Alnylam Pharmaceuticals, Inc. Investor update

Good morning, everyone. I'm Kelly Cronin, Senior Manager of Investor Relations at Alnylam, and I'm pleased to welcome you to the second event of Alnylam's 10th RNAi Roundtable series. Through this series, we aim to bring greater visibility to select near and midterm pipeline programs that we believe will define the next wave of transformative medicines emerging from our RNAi platform here at Alnylam. Today's event is focused on zilebesiran, our investigational RNAi therapeutic for patients with hypertension and high cardiovascular risk, or established cardiovascular disease, which we are advancing together with our partners at Roche. As a reminder, today's discussion will include forward-looking statements. We encourage you to review our most recent SEC filings for a more complete discussion of our risk factors.

During today's event, you'll hear first from Chief Research and Development Officer, Pushkal Garg, who will set the stage with an overview of Alnylam's organic product engine and the unique potential of RNAi therapeutics to transform cardiovascular care. Dr. Akshay Desai of Harvard Medical School and Mass General Brigham will then discuss the persistent burden of hypertension beyond the office setting, followed by Ashir Bhan, who will review clinical evidence supporting the potential for continuous control with zilebesiran. Simon Fox will then close out our prepared remarks with an overview of the integrated execution underway to realize zilebesiran's full potential. Following the prepared remarks, we will open the discussion for a question and answer session with our speakers, joined by Victoria Silva, who leads zilebesiran commercial strategy at Alnylam.

The Q&A will be moderated by Pushkal, and questions may be submitted at any time through the ask a question field within the webcast platform. With that, I'll turn it over to Pushkal.

Pushkal? Thanks, Kelly, and welcome everyone to today's RNAi roundtable focused on zilebesiran, which we believe has the potential to transform the treatment of hypertension by providing continuous control of blood pressure.

As many of you know, Alnylam has spent more than two decades pioneering an entirely new class of medicines based on RNA interference. What makes RNAi so remarkable is the combination of attributes you see here. Like a biologic scalpel, we can silence virtually any gene in the genome and intervene upstream of most traditional medicines. It's a catalytic mechanism, enabling highly potent medicines at low doses while remaining highly specific and reversible. And we can engineer long durations of effect that support very infrequent administration. Taken together, these attributes create an extraordinarily powerful therapeutic profile, and we've already demonstrated what this technology can deliver, translating the science into a growing portfolio of medicines for patients.

We've harnessed this natural phenomenon into a unique and sustainable innovation engine, which we believe will fuel sustained long-term growth. We continue to invest in the power of human genetics with access to data from more than 2 million lives, helping us identify and validate compelling new targets, advance RNAi delivery to major tissues throughout the body, and optimize our siRNA designs to enable increasingly potent, specific, and durable molecules across a wide range of clinical applications. We pair this innovation engine with a disciplined strategy for selecting the most compelling opportunities to advance to the clinic. Our therapeutic area agnostic approach focuses on diseases with high morbidity and mortality, where we can pursue highly genetically validated targets with a strong biologic rationale.

This integrated approach has enabled us to generate high-quality drug candidates and achieve historical clinical success rates well above industry benchmarks, building a high-value portfolio of programs targeting areas of tremendous unmet need. You can see the result of that strategy here in our industry-leading pipeline of RNAi therapeutics. With more than 25 programs spanning rare specialty and prevalent indications across multiple therapeutic areas, we believe this pipeline underscores the depth of opportunity ahead for Alnylam, and most importantly, our potential to deliver even more transformative medicines to patients. We're entering a period of significant clinical momentum with three pivotal studies underway and four important data readouts expected this year.

That momentum will build meaningfully through 2028 with a growing number of pivotal studies, at least five key data readouts each year, and the potential launch of mivelsiran and hereditary ATTR polyneuropathy, assuming positive phase III data and regulatory approval. Cardiovascular disease is one area where the power of RNAi offers the potential to make a major impact on the leading cause of death around the world. With our RNAi-based platform, we've built a diverse portfolio of therapies designed to address major drivers of cardiovascular morbidity and mortality, including obesity, type 2 diabetes, hypercholesterolemia, and hypertension. zilebesiran is a particularly compelling example of the unique potential of RNAi in cardiovascular disease. Hypertension remains one of the largest and most consequential drivers of cardiovascular risk, yet control remains inadequate for far too many patients.

