Alnylam Pharmaceuticals Q1 2024 Earnings Call Transcript

Quartr
Provided by Quartr
May 2, 2024

There are 15 speakers on the call.

Operator

Good day and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Quarter 1 2024 Conference Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a Q and A session. Please be advised that today's conference is being recorded.

Operator

And I would now like to hand the conference over to the company for their remarks. Please go ahead.

Speaker 1

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer Toby Tangular, Chief Commercial Officer Pushbul Garg, Chief Medical Officer and Jeff Fulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors. Alanine loans.com/events.

Speaker 1

During today's call, as outlined in Slide 2, Ivan will offer introductory remarks and provide some general context, Togo will provide an update on our global commercial progress, Push will review pipeline updates and clinical progress, and Jeff will review our financials and guidance followed by a summary of upcoming milestones before we open the call to your questions. I would like to remind you that this call will contain remarks concerning OneMain's future expectations, plans and prospects, which constitute forward looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our most recently periodic report on file with the SEC. In addition, any forward looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

Speaker 1

With that, I'll turn the call over to Yvonne. Yvonne? Thanks,

Speaker 2

Christine, and thank you, everyone, for joining the call today. 2024 is off to a very strong start and shaping up to be an impactful year for Alnylam. Commercially, in the Q1, we delivered robust product revenue growth for our 4 wholly owned medicines, achieving $365,000,000 in revenue or 32% year over year growth compared to Q1 2023. An important part of this was the continued momentum from our TTR franchise, which delivered 29% year over year growth versus Q1 2023. From a pipeline perspective, our zalbiziran hypertension program was a major highlight with positive results presented from the CARDIA-two Phase 2 study evaluating zalbiziran in combination with certain standard of care antihypertensive and the initiation of CARDIA-three.

Speaker 2

This program represents a significant opportunity to reimagine the treatment of hypertension and to position Alnylam as the leader in treating cardiovascular disease. To that end, we're on the cusp of reporting top line results from the HELIOS B Phase 3 study of lutrisiran in patients with TTR amyloidosis with cardiomyopathy. As we've highlighted previously, we have many reasons to be highly confident in a positive PDSP outcome, including the encouraging data from the APOLLO B study of patisiran. And we remain on track to report top line data from HELIOS B in late June or early July, which if positive is expected to support the filing of an sNDA by the end of this year. With this progress, we continue to advance our nylumpeethafitx25 goals, making for patients around the world with rare and prevalent diseases driven by a high yielding pipeline of 1st and or best in class product candidates from our organic product engine, all while delivering exceptional financial results.

Speaker 2

With that, let me now turn the call over to Tolga

Speaker 3

for a review of our commercial performance. Tolga? Thanks, Ivan, and good morning, everyone. Q1 was another strong quarter for our commercial portfolio, delivering $365,000,000 combined net product revenues as we continue our growth momentum with our rare and TTR franchises. Our overall portfolio grew by 32% in the Q1 versus prior year as we continue to steadily increase the number of patients on our therapies.

Speaker 3

First, let me summarize our Q1 TTR results. The TTR franchise achieved $264,000,000 in global net product revenues, representing a 4% increase compared with the Q4 of 2023 and 29% growth compared with the Q1 of 2023. Our U. S. Combined TTR sales of ONPATTRO and AMBUTRA increased by 3% compared with the Q4 of 2023 and a robust 35% year over year driven by continued strong Ambutra uptake.

Speaker 3

The U. S. Year over year growth was primarily driven by the following: a 39% increase in total demand versus the Q1 of 2023, which was driven by the strength of ongoing Ombutra patient uptake, more than offsetting the decrease in patients on ONPATTRO that switched to Ombutra. Inventory dynamics decreased reported growth by approximately 4% as both ONPATTRO and ONPATTRO inventory in the channel decreased in the quarter, another favorable sign of robust Q1 demand. Now let me turn to our international markets, where TTR franchise growth increased by 5% compared with the Q4 of 2023 and 23% year over year.

Speaker 3

The year over year growth was primarily driven by increased demand for Ambutra as new patient adds remain robust, including launches at the end of last year in Spain, Italy and Sweden and continued strong ONPATTRO performance in a few markets where Almutra is not yet available. As a reminder, Almutra is now reimbursed in all major international markets. Demand growth in international markets was partially offset by lower pricing in certain countries, primarily in Germany, as the end of the initial 6 month free pricing period for Ambutra occurred in Q2 2023 as previously reported. I would also like to provide additional color on the continued growth momentum of our TTR franchise in the U. S.

Speaker 3

We remain confident and very pleased with the impact we're seeing from Ambu Traina expanding the opportunity for our TTR franchise is reflected by the robust 35% year over year growth that we achieved in the Q1 of 2024. This is a growing category with significant unmet needs remaining. Importantly, leading marketing indicators remain aligned with our demand growth, galvanizing Amutra's market leadership both in patients and healthcare providers for the treatment of patients with hATTR amyloidosis with polyneuropathy. Here are some key highlights. More physicians are prescribing AMBUTRA, evidenced by the more than 50% year over year growth in our prescriber base.

