Research & Development
US Food and Drug Administration Approves Oxlumo for Primary Hyperoxaluria Type 1 to Lower Urinary Oxalate Levels in Pediatric and Adult Patients
25 November 2020 - - The US Food and Drug Administration approved Oxlumo (lumasiran) injection for subcutaneous use, the first-ever therapy available for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels in pediatric and adult patients, US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) said.

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 normal or near-normal levels.

Oxlumo demonstrated an encouraging safety and tolerability profile, with injection site reactions 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 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% mean reduction in urinary oxalate relative to baseline versus 12% reduction reported in response to placebo, resulting in a mean treatment difference of 53% 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%; p=0.001) and at or below 1.5x upper limit of normal2 (21/25 patients or 84 %; p=8.3 x 10-7), compared with none 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% 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% 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.

Oxlumo is expected to be available for shipment to healthcare providers in the US 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.
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