Together with our partners at Roche, we're exploring whether durable suppression of angiotensinogen can deliver more consistent blood pressure control and ultimately translate into a profound impact on cardiovascular outcomes. The urgency of that work becomes clear when we look at the projected burden of cardiovascular disease. Annual deaths due to cardiovascular disease around the world are projected to rise over 70%, from 20.5 million in 2025 to 35.6 million by 2050. Notably, high systolic blood pressure will remain the leading risk factor, with the CV deaths attributable to hypertension projected to increase from 11 million to nearly 19 million during that period. Despite this enormous and growing burden, hypertension has not seen the same degree of therapeutic innovation as areas such as lipids and obesity. Our aspiration is to bend this curve by investigating whether continuous durable blood pressure control with zilebesiran can reduce cardiovascular risk.

To put the magnitude of this unmet need into clinical context and dive deeper into why we've struggled to effectively manage hypertension in the past, I'll now turn it over to Dr. Akshay Desai.

Thanks very much, Pushkal. In the next 10 minutes, my job is to underscore for you the ongoing threat of hypertension as a global health priority. The burden of hypertension globally has steadily risen since 1990 in the U.S. and elsewhere, from an estimate of about 440 million prevalent cases in 1990 to more than 875 million cases by 2015, and nearly 1 billion cases prevalent in modern era. That is defined at a threshold of a blood pressure more than 140 millimeters of mercury, and we can anticipate that the prevalence would be estimated at the newer reduced thresholds that are recommended by current guidelines. This steady rise in the prevalence of hypertension is related to secular trends and risk factors for the development of hypertension, including normal aging, but also risk factors including obesity, insulin resistance, and diabetes that drive the hypertension epidemic.

Hypertension remains the leading risk factor for cardiovascular disease and associated disability and mortality worldwide, and the leading preventable approach to prevention of cardiovascular disease that we have. 10% of the global healthcare expenditure is estimated to be accounted for by hypertension, and this therefore represents an important target for ongoing attention. We know that hypertension contributes to changes in the vasculature, the heart, and in the kidney that predispose the development of a range of cardiovascular diseases, including ischemic heart disease, stroke, chronic kidney disease, and then a range of other cardiovascular disorders, including heart failure. As this slide shows, the cumulative burden of disability-adjusted life years associated with hypertension is quite substantial. At every blood pressure, the highest burden of disease is contributed by ischemic heart disease, with subsequent contributions by stroke, chronic kidney disease, and other disorders, including heart failure.

About 70% of the disability associated with hypertension and hypertension-related mortality is related to blood pressures that are measured more than 140 millimeters of mercury. But you can see that a third of the disability-adjusted life years are associated with blood pressures between 110 and 140 millimeters of mercury, which underscores the need for even more aggressive control of blood pressure to prevent disability and death in clinical practice. It's estimated that nearly $100 billion in global savings could be secured for more aggressive control of blood pressure in clinical practice, and this is really the opportunity for more effective hypertension therapies.

It's well established that blood pressure reduction is an effective way of reducing cardiovascular risk, and this data from a meta-analysis of nearly 123 studies comprising more than 600,000 patients highlights that with each 10-millimeter reduction in systolic blood pressure, there's about a 20% reduction in major cardiovascular events, a 17% reduction in coronary heart disease, a 27% reduction in stroke, and another 30% reduction in heart failure. These data underscore that with incremental blood pressure reductions, we can expect an incremental reduction in return on cardiovascular risk reduction. That said, we have a lot of effective medical therapies for hypertension, but these are heavily underutilized in clinical practice. When we look at the total burden of hypertension, only 40% of patients are identified as hypertensive and treated in clinical practice. Among those who are treated, only one in five is actually treated to guideline-recommended targets.