Speaker 3

We strongly believe hATTRPN is a condition that requires high engagement between healthcare professionals and their patients. Albutra offers the flexibility for this engagement to happen at the hospital, at an outpatient center or for many patients at home. In alignment with our patient access philosophy, we continue to demonstrate seamless access to AMUTRA with more than 99% of our patients having confirmed access and approximately 70% of patients having zero out of pocket costs. Last, we are monitoring adherence and compliance metrics, which show that more than 95% of our patients remain on therapy and comply with Almutra's quarterly dosing regimen. As we have previously communicated, we believe approximately 80% of the 25,000 to 30,000 patients with hATTRP polyneuropathy globally are undiagnosed or untreated, which represents a significant opportunity to find and treat more patients.

Speaker 3

Given that hATTR polyneuropathy is also a rapidly progressing disease, we believe patients and physicians stand to benefit most from a therapy that rapidly knocks down the disease causing protein with unparalleled speed, depth and duration. AmUTRA offers these benefits in a single quarterly dose and has the ability to reverse the polyneuropathy manifestations of HER TTR amyloidosis, combined with a favorable access track record and well established safety profile. With this foundation, we are in a position of strength as we embarked on a branded patient awareness campaign to raise patient awareness of the disease and the benefits of our Mutra and its unique rapid knockdown profile. Shifting to our rare franchise and the performance of GIVLARIN LUMO. Our global rare franchise delivered $101,000,000 in combined global net product revenue during the Q1, representing a solid 9% increase compared with the Q4 of 2023 and an impressive 40% growth compared with the Q1 of 2023.

Speaker 3

For Givlari, revenues increased by 21% in Q1 compared to the same period last year, with the following regional dynamics: a 28% increase in the U. S, primarily driven by growth in new patients on therapy with modest additional upside from favorable gross to net changes 10% growth in rest of the world, primarily driven by demand growth, which was partially offset by an increase in gross to net deductions year over year. For OXLuma, we delivered a robust 77% increase in revenues year over year, which was driven by the following regional dynamics. A 47% increase in the U. S, primarily driven by demand growth additional favorability from lower gross to net deductions, a robust 94% growth from rest of world markets, driven by increased demand, a favorable gross to net adjustment and the timing of orders in partner markets.

Speaker 3

Given the nature and magnitude of the rest of world's Q1 gross to net and partner market timing benefits, we anticipate that we will see a reduction in global sales for OXNUMA in Q2. In conclusion, we are very pleased with our continued growth momentum, delivering a robust 32% revenue growth versus prior year that positions us well to reach our 2024 net product revenue guidance. With that, I will now turn it over to Pushkal to review our recent R and D and pipeline progress. Pushkal?

Speaker 4

Thanks, Tulk, and good morning, everyone. Let's begin with our TTR franchise, where we eagerly await top line results from HELIOS B, our outcome study designed to expand the label for AMBUTRA to include the treatment of patients with hereditary and wild type ATTR amyloidosis with cardiomyopathy. As you're aware, on our Q4 earnings call in February, we announced enhancements to the Helios B statistical plan to optimize the study for success and to best support a strong and competitive label. These changes were informed by insights from the APOLLO B data and emerging data from the field. With these optimizations, we remain focused on clinical outcomes of death and hospitalization, which are critical to all stakeholders, but now plan to evaluate these outcomes in the overall population as well as the monotherapy population, which is where we believe Ambutra will have the largest treatment effect and will best demonstrate the drug's true impact.

Speaker 4

We also streamlined the secondary endpoint structure to focus on those clinical measures that we believe will best highlight Ambutra's potentially differentiated profile and its benefits on stabilization of this progressive disease. And we enhanced the overall statistical powering of the study by incorporating up to an additional 3 months of event collection at the tail end of the study period, the most critical period and firmly establishing HELIOS B as the longest placebo controlled study conducted to date in ATTR Centimeters. We remain on track to report top line results in late June or early July. At that time, we plan to provide P values on the primary and secondary endpoints as well as key details regarding safety. We also expect to provide some high level information on subgroups, including patients on baseline tafamidis.

Speaker 4

Full results are expected to be presented at a scientific congress soon thereafter. And assuming positive results from Helios B, we expect to submit a supplemental NDA to the FDA in late 2024. Turning now to zalbiziran, our investigational RNAi therapeutic being evaluated as a treatment for hypertension. We made some very exciting progress in the Q1 on this program. Hypertension is a global health crisis and the leading addressable cause of cardiovascular morbidity and mortality around the world.

