Alnylam Presents Positive Results from HELIOS-A Phase 3 Study of Investigational Vutrisiran

The 9-month results achieved the study’s primary endpoint, with vutrisiran showing improvement in the mean change from baseline in the modified Neuropathy Impairment Score (mNIS+7) as compared to external placebo data from the APOLLO Phase 3 study of patisiran. At 9 months vutrisiran also met all secondary endpoints, demonstrating improvement in quality of life as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) instrument and improvement in gait speed as assessed by the timed 10-meter walk test (10-MWT), both compared to the external placebo group. The majority of patients experienced improvement in neuropathy and in quality of life, both relative to baseline, showing the potential for vutrisiran to reverse polyneuropathy manifestations of hATTR amyloidosis. Vutrisiran also demonstrated an encouraging safety profile with no drug-related discontinuations or deaths. Based on these positive data, Alnylam has submitted a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for the approval of vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

“The HELIOS-A study results demonstrate that vutrisiran improves neuropathy, quality of life and gait speed as soon as 9 months – compared to the external placebo arm of APOLLO – in patients with hATTR amyloidosis with polyneuropathy, with an encouraging safety and tolerability profile. The reversal of polyneuropathy manifestations of disease demonstrated in patients treated with vutrisiran in the study, the encouraging safety profile, and the totality of data from the trial, reinforce our belief in the promise of our RNAi therapeutics’ mechanism of action, as first established with ONPATTRO^® (patisiran). Further, we are encouraged by the exploratory endpoint results showing the impact of vutrisiran on NT-proBNP, a marker of cardiac stress, and look forward to additional data on exploratory cardiac endpoints at the 18-month readout, expected in late 2021,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “With our NDA filing now completed, we look forward to potentially bringing vutrisiran to patients as a new treatment option for the polyneuropathy of hATTR amyloidosis with subcutaneous administration and quarterly dosing. The positive HELIOS-A study and our NDA filing are key milestones as we continue our progress towards building an industry-leading franchise of medicines for the treatment of ATTR amyloidosis and towards our goal of expanding in the future the population of patients who may benefit from treatment with an RNAi therapeutic.”

HELIOS-A Study Results

At 9 months, vutrisiran met the primary and all secondary endpoints in HELIOS-A, specifically:

• Vutrisiran achieved a rapid and sustained reduction in serum TTR levels with an 83 percent mean steady-state serum TTR reduction from baseline.
  • Consistent results in serum TTR level reduction were observed between the vutrisiran and patisiran arms of HELIOS-A, aligned with the therapeutic hypothesis.
• Vutrisiran treatment (N=122) resulted in a 2.24 point mean decrease (improvement) in mNIS+7 score from baseline at 9 months as compared to a 14.76 point mean increase (worsening) reported for the external placebo group (N=77), resulting in a 17.0 point mean difference relative to placebo (p equal to 3.54x10^-12).
  • Improvement in mNIS+7 from vutrisiran treatment was also 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 inclusion in the pre-specified cardiac subpopulation.
  • Patients randomized to the patisiran reference arm in HELIOS-A showed results consistent with the vutrisiran arm.
• Vutrisiran treatment resulted in a 3.3 point mean decrease (improvement) in Norfolk QoL-DN score from baseline at 9 months as compared to a 12.9 point mean increase (worsening) reported for the external placebo group, resulting in a mean 16.2 point difference relative to placebo (p equal to 5.43x10^-9).
• Patients treated with vutrisiran remained stable in gait speed (mean decrease of 0.001 meters/second in 10-MWT), while patients in the external placebo group demonstrated worsening (mean decrease of 0.133 meters/second in 10-MWT) (p equal to 3.10x10^-5).
• Improvement in the exploratory cardiac endpoint, NT-proBNP, a measure of cardiac stress, was observed in the vutrisiran arm in both the pre-specified cardiac sub-population and the modified intent-to-treat (mITT) population, relative to the external placebo group.
  • The cardiac subpopulation was defined as patients who had pre-existing evidence of cardiac amyloid involvement (baseline left ventricular wall thickness ≥1.3 cm and no aortic valve disease or hypertension in medical history). NT-proBNP adjusted geometric fold change from baseline was 0.95 for the vutrisiran cardiac subpopulation group (N=35) and 1.60 for the external placebo cardiac subpopulation (N=34) group, with an adjusted geometric fold change ratio of 0.60 (p equal to 0.0016) in favor of vutrisiran.
  • Similar results from baseline were seen in the mITT population in favor of vutrisiran relative to the external placebo group (p equal to 9.20x10^-7).
• In addition, vutrisiran demonstrated improvements in other exploratory endpoints measured at 9 months, including change from baseline in modified body mass index (mBMI) and the Rasch-built overall disability scale (R-ODS), relative to external placebo.

