Alnylam Pharmaceuticals announced positive Phase 3 results from the ILLUMINATE-A study of lumasiran, an investigational RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene encoding glycolate oxidase (GO) – in development for the treatment of primary hyperoxaluria type 1 (PH1).
The clinical data were presented at a late-breaking session at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress being held as a virtual event on June 6-9.
Lumasiran achieved the ILLUMINATE-A primary endpoint with a 53.5 percent mean reduction in urinary oxalate relative to placebo (p=1.7×10-14) and showed a 65.4 percent mean reduction in urinary oxalate relative to baseline. All tested study secondary endpoints were met, including the proportion of patients achieving near-normalization (84 percent) or normalization (52 percent) of urinary oxalate, compared with zero percent in the placebo group. Lumasiran administration was associated with an encouraging safety and tolerability profile, with no serious or severe adverse events (AEs) and with mild injection site reactions (ISRs) as the most common drug-related AE.
PH1 is an ultra-rare orphan disease caused by excessive oxalate production, and elevated urinary oxalate levels are associated with progression to end-stage kidney disease and other systemic complications.
Based on the ILLUMINATE-A results, Alnylam 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). In addition, the Marketing Authorisation Application (MAA) for lumasiran has been submitted to and validated by the European Medicines Agency (EMA), and has received Accelerated Assessment designation.
“We are very pleased to report positive Phase 3 results from the ILLUMINATE-A study of lumasiran. The substantial and sustained reductions in urinary and plasma oxalate reported demonstrate that lumasiran addresses the underlying pathophysiology of PH1 by reducing the production of the toxic metabolite responsible for the clinical manifestations of this serious and progressive disease. Thus, we believe lumasiran has the potential to have a favorable impact on disease manifestations, including nephrocalcinosis and renal stones, and overall disease progression, which we are continuing to evaluate in the ongoing ILLUMINATE program,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “The ILLUMINATE-A study represents the sixth positive Phase 3 study for an investigational RNAi therapeutic, and we believe it further highlights the transformational potential of this modality as a whole new class of medicines. Assuming favorable regulatory reviews, we look forward to bringing lumasiran to patients with PH1 around the world.”
“For those living with PH1, the continuous overproduction of oxalate can have a devastating impact on the kidneys and other organs. Current disease management strategies aim to lessen the damage to the kidneys, with liver transplantation as the only means to correct the metabolic deficiency and normalize the high oxalate production. As patients approach end-stage kidney disease, they may require intensive dialysis as a bridge to a dual liver/kidney transplant,” said Professor Jaap Groothoff, M.D., Ph.D., Head of the Department of Pediatric Nephrology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, The Netherlands. “Based on results from the ILLUMINATE-A study, lumasiran shows potential to substantially curb oxalate overproduction – the cause of progressive kidney failure in PH1. Reduction in hepatic oxalate production is expected to confer clinical benefit in PH1 patients and has the potential to change the course of disease.”
Efficacy Results
In the ILLUMINATE-A study (N=39), lumasiran met the primary efficacy endpoint of 24-hour urinary oxalate reduction from Month 3 to Month 6 (averaged across timepoints) relative to placebo and all tested secondary endpoints. Specifically, lumasiran treatment (N=26) in PH1 patients, aged six years and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73m2, resulted in 65.4 percent mean reduction in urinary oxalate relative to baseline, with a mean treatment difference of 53.5 percent relative to plac...
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