I'm Luca Issi, Senior Biotech Analyst here at RBC Capital Markets, today is a great privilege to have Ionis with the Fireside Chat representing the company. We have Brett Monia, Chief Executive Officer. Brett, thanks so much for joining us. How are you doing today?
I'm doing great. Thanks, Luca. It's really, really great to be here, and thanks for the opportunity.
Fantastic. We have a long list of questions here, but maybe before I ask you about the individual programs, can you just talk big picture about what progress has the organization made over the last few months, and maybe most importantly, what's ahead here for Ionis?
Sure. Happy to. Things are really exciting today at Ionis. You know, in our business, the biotech focused on therapeutics, what's really important is to drive value, is to deliver transformational medicines to the market over and over again in a sustained manner. We're doing exactly that. Today we have 7 medicines in phase 3 development, really leading in our sector with such a rich pipeline.
These 7 medicines are being developed across 9 specific indications, both rare in-indications as well as broad indications. Many of these are wholly owned by Ionis. Some are partnered. This phase 3 pipeline is mostly derived from our rich industry-leading, what we think is industry-leading neurology franchise as well as cardiovascular franchise.
We're really thrilled to have reported great success already this year. We've had our drug, Qalsody, approved for a genetic cause of ALS just a few weeks ago. It's now launched with our partner, Biogen. They're doing a great job. It's the first disease-modifying treatment for a genetic cause of ALS ever approved.
We're also very pleased to have reported very positive phase 3 data for Eplontersen at the AAN just a few weeks ago. That medicine is under regulatory review by the FDA with a PDUFA date of December of this year. We're prepared to launch with our co-commercialization partnership with AstraZeneca early next year. We're planning to file for other regulatory approvals throughout this year and next year.
The late-stage pipeline as well as the mid-stage pipeline is really firing on all cylinders, and we're seeing strong potential to deliver more medicines time and time again in a sustainable manner this year, next year, and for many years to come. We're in good shape.
Fantastic. Great overview. Maybe if I may, on TTR polyneuropathy, you already talked about it. Again, congrats on the impressive data. Can you just maybe highlights, recaps on the highlights from that data, and maybe how should we think about that data in the context of some of your competitors?
The highlights of the data are this, the efficacy and the safety was everything we had hoped it would be. Safety was pristine, very clean, excellent compliance throughout the 66 weeks of treatment, and the efficacy was highly competitive.
What we saw was in our co-primary endpoints, a highly statistically significant benefit against both the measure of neurological disease progression, mNIS+7, where we essentially halted the progression of the disease compared to historical placebo. We had more than 50% of the patients actually improve, so they, their disease actually reversed compared to their baseline values. In the other co-primary endpoint, Norfolk Quality of Life, it was even better.
We actually showed a mean slowing reduction of disease progression in Norfolk that was below baseline, with 60, more than 60% of the patients improving compared to their baseline measures. What that means is patients are actually reversing their disease. It's a very competitive profile from efficacy and safety standpoint.
We also hit on all 4 key secondary endpoints, including a measure of cachexia, which is really what these patients usually succumb to, wasting of disease, highly statistically significant. This is a market that is essentially untapped today. You know, the prevalence for TTR polyneuropathy is estimated to be about 50,000 patients. It's a fatal disease. Far less than 20% of the patients actually have been put on treatment to date.
This is a market creating, this is a market building opportunity. We're well-positioned to take advantage of this open market. We have great efficacy, as I said. The other advantages that we think that patients are really asking for that we can provide is the ability to, for the patients to self-administer the drug themselves using a simple subcutaneous auto-injector, monthly treatment. Simple, the medicine is very stable. It's stable at room temperature. It's easy to use. What we have learned from extensive market research, as has our partner, AstraZeneca, with their market research, is that this is what patients want.
They want the ability to control and manage the disease themselves, not rely on a healthcare provider to make an appointment and have their drug administered by a healthcare provider. Physicians, too. Physicians do not want the cumbersome setup of appointments and having to schedule and all that and to have to hire staff for this as well.
We think this is a very competitive profile for a market that's wide open, and it also bodes very well for the larger indication, TTR cardiomyopathy, which is, of course, a much larger indication. As I said, 500,000 or so patients with prevalence worldwide, and the safety and the efficacy, we think is gonna read right through to that.
Great, great. Super helpful. Since you already mentioned maybe TTR cardiomyopathy, that's a good way to maybe pivot to cardiomyopathy. Can you just remind us the rationale behind your recent decision to upsize the phase 3 and make it longer? What was behind that decision? Was that informed in any sort, form, or shape by maybe an event rate that was a little bit lower than you originally anticipated? Or any thoughts there?