Speaker 4

Unfortunately, despite available therapies, up to 80% of patients have uncontrolled disease. And beyond poor control, there are a number of other aspects of hypertension management that contribute to increased cardiovascular risk, namely poor medication adherence, variability in blood pressure and lack of nighttime dipping. We believe that zalbuterin has the potential to address all of these unmet needs and improve cardiovascular outcomes by providing tonic control of blood pressure. At the ACC conference a few weeks ago, we presented the full results from the positive KARDIA II Phase II study that evaluated the efficacy and safety of a single subcutaneous dose of albiziran when added to 1 of 3 standard of care antihypertensives: a thiazide like diuretic, indapamide, a calcium channel blocker, amlodipine or an angiotensin receptor blocker, omesartan. The study achieved its primary endpoint demonstrating clinically statistically significant placebo adjusted reductions of up to 12.1 millimeters of mercury in 24 hour mean systolic blood pressure at month 3 as measured by ambulatory blood pressure monitoring when zalbusiran was added to 1 of the 3 background medications.

Speaker 4

The study also achieved the key secondary endpoint demonstrating clinically significant adlib reductions in office systolic blood pressure at MUM-three across all 3 independent cohorts. Finally, zolmesiran demonstrated an encouraging safety and tolerability profile when added to standard of care antihypertensives. We are very excited by these results, showing additive efficacy and good tolerability on top of 2 agents with orthogonal mechanisms and on top of an ARB, which also works in the RAS pathway, which support continued development. To that point, we recently initiated the CARDIA-three Phase 2 study, which will evaluate zolbitiran on top of 2 or more agents in patients who are at high cardiovascular risk. As this slide shows, we and our partners at Roche have robust plans to bring Xalbiziran forward as an agent that can reshape the treatment of cardiovascular disease.

Speaker 4

This includes our intention after CARDIA-three to run a cardiovascular outcomes trial, where we can demonstrate the benefits of tonic blood pressure control in patients at high CV risk by showing reductions in cardiovascular morbidity and mortality. Wrapping up with the pipeline, our extrahepatic efforts in the CNS continue to progress this quarter as well. As we announced on our Q4 earnings call, we received FDA clearance to initiate the multiple dose portion of the Phase I study of mybelsiran, formerly known as ALN APP in early onset Alzheimer's disease, and remain on track to initiate a Phase II study in cerebral amyloid angiopathy early this year. So in sum, we've made great progress in advancing our pipeline and platform with much more to come. As a reminder, we plan to file proprietary INDs for 9 programs by the end of 2025 against targets in the liver, CNS, muscle and adipose.

Speaker 4

If we include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of our clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Speaker 5

Thanks, Pushkar, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q1 2024 financial results and discussing our full year guidance. Starting with a summary of our P and L results for Q1 2024 compared with Q1 2023. Total product revenues for the quarter were $365,000,000 or 32% growth versus the Q1 of 2023, with both our TTR and rare freight franchises reporting strong growth of 29% 40%, respectively, primarily driven by strong demand as Tolga previously highlighted. Net revenue from collaborations for the quarter was $119,000,000 or a 2 25 percent increase compared to the Q1 of 2023.

Speaker 5

The increase was primarily due to revenue recognized under our collaboration and license agreement with Roche, including $65,000,000 of milestone revenue associated with initiation of the zobisiran CARDIA3 clinical trial and an increase in revenue recognized under our collaboration agreement with Regeneron. Royalty revenue for the quarter was $11,000,000 or a 63% increase compared to the Q1 of 2023. The increase was driven by higher LEPO sales compared to the same period in 2023. Gross margin on product sales was 85% for the quarter, which was consistent with the Q1 of 2023. We expect our gross margin on product sales will be lower for the balance of 2024, driven by higher royalties paid on IMVUTRA as IMVUTRA growth continues at a brisk pace.

Speaker 5

Our non GAAP R and D expenses increased 13% in the Q1 compared to the same period in 2023, primarily driven by increased investments in zolbusiran, our HELIOS B trial and our preclinical pipeline. Our non GAAP SG and A expenses increased 15 percent in the Q1 compared to the same period in 2023, lower than our 32% growth in product sales as we continue to deliver operating leverage on our journey to achieving profitability. The source of SG and A expense growth was primarily related to TTR marketing investments to help drive polyneuropathy patient finding efforts as well as increased investment in preparation for a potential launch cardiomyopathy next year. Our non GAAP operating gain for

Speaker 6

the quarter was

Speaker 5

$2,000,000 representing more than a $100,000,000 improvement compared with Q1 2023, primarily driven by strong top line results both in products with sales as well as revenue from collaborations as previously highlighted. Finally, we ended the quarter with cash, cash equivalents and marketable securities of 2,400,000,000 dollars in line with the $2,400,000,000 we reported at the end of 2023. We continue to believe our current cash balance will be sufficient to bridge us to a self sustainable financial profile. Now

Speaker 4

I'd like

Speaker 5

to turn to our financial guidance for 2024. Today, we are reiterating our 2024 guidance as presented during our earnings call in February. We anticipate combined net product revenues for our 4 wholly owned commercial products will be between $1,400,000,000 and $1,500,000,000 corresponding to a 13% to 21% growth rate at January 31 at FX rates. Q1 was a strong start to the year, giving us confidence in our ability to meet or exceed our product sales guidance. We will, of course, carefully review our progress at Q2 to determine if any changes to our guidance are warranted.