In the study and as previously reported with topline results from the HELIOS-A study, vutrisiran demonstrated an encouraging safety and tolerability profile relative to placebo with 9 months of dosing and there were no drug-related discontinuations or deaths. There were two study discontinuations (1.6 percent) due to adverse events in the vutrisiran arm by Month 9, both due to death, neither of which was considered related to study drug. There were two serious adverse events (SAEs) considered related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection. Treatment emergent adverse events (AEs) occurring in 10 percent or more patients included diarrhea, pain in extremity, fall, and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with external placebo arm. Injection site reactions (ISRs) were reported in five patients (4.1 percent) and were all mild and transient. There were no safety signals regarding hematology, renal function or liver function tests (LFTs).

“The results of the HELIOS-A Phase 3 study underscore the potential of vutrisiran as an attractive new treatment option that can be administered subcutaneously once every three months, considerably simplifying the treatment for patients with hATTR amyloidosis with polyneuropathy, a progressive, life-threatening, multi-system disease,” said David Adams, M.D., Ph.D., Department of Neurology, Bicetre hospital, Greater Paris University Hospitals, AP-HP, University Paris Saclay and Principal Investigator for the HELIOS-A trial. “The data released today are encouraging for the amyloidosis community who suffer from this devastating disease as we continue to see exciting progress from ongoing research focused on meeting the needs of this diverse group of patients.”

Regulatory Submissions

Alnylam also announced that it has submitted an NDA to the U.S. FDA for the approval of vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast-Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. The Company plans to follow the FDA submission with regulatory filings in Brazil and Japan. The Company also plans to submit a Marketing Authorisation Application (MAA) in the EU upon obtaining the results of the 18-month analysis from the HELIOS-A Phase 3 Study, as previously aligned with the European Medicines Agency (EMA).

Conference Call

Alnylam management will discuss the full 9-month results from the HELIOS-A Phase 3 clinical trial via conference call on Monday, April 19th at 4:00 pm ET. A webcast presentation will also be available on the Investors page of the Company’s website, www.alnylam.com. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 9580096. A replay of the call will be available beginning at 7:00 pm ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 9580096.

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 allows 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 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 primary endpoint is the change from baseline in mNIS+7 score at 9 months, relative to an external placebo group (APOLLO). Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT, relative to an external placebo group. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 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. 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 study period, all patients are eligible to receive vutrisiran for an additional 18 months as part of an open-label extension study.

About hATTR Amyloidosis

Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) 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 vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with an encouraging safety profile for patients with hATTR amyloidosis with polyneuropathy, encouraging exploratory cardiac endpoint results, the expected timing of regulatory filings for vutrisiran outside the U.S., building an industry-leading franchise in medicines for the treatment of ATTR amyloidosis and further growing the population of hATTR amyloidosis patients with polyneuropathy who may potentially benefit from treatment with an RNAi therapeutic, becoming a leading biotech company, 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 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 Annual Report on Form 10-K 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 RNAi therapeutics or investigational uses of previously approved therapeutics. 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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