you get this RNA sequestration. And that's a gain of function toxicity due to the toxic RNA. And then that toxic RNA is also -- can be translated to protein products. They're called these dipeptide repeats. And some of those dipeptides have been demonstrated to be toxic to cells. And so you have sort of a mixture of effects occurring. I think most of the scientific data suggest that the loss of C9ORF 72 protein by itself is not causing the disease. So I think replacing it is probably unlikely to benefit outpatients. But there is data that suggests that these toxic gain functions in context of this reduced amount of C9ORF protein that would normally help process some of these toxic molecules out of the cell, maybe what's contributing to the disease. And so the way we've designed our drug is to reduce these toxic variants, the toxic RNA, as well as the dipeptides and not affect the expression of the normal -- the remaining protein that's being produced in the cell. So we're not going to replace that protein, but we're not going to further reduce it with the way we've designed our antisense drug. And so Biogen is executing on a Phase I/II study with that drug. It should -- it's a dose escalation study, partly focused on safety and tolerability. With some biomarker work built in.

Okay. Okay. And then in this SOD1 study, you show an efficacy benefit. Is this study big enough, long enough to share something similar?

Unlikely. So I just -- again, we can always be surprised. But C9ORF doesn't have this very aggressive form of ALS that you see with SOD1 patients. So there's not a good genotype-phenotype correlation. And just garden mill ALS, it's -- again, I don't want to dismiss how devastating it is to patients. It's an aggressive disease. But in the short period of time that we're studying this, we're unlikely to see a meaningful clinical changes that we can detect differences there.

Yes. Okay. Okay. That context makes a lot of sense. Let's talk a little bit about your tau program because that was a cool discussion with Al yesterday. And I guess, maybe just to set the stage, talk about the mechanism of action the downstream impact in different forms of tau and really why this is different than a straight up monoclonal antibody approach.

Yes. So I suspect I'll discuss the rationale for tau. It's a protein that forms these intercellular aggregates called tau tangles that appear pathologically with symptom onset. So it's the closest pathological change that we see to onset of symptoms in Alzheimer's patients. And it is an intercellular aggregate of protein. And so our approach is different than the antibodies and that what we're doing is preventing the production of that intracellular form of the protein. And therefore, depleting the pool that can form these aggregates. And one of the advantages that we have is that we're targeting all forms of tau. So not just posole form or specific splice variants, but all forms of tau would be reduced by our drug. And the other biology that's going on is that there looks like there's some transmission from cell-to-cell at these toxic tau aggregates. So that's where the antibodies are trying to target, is preventing this cell-to-cell transmission with tau. We also would do that by lowering the intracellular concentration with tau. So we not only would prevent the cell transmission. But we would prevent the tau from even being produced or localized in the cells. But we've seen preclinical data that one of the aspects of tau is that you caused this excited toxicity in cells. And by reducing the expression of tau, we reduced that excited toxicity that's occurring. And we can document that in mouse models that's occurring. So we're very optimistic that we're on target, that this isn't -- the other alternate target for AD. That really hasn't been explored to date.

Well. Right, right. Yes. No, we've had some antibody setbacks, but your point is well taken that they're testing a really specific hypothesis, I might only access a small amount of tau in the brain. I guess the flip side of this, and I'd be curious how you're thinking about it, Frank. How do you get comfort with the safety of this approach since theoretically you inhibit all forms of tau at the gene level? And I'm sure you know much more about the evolutionary role of it than I do, but at least we've read that it's this critical cytoskeletal protein?

Yes. So it has a name that sounds scary. And just the biology hasn't fully supported the concerns there, is that it's a microtubule associated protein. That in the knockout mice, it's actually fairly benign phenotypes that they're produced. And so that's the limit condition. We're not knocking it out or reducing the expression. And so it's important to keep that in mind. And based on the transgenic animals as well as our own data, looking at the consequences for lowering tau tale in the preclinical species, we're very comfortable with the level of reduction that we're achieving and the safety of doing that.

Yes. Okay. All right. So can you walk through the design of your ongoing study? And I don't think it's a very long duration. So is this more of a safety biomarker or some?

Exactly.

Yes. Please go ahead.