Speaker 5

Our collaboration and royalty revenue guidance range is $325,000,000 to $425,000,000 And lastly, our guidance for combined non GAAP R and D and SG and A expenses remains a range between $1,675,000,000 $1,775,000,000 the midpoint of which reflects 9% growth compared with 2023. Let me now turn to from financials and discuss some key goals and upcoming milestones slated for early and mid-twenty 24. We expect 3 trial initiations in early 2024, including a Phase 2 study for mybesopramodelsiran in patients with cerebral amyloid angiopathy, Part B of the Phase 1 study of ALN KHK in Type 2 diabetes and a Phase 1 study of ALN BCAT in hepatocellular carcinoma. And has been highlighted, we remain on track to report top line results from the HELIOS B study of vutrisiran in late June or early July. Given how important the readout is, we plan to enter a quiet period beginning May 13 in advance of those results.

Speaker 5

Let me now turn it back to Christine to coordinate our Q and A session. Christine?

Speaker 1

Thank you, Jeff. Operator, we will now open the call your questions.

Operator

Thank you. At this time, we will conduct a question and answer session. Our first question comes from the line of David Lebowitz with Citi. You may go ahead.

Speaker 6

Thank you very much for taking my question. I'm curious, there has been some talk recently about what is considered to be the relevant improvement over the control arm, certainly on the monotherapy side to make it easier to compare one drug versus another. And numbers have been bandied about 30% relative improvement versus 42% relative improvement. I'm just curious, I know that information won't come in the top line release, but what are your thoughts on that discussion? And how do you think we should think about it?

Speaker 2

Thanks, Dave, for the question. Just as a reminder, HELIOS B is an outcome study, and that's really what we need to deliver from the study. And it's quite clear in discussions with regulators, payers and physicians that if we're able to show a benefit on outcomes, this will be an important medicine. Clearly, we made some changes to the statistical plan, which we shared in some detail on our last call, and we're happy to reprise the rationale behind that. But at this point in time, I think the best way to look at this is delivering outcomes in this study will be the important results.

Speaker 2

And we also expect to see some other aspects of differentiation if we consider the results that we got out of HDSB with respect to stabilization of diseases. So I think if we're able to deliver all this, we believe that we'll have a differentiated profile that will be an important contribution to managing the disease in these patients. Bhushka, is there anything you want to add?

Speaker 4

Yes. I mean, maybe I agree with everything you said, Ivana. Dave, maybe just a couple of other points. I mean, again, when it comes to clinical outcomes such as death and hospitalization, any change is considered clinically significant. And I think it's important to again go back to the unmet need in this disease.

Speaker 4

This is a a steadily progressive disease where month on month patients continue to decline. They experienced hospitalizations, worsening quality of life, worsened physical function and ultimately, unfortunately, succumb to this disease. And whether you're on a once a day stabilizer or twice a day stabilizer, patients the clinical trial data suggest that patients unfortunately continue to decline and the orthogonal class of medicines could be helpful here. So we're encouraged by the APOLLO B data. We're looking to demonstrate outcomes and

Speaker 7

we think that clinicians will

Speaker 4

be looking at the magnitude of effect as well as when separation occurs as well as whether there's evidence of disease stabilization, which is really important looking at the totality of the data. So we're looking forward to report the results in late June early July.

Speaker 3

Thanks, Vishal.

Speaker 6

Thank you very much for taking my question.

Operator

One moment for our next question. Our next question comes from the line of Paul Matteis with Stifel. You may go ahead.

Speaker 8

Thanks so much for taking my question.

Speaker 3

I wanted to ask

Speaker 9

just about what Alnylam may look like organizationally in a scenario where Helios B works versus one where it fails. Jeff, if Helios B succeeds, do you expect to be changing guidance as it relates to spending and ramping up infrastructure ahead of the cardiomyopathy launch? And then conversely, if Helios B doesn't work, as you guys talk about 9 INDs by the end of 2025 or 15 if you include partner programs, Do you feel like that still stands? Do you think Alnylam is still going to have the balance sheet to execute upon that? Or are you going to have to prioritize within the R and D pipeline?

Speaker 9

Thank you.

Speaker 5

Yes. Hi, Paul. Thanks for the question. Let me start with the first one, which I think was around our guidance this year and whether or not that would need to change on the spending side if we have a positive Helios B result. The answer is no.

Speaker 5

The guidance reflects what we think we need for the year with a positive Helios B result. I don't anticipate that we would be raising the guidance. We think we have plenty of opportunity to invest behind the opportunity to drive success. I think the other questions were around how might things evolve if we were in the unlikely scenario of a failed Helios B. Certainly, we would need to look at prioritization across the business in that scenario.