What I just highlighted as what we think is as a competitive advantage for polyneuropathy holds for cardiomyopathy as well. In addition, a very significant competitive advantage for this very large market opportunity, TTR cardiomyopathy, is the design of our phase 3 cardiomyopathy trial design. This is a landmark trial design. This is the largest trial that's ever been done in this patient population, the largest and the longest.
We upsized the trial last year for several and very important reasons. First, recognizing the fact that all investigational medicines that are in development today for TTR cardiomyopathy were powered, were designed based on the original ATTR-ACT study that Pfizer conducted for Tafamidis. However, those patient demographics today largely do not exist today as they did back then.
That trial was designed nearly a decade ago. Based on far better disease awareness in this disease area as well as better diagnostics today than they were back then. Disease awareness really didn't exist for TTR cardiomyopathy back when Tafamidis was developed. Patients are being diagnosed with much milder disease today, right? It's clear it's now published by several KOLs in the field. This was really what drove...
Our understanding of the evolving landscape of patients, the demographics of TTR cardiomyopathy, is really what drove us to say, "We need to resize this study to account for a change in patient demographics to ensure for a successful study outcome and to ensure for the richest data set that we can possibly get from this, from this study, including subpopulations of patients."
That's really what drove it, not so much about blinded event rates. Sure, we were tracking blinded event rates. That was early in the study, and those events usually really kick in in the last third of a cardiovascular outcome trial. This has been very well-received by the KOL community. It's been said that this is necessary, the changing demographics, to ensure for a very successful study.
What it also allows us to do, has allowed us to do, was to give us the space with the size of the study to be able to prioritize sites, and slow down or stop enrollment in sites where Tafamidis is used heavily, as well as where diagnosis is happening in much milder disease. We're prioritizing sites where disease awareness is less well, as well as where Tafamidis usage isn't available. That's working exactly well.
What we wanted to do in this study was to have about 50% of the patients naive that'll be treated with eplontersen and about 50% of the patients in the study in which we're using Eplontersen on top of tafamidis, so that we can make claims when we get to the market, what added benefit does Eplontersen offer to patients on top of standard of care?
How does our drug, Eplontersen, compare to Tafamidis directly? That's exactly the way it's playing out right now. We're very pleased with the trial design. We think that that is an added, really an added advantage for Eplontersen in this, in this really, really big market.
Great. Great, great. Super helpful. I think investors are on the edge of their seats waiting for both the BridgeBio data, I think in July, as well as the AdCom for Alnylam. What do you think is best-case scenario versus worst-case scenario for Ionis into those events?
Just to say it, Lugo, you know, we are 100% focused on Eplontersen, less on competitive markets, especially in the stabilizers, which is a very different mechanism, Acoramidis being a stabilizer compared to a silencer. To try to answer your question, for Acoramidis, I think the readout's this summer, cardiovascular outcome trial, a stabilizer, not a silencer. I don't see a downside to whatever that outcome is.
What we're particularly interested in seeing is whether the demographics, which is a milder patient population, which I just covered. The fact is that, you know, the information that now supports the fact that these patients with cardiomyopathy are a milder patient population is actually reflected in the demographics of the Acoramidis phase 3 trial. There's a lot of data supporting this.
What we're really interested in seeing is in the placebo group, does that milder patient population translate to fewer cardiovascular events, right? That would bode very well for our trial design. It actually provides added support for the reasoning why we upsized this, our study as well. Of course, we'll be interested to see how a silencer like Acoramidis compares to Tafamidis, cross-trial comparisons with all those caveats.
That's really what we're interested in there. As far as the Apollo B AdCom, really, we don't see this as having any real read-through to silencers that are in development. With hard endpoints, that's, you know, looking at cardiovascular mortality, cardiovascular events.
This is, this was a trial that was done as a functional readout, a short trial, 12 months, looking at 10-minute or 6-minute walk distance. Very little read-through because you know, the standard of care today is outcome. Tafamidis proved a reduction in mortality. That's what you're gonna need to show, not an improvement in, in a walk test. That's the, that's the bar. Very little read-through there. I think the main focus will be, will be the clinical meaningfulness of the increase, which I think is like 15 meters compared to placebo. And how meaningful that is to a cardiologist, which will be interesting to hear the discussion.
I think the other key aspect of that outcome will be, why the patients that were on Tafamidis not do better on top of, you know, the silencer and stuff. But, those are small numbers, I don't really see much read-through there. We're focused on our phase 3 program.
Got it. Super helpful. Maybe last one on TTR cardiomyopathy. How are you thinking about the commercial strategy there? You know, it's my understanding obviously Alnylam is using Medicare Part B versus maybe you guys are thinking more Medicare Part D. Walk us through what you're thinking there, you and AstraZeneca's thinking on the commercial opportunity and what's the market access strategy for that market.
