Alnylam Announces New Data from ATTR Amyloidosis Programs at the Peripheral Nerve Society’s 2021 Annual Meeting

− Phase 3b Open-Label Study Showed Treatment with Patisiran Achieved Rapid and Sustained Reduction in Serum TTR Levels in hATTR Amyloidosis Patients with Polyneuropathy Progression Following Orthotopic Liver Transplant –

− Additional Results from Pre-specified Patient Subgroups Analysis Included with Encore Presentation of HELIOS-A Phase 3 Study of Investigational Vutrisiran −

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive results from a Phase 3b open-label study conducted to evaluate the safety, efficacy and pharmacokinetics (PK) of patisiran in hereditary ATTR (hATTR) amyloidosis patients with polyneuropathy progression after receiving an orthotopic liver transplant (OLT). In patients treated with patisiran, the median reduction in serum TTR levels compared to baseline was 91 percent, measured as an average of the month six and month 12 reduction. In addition, the safety profile of patisiran was consistent with the previously reported safety results observed in the APOLLO Phase 3 study. Patisiran is the established name for ONPATTRO^®, which is approved in the United States, Canada and Japan for the treatment of the polyneuropathy of hATTR amyloidosis in adults, and in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy. These data will form the basis of post-approval supplements which have the potential to change labeling for ONPATTRO where approved, including in the European Union.

In addition, positive results from the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, were presented today with additional data from pre-specified patient subgroups. Improvement in the modified Neuropathy Impairment Score (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy score (Norfolk QOL-DN) from vutrisiran treatment was consistently observed across all pre-specified patient subgroups, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline Familial Amyloid Polyneuropathy (FAP) stage, and in a pre-specified cardiac subpopulation. These data were presented as posters during the 2021 Peripheral Nerve Society’s Annual Meeting, and the HELIOS-A results will also be featured during the Richard A.C. Hughes - Clinical Science Highlights Presentation on Sunday, June 27^th.

“We are excited to share new data from our TTR clinical program at this year’s PNS virtual conference, which help demonstrate the potential of patisiran and vutrisiran for a broad group of patients with hATTR amyloidosis with polyneuropathy. Patients with hATTR amyloidosis who experience polyneuropathy progression post-OLT have a significant treatment need and the results of the Phase 3b study of patisiran demonstrated robust TTR knockdown, improved neuropathy, and quality of life after 12 months of treatment,” said John Vest, M.D., Vice President of Clinical Research at Alnylam. “In addition, results from our HELIOS-A study of investigational vutrisiran underscore the potential of vutrisiran as an attractive potential new treatment option for hATTR amyloidosis patients with polyneuropathy with subcutaneous administration and quarterly dosing.”

Results of Patisiran in Patients with hATTR Amyloidosis Post-OLT

Historically, OLT has been used to slow disease progression in patients with early stages of hATTR amyloidosis; however, some patients experience disease progression after the transplant due to continued amyloid deposition of wild-type TTR on top of existing amyloid deposits in tissues. In the Phase 3b study conducted across several European countries, 23 patients who showed polyneuropathy progression post-OLT (based on an increase in polyneuropathy disability [PND] score) received patisiran infusion (0.3 mg/kg) every three weeks for 12 months.

Results from the study show that at month 12, patisiran treatment resulted in an improvement in neuropathy, as demonstrated by a 3.7 point decrease in the mean total neurological impairment (NIS) score from baseline. Patisiran treatment also resulted in an improvement in quality of life with a 6.5 decrease in mean total Norfolk Quality of Life-Diabetic Neuropathy score (Norfolk QOL-DN) and autonomic symptoms with treatment resulting in a 5.0 decrease in the least squares (LS) mean total COMPASS-31 score from baseline. Patisiran treatment also demonstrated stabilization in other endpoints, including measures of disability like the Rasch-built Overall Disability Scale (R-ODS) and nutritional status with the modified body mass index (mBMI) which were both stable relative to baseline at month 12.

Patisiran also demonstrated an encouraging safety and tolerability profile after 12 months of treatment and there were no drug-related study discontinuations or deaths. There was one serious adverse event (SAE) considered related to patisiran by the study investigator, consisting of an infusion reaction, which resolved without intervention and without change in patisiran treatment. Treatment emergent adverse events (AE) were consistent with those seen in the Phase 3 APOLLO study. The most common observed AE was diarrhea. There was one case of liver transplant rejection observed during the study which was deemed unrelated to patisiran by the study investigator. There were no safety signals regarding hematology, renal function or liver function tests (LFTs).

About ONPATTRO^® (Patisiran)

ONPATTRO is an RNAi therapeutic that was 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 blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body’s tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, visit ONPATTRO.com.

ONPATTRO Important Safety Information

Infusion-Related Reactions

Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19 percent of ONPATTRO-treated patients experienced IRRs, compared to 9 percent 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, paracetamol, 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 respiratory-tract infection (29 percent) and infusion-related reactions (19 percent).

About Vutrisiran

Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary (hATTR) and wild-type (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency or any other health authority.

About the HELIOS-A Phase 3 Study

HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 score at nine months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension.

About hATTR Amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

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 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) is leading 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 genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO^® (patisiran), GIVLAARI^® (givosiran), OXLUMO^® (lumasiran), and Leqvio^® (inclisiran) being developed and commercialized by Alnylam’s partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six 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 expectations, plans, aspirations, and goals, including those related to results from a Phase 3b open-label study of patisiran and the potential benefit of patisiran treatment for patients with polyneuropathy progression after receiving an OLT, the use of the Phase 3b data to support post-approval supplements which have the potential to change labeling for ONPATTRO where approved, including in the European Union, vutrisiran and its potential as an attractive new treatment option for hATTR amyloidosis patients with polyneuropathy with subcutaneous administration and quarterly dosing, and the 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; 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; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, 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 (or vutrisiran, if approved) 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, Regeneron and Vir; the outcome of litigation; the risk of 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.

This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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