Yes. So it's a 3-month study. So it's a dose escalation study. So starting at low dose. Patients are given treated over a 3-month period of time. And then we're monitoring for both safety, but importantly, for a duration of effect, looking at biomarkers for a significant period of time after we stop dosing. And depending on the arm of the study that they come into, there's a little bit of varied quality and how long we monitor. But the goal of the study is really to measure the safety of the drug. But to get good pharmacodynamic data that tell us what dose produces what level of knockdown, that also give us information about how long that knockdown is sustained in patients. And so it will end up being a robust data set. We have a number of doses that we've evaluated, looking at both monthly and quarterly dosing in patients. And so it will be your nice data set that we'll be able to describe.

Yes, yes. Okay. I'm not sure if you've disclosed this, but just kind of thinking out loud here. How do the dose levels compare to what you're exploring in ALS and what you explored in Huntington's? Again, I know some speculation from tominersen and I don't want to fuel that. But if we think about therapeutic index, are the dose levels similar here to tominersen? Or are they lower, more like ALS? Any color would be interesting.

Yes. So they're -- we haven't disclosed. But our drugs are -- it's a platform-based technology. And so one of the advantages we can take the eventual earnings for one drug and apply to the next drug in our platform.

Yes. Yes. Okay. Fair enough. Do you want to just maybe make some brief comments on Fuse ALS? This is one where, I think you're pursuing all patients and going right into late stage trials, if I'm correct? So the biological rationale and your confidence for moving ahead that quickly, with real investment and a real trial right away.

Right. So the FUS is another genetic cause of ALS. It's a rare form of ALS, but it does have a distinct patient population have mutations in the plus gene. And like SOD1, there's a good genotype to phenotype correlation. So specific mutations cause an aggressive form of the disease. And I should point out that even the garden-variety of FUS is an aggressive form of ALS. So one of our investigators, if you have a FUS mutation that has a very rapid progressing form of the disease, it's like a SOD1 patient on fire. So in that case, the duration of disease from symptom to onset to succumbing to the disease can be as short as 6 months, in that case. So this -- with that sort of background, and there's good target rationale. So FUS is because it's an already binding protein that the mutations cause misfolding the RNA binding protein and appears to be a toxic being a function that's occurring in those proteins. And we have preclinical data to support them. So this differs a little bit from other programs. And that's part of the reason we have confidence is that this drug was part of an expanded access program or capacity use program, where there were some patients by -- that were given the drug buyer or investigator partner, Dr. Neal Schneider at Columbia. So if he's treated greater than 10 patients already with the drug that initially started off in a dose escalation within each subject, they got up to what we think is a therapeutic dose based on all the modeling. And the later patients is putting up that therapeutic dose. So we have a lot of human safety already with the drug, that sort of eliminates the need to do a dose escalation safety study. And that's part of the reason that we have a lot of confidence. We've been working with regulatory agencies over the past few months. And they're all very supportive of the program and getting this to patients as quickly as possible. This is one of the few examples where the regulatory agencies, in my experience, have been very constructive and partnered with us and trying to get this patient this drug to patients quickly. So the design of the study will be an open -- a placebo-controlled trial in a limited number of FUS patients that based on our statistic modeling and discussions with the agency should be sufficient to support registration of the drug.

Great. So I want to ask about one last thing that just kind of thinking about, after we had our discussion with modeling this morning and done, and that is really you guys were in neuromuscular for a period in myotonic dystrophy and then had the setback because of biodistribution to the muscle is so hard. But more recently, talked about neuromuscular R&D Day. I think you have private company, Aero Bio. And just kind of curious about your path towards resurrecting your efforts there, maybe using drug conjugation as -- if that kind of seems to be a compelling approach.

Yes. No, we're clearly in that space. We've been looking at conjugates for other tissues, and we're making great progress and finding conjugates that we can use for skeletal muscle. That program, the mytonic dystrophy program, we should say, is partnered with Biogen and so we are working hand-in-hand with our Biogen colleagues to advance another drug for treating the muscle aspects of mytonic dystrophy. We're also working with Biogen to treat the CNS aspects of the disease. So mytonic dystrophy isn't just a muscle disease. These patients also have CNS complications. And so we feel it's really important that we treat all aspects of the disease for these patients.

Got it. I don't think there's probably not much you can say there on timing, right? Just...

So we're working very hard. So we'll -- I feel a personal obligation to these patients. I feel a little bit like McArthur coming back to the Philippines that we're going to come back based on what we see. We think it should be a treatable disease.

Yes. Okay. All right. Great, Frank. Well, thank you so much for highlighting a bunch of these programs. And always great to do a panel with you. So I appreciate you taking the time.

Well, thank you.

All right. Thanks, everybody.