Speaker 5

And we're doing the work on that. If we're in that scenario, again, we think that's unlikely, but we would be prepared to talk to the market about the prioritization decisions that we would make in that outcome. I also think it's important just

Speaker 2

to reflect on the magnitude of opportunity that we have in front of us as a company. I mean, Vishal touched on the richness of our pipeline, currently 15 programs in the clinic. We're looking at doubling that number by 2025. So as we look out at the opportunity set in front of us at Alnylam, we couldn't be more excited about being able to move forward the programs that we have. So we're obviously looking forward to a positive outcome from ADS B and then really continuing to drive the pipeline that's in front of us.

Speaker 9

Thank you.

Operator

One moment for our next question. Our next question comes from Maury Raycroft with Jefferies. You may move ahead.

Speaker 8

Hi. Thanks for taking my question. In both Attribute and Attract studies, the slope of the Kilometers curve for events gets steeper in the last few months of those studies. And I think it was mentioned in the prepared remarks that that's a critical time for Healios B. Should we expect a similar trajectory for the placebo arm in the last few additional months for Healios B that you added to the stats plan?

Speaker 8

And would that widen the delta? And can you talk a little bit more about what your expectations are for the events during that time of the site?

Speaker 2

Yes. No, that's a great question. And clearly, I think the critical period of the study, as you say, is at the end of the study and this disease where patients continue to progress. So we do expect that that's a period where we'll see most events. Vishal, anything else you want to add?

Operator

I don't think

Speaker 4

there's anything to add, Ivana, you covered it.

Speaker 8

Okay. Okay. Thanks for taking my question.

Operator

One moment for our next question. And our next question comes from Gary Nachman with Raymond James. You may proceed.

Speaker 10

Thanks. Good morning. So, in ATTR Centimeters, are you still just thinking of VUTRI as primarily a monotherapy drug as tafamidis continues to grow as standard of care in ATTR Centimeters. If the combo data with TAF are positive enough and show enough of a benefit over TAF alone, would you reconsider that thinking? And what are you doing now to prepare for the launch in Centimeters?

Speaker 10

Just some details there would be helpful. Thank you.

Speaker 2

Yes. There are some really good questions there. So Tolga, maybe you want to talk about how we're looking at the cardiomyopathy market and how we're preparing for launch. I mean, clearly, we're playing to win in this space. We're very excited about the opportunity

Speaker 7

of getting into this very rapidly growing category. Tolga? Yes. Thank you. That's exactly right.

Speaker 7

We're really here to play to win. And look, at the end of the day, we need to look at the fundamentals of this category. There are 80 patients 80% of the patients remain undiagnosed. This is a rapidly and progressing disease with irreversible damages. And frankly, patients and physicians are both looking at quickly be able to deal with the disease as quickly as possible.

Speaker 7

So if you look at the pharmacodynamics of what Amutra has to offer and how we impact the disease causing protein at the upstream and rapidly knocking down that toxic protein, that is going to be a key clear differentiator. At the end of the day, we know that AMUTRA provides speed, depth and duration as early as the first dose. And this is what physicians are really looking for. It is true and it's great to see that Tafamidis is making great progress, but it's not just the standard of care, it's the only care in this category. So one needs to remember that.

Speaker 7

And I think they have just reiterated the fact that the LOE in the U. S. In particular is going to remain until the end of 2028, which really means, mainly because of the access pressures, but also again, the way this product is going to be positioned and obviously, pending on the data, we need to demonstrate. We believe we're going to be able to actually be the first line agent. And after all, there are going to be, as Pushkar indicated, a substantial number of patients who are being treated that are continuing to progress.

Speaker 7

And we believe physicians and patients

Speaker 3

are looking for an alternative.

Speaker 7

And in that case, we believe it's going to be a very important option in the armamentarium of the physicians in this difficult disease. It's absolutely spot on, Told. And I think

Speaker 2

it's just instructive when you reflect on our expanded access program, where within a matter of very short space time, we maxed out on the program. I think that again is just an illustration of the level of unmet medical need space and the fact that patients continue to progress on tafamidis and they're looking for alternative therapies.

Speaker 3

Next question?

Operator

A moment for our next question. Our next question comes from the line of Tazeen Ahmad with BofA Securities. You may proceed.

Speaker 11

Hi, good morning. Thanks for taking my questions or question. I appreciate all the color you've been giving about expectations for what to show at the top line. But in terms of trying to drill into the detail on mortality specifically, fully understanding there's a lot of under met need even with what's available right now. How important is it going to be to know when the mortality benefit kicks in for VUTRI?

Speaker 11

So I think for Tafam, it is that benefit in the Pfizer study started around month 2018. Is it going to be important to have a number at the end that hovers around that month 2018 or potentially could it be better than that? Thanks.

Speaker 7

Scott, you have one for you?

