With lumasiran on the FDA's doorstep, Alnylam reads out new PhIII data in PH1
Just over a month away from its December PDUFA date, Alnylam flaunted new data from two Phase III studies to back lumasiran in primary hyperoxaluria type 1 (PH1), a rare liver condition.
The Cambridge, MA-based biotech snagged a priority review for the candidate back in June, and got positive feedback from the EMA’s Committee for Medicinal Products for Human Use just last week. Lumasiran uses RNA interference (RNAi) to silence the gene for glycolate oxidase, an enzyme used in the production of oxalate.
On Thursday at this year’s ASN Kidney Week, Alnylam read out 6-month results from a study in children between 3 months and 6 years old, and 12-month results from a trial in patients older than 6 years.
In the latter study, dubbed ILLUMINATE-A, patients initially placed in the treatment arm were shown to maintain a reduction in 24-hour oxalate excretion, with a 64% mean reduction relative to baseline. Of this group, 88% achieved normal or near-normal urinary oxalate levels, according to Alnylam. Patients with PH1 tend to overproduce urinary oxalate, which potentially leads to kidney stones, or in some cases kidney failure at a young age.
Those who were initially in the placebo arm but crossed over to lumasiran showed a 57% mean reduction in 24-hour urinary oxalate excretion after 6 months of treatment, the company announced. About 77% of these patients reached normal or near-normal urinary oxylate levels.
Alnylam says there were no deaths, serious adverse events (SAEs), treatment interruptions or discontinuations linked to the drug. One patient experienced urosepsis, but the biotech said it was unrelated to the experimental candidate. Some patients experienced mild injection site reactions, including erythema, pain, pruritus, or swelling.
As for the pediatric study, ILLUMINATE-B, those in the treatment arm showed a 72% mean reduction in spot urinary oxalate to creatinine ratio from baseline, averaged across months 3 to 6, according to the biotech. Half of patients experienced normal or near-normal urinary oxalate levels.
A preliminary analysis also showed that 8 of 18 patients — about 44% — had improvements in nephrocalcinosis. At baseline, 14 patients experienced the disorder, characterized by too much calcium deposition in the kidneys. At the 6-month mark, no patients worsened, 10 remained stable, and 8 showed bilateral or unilateral improvements, Alnylam said.
The biotech reported no deaths, SAEs, discontinuations of treatment or withdrawals from the study. The efficacy and safety results, it said, were similar to those observed in ILLUMINATE-A. Like that study, one patient experienced an SAE that the biotech said wasn’t linked to the drug (in this case, a viral infection).
In an ongoing Phase II open-label extension study, researchers observed sustained reductions in urinary oxalate excretion and an “acceptable safety profile,” according to Alnylam. They also found that after long-term treatment, fewer patients had renal stones. Prior to the study, 6 of 20 patients reported renal stones. In the Phase I/II Part B study, 4 of 20 patients reported them. And during Phase II (with up to 22 months of treatment), no patients reported them, Alnylam said.
“Based on longer term follow-up from the ILLUMINATE-A and Phase 2 open-label extension studies, investigators presented data showing enduring reductions of urinary oxalate – the disease-causing metabolite in PH1. Moreover, we believe that newly presented results of exploratory endpoints provide preliminary evidence that reductions in urinary oxalate may lead to reduced rates of renal stone events and improve nephrocalcinosis in some patients,” Pritesh Gandhi, VP and general manager of the lumasiran program, summarized in a statement.
Around 2011, major companies like Pfizer and Abbott bailed from the RNAi field, eating heavy losses. But Alnylam CEO John Maraganore remained steadfast, pledging to bring 5 RNAi drugs into late-stage development by 2015.
If approved, lumasiran would be Alnylam’s third approved drug in the last three years. The biotech has two other RNAi drugs in late-stage development, including inclisiran (now partnered with Novartis), plus a label expansion for patisiran in the works. Seven other candidates are in early-stage development, including one for Covid-19.