FDA Approves Oxlumo

FDA Approves Oxlumo (lumasiran) for the Treatment of Primary Hyperoxaluria Type 1

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Nov. 24, 2020-- Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, announced today that the U.S. Food and Drug Administration (FDA) approved Oxlumo (lumasiran) injection for subcutaneous use, the first-ever therapy available for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. PH1 is an ultra-rare genetic disease characterized by oxalate overproduction. The excess production of oxalate 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, nephrocalcinosis, progression to kidney failure, and systemic organ dysfunction. In ILLUMINATE-A – the largest controlled Phase 3 study ever conducted in PH1 – Oxlumo was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients achieving normal1 or near-normal2 levels. Oxlumo demonstrated an encouraging safety and tolerability profile, with injection site reactions (ISRs) as the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, the safety and efficacy of Oxlumo were demonstrated in patients under the age of six, and results showed reduction of urinary oxalate and an overall safety and tolerability profile consistent with that demonstrated in ILLUMINATE-A.

“The approval of Oxlumo is a further testament to the impact RNAi therapeutics can have in transforming the treatment of severe, life-threatening diseases like PH1. Results from the ILLUMINATE-A and ILLUMINATE-B studies demonstrate that Oxlumo addresses the underlying pathophysiology of PH1 in adults, children and infants, and we believe this newly approved medicine has the potential to change the course of this progressive disease,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “Oxlumo marks our third FDA approval in less than three years, positioning us to meet or exceed our Alnylam 2020 strategy and goals, and further highlighting the productivity of our RNAi platform and the speed at which we can bring innovative medicines to patients. For patients and families impacted by PH1, this is an historic moment, as Oxlumo represents the first, targeted therapeutic option available to them. We are grateful to all the investigators, staff and patients who participated in the ILLUMINATE clinical studies, and to their families, caregivers and patient advocates. This moment is what we all had hoped for.”

The FDA approval of Oxlumo was primarily based on positive results from the randomized, double-blind, placebo-controlled ILLUMINATE-A Phase 3 study, with results presented in June 2020 at the 57th European Renal Association – European Dialysis and Transplant Association Virtual Congress. The FDA also took into consideration positive interim results from the single-arm, open-label ILLUMINATE-B Phase 3 pediatric study. Primary analysis results from the ILLUMINATE-B study were presented in October 2020 at the virtual American Society of Nephrology Annual Congress.

In ILLUMINATE-A, the efficacy and safety of Oxlumo were evaluated in 39 patients ages six and older with relatively preserved renal function (estimated glomerular filtration rate [eGFR] at or above 30 mL/min/1.73m2) and a documented diagnosis of PH1. The study, conducted in eight countries around the world, is the largest interventional study conducted specifically in PH1. Patients were randomized 2:1 to receive three monthly doses of Oxlumo or placebo at 3 mg/kg followed by a quarterly dosing regimen. The study showed that Oxlumo met its primary endpoint, percent change in 24-hour urinary oxalate (corrected for body surface area and averaged from months three to six). Specifically, treatment with Oxlumo resulted in a 65 percent mean reduction in urinary oxalate relative to baseline versus 12 percent reduction reported in response to placebo, resulting in a mean treatment difference of 53 percent relative to placebo (p=1.7x10-14). In addition, Oxlumo achieved statistically significant results for all six tested secondary endpoints, including the proportion of patients achieving urinary oxalate levels at or below upper limit of normal1 (13/25 patients or 52 percent; p=0.001) and at or below 1.5x upper limit of normal2 (21/25 patients or 84 percent; p=8.3 x 10-7), compared with none (0/13) of the patients receiving placebo. During the primary analysis period, Oxlumo demonstrated an encouraging safety and tolerability profile, with no serious or severe adverse events. The most common adverse reaction was ISRs (reported in at least 20 percent of patients); ISRs occurred at various time points during the study period and included erythema, pain, pruritus, and swelling. These symptoms were generally mild and resolved within one day of the injection and did not lead to discontinuation of treatment.

