Alnylam Pharmaceuticals : HELIOS-B Topline Results Transcript

Alnylam Pharmaceuticals Conference Call to Discuss HELIOS-B Phase 3 Topline Results -

Conference Call Script

June 24, 2024

Christine Lindenboom - Senior VP, Investor Relations & Corporate Communications

Good Morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are:

1. Yvonne Greenstreet, Chief Executive Officer; o Pushkal Garg, Chief Medical Officer; and
   o Tolga Tanguler, Chief Commercial Officer.

Also joining us on the line and available for Q&A are:

1. Akshay Vaishnaw, Chief Innovation Officer; o Jeff Poulton, Chief Financial Officer; and
   o John Vest, Senior Vice President of Clinical Research.

For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the investor's page of our website, alnylam.com/events.

Now, turning to today's call, as outlined in slide 2:

1. Yvonne will provide some opening comments;

1. Pushkal will provide an overview of ATTR amyloidosis with cardiomyopathy and

discuss the HELIOS-B study and topline results in more detail;

1. Tolga will review our commercialization strategy with vutrisiran in ATTR-CMo and we will then open the call for your questions.

Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam'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-recent quarterly 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 obligations to update such statements.

With that, I will now turn the call over to Yvonne.

Yvonne Greenstreet - Chief Executive Officer

Thanks Christine, and thank you everyone for joining the call this morning.

As you saw in our press release, we are announcing positive topline results from our HELIOS-B Phase 3 trial of vutrisiran, our investigational RNAi therapeutic that was evaluated in patients with ATTR amyloidosis with cardiomyopathy. First and foremost, the study met the primary and ALL secondary endpoints in the overall AND monotherapy populations. Let me be clear: this is THE BIG WIN scenario. We are thrilled with these results and what they mean for patients, physicians, families, caregivers - everyone in the ATTR amyloidosis community. In addition, this is a landmark moment for Alnylam. What a remarkable journey it has been in our quest to address this major unmet medical need. Indeed, it has been over ten years since we first began to explore the potential of RNAi mediated knockdown of TTR to achieve transformative therapeutic benefit in patients with ATTR amyloidosis with cardiomyopathy. And as Pushkal will describe for you in a moment, we now have hard, outcomes-based evidence that rapid knockdown of toxic TTR can significantly improve cardiovascular outcomes in these patients.

ATTR amyloidosis is a fatal disease that robs patients of their ability to live a normal life. The median survival ranges from two and a half to five and a half years, a natural history that is worse than many cancers. More than 80% of ATTR-CM patients remain untreated and for those that are treated, the majority of patients continue to progress in their disease course so there is significant unmet need in this disease.

With the HELIOS-B results now in hand, we intend to advance vutrisiran to a supplemental NDA filing later this year for the treatment of ATTR-CM, using a Priority Review Voucher in the U.S., with additional global regulatory filings to follow. Later in this call, Tolga will walk you through how we plan to bring vutrisiran to patients around the world living with this devastating disease. Assuming regulatory approval, we believe expansion of AMVUTTRA's label to include ATTR-CM represents a

major inflection point in our journey toward becoming a top-tier biopharma company. Moreover, we believe these positive HELIOS-B results provide the critical key to unlocking the next wave of our significant topline growth and our ability to achieve a self-sustainable financial profile.

The results from HELIOS-B show the true power of the RNAi mechanism of action, supporting what we believe to be a highly differentiated therapeutic profile, and positioning vutrisiran as the new Standard of Care in ATTR cardiomyopathy. Moreover, this achievement highlights Alnylam's expertise in clinical trial design, deep track record of conducting trials in the ATTR space, thoughtful approach to patient selection, conservative powering of our pivotal studies, and rigorous approach to implementation, training, and oversight of clinical assessments. This is all driven by a corporate culture devoted to a passion for excellence and a deep commitment to patients.

Before I hand it over to Pushkal, I'd like to take a moment to acknowledge the patients, their families and caregivers, and the investigators and study staff across the globe who participated in HELIOS-B and made this important medical advancement possible. I'd also like to acknowledge our team at Alnylam who went above and beyond and pored over every detail to ensure trial success. I am proud of our team, and I look forward to the next phase of our TTR journey.

With that, let me now turn it over to Pushkal to review the HELIOS-B topline results in more detail. Pushkal?