Speaker 4

Yes. Thanks, Tazeen. Look, I think what we've seen in terms of mortality separation, if I call both for tafamidis and the aciramidis data that are under review is around month 18 is when we start to see the mortality separation. Look, we're encouraged by what we saw coming out of actually the original APOLLO data and then the APOLLO B data where we seem to see evidence again in underpowered studies of separation on mortality occurring earlier, roughly month 9 or so. So we'll have to see in HELIOS B if we're able to recapitulate those results in this larger powered study.

Speaker 4

Again, I think it's going to be important to look at the totality of all the data that come out. Obviously, that will be one parameter. What is the mortality difference? When is it emerging? What about hospitalizations?

Speaker 4

And then again, what's happening in terms of disease stabilization? So we think all of those are going to be important parameters. But look, the early data that we've seen from APOLLO and particularly APOLLO B, which is in the same patient population, gives us a lot of confidence that we should be able to see a substantial effect and potentially earlier separation.

Speaker 3

Thanks, Cisco. Next question?

Operator

One moment for our next question. Our next question comes from the line of Ritu Baral with TD Cowen. You may proceed.

Speaker 12

Good morning, guys. Thanks for taking the question. I want to thank you for the detail that you've given on the top line release, but I wanted to just dig a little further if I could. Kushkal and Yvonne, when you mentioned that you would give us some more details on subpopulation, Will you be able to give us sort of drivers of potential composite benefit of the TAF subpopulation or the composite I'm sorry, combined subpopulation as well, just given the conversation investor conversation and focus on hospitalizations driving previous data sets, will we get sort of a tell on what the major drivers are? And then just a very quick follow-up on data release.

Speaker 12

You dropped proBNP and echo parameters, to exploratory endpoints. And those are ones that at least our KOLs actually deeply, deeply value. We were wondering if those would be released with first medical presentation.

Speaker 2

Yes, Ritu. I mean, I think that's a yes, it's a good question. And I think we've been quite clear about how we're going to be handling the release. I mean, clearly, we're going to show kind of P values for the primary endpoints and key secondary endpoints. So we're going to provide some information on safety.

Speaker 2

Obviously, that's an important consideration. And we said we will give some information with respect to subgroups. I know we're interested in the tafamidis subgroup. But I think that's where we stand at this point in time. We're kind of obviously looking forward to being able to share the top line results.

Speaker 2

We're still on track for end of June, early July. And then, of course, we'll present fulsome data at a Proximal Medical Congress. So stay tuned. We will be providing some additional color over and above P values for the primary and secondary endpoints, but that's probably all we can say at this point in time. Your second question?

Speaker 4

I think Ritu, you were just talking about the NT proBNP and the ECHO data. Look, I think we haven't mapped out exactly what will be in the top line presentation. Obviously, it will be limited in terms of what we can I want to make sure that we work with the investigators to make sure that there's a fulsome presentation? But you can imagine with a data set like this that there'll be a number of presentations to speak to the various aspects of

Speaker 2

the data.

Speaker 4

And certainly BNP, ECHO, etcetera, which are important parameters that we're reporting on.

Speaker 2

Absolutely, Prashant. I mean, we're clearly very interested in those parameters, but you kind of have to prioritize how many secondary endpoints you have with respect to managing alpha. And clearly, we're pretty confident about what we're going to be able to demonstrate with those additional endpoints. But they're going to be endpoints that we'll be able to share. But we really wanted to prioritize the very clinically relevant secondary endpoints, and we've discussed what those are with respect to disease progression, mortality as well as 6 minute walks off in KCCQ.

Speaker 12

Great. Thank you.

Speaker 2

Thanks. Yes.

Operator

One moment for our next question. And our next question is from Jessica Fye with JPMorgan. You may proceed.

Speaker 11

Hey guys, good morning. Thanks for taking my question. For

Speaker 12

Helios B,

Speaker 11

when you talk about any impact on outcomes being clinically meaningful, on the one hand, I completely hear you that there are outcomes. But then again, when we ask physicians about this, they usually have a magnitude or a threshold in mind that's not just any benefit. So I'm curious how to kind of reconcile that or maybe you could just elaborate there?

Speaker 4

Yes. Look Jessica, I think, I don't know that I can give you a lot more information other than to say, just have to again remember what the unmet need in this disease is. They are patients who currently a large number of patients as Tolga has outlined, many of them are undiagnosed and untreated, who have a steadily progressive disease that leads to irreversible damage and ultimately patients pass away. And so what I think and as evidenced by as Devon highlighted, our EAP experience after APOLLO B and that was in the setting without any outcomes benefit being demonstrated in IV drug, we rapidly enrolled a population of patients, many of whom were progressing on tafamidis, which was the only available therapy to them. So it highlights the unmet need.

Speaker 4

So we think that when we come forward with hopefully a positive HELIOS B showing an outcomes benefit, a mortality and hospitalization along with these other differentiating factors that we've talked about and an orthogonal mechanism that rapidly knocks down the disease causing protein of this disease that we think that that's going to address the key unmet needs for these patients. So we're looking forward to that, and we'll let the data speak for themselves.