In ILLUMINATE-B, a study in PH1 patients under the age of six with relatively preserved renal function (eGFR above 45 mL/min/1.73m2), Oxlumo was evaluated in 18 patients during the primary analysis, including infants as young as three months old. It was administered according to a weight-based dosing regimen across three body weight categories (less than 10 kg; 10 to less than 20 kg, and 20 kg or higher). In the primary analysis, Oxlumo demonstrated a 72 percent mean reduction in spot urinary oxalate:creatinine ratio from baseline to month six (averaged from months three to six) – the primary endpoint of the study. The reduction of oxalate was consistent across all three body weight categories. In addition, Oxlumo demonstrated positive results across secondary endpoints, including additional measures of oxalate. There were no serious or severe adverse events related to study drug, and the overall safety and tolerability profile of Oxlumo was consistent with that observed in the ILLUMINATE-A pivotal study.

“PH1 patients experience progressive and often inevitable decline in kidney function. As the disease advances, so does the risk of end-stage kidney disease and systemic spread of oxalate beyond the kidneys endangering other organs, including the eyes, bones, skin and heart. This condition, systemic oxalosis, leads to multi-organ dysfunction and death. The age of onset, rate of disease progression, and associated clinical manifestations can vary significantly from patient to patient, even among members of the same family, making PH1 a particularly challenging condition to diagnose and treat. Until today, there had been no approved nonsurgical treatment options available that curb oxalate overproduction in patients with PH1, with liver transplantation being the only preemptive treatment approach to address the underlying metabolic defect in these patients,” said Jeffrey M. Saland, M.D., Professor and Chief, Pediatric Nephrology and Hypertension, Jack and Lucy Clark Department of Pediatrics, Mount Sinai Kravis Children’s Hospital, New York City and Investigator on the ILLUMINATE-A trial. “The consistent efficacy and safety profile of Oxlumo demonstrated in the ILLUMINATE-A and -B trials both in adults and children from as young as a few months old, combined with an infrequent dosing regimen that leads to rapid and sustained reduction of oxalate production, make Oxlumo an attractive therapeutic option to reduce the oxalate burden responsible for the severe clinical manifestations that individuals suffer due to PH1.”

“Many people impacted by PH1 face persistent anxiety related to the unpredictable nature of their condition, in terms of the uncertainty of how quickly their disease may progress, and the prospect of needing intensive dialysis and a kidney/liver transplant that threaten their physical, emotional and financial health,” said Kim Hollander, Executive Director of the Oxalosis and Hyperoxaluria Foundation. “The FDA approval of Oxlumo represents a new path forward for many, providing an effective treatment option and a sense of hope.”

“PH1 has had a profound impact on my son’s life from a physical, emotional and social standpoint. As a young boy, it has been draining for him to be constantly in pain, live through countless kidney stones – experiencing them on a regular basis – have limited control of his body, miss out on school and not be able to participate in sports,” said Amy Bowders, the mother and caregiver of a 12-year old boy diagnosed with PH1. “With the approval of Oxlumo, we are truly hopeful and optimistic about the future for patients affected by PH1.”

Oxlumo is expected to be available for shipment to healthcare providers in the U.S. by year-end. HCPs can initiate the process now by visiting www.AlnylamAssist.com and completing and submitting a Start Form.

Oxlumo was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease Designations. With the approval of Oxlumo, the FDA has granted Alnylam a pediatric rare disease priority review voucher that entitles the Company to designate a single new drug application to qualify for a priority review in the future. On November 19, the European Commission granted marketing authorization for Oxlumo for the treatment of PH1 in all age groups, following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP). Lumasiran was previously granted Priority Medicines (PRIME) Designation by the European Medicines Agency (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.

The safety and efficacy of Oxlumo are also being evaluated in the ongoing ILLUMINATE-C Phase 3 clinical trial in patients of all ages with advanced PH1, including patients on dialysis. Together, the ILLUMINATE studies comprise a comprehensive clinical development program intended to demonstrate the safety and efficacy of Oxlumo across the full spectrum of patients diagnosed with PH1.

Visit OXLUMO.com for more information, including full Prescribing Information.

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)

IMPORTANT SAFETY INFORMATION

Adverse Reactions
The most common adverse reaction that occurred in patients treated with Oxlumo was injection site reaction (38%). Symptoms included erythema, pain, pruritus, and swelling.

Pregnancy and Lactation
No data are available on the use of Oxlumo in pregnant women. No data are available on the presence of Oxlumo in human milk or its effects on breastfed infants or milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Oxlumo and any potential adverse effects on the breastfed child from Oxlumo or the underlying maternal condition.

For additional information about Oxlumo, please see the full Prescribing Information.