Treating the Untreatable, FDA Greenlights First-Ever PH1 Treatment


The U.S. Food and Drug Administration (FDA) approved Alnylam Pharmaceuticals’ Oxlumo (lumasiran) for primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in children and adults. PH1 is an ultra-rare genetic disease marked by overproduction of oxalate, which causes deposits of calcium oxalate crystals in the kidneys and urinary tract and can lead to painful and recurrent kidney stones, nephrocalcinosis, progression to kidney failure and system organ dysfunction. It is the first treatment ever approved for this indication.

There are only about 1,000 to 1,700 PH1 patients in the U.S. and Europe. Typically, it is children who suffer from the disease.

“PH1 affects patients of all ages,” said Sally-Anne Hulton, consultant pediatric nephrologist, Birmingham Women’s and Children’s Hospital NHS Trust, UK. “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.”

Norman Stockbridge, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, stated, “The approval of Oxlumo represents a great triumph of community involvement to address a rare disease. It is a result of input from patients, treating physicians, experts and sponsors at a patient-focused drug development meeting and through other collaborative efforts.”

Oxlumo decreases oxalate production. It is an RNA interference (RNAi) therapeutic. It works by degrading HAO1 mRNA and decreasing the synthesis of glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1.

In the ILLUMINATE-B pediatric Phase III trial, the drug demonstrated an efficacy and safety profile consistent to that in the ILLUMINATE-A trial in patients ages six and older with relatively preserved renal function and a documented diagnosis of PH1. The ILLUMINATE-A trial evaluated 39 patients who were randomized 2:1 to receive three monthly doses of Oxlumo or placebo followed by a quarterly dosing schedule. The drug hit the primary endpoint, percent change in 24-hour urinary oxalate. It demonstrated a 65% mean reduction in urinary oxalate relative to baseline compared to 12% in the placebo arm. This mean treatment difference was 53%. It also hit statistically significant results for all six secondary endpoints.

The company expects to have the drug available for physicians and patients in the U.S. by the end of the year. The drug was reviewed by the FDA under Priority Review. It had previously received Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease Designations.

In addition to the approval, the FDA granted Alnylam a pediatric rare disease priority voucher. This entitles Alnylam to designate a single New Drug Application (NDA) to qualify for priority review in the future. In some cases, companies sell these vouchers to other companies, depending on their priorities—early review or cash.

“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 PHA1,” said Akshay Vaishnaw, president of R&D for Alnylam. “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 disease.”

Oxlumo is the third therapy of Alnylam’s to be approved by the FDA in less than three years. Vaishnaw notes that it puts the company in position to meet or exceed its Alnylam 2020 strategy and goals and emphasizes the productivity of the company’s RNAi platform.


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