The market access strategy is global. We think another big advantage for our program is to utilizing the global strength, the presence of AstraZeneca commercially in the cardiovascular setting. Of course, I mean, AstraZeneca is a powerhouse already in heart failure. We're already with AstraZeneca, Ionis, and AstraZeneca in the field with our medical affairs teams building the case for Eplontersen.
The polyneuropathy data is a great tool to be able to speak to KOLs and investigators about how great this program is, what's coming for cardiomyopathy. A lot of these patients present not in neurology offices, the polyneuropathy patients, they present in cardiology offices, nephrologists, GI docs, and so on.
We are having the strength of AstraZeneca already in doctor's offices talking about their heart failure drugs and saying, talking also about Eplontersen for this mixed phenotype patient population is a big advantage. Our drug, Eplontersen, as well as our other drugs are, would be classified as Part D drugs, right?
However, regarding the IRA, the fact of the matter is that TTR amyloidosis is defined as a orphan drug disease for TTR amyloidosis. It's not been carved out neuropathy versus cardiomyopathy. So it's one orphan disease and therefore it's not subject to maximum fair price negotiations. We're free and clear there for TTR amyloidosis to not have any negative impact by the Inflation Reduction Act.
In fact, we actually have an advantage from the Inflation Reduction Act. You know, one of the things about Part D drugs that were disadvantaged versus Part B drugs in the past was the out-of-pocket expenses that patients were subjected to until they got to a certain point, which could have been very expensive for Medicare patients, of course, very expensive for these patients.
That's largely gone away with the Inflation Reduction Act, which makes our at-home self-administered product by patients administering to themselves even more advantage. The cap is at $2,000 annually, and that is easily manageable for by the manufacturer with patient communities and so on. We don't see any hindrance to the IRA. In fact, we see advantages for Eplontersen.
Got it. Got it. Super helpful. Maybe if I can pivot to the CNS franchise, obviously congrats on Tofersen. Obviously relatively small indications. What are your expectations for the launch? Maybe were you surprised by pricing? You know, obviously Biogen decided to price this on par with Amylyx, despite a much smaller indications. Were you surprised by that?
As a reminder, Tofersen, and I said it earlier, is we're very proud of Tofersen. It really is the first disease-modifying treatment for any cause of ALS. Patients are gaining strength. They're living longer. I mean, all indications are, and that'll be proved out, we think, in long-term, in real-world treatment, in the real-world treatment setting.
It is a very small subject segment of the ALS community. It's also a stepping stone for future development of ALS drugs for even larger markets, including our own. We have two other drugs in clinical development that are targeting genetic and non-genetic causes of ALS, including sporadic ALS, which is the majority of patients.
The learnings that we've learned from Tofersen are will be directly applicable to these other medicines for ALS, and we've already applied them to our other clinical trials. It also bodes very well for the platform in being able to deliver a disease-modifying treatment for ALS because it's the same platform for the other causes of ALS. Tofersen because of a design issue with the phase 3 VALOR study, did not hit its primary endpoint in the phase 3 VALOR study, so it was approved as an accelerated approval path.
It wasn't approved for full approval, and that really weighed into Biogen's decision on pricing, to price accordingly, had it been approved, you know, with full approval and the phase 3 results were very positive, maybe we would have saw something different there. You know, Biogen is very conscious of the patient community and want to do what's right for these patients, and they priced it accordingly.
Got it. Got it. Super helpful. Maybe since you mentioned sporadic ALS, you're going after sporadic ALS using Ataxin-2. I think on ClinicalTrials.gov, you recently added another portion of trial that I believe is randomized and relatively large. How are you thinking about accelerating development of that molecule, given that now you know you can use NFL as a potential surrogate biomarker for approval?
One of the key learnings from the QALSODY, and again, this is a really I know I used this word once for Eplontersen already, but the SOD1 ALS approval is really a landmark for ALS. It really has to be appreciated in that vein.
We have shined a light on how ALS drugs will be developed in the future. Neurofilament light chain, the evidence that neurofilament light chain is a biomarker that predicts disease progression and outcome in ALS is now validated, right? This shines a light on how ALS drugs will be approved, including ours in the future, to bring more medicines to this patient community, which is in desperate need.
We will have already adapted our trials for FUS-ALS as well as Ataxin-2 for sporadic ALS, utilizing a neurofilament light chain not only as an endpoint to show that patients are benefiting a biomarker, but also to be able to select patient populations based on their progression rates using neurofilament light chain.
As many that are familiar with drug development, especially neurodegenerative diseases, you do a run-in period in which you look at the progression of the disease historically. Now having neurofilament light chain as a more quantitative and precise measure of how to quantify and stratify these patients, it will bode very well for success in the future. The Ataxin-2 program is in phase two development.
The objective, it's a dose looking at different dose cohorts, including the added dose to look at additional doses to make sure that we have the right readout to support a decision to go to phase 3 development. What's the right dose? What's the right dosing frequency? A lot of our neurological disease drugs today, including our tau program for Alzheimer's, for example, is being dosed biannual.