Speaker 11

Thank you.

Operator

One moment for our next question. Our next question comes from the line of Costas Buluris with BMO Capital Markets. You may proceed.

Speaker 10

Good morning, everyone. Thanks for taking our question and congrats on the progress. A question from us on Helios B just for a change. How important do you think is the ratio between hospitalization events and deaths as a metric, especially when we compare different drugs? Do you look at this ratio as an important metric?

Speaker 10

Or you just look at those 2 types of events together as a composite? Thank you.

Speaker 7

Thanks for the question, Priscilla, this is on to you.

Speaker 4

Yes. No, I think it's an interesting question, Kots. I think in general, we look at them together and we don't make a huge distinction here. I mean, I think part of the reason that composite endpoints like this were created was because hospitalizations tend to correlate very strongly with mortality events. And so and these are both clinically meaningful outcomes.

Speaker 4

And so we would expect that they will both go directionally in the same direction. That's what we've seen with other drugs. That's what we've seen throughout the cardiovascular disease area with lots of drugs and lots of different diseases, disease classes. So we would expect them to go in similar directions cost us and I think the main thing is seeing a benefit hopefully in both of those, the trend in the right direction.

Speaker 10

Thank you. Very helpful.

Operator

One moment for our next question. And our next

Speaker 13

In ATTR, what proportion of patients do you think are mixed phenotype in the real world? And how is this being defined both by doctors and by payers? And do you see silencers as more likely to gain a larger share in this population versus stabilizers longer term when we look to the cardiomyopathy expansion? Thanks.

Speaker 2

I think first, Tolka will follow-up.

Speaker 4

Yes. Ellie, I think you raised a very important question and I think we've oftentimes people have sort of classified these as 2 very distinct diseases, polyneuropathy and cardiomyopathy, when in fact, it's the same protein when it's misfolded, it's causing both manifestations of the disease. And I would we've seen, for example, that in the hereditary population when we looked in the APOLLO and HELIOS A that more than half of those patients had concomitant cardiomyopathy. And conversely, studies that have been done in cardiomyopathy patients, suggest that a significant proportion of those patients may have polyneuropathy manifestations. So there are reports ranging from 15% to 30% or more of patients with wild type ATTR or V122I, for example, which might have a primary cardiomyopathy manifestation have concomitant polyneuropathy.

Speaker 4

And certainly, we've seen that with the silencer class of drugs, particularly with patiosiran and Ambutra that the magnitude of effect in polyneuropathy is really quite unsurpassed in terms of its clinical profile. And so it'll be interesting to see and Tolga can probably comment more about this, how clinicians will make decisions when they have patients who have multiple manifestations of this disease when they hopefully have multiple classes of therapies available.

Speaker 7

Yes. No, I mean just to add one quick point on that is, if you look at the clinical practice of how physicians actually diagnose and treat this disease, it starts with the suspicion. And the suspicion usually doesn't necessarily start whether you have cardiac manifestation of diseases or the polyneuropathy manifestations of this disease. Eventually, based on the data we have, obviously, both with ONPATTRO and Almutra, physicians are absolutely looking for neuropathic manifestations to make sure that they can treat this as effectively as possible. And the disease is treated always through multidisciplinary centers.

Speaker 7

So at the end of the day, physicians don't just look at the patients with whether they have Centimeters, PN or mixed phenotype. They go through how to best understand the disease and then through a multidisciplinary approach, try to treat the disease in the best possible way and based

Speaker 3

on the indications of the products. Thanks, Toca. Next question?

Operator

One moment for our next question. Our next question comes from the line of Gena Wang with Barclays. You may proceed.

Speaker 1

Thank you. Sorry, I will ask another in neutral question. So regarding the subgroup, the top line you will share, will you share the subgroup information on both primary and secondary endpoint? And also in the scenario that Helios B is positive, will you also at some point lower and neutral price to be competitive compared to, say, tafadamis and other drugs?

Speaker 2

So I'll just take the pricing question. I mean, I think it's really too early for us to talk about kind of specific kind of pricing approaches here. Just to remind you, and Togka touched on this in his introductory remarks. I mean, we will obviously bear in mind our patient access principles and we'll be making sure that we have considerations around access and affordability to make sure that patients are going to be able to benefit from what we hope will be a medicine with a very robust profile. Frisko, do you want to take the question on Yes.

Speaker 4

I mean, Gina, I don't know that there's a lot more that I can add in terms of the remarks that I made and then Yvonne has reiterated in terms of the top line. We plan again to speak to the primary endpoint, which is now in the 2 populations, the secondary is across those populations, safety and we'll make some commentary around subgroups. But it's hard to give you anything more than that today. That's our plan.

Speaker 3

Thanks. Thanks. Thanks. Next question.

Operator

One moment for our next question. Our next comes from the line of Salveen Richter with Goldman Sachs. You may proceed.

