RARE Daily

Alnylam Reports Positive Results from Phase 3 Study of PH1 in Kids

September 30, 2020

Rare Daily Staff

Alnylam Pharmaceuticals reported positive topline results from the ILLUMINATE-B pediatric phase 3 study of lumasiran for the treatment of primary hyperoxaluria type 1 in children under six years of age.

Primary hyperoxaluria type 1 (PH1) is an ultra-rare disease in which excessive oxalate production 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 and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. As the excess oxalate can no longer be effectively excreted, it accumulates and crystallizes in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a few patients respond to vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.

Lumasiran is an experimental, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in development for the treatment of PH1. HAO1 encodes glycolate oxidase (GO). By silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology of PH1.

ILLUMINATE-B is the seventh phase 3 study of an RNAi therapeutic that has yielded positive results, and the first-ever study evaluating the safety and efficacy of this new class of medicines in children under the age of six, including infants. Topline results demonstrate a clinically significant reduction in urinary oxalate levels relative to baseline in children as young as four months old.

“The safety and efficacy of lumasiran are consistent with that reported for the ILLUMINATE-A study in patients six and older, demonstrating that lumasiran can significantly reduce the hepatic production of oxalate across all ages, which we believe can thereby address the underlying pathophysiology of PH1,” said Pritesh Gandhi, vice president and general manager, Lumasiran Program at Alnylam. “The current standard of care for young children and infants diagnosed with PH1 is burdensome, including the frequent need for gastrostomy tube placement to enable hyperhydration, and, for those who have progressed to advanced disease, the risks associated with performing dialysis and, ultimately, organ transplantation. Thus, we believe, a meaningful reduction in urinary oxalate levels has the potential to favorably impact disease progression and management in very young patients.”

ILLUMINATE-B is a single arm, open-label, multicenter phase 3 trial that enrolled 18 patients with PH1 under the age of six (range: 3-72 months), with an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2 or normal serum creatinine if less than 12 months old, at nine study sites, in five countries around the world. Lumasiran was administered according to a weight-based dosing regimen. 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.

At six months, relative to baseline, lumasiran demonstrated a clinically meaningful reduction in spot urinary oxalate:creatinine ratio. Reduction of urinary oxalate relative to baseline was consistent across all three body weight categories (less than 10 kg; 10 kg to less than 20 kg, and 20 kg or higher). Lumasiran demonstrated positive results across secondary endpoints, including additional measures of urinary and plasma oxalate. There were no serious or severe adverse events related to study drug, and the overall safety and tolerability profile of lumasiran was consistent with that observed in the ILLUMINATE-A study. Full ILLUMINATE-B study results will be presented at the American Society of Nephrology virtual congress in late October.

“The ILLUMINATE-B results signal hope for the many families with children whose lives are deeply impacted by PH1. This is especially encouraging given that children as young as a few months old could benefit from the therapeutic approach that lumasiran offers, curbing production of oxalate at its source,” said Kim Hollander, executive director of the Oxalosis and Hyperoxaluria Foundation.

Lumasiran has received U.S. and EU Orphan Drug designations, Breakthrough Therapy and Rare Pediatric Disease designations from the U.S. Food and Drug Administration, and a Priority Medicines (PRIME) designation from the European Medicines Agency. Alnylam has filed a New Drug Application for lumasiran with the FDA, for which it has been granted Priority Review with an action date of December 3, 2020 under the Prescription Drug User Fee Act. In addition, an application to market lumasiran has been submitted to and validated by the EMA and has received Accelerated Assessment designation.

Alnylam is also conducting ILLUMINATE-C, a global single-arm phase 3 study of lumasiran in PH1 patients of all ages with advanced renal disease, including patients on dialysis, with results expected in 2021.

Photo: Kim Hollander, executive director of the Oxalosis and Hyperoxaluria Foundation.


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