Continued Treatment with Patisiran in Open-Label Extension Period Showed Evidence of Sustained Benefit across Measures of Functional Capacity and Health Status and Quality of Life, as well as Cardiac Stress and Injury, through 18 Months

Safety Profile Consistent with that Observed in 12-Month Double-Blind Period, with No New Safety Findings

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced new results from an interim analysis of exploratory data from the open-label extension (OLE) period of 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 at the Annual Congress of the Heart Failure Association of the European Society of Cardiology (Heart Failure 2023; May 20-23, 2023). The Company previously announced that APOLLO-B achieved its primary endpoint and met its first secondary endpoint during the 12-month double-blind (DB) period and that it has submitted the 18-month data to the U.S. Food and Drug Administration (FDA) as an amendment to the supplemental New Drug Application (sNDA) for patisiran for the treatment of the cardiomyopathy of ATTR amyloidosis.

The 18-month findings indicate that the favorable effects on functional capacity and health status and quality of life, as measured by the 6-Minute Walk Test (6-MWT) and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), respectively, observed during the DB period were sustained with continued patisiran treatment during the OLE period. Patients treated with patisiran through 18 months also appear to have maintained relative stability of NT-proBNP and Troponin I levels, measures of cardiac stress and injury, respectively. Patients who crossed over from placebo in the DB period to patisiran during the OLE period appear to show slowing of disease progression or relative stabilization across these same endpoints at Month 18. While the APOLLO-B study was not designed to show benefits in cardiac outcomes between patisiran and placebo, evidence of favorable, but non-statistically significant, trends were observed for composite all-cause death and hospitalization, and mortality analyses across the DB and OLE periods.

“We are pleased to share encouraging new data from our APOLLO-B OLE study, which we believe continue to support the potential for patisiran to be an important therapeutic option for patients with ATTR amyloidosis with cardiomyopathy,” said Rena N. Denoncourt, Vice President, TTR Franchise Lead. “The results demonstrate that serum TTR reduction with an RNAi therapeutic has the potential to provide sustained clinical benefit through 18 months of treatment. These data, in conjunction with the observed decline in placebo-treated patients during the DB period, reinforce the importance of early treatment initiation in ATTR amyloidosis. We remain steadfast in our commitment to bring patisiran to patients with ATTR amyloidosis with cardiomyopathy who currently have limited treatment options.”

APOLLO-B 18-Month Study Results

APOLLO-B is a Phase 3, randomized, DB, placebo-controlled multicenter global study to evaluate the effects of patisiran on functional capacity 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. Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month DB treatment period. After 12 months, all patients were eligible to enter the OLE period of the trial to receive patisiran. An analysis performed at Month 18 indicated:

  • Favorable effects on functional capacity (6-MWT) and health status and quality of life (KCCQ-OS) were sustained in patients receiving patisiran through 18 months. In patients who received placebo during the DB period, initiation of patisiran in the OLE period was associated with a slower rate of worsening (6-MWT) or relative stability (KCCQ-OS) at Month 18 compared with the DB period.

    • For 6-MWT, the mean change from baseline to Month 18 was -9.2 meters in patients initially randomized to patisiran, consistent with the Month 12 assessment. For patients initially randomized to placebo, the mean change from baseline to Month 12 was -25.4 meters and to Month 18 was -31.1 meters.
    • For KCCQ-OS, the mean change from baseline to Month 18 was +0.2 points in patients initially randomized to patisiran, and -4.0 points in patients initially randomized to placebo.
  • Continued treatment with patisiran through 18 months was also associated with relative stability in biomarker measures of cardiac stress (NT-proBNP) and cardiac injury (Troponin I). Patients who received placebo in the DB period showed steadily rising cardiac biomarker levels up to Month 12, which then appeared to slow or stabilize after initiating patisiran in the OLE period.

    • The geometric mean fold-change from baseline at Month 18 in NT-proBNP was 1.17 for patients who continued on patisiran, and 1.53 for placebo-crossover patients.
    • The geometric mean fold-change from baseline at Month 18 in Troponin I was 1.09 for patients who continued on patisiran, and 1.21 for placebo-crossover patients.
  • Additionally, while the APOLLO-B study was not designed to show a treatment difference in death and hospitalizations between patisiran and placebo in the DB or OLE period, and no statistically significant differences were achieved, evidence of favorable trends were observed for these composite endpoints. The analyses of outcomes included all available data from the DB and OLE periods at the time of the Month 18 data-cut.

    • The point estimate of hazard ratio (HR) for the composite of all-cause mortality and frequency of all-cause hospitalization and urgent heart failure visits was 0.801 (95% CI, 0.573–1.118).
    • The HR for all-cause mortality was 0.554 (95% CI, 0.281–1.094).

Patisiran demonstrated an encouraging safety profile through 18 months of treatment, consistent with the underlying disease and the known safety profile of patisiran, with no new safety concerns identified. The majority of adverse events (AEs) were mild or moderate in severity. The most common treatment-related AE was infusion-related reactions (14.1 percent).

As previously announced, the U.S. FDA has set an action date of October 8, 2023 under the Prescription Drug User Fee Act (PDUFA) and noted that they are planning to convene a meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the application. Patisiran is the established name for ONPATTRO®, which is approved by the U.S. FDA for the treatment of the polyneuropathy of hereditary ATTR amyloidosis in adults.

To view the APOLLO-B 18-month results presented at Heart Failure 2023, please visit Capella.

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%).

For additional information about ONPATTRO, please see the full U.S. Prescribing Information.

About ONPATTRO® (patisiran)

ONPATTRO (patisiran) 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. Patisiran is also being evaluated for the treatment of the cardiomyopathy of ATTR amyloidosis; the safety and efficacy of patisiran in this indication have not been established or evaluated by the FDA, EMA or any other health authority.

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 potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway 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 Pharmaceuticals (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), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is 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

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam’s projected commercial and financial performance, should be considered forward-looking statements. 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; Alnylam’s ability 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 Alnylam’s 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 Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam’s research and development programs, including as may arise from recent disruptions in the supply of non-human primates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO or AMVUTTRA 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 a current government investigation 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 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q 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.

This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. 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. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.

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Alnylam Pharmaceuticals, Inc.

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