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Alnylam Receives Approval for OXLUMO™ (lumasiran) in the European Union for the Treatment of Primary Hyperoxaluria Type 1 in All Age Groups

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the European Commission (EC) has granted marketing authorization for OXLUMO™ (lumasiran), an RNAi therapeutic, for the treatment of primary hyperoxaluria type 1 (PH1) in all age groups.

PH1 is an ultra-rare orphan disease characterized by excessive oxalate production, which can lead to life threatening end-stage renal disease (ESRD) and other systemic complications. Heterogeneity in disease manifestation often contributes to delays in diagnosis – particularly in adult PH1 patients, with a median time from symptoms onset to diagnosis of approximately six years. Untreated PH1 leads to progressive kidney damage; patients with advanced kidney disease require intensive dialysis to help filter waste products, including oxalate, 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.

“Prior to now there have been no approved treatment options for PH1 in Europe, so this is a potentially life-changing milestone for people diagnosed with this ultra-rare, debilitating disease - many of whom are infants and children - and their families. Lumasiran will address the urgent unmet need that exists for patients with PH1 and its approval today marks our continued commitment to rare disease communities,” said John Maraganore, Ph.D., Chief Executive Officer, Alnylam Pharmaceuticals. “Alnylam has taken lumasiran from identification of compound to regulatory approval in just six years and we will progress with the same sense of urgency as we work with national reimbursement bodies across Europe to bring lumasiran to patients.”

Lumasiran is an RNAi therapeutic targeting the hydroxyacid oxidase 1 (HAO1) mRNA that encodes glycolate oxidase (GO) – an enzyme upstream of the disease-causing defect in PH1. By degrading the HAO1 mRNA and reducing the synthesis of GO, lumasiran stops the production of oxalate – the toxic metabolite that directly contributes to the clinical manifestations of PH1.

“PH1 affects patients of all ages. It is particularly devastating when infants are born with the condition and develop kidney failure within the first few months of life. PH1 patients develop kidney stones from the overproduction of oxalate, and in many we see a progressive decline in kidney function, which can ultimately lead to life-threatening end-stage kidney disease. Until recently the only treatment options available have been combined liver and kidney transplantation, with vitamin B6 slowing down kidney failure in a limited number of sensitive patients,” said Sally-Anne Hulton, M.D., Consultant Paediatric Nephrologist, Birmingham Women’s and Children’s Hospital NHS Trust, UK. “For the first time, lumasiran provides those of us treating PH1 children and adults with a new therapeutic option to tackle the root cause of this disease and prevent the production of oxalate. The data show meaningful and sustained reductions in urinary and plasma oxalate with an encouraging safety and tolerability profile, providing us with hope for improving care for these patients.”

“In line with our Patient Access Philosophy, Alnylam is committed to being as innovative commercially as we have been scientifically,” said Brendan Martin, Acting Head of CEMEA, Alnylam. “While the ability to enter into innovative agreements varies by country and local regulations, we intend to work with health authorities across Europe to achieve responsible and sustainable access arrangements for lumasiran that address the diverse patient population affected by PH1, which ranges from infants to adults, and we will adapt to the local context. Our goal is to ensure that all patients in need have access to lumasiran while minimizing budget uncertainty for health services.”

The approval in the European Union is based on efficacy and safety findings from both the ILLUMINATE-A and ILLUMINATE-B Phase 3 studies of lumasiran. In the ILLUMINATE-A study conducted in adults and children six years or older, lumasiran achieved the primary endpoint with a 53 percent mean reduction in urinary oxalate relative to placebo and showed a 65 percent mean reduction in urinary oxalate relative to baseline. Eighty-four percent of patients achieved normal1 or near-normal2 levels of urinary oxalate and more than half of patients (52 percent) reached normalization, compared to zero percent in the placebo group. 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. In the ILLUMINATE-B Phase 3 study, the efficacy results and safety profile of lumasiran in infants and children under the age of six years were found to be similar to those observed in ILLUMINATE-A. Results from the ILLUMINATE-B pediatric study were presented on October 22 at the virtual American Society of Nephrology (ASN) Annual Congress.

Lumasiran was granted Priority Medicines (PRIME) designation by the EMA as well as Orphan Designation in the European Union. Lumasiran 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. This approval in the European Union follows the positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2020. Alnylam has 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).

Footnotes:

1 Normal is defined as urinary oxalate levels at or below the upper limit of normal (ULN; ≤ 0.514 mmol/24 hr/1.73 m2 ).
2 Near-normal is defined as urinary oxalate levels at or below 1.5 x ULN (≤ 0.771 mmol/24 hr/1.73 m2 ).

About OXLUMO™ (lumasiran)

OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1 and lumasiran 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. Lumasiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology designed to increase potency and durability. In the pivotal ILLUMINATE-A study, lumasiran 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, lumasiran demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A. Lumasiran is administered via subcutaneous injection once monthly for three months, then once quarterly thereafter at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional.

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.

Important Safety Information

Contraindications

Severe hypersensitivity to lumasiran or any of the excipients.

Severe or end-stage renal impairment

Treatment with lumasiran increases plasma glycolate levels, which may increase the risk of metabolic acidosis or worsening of pre-existing metabolic acidosis in patients with severe or end‑stage renal disease. These patients should therefore be monitored for signs and symptoms of metabolic acidosis.

Moderate or severe hepatic impairment

In patients with moderate or severe hepatic impairment there is a potential for decreased efficacy. Therefore, efficacy should be monitored in these patients.

Adverse Reactions

The most common adverse reaction reported was injection site reaction (32%) and abdominal pain (21%).

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, GIVLAARI® (givosiran), approved in the U.S., EU, Brazil, and Canada, and OXLUMO™ (lumasiran) approved in the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. 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 prevent or inhibit oxalate over-production in PH1 patients, meet urgent unmet needs of PH1 patients across all age groups, and have a favorable impact on PH1 disease manifestations, Alnylam’s plans to progress with discussions and negotiations with national reimbursement bodies across Europe and intention to work with health authorities across Europe to achieve responsible and sustainable access arrangements for lumasiran that address the diverse patient population affected by PH1, and to adapt to local requirements, its goal to ensure that all patients in need have access to lumasiran while minimizing budget uncertainty for health services, 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 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 in other countries, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO, GIVLAARI and OXLUMO; progress in continuing to establish an ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO, GIVLAARI and OXLUMO, 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 product candidates, including eye and CNS product candidates, 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.

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