Alnylam Presents Additional Results from the APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy at Heart Failure Society of America Annual Meeting

– New Data Further Support Potential for Patisiran to be an Effective Treatment for Cardiomyopathy of ATTR Amyloidosis –

– Data from Exploratory Endpoints, Including Cardiac Biomarkers and Imaging, Suggest Favorable Impact of Patisiran on Measures of Cardiac Stress, Injury, Structure, and Function at Month 12 –

– Treatment with Patisiran Demonstrated Generally Consistent Benefit Across Prespecified Patient Subgroups on Functional Capacity as Measured by the 6 Minute Walk Test (6-MWT) and Health Status and Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ-OS), Compared to Placebo at Month 12 –

– Patisiran Demonstrated Encouraging Safety and Tolerability Profile in Patients with ATTR Amyloidosis with Cardiomyopathy –

– Alnylam to Webcast Investor Event Today at 8:00 p.m. ET –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced results from exploratory endpoints and additional analyses of prespecified patient subgroups for the primary and secondary endpoints in the APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy. The results were presented during a moderated poster session at the Heart Failure Society of America’s Annual Scientific Meeting on September 30, 2022. The Company previously announced that the 12-month study achieved its primary endpoint and met its first secondary endpoint at the 18^th International Symposium on Amyloidosis in September 2022.

The 12-month findings across a comprehensive set of exploratory endpoints suggest that treatment with patisiran was associated with favorable impacts on key measures of cardiac stress and injury, NT-proBNP and Troponin I, respectively. In addition, favorable impact of patisiran relative to placebo was seen in several echocardiographic parameters and technetium scintigraphy uptake. Results from an analysis of prespecified patient subgroups were also presented, demonstrating generally consistent benefit across subgroups for the primary and secondary endpoints of 6-MWT and KCCQ-OS, respectively. As previously shared, patisiran also demonstrated an encouraging safety and tolerability profile in patients with ATTR amyloidosis with cardiomyopathy.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited,” said Parag Kale, M.D., Staff Cardiologist, Heart Transplant Department at Baylor University Medical Center. “It’s impressive to see that the effects of patisiran on functional capacity and quality of life in the APOLLO-B study were maintained across key patient subgroups, and corroborated by favorable changes in exploratory measures of NT-proBNP and Troponin I, cardiac biomarkers that are often used in clinical practice to assess patients with cardiomyopathy due to ATTR amyloidosis.”

APOLLO-B Study Results

APOLLO-B is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the effects of patisiran on functional capacity, health status and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 sites in 21 countries. Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Exploratory Endpoints

At 12 months, the results of the exploratory endpoints presented today are as follows:

• Results on NT-proBNP, a measure of cardiac stress, favored patisiran compared to placebo.
  • NT-proBNP adjusted geometric mean fold change from baseline at Month 12 was 1.11 for the patisiran group and 1.38 for the placebo group, with an adjusted geometric mean fold change ratio of 0.80 (nominal p equal to 1.825x10^-5) in favor of patisiran.
• Results on Troponin I, a biomarker of myocardial injury, favored patisiran compared to placebo.
  • Troponin I adjusted geometric mean fold change from baseline at Month 12 was 1.13 for the patisiran group and 1.30 for the placebo group, with an adjusted geometric mean fold change ratio of 0.87 (nominal p=0.0011) in favor of patisiran.

• Results on several exploratory analyses of echocardiographic parameters at Month 12, including global longitudinal strain (p=0.0324), LV mass (p=0.0402), and LV end-diastolic volume (p=0.0508), favored patisiran (all nominal p values) compared to placebo. No significant differences were seen in mean or relative LV wall thickness or cardiac output.
• Cardiac uptake of technetium on scintigraphy imaging was assessed in a planned cohort of patients, with 37 patients in the patisiran arm and 28 patients in the placebo arm evaluable at Month 12. Among evaluable patients with both baseline and Month 12 results (37 patisiran and 28 placebo), all patients in the patisiran arm (100%) reduced or demonstrated no change in the Perugini grading scale at Month 12 relative to baseline. Of the evaluable patients in the patisiran arm, 37.8% demonstrated a reduction of ≥1 Perugini grade, including 3 (8.1%) patients who reduced by ≥2 Perugini grades at Month 12. No evaluable placebo patients demonstrated a reduction from baseline in Perugini grade at Month 12.