Pushkal Garg - Chief Medical Officer

Thanks Yvonne, and good morning, everyone. It is a tremendous joy and an honor for me to be sharing these exciting topline results with you on behalf of all my colleagues at Alnylam.

As most of you know, ATTR amyloidosis is a multi-system disease caused by misfolded transthyretin protein which deposits primarily in the heart and the nerves, resulting in cardiomyopathy and polyneuropathy that are progressively debilitating and ultimately fatal. We estimate that there are approximately 50,000 patients worldwide with the hereditary form of the disease and many multiples of that - several hundred thousand, in fact - with the wild-type form.

By rapidly knocking down TTR in the liver, RNAi therapeutics act upstream to lower circulating levels of the pathogenic protein. Our therapeutic hypothesis is that this in turn reduces amyloid deposition in the heart and nerves, thereby having the potential to halt or even improve manifestations of disease. We have seen the transformative impact that rapid knockdown of TTR has had on the treatment of polyneuropathy in hereditary ATTR amyloidosis patients, where both ONPATTRO and AMVUTTRA have demonstrated substantial improvements in neuropathy impairment and quality of life. And as I'll describe in a moment, we now have the first definitive clinical evidence demonstrating the ability of RNAi therapeutics to improve cardiovascular outcomes.

Let me now turn to the HELIOS-B study, and briefly remind you of the study design. HELIOS-B enrolled 655 patients with ATTR amyloidosis w/ cardiomyopathy, either the wild-type or hereditary form of the disease. Patients had to have clinical symptoms or established heart failure as assessed by a physician. Importantly, these were patients who were enrolled in the modern era, where patients are identified earlier in their disease via non-invasive methods, and patients' heart failure management has improved via use of other medications such as diuretics and SGLT2 inhibitors. And as we've discussed, 40% of patients were on an active drug - tafamidis -- at baseline and others were able to start stabilizers during the study.

Patients were randomized 1:1 to receive a 25 mg dose of vutrisiran or placebo administered subcutaneously once every three months during a double-blind treatment period of up to 36 months. The primary endpoint was the composite outcome of all-cause mortality and recurrent CV events, assessed in two populations: the overall population and the monotherapy population, defined as those patients who were not on tafamidis at baseline. In addition, the study included a number of secondary endpoints, which were also tested in both populations.

Let me now review each of these endpoints in greater detail.

This table shows the full list of prespecified primary and secondary endpoints for the HELIOS-B study. In addition to the primary composite of all-cause mortality and recurrent cardiovascular events, the secondary endpoints we tested focused on important clinical measures that we

believed could best highlight vutrisiran's potentially differentiated profile and its impact on disease progression. These secondaries are all listed here and were tested hierarchically in this order. The first secondary endpoint was the change from baseline in the 6-minute walk test, a measure of functional capacity. Next is the change from baseline in the Kansas City Cardiomyopathy Questionnaire, a validated measure of health status and quality of life in patients with heart failure. Third was all-cause mortality as a stand-alone endpoint, which is recognized as the most stringent measure of efficacy in this disease. And last is New York Heart Association classification, which is a common assessment that physicians use to monitor disease progression in their patients.

Let me take a moment to provide a bit more context on the secondary endpoint of all-cause mortality. We wanted to use the opportunity of this pivotal trial to fully demonstrate the impact of vutrisiran on mortality alone, which is THE highest bar for efficacy. With the understanding that targeted therapies for ATTR cardiomyopathy don't immediately impact mortality, in this analysis we included up to 6 months of data from the OLE period to increase the exposure time for up to 42 months. This prespecified ITT analysis therefore compares the experience of patients who were randomized to vutrisiran against those who received placebo during the double-blind period and then crossed over to receive active drug. Thus, this is indeed a stringent test of mortality.

Let me now walk you through the results. Remarkably, vutrisiran achieved statistical significance on every endpoint we tested - 10 out of 10 - in both populations.

• HELIOS-Bmet the primary endpoint, achieving a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular events in both the overall and monotherapy populations. In the overall population, the hazard ratio was 0.718, corresponding to a relative risk reduction of 28%, with a p-value of 0.0118. In the monotherapy population, the hazard ratio was 0.672, corresponding to a relative risk reduction of 33%, with a p-value of 0.0162.
• On the first secondary endpoint, vutrisiran demonstrated a significant improvement in change from baseline in the 6-minute walk test at 30 months relative to placebo in BOTH populations, with p-values less than 0.025.

