Alnylam Completes Rolling Submission of New Drug Application to the U.S. Food and Drug Administration and Submits Marketing Authorization Application to the European Medicines Agency for Lumasiran for the Treatment of Primary Hyperoxaluria Type 1



Treatment for Primary Hyperoxaluria Type 1 (PH1)

Alnylam Completes Rolling Submission of New Drug Application to the U.S. Food and Drug Administration and Submits Marketing Authorization Application to the European Medicines Agency for Lumasiran for the Treatment of Primary Hyperoxaluria Type 1

CAMBRIDGE, Mass.–(BUSINESS WIRE)– April 07, 2020 — Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced the completion of the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for lumasiran, an investigational RNAi therapeutic targeting glycolate oxidase (GO), in development for the treatment of primary hyperoxaluria type 1 (PH1). PH1 is an ultra-rare, life-threatening disease impacting the kidneys and other vital organs; it affects infants, children, and adults.

In the U.S., lumasiran has previously received Pediatric Rare Disease Designation, Orphan Drug Designation, and Breakthrough Therapy Designation for the treatment of PH1, based on data showing a substantial reduction in urinary oxalate, the key toxic metabolite responsible for the clinical manifestations of the disease.

The Company also announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for lumasiran for the treatment of PH1. Lumasiran has been granted Priority Medicines (PRIME) Designation by the EMA as well as Orphan Drug Designation in the European Union. Lumasiran has also been granted an accelerated assessment by the EMA which is awarded to medicines deemed to be of major public health interest and therapeutic innovation. Accelerated assessment potentially provides a reduced review timeline from 210 to 150 days once the MAA is filed and validated.

“PH1 can affect people of all ages, from infants, to children, to adults, as well as their families and those who care for them. PH1 causes a progressive decline in kidney function and can lead to end-stage renal disease, at which point patients need intensive dialysis until they are able, and eligible, to receive dual liver/kidney transplantation,” said Pritesh J. Gandhi, PharmD., Vice President and General Manager, Lumasiran Program at Alnylam. “Given the unmet need in PH1 and the encouraging lumasiran Phase 3 data, Alnylam maintained its commitment to meet our target dates for timely NDA and MAA submissions, even under the challenging prevailing circumstances. We now look forward to working closely with the FDA and EMA to bring this innovative medicine to patients and their families.”

Topline data from the pivotal ILLUMINATE-A Phase 3 study show that lumasiran met its primary efficacy endpoint and all tested secondary endpoints. Specifically, lumasiran met the primary efficacy endpoint of percent change from baseline, relative to placebo, in 24-hour urinary oxalate excretion averaged across Months 3 to 6 (p value less than 0.0001). Epidemiological data show a strong relationship between urinary oxalate reduction and long-term kidney function loss. The study also achieved statistically significant results for all six tested secondary endpoints (p value less than or equal to 0.001), including the proportion of patients achieving a near-normalization or normalization of urinary oxalate, relative to placebo. Lumasiran demonstrated an encouraging safety and tolerability profile consistent with previous reports from earlier studies.

Complete results from the ILLUMINATE-A study included as part of the FDA rolling submission and EMA filing applications are planned to be presented at the OxalEurope International Congress, currently scheduled for June 16, 2020 in Amsterdam.

About Lumasiran

Lumasiran is an investigational, subcutaneously administered RNAi therapeutic targeting glycolate oxidase (GO), in development for the treatment of primary hyperoxaluria type 1 (PH1). GO is encoded by the hydroxyacid oxidase 1 (HAO1) gene. Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables quarterly subcutaneous maintenance dosing with increased potency and durability and a wide therapeutic index. Lumasiran has received both U.S. and EU Orphan Drug Designations, a Breakthrough Therapy Designation and pediatric rare disease designation from the U.S. Food and Drug Administration (FDA), and a Priority Medicines (PRIME) designation from the European Medicines Agency (EMA). The safety and efficacy of lumasiran have not been evaluated by the FDA, EMA or any other health authority.

About the ILLUMINATE-A Phase 3 Study

ILLUMINATE-A (NCT03681184) is a randomized, double-blind, placebo-controlled trial, designed to enroll approximately 30 patients with PH1 ages six and above, at 16 study sites, in eight countries around the world. To date, this is the largest interventional study conducted specifically in PH1. Patients were randomized 2:1 to lumasiran or placebo, with lumasiran administered at 3 mg/kg monthly for three months followed by quarterly maintenance doses. The primary endpoint for the study was the percent change from baseline in 24-hour urinary oxalate excretion averaged across Months 3 to 6 in patients treated with lumasiran as compared to placebo. At six months, lumasiran met the primary endpoint in patients with PH1 (p value less than 0.0001) and achieved statistically significant results for all six hierarchically-tested secondary endpoints (p value less than or equal to 0.001), including the proportion of lumasiran patients that achieved near-normalization or normalization of urinary oxalate levels, relative to placebo.

There were no serious or severe adverse events in the study, and results showed that lumasiran was generally well tolerated with an overall safety profile generally consistent with that observed in Phase 1/2 and open-label extension studies of lumasiran. Full ILLUMINATE-A study results will be presented in 2020.

About Primary Hyperoxaluria Type 1 (PH1)

PH1 is an ultra-rare disease in which excessive oxalate production results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a minority of patients are fully responsive to Vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.

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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its “Alnylam 2020” strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA.

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 implications of the positive topline results from the ILLUMINATE-A study, the submissions of an MAA to the EMA and an NDA to the FDA, the potential for a reduced review timeline by the EMA, as well as the pediatric rare disease designation for lumasiran from the FDA, and expectations regarding the continued execution on its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics, 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: potential risks to Alnylam’s business, activities and prospects as a result of the COVID-19 pandemic, or delays or interruptions resulting therefrom; 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, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its expected range during 2020; Alnylam’s ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam’s and others developing products for similar uses; Alnylam’s ability to manage its growth and operating expenses within the ranges of its expected guidance and achieve a self-sustainable financial profile in the future, obtain additional funding to support its business activities, and establish and maintain strategic business alliances and new business initiatives; Alnylam’s dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, and Ironwood, for assistance with the education about and promotion of GIVLAARI; 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 other filings that Alnylam makes with the SEC. 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.

Source: Alnylam Pharmaceuticals, Inc.

Posted: April 2020

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