Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Hi. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome John Maraganore, the CEO of Alnylam. This is a fireside chat format. Thanks for joining us today, John.

Pleasure to be here, Maury. Thank you.

So maybe to start off, if you can provide a 1-minute overview of Alnylam.

Yes. Thanks. Alnylam is the pioneering company in RNAi therapeutics. We brought 4 products to the market, 3 that we directly commercialize globally, 1 that we're partnered with Novartis. And all of these medicines, at least in our view, have really been transformative for patients. So we're really excited about that and helping the patient communities that we serve. On top of it, we built a clinical portfolio of over a dozen programs in active clinical development. This includes Vutrisiran, which is in registration that's destined to be -- if it's approved, our fifth RNAi therapeutic that we bring to market. We also have programs like our APOLLO-B and HELIOS-B studies that are going to potentially expand the opportunity for ONPATTRO and then Vutrisiran. And then some exciting programs like our hypertension program that we may talk about as well. And then the third part of Alnylam, really, which is the soul of the company, is the product engine that we built over this time, delivering 2 to 4 new INDs per year, a real source for organic, sustainable innovation. Then everything about Alnylam is encapsulated with our P5x25 goals for the next 5 years, which we can talk about as well.

Great. Sounds good. And you had a good first quarter for ONPATTRO with greater than 1,500 patients worldwide on drug. Can you talk more about patient numbers or any other ONPATTRO metrics you're seeing in the last couple of weeks with COVID easing up in the United States? And how you're thinking about 2Q sales as well as the remaining quarters of 2021?

Yes. I mean we're really pleased with Q1. It was a strong quarter for us, double-digit growth relative to Q4 of last year. We ended Q1 with over 1,500 patients on commercial products. So we're off to a good start in 2021 with the product. And now we don't provide separate revenue guidance for ONPATTRO. We have all of our products together. And we did reaffirm guidance in Q1 for our combined portfolio of 3 products to be between $610 million and $660 million for full year 2021. So again, we're off to a great start and really pleased with ONPATTRO performance. in all regions, including the U.S. as well.

Got it. And I've been pretty surprised just with how things are opening up around COVID. I guess are the -- is the U.S. opening up, is it in line with your expectations or potentially better?

Yes. Look, we are really happy with how patient flows through the health care system have been improving of late. We had a tough January and February, as everybody may remember, with COVID really being at its peak in the U.S. But at the end of February into March, we saw a very nice recovery of patient flows through the health care system. And we certainly are optimistic that that's improving in Q2 when we should see that evidenced throughout the course of the year as long as the pandemic stays under control.

Got it. Okay. And for ATTR, it seems like most revenue growth is driven by the mixed phenotype hATTR patients who are on a stabilizer for cardiomyopathy. Can you talk about how these patients are identified? Whether it's identified by Pfizer or Alnylam, and the process for how they get onto the combo treatment.

Yes. So just as a reminder, Maury, ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary ATTR amyloidosis. And to your point, it's a multisystem disease. So many patients present with a mixture of symptoms, polyneuropathy, together with cardiomyopathy. ONPATTRO was used to treat the cardiomyopathy -- treat the polyneuropathy of the disease and tafamidis is used to treat the cardiomyopathy of the disease. So there is a dynamic that's out there of combination use that we're aware of in the U.S. market. We don't see that as much in the rest of world. What we see in the rest of world are patients being switched from being on a TTR stabilizer to come on to ONPATTRO or naive patients coming directly on ONPATTRO without even going on a stabilizer. So depending on the country that we're in, when we talk about this and the region, the dynamic can be different. But there's certainly a lot of recognition of the burden of polyneuropathy in patients with so-called mixed phenotype hereditary disease. And that certainly is an opportunity for patients to benefit from a drug like ONPATTRO, which can help with their polyneuropathy.

Got it. Okay. And so maybe digging into that a little bit more. So based on what you're seeing commercially, would you characterize doctors as being more liberal than expected with their use of combo treatment with ONPATTRO and stabilizer? And can combo use be viewed as a forward-looking indicator for ATTR cardiomyopathy.

Yes. I mean we really can't say very much about the prescribing habits, Maury. Again, this is really a U.S. phenomenon, and this is really about treating the polyneuropathy associated with these patients' disease. And that's how ONPATTRO is being used. So I think we'll have to really wait for the KARDIA-B studies, the Phase III studies, to read out to ultimately help us understand how a drug like ONPATTRO might be used in those patients once it's labeled for cardiomyopathy specifically.

Makes sense. Makes sense. And also wondering if you could talk more about the commercial dynamics with Pfizer right now, and how that changes after you get the KARDIA-B studies reading out and you start marketing for cardiomyopathy?

Yes. I mean, look, it's -- again, we're labeled currently for the polyneuropathy of hereditary ATTR. It's premature to comment or speculate on commercial dynamics for cardiomyopathy until we have a label, until we have a product that's approved for that segment. We have currently marketed and will always market our products consistent with the label that has been granted to it. So right now, it's really hard to speculate because we don't have an approved indication in cardiomyopathy.

Makes sense. Makes sense. And for the opportunity for cardiomyopathy, I guess, are you pleased with what you're seeing from Pfizer's perspective with tafamidis?