Analyses of Prespecified Patient Subgroups

• Prespecified patient subgroup analyses were conducted for the primary and first secondary endpoints, evaluating patisiran compared to placebo across baseline tafamidis use, age, ATTR amyloidosis type (hereditary and wild-type), New York Heart Association (NYHA) functional classification, baseline 6-MWT score, NT-proBNP level and region. At Month 12, a generally consistent benefit in 6-MWT and KCCQ-OS was observed with patisiran compared to placebo across the prespecified patient subgroups.
• Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR of 87% in the full analysis set, 84% for patients receiving tafamidis at baseline and 88% for those not receiving tafamidis at baseline.
• Composite outcomes secondary endpoints for the study did not achieve statistical significance over 12 months. In the overall population, the hazard ratio (95% CI) for time to first event (all-cause hospitalization, urgent HF visit, or a death event) was 0.839 (0.557, 1.263), directionally favoring patisiran over 12 months; subgroup analyses by baseline tafamidis use showed similar trajectories. In addition, all-cause mortality (determined in accordance with the pre-defined statistical analysis plan, which excluded death due to COVID-19, and treated cardiac transplant as a death event consistent with other studies in the field) directionally favored patisiran vs placebo. In the overall population, all-cause deaths were observed in 10 (5.6%) placebo vs 4 (2.2%) patisiran patients, resulting in a hazard ratio of mortality of 0.355 (0.110, 1.138); similar results were observed in subgroups of patients based on use of tafamidis at baseline.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, with 12 months of dosing. The majority of adverse events (AEs) were mild or moderate in severity. Treatment emergent AEs occurring in 5% or more patients in the patisiran group and observed at least 3% more commonly than in the placebo group included infusion-related reactions (12.2% vs 9.0%), arthralgia (7.7% vs 4.5%), and muscle spasms (6.6% vs 2.2%). In the safety analysis there were 5 deaths (2.8%) observed in patisiran-treated patients and 8 deaths (4.5%) observed in the placebo group.

“Data from the APOLLO-B exploratory endpoints, coupled with evidence of a generally consistent benefit across pre-specified patient subgroups in the 6-MWT and KCCQ-OS, reinforce our belief that TTR silencing with patisiran has the potential to address multiple aspects of ATTR amyloidosis, including cardiac manifestations of disease,” said Rena N. Denoncourt, Vice President, TTR Franchise Lead at Alnylam Pharmaceuticals. “We remain steadfast in our commitment to develop impactful RNAi therapeutic options for patients living with all forms of ATTR amyloidosis as evidenced by today’s data and the recent approvals of AMVUTTRA^® (vutrisiran) for adult patients with hATTR amyloidosis with polyneuropathy in the U.S., the European Union, and Japan.”

Alnylam plans to submit a supplemental new drug application (sNDA) for patisiran as a potential treatment for patients with ATTR amyloidosis with cardiomyopathy for review by the United States Food and Drug Administration (FDA) in late 2022.

To view the APOLLO-B data presented at HFSA, please visit Capella.

Investor Webcast Information

Alnylam Management and Mat Maurer, M.D., Arnold and Arlene Goldstein Professor of Cardiology at Columbia University, will discuss the APOLLO-B results via webcast on September 30, 2022, at 8:00 p.m. ET. The webcast will be available on the Investors section of the Company’s website at www.alnylam.com/events. An archived webcast will be available on the Company’s website approximately two hours after the event.

About ONPATTRO^® (patisiran)

ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information, visit ONPATTRO.com.

ONPATTRO Indication and Important Safety Information

Indication

ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Important Safety Information

Infusion-Related Reactions

Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

Reduced Serum Vitamin A Levels and Recommended Supplementation

ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Adverse Reactions

The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

About ATTR Amyloidosis

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract. There are two different types of ATTR amyloidosis – Hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and Wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, while wtATTR amyloidosis is estimated to impact 200,000 – 300,000 people worldwide.

About LNP Technology

Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals

Alnylam (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), AMVUTTRA® (vutrisiran) and Leqvio® (inclisiran) being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylam’s views with respect to the safety and efficacy of patisiran for the treatment of ATTR amyloidosis with cardiomyopathy, the potential of treatment with patisiran to address multiple aspects of ATTR amyloidosis, including cardiac manifestations of disease, based upon data from the APOLLO-B exploratory endpoints, as well as evidence of a generally consistent benefit across pre-specified patient subgroups in the 6-MWT and KCCQ-OS, Alnylam’s commitment to develop impactful RNAi therapeutic options for patients living with all forms of ATTR amyloidosis, the expected timing of the submission of a sNDA for patisiran for review by the FDA, and Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; the potential impact of the recent leadership transition on Alnylam’s ability to attract and retain talent and to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates, including patisiran and vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including patisiran and vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO, AMVUTTRA or OXLUMO in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population.

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