Does this, based on the longevity of Ataxin-2 reduction and neurofilament light chain reduction, if we see it, will that support even in, you know, biannual dosing in phase 3 development? There's a lot of data we need to learn, and that's the main reason why we added another cohort to the phase 2 study.
Great. Great. Super helpful. Maybe if I may, let's pivot to HAE for a few minutes. Can you just remind us the rationale behind that target and how you design the phase 3? If I recall it correctly, the phase 3 has 3 arms, placebo Q4W and Q8W. Is the Q8W nice to have or should we think about that an important requirement to have a commercially viable product here?
We're very excited about our third near-term commercial opportunity for Ionis to bring to the market ourselves, Donidalorsen, as a prophylactic treatment for hereditary angioedema. In our phase, our phase 2 data was stunningly positive. It basically checked each box that patients and physicians are desperately in need of, in search of.
That is better efficacy, better convenience, and better tolerability. We showed in the phase 2 study, which has now been replicated in the phase 2 long-term open label extension for a year of treatment, efficacy on the order of about 95% reduction in HAE attacks compared to placebo over time. That is really unprecedented. That's the best reduction in attacks.
Ninety-nine percent of the patients were actually attack-free for up to a year in the open label extension. This is with excellent tolerability as a simple self-administered, low volume treatment, painless treatment, using an auto-injector. Patients just like Eplontersen that I described earlier. It's the same setup. More convenient than what's out there today.
Standard of care, of course, is Takhzyro, which is more than 75% of the patients are being dosed, biweekly every 2 weeks. What we're offering is every 4 weeks, with better tolerability and better efficacy. That's the competitive profile that we think is a winner in this prophylactic setting. Based on the phase 2 data, which showed long-lasting reductions in the target kallikrein.
To your question, hyperactivity of the kallikrein pathway is what causes hereditary angioedema. We're blocking that pathway based on the long-term treatment in which we suppress the pathway long time, long term. We also have an arm in the phase 3 study for every 2 months dosing, which further will enhance the profile for this drug.
Do we need bi-monthly, every 2-month dosing to win in this market? We don't believe so. Monthly, with this efficacy profile and this safe tolerability profile, is a winner based on all of the market research we've done to date. Having in our label the flexibility to dose every 2 months if the patient chooses to do that is just added benefit. It just provides better flexibility for the patient to at least try every 2 months dosing. They could always come back to monthly dosing, if they choose to, which is still really convenient for patients.
Great. I know we're running out of time, but I do wanna ask a bigger picture question about your relationship with Biogen. Obviously, they have a new CEO in place. It looks like Viehbacher is clearly focused on both costs as well as M&A. How has your relationship with Biogen changed now that there's a new CEO in place?
We have several, obviously, partnerships. They're all going well. We have two strategic partnerships, one with AstraZeneca and one with Biogen. Biogen's focused on neurology. It's going great. It really is. You know, we were very pleased to hear, and in speaking with the leadership at Biogen over the last, you know, number of months, how much they appreciate the Ionis partnership.
It's really a key component to their future growth, their pipeline. We feel the feelings are mutual. We really respect and honor our partnership with Biogen. It's very pleasing to have heard leadership at Biogen say publicly how important the tau program is to them.
This is a great looking program, for Ionis, for Alzheimer's disease. I mean, we were able to show things that have never been shown before, including reversal of neurofibrillary tangles by PET imaging in phase 1, 2 studies that we conducted. Also the Angelman's program has been highlighted as a key priority for them, also coming from Ionis, as well as several other programs. The partnership with Biogen is great. It's very strong. God bless you. We look forward to, you know, continuing our relationship with Biogen for years to come.
Great. Maybe if I can press on that. It's clearly focused on cost. Does the fact that he's now focused on cost kind of raises the bar in terms of go, no-go decision for some of the earlier programs that you have in the pipeline, or is that not the right way to think about it?
Well, time will tell. You know, nothing has been, there's no change in philosophy in the relationship, but time will tell. All companies, at times during their evolution, during their journey, have cost-cutting times in their time. Biogen has stated they are. It's very possible that fewer programs will be taken by Biogen that Ionis offers to them.
That's a win for us in many ways, because we are prioritizing the Ionis fully owned neurology pipeline ourselves, and this will allow us to grow that pipeline and bring more neurology products to the market, ourselves and commercialize them. It's really a win-win for Ionis. Biogen is still a very strong partnership. Programs are moving along really well. We also expect to be able to expand our own neurology pipeline, over the coming years.
Fantastic. Thanks so much for joining us here. Thank you, Brett, for the conversation. Fantastic.
Thanks.
Looking forward to the next conversation.
Appreciate it.
Thank you. Yep.
Thanks, Luca.