• Vutrisiran-treatedpatients also demonstrated an improvement in health status and quality of life relative to placebo, as measured by the KCCQ, also in both populations, and again, with p-values less than 0.025.
• Next, let's turn to the pre-specified secondary endpoint of all-cause mortality. Here we were thrilled to see, in BOTH populations, statistically significant and highly clinically relevant reductions in all-cause mortality. In the overall population, the hazard ratio was 0.645, corresponding to a relative risk reduction of 36%, with a p-value less than 0.025. In the monotherapy population, the hazard ratio was 0.655, corresponding to a relative risk reduction of 35%, with a p-value less than 0.05.
• The final secondary endpoint, NYHA class, was analyzed as a percentage of patients in each arm that either were stable or showed improvement at month 30. Here, too, we saw statistically significant benefits in BOTH populations, with p-values less than 0.025.

Thus, we observed truly remarkable results in this study, with vutrisiran meeting an extraordinarily high bar for efficacy, with statistical significance on ALL 5 pre-specified endpoints in each of the two study populations, highlighting the powerful impact of vutrisiran and its mechanism of action on this disease.

Finally, it was important to assess the consistency of treatment effect across key patient subgroups enrolled in HELIOS-B. In particular, we assessed the consistency of effect in patients receiving baseline tafamidis, wild-type and hereditary disease, and multiple measures of disease severity.

And we were very pleased to see that the effects of vutrisiran on the primary and all secondary endpoints were in fact consistent across all key subgroups, including patients on background tafamidis, where we saw evidence of additive effects.

Now let's turn to the topline safety results. Vutrisiran demonstrated encouraging safety and tolerability, consistent with its established profile. Rates of AEs, SAEs, and AEs leading to discontinuation were similar between the vutrisiran and placebo arms. No AEs were seen greater than three percent more frequently in the vutrisiran arm compared to the placebo arm.

These remarkable results of vutrisiran in a contemporary population of patients with ATTR cardiomyopathy - with clinical benefits seen on every single one of this rigorous set of endpoints - highlight the power of the RNAi mechanism of action and suggest that vutrisiran has the potential to become the new standard of care in ATTR cardiomyopathy.

Specifically, we observed:

• 28% and 33% reductions in the composite of all-cause mortality and recurrent CV events in the overall and monotherapy populations, respectively, AND
• 36% and 35% reductions in all-cause mortality in the overall and monotherapy populations, respectively
• These outcome benefits were accompanied by clinically significant benefits on 6MWT, KCCQ, and NYHA class, all of which are key measures of disease progression
• We observed consistent effects in all key subgroups, including patients who were on baseline tafamidis
• And finally, vutrisiran demonstrated encouraging safety and tolerability, consistent with its established profile.

We look forward to presenting detailed results from the HELIOS-B study at an upcoming medical conference. We've submitted these data as a Late-Breaking Abstract to the European Society of Cardiology meeting, taking place August 30th through September 2nd in London.

As Yvonne mentioned, and consistent with our previous guidance, we now plan to engage with regulators and advance vutrisiran toward a supplemental NDA filing in the U.S. in late 2024, with additional global regulatory filings thereafter. In the U.S., we plan to use our Priority Review Voucher to accelerate the regulatory review process in hopes of bringing this medicine to patients as quickly as possible.

I'd like to extend my thanks and admiration to my many Alnylam colleagues who always maintained their belief in our mission and sweated every detail to deliver a high quality study. Likewise, I am grateful to the investigators, site staff and partners and vendors who worked with us. And most of all, I want to extend my heartfelt thanks to the patients who volunteered to participate in this study,

which we hope will allow us to bring this medicine to ATTR cardiomyopathy patients around the world who need additional therapies for this devastating disease.

And with that, I will now turn the call over to Tolga. Tolga?

Tolga Tanguler - Chief Commercial Officer

Thanks Pushkal, and good morning everyone. We are thrilled about the outstanding results observed in HELIOS-B and what this potentially represents for patients with ATTR amyloidosis with cardiomyopathy across the globe.

