20 October 2020 - - The Committee for Medicinal Products for Human Use of the European Medicines Agency has adopted a positive opinion recommending approval of lumasiran, an investigational RNAi therapeutic targeting the hydroxyacid oxidase 1 mRNA encoding glycolate oxidase in development for the treatment of primary hyperoxaluria type 1, US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) said.

If approved by the European Commission, lumasiran will be marketed in Europe under the brand name Oxlumo.

PH1 is an ultra-rare orphan disease characterized by excessive oxalate production, which can lead to end-stage renal disease and other systemic complications. PH1 affects approximately 3.5 to 4 individuals per m in Europe and the United States.

Heterogeneity in disease manifestation often contributes to delays in diagnosis, with a median time to diagnosis of approximately six years.

PH1 leads to progressive kidney damage, and patients with advanced kidney disease require intensive dialysis to help filter waste products 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.

The positive opinion is based on efficacy and safety findings of Oxlumo in PH1 patients, including data from both the ILLUMINATE-A and ILLUMINATE-B Phase 3 studies.

Key primary and secondary endpoints included the reduction of urinary and plasma oxalate, and the proportion of patients achieving normalization or near-normalization of urinary oxalate in response to Oxlumo relative to placebo.

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.

Topline results from the ILLUMINATE-B pediatric study were reported in September; results from the primary analysis will be presented at the upcoming virtual American Society of Nephrology Annual Congress on October 22.

Oxlumo was granted Priority Medicines (PRIME) designation by the EMA as well as Orphan Designation in the European Union.

Oxlumo 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.

Alnylam filed a New Drug Application with the US Food and Drug Administration. 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).

OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 for the treatment of primary hyperoxaluria type 1 in all age groups. HAO1 encodes glycolate oxidase, an enzyme upstream of the disease-causing defect in PH1.

Oxlumo 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.

In the pivotal ILLUMINATE-A study, Oxlumo 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 were the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, Oxlumo demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A.

Oxlumo utilizes Alnylam's Enhanced Stabilization Chemistry -GalNAc conjugate technology designed to increase potency and durability.

Oxlumo is administered via subcutaneous injection once monthly for three months, then once quarterly at a dose based on actual body weight.

For patients who weigh less than 10 kg, maintenance dosing remains monthly. Oxlumo should be administered by a healthcare professional. The safety and efficacy of Oxlumo are under evaluation by the FDA.

ILLUMINATE-A (NCT03681184) is a six-month randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study (with a 54-month extension period) to evaluate the efficacy and safety of lumasiran in 39 patients, age six and older, with a documented diagnosis of PH1.

Patients were randomized 2: 1 to receive three monthly doses of lumasiran or placebo followed by quarterly maintenance doses at 3 mg/kg.

The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to the average of months 3 to 6 in the patients treated with lumasiran as compared to placebo.

Treatment arms were stratified at randomization based upon mean 24-hour urinary oxalate during screening (≤ 1.7 or > 1.7 mmol/24hr/1.73m2).

Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate, nephrocalcinosis, renal stone events, safety and tolerability.

ILLUMINATE-B (NCT03905694) is a six-month, single arm, open-label, multicenter Phase 3 trial (with a 54-month extension period) that enrolled 18 patients with PH1 under the age of six.

Lumasiran was administered according to a weight-based dosing regimen. Patients below 10 kg of body weight received three monthly loading doses of lumasiran at 6 mg/kg followed by monthly maintenance doses at 3 mg/kg; patients at or above 10 kg but lower than 20 kg of body weight received three monthly loading doses at 6 mg/kg followed by quarterly maintenance doses; patients above the 20 kg body weight received three monthly loading doses at 3 mg/kg followed by quarterly maintenance doses.

The primary efficacy endpoint of the study was the percent change from baseline to Month 6 in spot urinary oxalate: creatinine ratio averaged across Months 3 to 6.

Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate, nephrocalcinosis, renal stone events, safety, and tolerability.