Alnylam phase 3 links lumasiran to 'clinically significant' improvement in infants

John Maraganore casual
Alnylam CEO John Maraganore (Alnylam)

A phase 3 trial has linked Alnylam’s lumasiran to a “clinically significant” decline in a substance that drives negative outcomes in children with a rare kidney disease. The top-line readout comes months before the FDA is due to rule on whether to approve the RNAi therapeutic in older patients. 

Lumasiran targets glycolate oxidase to counter the overproduction of oxalate that leads to kidney damage in patients with primary hyperoxaluria type 1 (PH1). Alnylam presented data from a phase 3 trial of the drug in PH1 patients aged six years and older late last year, setting it up to win approval in the population in the U.S. by the end of 2020.

In parallel, Alnylam has worked to show whether lumasiran works in PH1 patients aged under six years. Alnylam presented top-line findings from the phase 3 trial in infants and young children today.

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Investigators enrolled 18 subjects aged 3 to 72 months and gave them subcutaneous injections of lumasiran. After six months, investigators assessed whether lumasiran had driven a reduction in urinary oxalate excretion from baseline.

Alnylam said, “lumasiran demonstrated a clinically meaningful reduction in spot urinary oxalate:creatinine ratio” at six months. The statement to disclose the top-line findings lacks numbers or comments on statistical significance. Alnylam provided p-values when it disclosed top-line results from the study in older children and adults late last year.

A clearer picture of how well lumasiran works in infants and young children should emerge next month, when Alnylam plans to share the full results at the American Society of Nephrology's annual meeting. For now, Alnylam is free to shape the narrative.

“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,” Pritesh Gandhi, general manager of the lumasiran program, said in a statement.

However strong the data are, the trial represents another milestone for the nascent RNAi sector. The study marks the first time the safety and efficacy of an investigational RNAi therapeutic have been tested in such young children, according to Alnylam. Declines in oxalate levels were consistent across all weight categories, which started below 10 kg, and no patients suffered serious or severe adverse events related to the study drug.

The lack of safety red flags is a positive for the broader lumasiran program. Lumasiran is undergoing priority review in older patients at the FDA and following the accelerated assessment pathway in the EU. Alnylam is also running a third phase 3 in PH1 patients with advanced renal disease, including people on dialysis, that is scheduled to read out next year. 

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