I mean, look, it clearly -- I mean, Pfizer's success in the cardiomyopathy setting clearly shows that this is a very high unmet need disease. And there are a large number of patients with wild-type ATTR that are being recognized. And it's really ultimately a market that we expect to be or predict to be in the hundreds of thousands worldwide with wild-type ATTR. So when we -- if and when we get approved in wild-type ATTR, that's going to be an expansion of our overall commercial opportunity when we get there. So that's something to look forward to for sure.

Right. Makes sense. And just wondering if you can summarize totality of cardiomyopathy data. You've collected from mixed patients treated in your polyneuropathy studies and in the real-world setting as well. I guess what's the most compelling data that you've seen? And how does that derisk your ongoing cardiomyopathy studies?

Yes. I think here, we have to really rely on clinical study results out of our investigational efforts. And with patisiran, specifically, which is the nonbranded name for ONPATTRO, as you know, that we have to look back at the APOLLO exploratory endpoint data that were generated in the cardiac subpopulation, which shown improvement and stabilization of NT-proBNP, left ventricular wall thickness, longitudinal strain and also a 10-meter walk distance -- I'm sorry, 10-meter walk time. And we were also able to show in a post-hoc analysis an improvement in hospitalization and mortality. But a caveat here with that study is that it was a study done in a predominantly polyneuropathy population, okay? So we have to keep that in mind as we think about that. The safety was encouraging in that population as well, consistent with what's in the label. And all of those data were published by Solomon S et al. in circulation. Now more recently with patisiran, there was a study by Fontana et al. published in JACC that was a small open-label study of patisiran in patients with mixed phenotype, where serial PYP scans were performed at baseline and then at 12 months of treatment. And in that study, they were able to show a regression of cardiac amyloid, both by PYP scans, but also cardiac MRI. And that's an important and potentially meaningful result, and we look forward to seeing how that might play out in the APOLLO-B study for patisiran and then obviously with Vutrisiran. And then finally with Vutrisiran in the HELIOS-A study, we did have 10-meter walk time as a key secondary endpoint in the study and also NT-proBNP as a biomarker that we looked at in 9 months. And in both cases, we showed encouraging results. And then, of course, we expect to have more data at 18 months with Vutrisiran that will also include serial PYP scans. So it's a bit of a long-winded answer, just to say there's a lot of interesting hypothesis generating data that gives us encouragement. But obviously, we'll have to wait for the randomized studies to read out with both APOLLO-B and HELIOS-B until we can be confident about the effects of our drugs in the cardiomyopathy setting.

Makes sense. And BridgeBio, they posted a polyneuropathy trial recently on clinicaltrial.gov and their cardiomyopathy study is supposed to read out by year-end '21, early 2022. How should investors think about that drug? And what are you going to be looking for in their data as they read out?

Yes, I mean, look, I think the BridgeBio AG10 Acoramidis is an interesting TTR stabilizer. Obviously, I'll certainly let you ask them the questions about how they view their drug. From everything that we've seen, it's a twice-daily drug as a TTR stabilizer. I'm not completely convinced of the competitive profile relative to tafamidis. So it seems like it's another TTR stabilizer for the most part. I think, look, there's no doubt that this is going to be a market with multiple products that are out there, including RNAi therapeutics, stabilizers like diflunisal, tafamidis, maybe Acoramidis, antisense oligonucleotide, antibodies for clearing amyloid plaque, gene editing potentially in the future. So it's going to be a space that's not too dissimilar from other markets like multiple sclerosis or rheumatoid arthritis, where there are multiple therapeutic modalities that are used and available for patients, which is great news for patients. But specifically in the BridgeBio program, I would expect their trial to show positive results given that it's placebo-controlled, and that it's a stabilizer. And let's see how it ultimately goes from a regulatory and market perspective. But again, I think those questions are better handled by them, not by us.

Makes sense. And what's the latest you're seeing about gene editing data from Intellia that could be reported midyear? I guess how does that impact your strategy?

Yes. I mean, look, we expect the gene editing data to be very positive. There's no reason to believe that they won't be able to reproduce the primate data that they have presented previously. So I'm expecting that to be reproduced. The big question is really around safety. And the safety is really the long-term safety implications of editing a genome where you could get double-strand DNA breaks in nontarget sites, which could result in untoward effects that could be uncertain for some period of time. There's also a question in our mind about the merits of removing TTR from the body. It's one thing to knock it down reversibly but removing it outright, I think, has some question marks associated with it that will have to get worked out. Even if they're successful with everything they're doing technically, we do think that the development path forward is going to be complicated for them because they'll have to do studies against active comparators. And that will make the development path more complicated for them than otherwise, number one. But I think the bigger issue is really around access. This is a drug as a one-and-done type of therapy that will have to be priced in the millions of dollars per patient per year in order for a market to be meaningfully achieved with the product. And I think payers for a drug that would be given to patients in their 60s, 70s and 80s may take pause around that type of access opportunity. When there are other drugs that are available, in the marketplace that have been proven to be effective that are far less expensive. So I think that's going to be a bigger challenge with a gene-editing based approach. But there's no doubt at the end, as I said a minute ago, that this is a market that is going to be welcoming of many treatment options for patients. And so I believe that there'll be small molecule stabilizers, silencers, gene editing, antisense, et cetera, that will ultimately be out of this marketplace.

Got it. And you talked earlier about the PYP scans. Just wondering for the community setting. Are you getting more patients that are brought onto the radar from the community setting? And maybe if you can talk a little bit more about that.