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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

– OXLUMO is the First Therapeutic Approved for the Treatment of PH1, and the Only Therapy Proven to Lower Harmful Oxalate Levels that Drive the Progression of PH1 Disease – CAMBRIDGE, Mass.--(BUSINESS

· 11/19/2020 07:05

– OXLUMO is the First Therapeutic Approved for the Treatment of PH1, and the Only Therapy Proven to Lower Harmful Oxalate Levels that Drive the Progression of PH1 Disease –

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- 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:

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