Alnylam has a tremendous opportunity to transform the treatment paradigm based on these results and the significant unmet patient needs in ATTR amyloidosis with cardiomyopathy. We estimate that ATTR-CM represents a 10-fold larger prevalence than hereditary ATTR with polyneuropathy, where AMVUTTRA is the current market leader.

The vast majority (~ 80%) of the estimated 200 to 300 thousand patients living with ATTR-CM remain untreated. The good news is that diagnosis and treatment rates are improving rapidly, and will only accelerate with more voices - including our own - fueling awareness and urgency to treat.

At the same time, we also know that there is significant need for new treatment options. Our research with physicians tells us that of those patients who are treated with currently available options, nearly three quarters experience only partial or no response to treatment. For this majority of underserved patients, this can mean debilitating and irreversible declines in functional capacity and quality of life, as well as hospitalizations and death.

In short, the ATTR-CM market is large, it is rapidly expanding and there remains very significant unmet need. It is primed for a transformative medicine.

In this context, assuming regulatory approval, we believe vutrisiran has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CM, with a first line and market-leading profile that would include:

• First, a unique and highly differentiated mechanism of action vs current treatment options that works upstream, enabling rapid knockdown of TTR at the source that is deep and durable
• Second, for a disease where the median survival is 2.5 to 5.5 years, what patients and physicians really want is a clear impact on mortality. Beyond that, they want to see benefits on preservation of function and quality of life, and we've delivered these results across ALL trial subgroups.
• Third, an attractive quarterly dosing schedule that aligns with physician visits, supporting strong adherence, with site of care flexibility; and
• Finally, favorable payer dynamics due to its HCP-administered dosing resulting in lower out of pocket costs for patients, in a market where we expect payers to favor monotherapy use for the next several years.
• These data also provide us the opportunity to position vutrisiran for today AND beyond tafamidis loss of exclusivity.

Let me also share how we are preparing for this potentially monumental launch, assuming regulatory approval.

Over the last decade we have been deeply committed to succeeding in ATTR amyloidosis and understanding the unique needs of this community. We have already established market leadership in hATTR amyloidosis with polyneuropathy, driving significant growth in the category and attaining about 90% share in the polyneuropathy market with our two TTR-targeting therapies, ONPATTRO and AMVUTTRA. Through our Patient Access Philosophy, we have confirmed access for over 99% of patients, while ensuring that about 70% of patients have zero out-of-pocket costs. Furthermore, AMVUTTRA, with its quarterly dosing schedule, has demonstrated a very high rate of adherence and compliance.

As we prepare for the anticipated launch of AMVUTTRA in ATTR-CM, assuming regulatory approval, we will leverage the foundational capabilities we have built in the hereditary polyneuropathy segment while expanding into the potential treatment of a significantly larger patient population.

While we appreciate that our foundational capabilities position us well for this potential launch, we also recognize that scaling these capabilities to ensure Vutrisiran becomes the standard of care in ATTR-CM is absolutely critical.

We have a strong foundation to build from as we scale. That includes:

• Our deep relations with TTR centers,
• A global and highly specialized and integrated customer facing team that delivers a seamless experience for patients and physicians
• Our track record of creating strong payer and health system partnerships that supports exceptional patient access, not only in the U.S. but also across all major global markets including Canada, Europe and Japan, as well as
• Our award-winning patient support services teams, that have enabled us to help patients access their Alnylam treatments quickly, with one of the fastest timelines in transition from start form to therapy in the industry and also support over 95% patient adherence.

Finally, I'd like to join my colleagues in expressing how excited I am about the HELIOS-B results. It is truly a remarkable achievement for Alnylam, for RNAi therapeutics, and, most importantly, for the ATTR amyloidosis community. With these exciting top line results, we believe Alnylam is superbly positioned to deliver this transformative medicine to patients with ATTR amyloidosis with cardiomyopathy, and we believe it has the potential to be utilized as a first line treatment and to become the new standard of care for this rapidly progressing fatal disease.

I will now hand it back to Yvonne for some additional remarks.

Yvonne Greenstreet - Chief Executive Officer

Thanks Tolga. As you've heard from Pushkal, we believe that the HELIOS-B results support vutrisiran's potential to become the new standard of care in ATTR-CM. And as you just heard from Tolga, we believe vutrisiran is well positioned to address the significant unmet need in ATTR amyloidosis with cardiomyopathy, given the large and growing population of those untreated, and for those that are treated and continue to experience disease progression.