Speaker 11

Thanks for taking our question. This is Tommy on for Salveen. So beyond the top line and regarding data analysis presented on the forward, would you include detailed analysis on who were defined as path progressors given the unmet need in this population and just to see how IMBRUITRA could benefit these patients? Thank you.

Speaker 4

Yes. Tommy, I think what you're asking about is actually deeper cuts of the data. And certainly, this is going to be a very rich and large data set. So you can imagine that we'll be looking at this in a lot of different ways. But again, I think I guess the primary thing I would focus on is the fact that we will have a pretty robust data set both with the drug treated as a monotherapy and in patients who came in on tafamidis.

Speaker 4

And I think you have to ask yourself why would someone who's on a drug decide to enroll in a 3 plus year clinical trial. And that really indicates that they will they are obviously not satisfied with how they're feeling or functioning at that moment in time. And so I think our combination group where we do have a sizable portion of patients and we'll be able to report on that will help address part of your question.

Operator

Our next question comes from the line of Mike Ulz with Morgan Stanley. You may proceed.

Speaker 14

Good morning. Thanks for taking the question. Maybe just a follow-up on the launch preparation question. Just curious what you guys have sort of done so far in preparing for a potential launch? And then what are the sort of remaining steps that will be triggered by positive data from Helios B?

Speaker 2

That's a great question. I'm going to pass it on to Saldan. I just want to kind of underscore how pleased I am actually with the commercial footprint that we built. And I think if you look at our performance with respect to Amvutra in patients with polyneuropathy, I think we're really demonstrating strong growth momentum here, and I'm just really pleased with how the commercial organization is focusing on meeting the needs of patients. In this indication, I have no doubt that we'll do the same, assuming a positive HELIOS B and being able to launch into the cardiomyopathy indication.

Speaker 2

But Tolga, you may have some specific comments about how we're thinking about launching to what I think is going to be actually one of the most exciting categories.

Speaker 7

You took a little bit of wind away, Bahn, because I was just going to highlight the fact that despite competition, the growth of our TTR franchise now in the U. S. Is 35% year over year, which is quite important, and I think it's an important indicator of the growth momentum that we've built. Look, we have a great brand, great data in polyneuropathy, which clearly demonstrated 90% market share in Europe and Japan, we actually do compete with tafamidis in the same indication. And now in the U.

Speaker 7

S, we're essentially established a very important stronghold in centers that actually treat both cardiomyopathy and polyneuropathy. We obviously strictly promote our pulmonarypathy indication, but the asset the product is now known by both by cardiologists who also tend to diagnose this disease as well as neurologists. Therefore, we're really well positioned to launch the pending the Helios B outcome results, which is going to be obviously very critical. And as Ivan indicated, we're going to play to win. We have a great footprint, a well informed and trained organization, not just in the customer facing side, but also patient facing side.

Speaker 7

And we also are very cognizant that this opportunity is going to be tenfold of the opportunity that we currently have. Therefore, we're going to make the right appropriate adjustments and make sure that we are clearly differentiated and more importantly, set ourselves so that the product is affordable and accessible to the patients. Thanks,

Speaker 2

Tolga.

Operator

I think we're taking one more question. That's my understanding. And our last question comes from the line of Whitney Ijem with CG. You may move ahead.

Speaker 11

Hey guys, thanks for taking the question. And I'm just going to throw one non HELIOS B question in there, because there will be catalysts after that. So can you help remind us, I guess, for Part B of the ALN APP study, what we should expect to see later this year, particularly around any biomarker or imaging data?

Speaker 4

Yes. Thanks, Whitney for your question about APP. It's a program that we're incredibly excited about. The data that we shared last year really suggest that we can have pretty profound impacts on the protein on amyloid precursor protein as well as the downstream isoforms of AB-forty and forty two that are involved in both Alzheimer's disease and CAA. We have the Part B that's ongoing and we hopefully will show ongoing data with regard to knockdown safety as well as imaging and biomarker data.

Speaker 4

So look for that as something we're also going to be initiating our CAA study soon. We're very excited about the opportunity. That's the 2nd leading cause of hemorrhagic stroke, major with really no available treatments for these patients. And we think that lowering APP could be beneficial in that disease. We'll be kicking off of Phase 2 shortly.

Speaker 4

And we've also announced that we plan to kick off a Alzheimer's disease study at or around year end of this year. So this is a really exciting program. And then it allows us then with our colleagues at Regeneron to move forward a number of other programs in the CNS space. So thanks for your question. Lots of excitement there.

Speaker 2

Great. Thank you, Pascal, and thank you everyone for joining us on the call. We're really proud of our strong start to 2024. We've delivered robust commercial growth and exciting pipeline progress. And we look forward to executing on the remainder of our 2024 goals and our path to becoming a top tier biotech company.

Speaker 2

So thanks, everyone, and have a great day.

Operator

Thank you, everyone, for your participation in today's conference. This

Speaker 1

does conclude the conference and

Operator

you may now disconnect.

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Earnings Conference Call
Alnylam Pharmaceuticals Q1 2024
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