Alnylam Reports Positive Early Results of Phase 3 PH1 Study

Alnylam reported positive data from a 12-month analysis of its phase 3 ILLUMINATE-A study of Oxlumo to treat the ultra-rare kidney disease primary hyperoxaluria that showed improvements in nephrocalcinosis, a key indicator of disease progression in primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is characterized by oxalate overproduction in the liver. The excess 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 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. PH1 is associated with a progressive decline in kidney function, which exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and deposition of oxalate in bones, eyes, skin, and heart, leading to severe illness and death. PH1 is an ultra-rare genetic disease that affects an estimated one to three individuals per million in the United States and Europe.

Oxlumo is the first-ever treatment approved for PH1 in both children and adults. It is an RNAi therapeutic targeting hydroxyacid oxidase 1, the gene encoding glycolate oxidase. 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.

Among 24 patients in ILLUMINATE-A who had been treated with lumasiran for 12 months and had valid renal ultrasounds at baseline, 46 percent of patients experienced improvement in nephrocalcinosis grade relative to baseline, 17 percent remained stable, and 13 percent experienced worsening. A total of 25 percent did not have ultrasounds available at 12 months.

Of 14 patients with baseline nephrocalcinosis and available ultrasounds, 79 percent showed improvement relative to baseline, and of those who improved, 73 percent improved in both kidneys.

Injection site reactions were the most common drug-related adverse reaction.

“These early data provide emerging evidence demonstrating improvements in nephrocalcinosis in some patients,” said Pushkal Garg, chief medical officer at Alnylam. “Notably, the majority of patients with baseline nephrocalcinosis and available ultrasounds experienced improvement, often in both kidneys, after 12 months of treatment—an encouraging sign indicating the potential of OXLUMO to improve renal outcome measures in patients with PH1.”

Photo: Pushkal Garg, chief medical officer at Alnylam

Author: Rare Daily Staff