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Alnylam Receives Positive CHMP Opinion for OXLUMO™ (lumasiran) for the Treatment of Primary Hyperoxaluria Type 1 in All Age Groups

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of lumasiran, an investigational RNAi therapeutic targeting the hydroxyacid oxidase 1 (HAO1) mRNA – encoding glycolate oxidase (GO) – in development for the treatment of primary hyperoxaluria type 1 (PH1). If approved by the European Commission (EC), lumasiran will be marketed in Europe under the brand name OXLUMO™.

PH1 is an ultra-rare orphan disease characterized by excessive oxalate production, which can lead to end-stage renal disease (ESRD) and other systemic complications. PH1 affects approximately 3.5 to 4 individuals per million in Europe and the United States. Heterogeneity in disease manifestation often contributes to delays in diagnosis, with a median time to diagnosis of approximately six years. PH1 leads to progressive kidney damage, and patients with advanced kidney disease require intensive dialysis to help filter waste products from their blood until they are able and eligible to receive a dual or sequential liver/kidney transplant, an invasive procedure associated with a high risk of morbidity and mortality, and life-long immunosuppression.

“This positive CHMP opinion recognizes the potential of OXLUMO to address the urgent unmet need that exists for patients of all ages impacted by primary hyperoxaluria type 1. Since there are no approved pharmacologic treatment options for PH1, we believe this is very encouraging news for those living with this ultra-rare, potentially life-threatening disease and for their families,” said Brendan Martin, Acting Head of Europe, Canada, Middle East and Africa (CEMEA), Alnylam Pharmaceuticals.

“People living with PH1 experience a progressive decline in kidney function due to the overproduction of oxalate, which can lead to end-stage renal disease. Current treatment approaches aim to delay progression to renal failure but do not prevent oxalate overproduction,” said Pushkal Garg, M.D., Chief Medical Officer, Alnylam Pharmaceuticals. “In clinical trials, OXLUMO has demonstrated clinically meaningful and sustained reductions in urinary and plasma oxalate, and an encouraging safety and tolerability profile. We’re pleased that the CHMP has recognized the urgent need for new treatments across all age groups with inclusion of the ILLUMINATE-B results for the initial approval recommendation.”

The positive opinion is based on efficacy and safety findings of OXLUMO in PH1 patients, including data from both the ILLUMINATE-A and ILLUMINATE-B Phase 3 studies. Key primary and secondary endpoints included the reduction of urinary and plasma oxalate, and the proportion of patients achieving normalization or near-normalization of urinary oxalate in response to OXLUMO relative to placebo. Findings from the ILLUMINATE-A pivotal study were presented in June 2020 at the virtual European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress. Topline results from the ILLUMINATE-B pediatric study were reported in September; results from the primary analysis will be presented at the upcoming virtual American Society of Nephrology (ASN) Annual Congress on October 22.

OXLUMO was granted Priority Medicines (PRIME) designation by the EMA as well as Orphan Designation in the European Union. OXLUMO was also granted an Accelerated Assessment by the EMA, which is awarded to medicines deemed to be of major public health interest and therapeutic innovation and is designed to bring new treatments to patients more quickly. Alnylam filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA). The FDA has granted a Priority Review for the NDA and has set an action date of December 3, 2020 under the Prescription Drug User Fee Act (PDUFA).

About OXLUMO™ (lumasiran)

OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) in all age groups. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1. OXLUMO works by degrading HAO1 messenger RNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate – the toxic metabolite responsible for the clinical manifestations of PH1. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. Injection site reactions (ISRs) were the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology designed to increase potency and durability. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly at a dose based on actual body weight. For patients who weigh less than 10 kg, maintenance dosing remains monthly. OXLUMO should be administered by a healthcare professional. The safety and efficacy of OXLUMO are under evaluation by the FDA.

About ILLUMINATE-A Phase 3 Study

ILLUMINATE-A (NCT03681184) is a six-month randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study (with a 54-month extension period) to evaluate the efficacy and safety of lumasiran in 39 patients, age six and older, with a documented diagnosis of PH1. Patients were randomized 2:1 to receive three monthly doses of lumasiran or placebo followed by quarterly maintenance doses at 3 mg/kg. The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to the average of months 3 to 6 in the patients treated with lumasiran as compared to placebo. Treatment arms were stratified at randomization based upon mean 24-hour urinary oxalate during screening (≤ 1.7 or > 1.7 mmol/24hr/1.73m2). Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate (eGFR), nephrocalcinosis, renal stone events, safety and tolerability.

About ILLUMINATE-B Phase 3 Study

ILLUMINATE-B (NCT03905694) is a six-month, single arm, open-label, multicenter Phase 3 trial (with a 54-month extension period) that enrolled 18 patients with PH1 under the age of six. Lumasiran was administered according to a weight-based dosing regimen. Patients below 10 kg of body weight received three monthly loading doses of lumasiran at 6 mg/kg followed by monthly maintenance doses at 3 mg/kg; patients at or above 10 kg but lower than 20 kg of body weight received three monthly loading doses at 6 mg/kg followed by quarterly maintenance doses; patients above the 20 kg body weight received three monthly loading doses at 3 mg/kg followed by quarterly maintenance doses. The primary efficacy endpoint of the study was the percent change from baseline to Month 6 in spot urinary oxalate:creatinine ratio averaged across Months 3 to 6. Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate (eGFR), nephrocalcinosis, renal stone events, safety, and tolerability.

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 small minority of patients respond 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 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 (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., Brazil 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 safety and efficacy of lumasiran as demonstrated in the ILLUMINATE-A and ILLUMINATE-B Phase 3 studies and the potential for lumasiran to meet urgent unmet needs of PH1 patients across all age groups and have a favorable impact on PH1 disease manifestations, Alnylam’s expectations regarding the implications of the positive opinion recommending approval of lumasiran by the CHMP and the timeline for the potential approval of lumasiran by the EC following the positive CHMP opinion, [Alnylam’s expectations with respect to the review timeline for the lumasiran NDA by the FDA], Alnylam’s plans, assuming regulatory approvals, to bring lumasiran to patients with PH1 around the world, 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: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam’s business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam’s ability to execute business continuity plans to address disruptions caused by the COVID-19 or any future 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, 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 revised 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 guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to 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, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; 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 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.

Contact information

Alnylam Pharmaceuticals, Inc.
Fiona McMillan
(EU & Canada Head of Communications)
+44 7741655570

Christine Regan Lindenboom
(Investors and Media)
+1-617-682-4340

Josh Brodsky
(Investors)
+1-617-551-8276

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