Alnylam drops early filing plan for porphyria drug givosiran

Alnylam says it will wait for the final results of a phase 3 trial of acute hepatic porphyria (AHP) drug givosiran before filing, rather than pressing ahead on the strength of interim results.

The gene-silencing specialist revealed last month that it was considering regulatory submissions based on an early readout of biomarker data from the ENVISION trial, but after discussions with the FDA now says it will wait for data on porphyria attack rates due next year. A "rolling" application will start before year-end with the outcomes data added in later, likely in mid-2019.

The earlier results showed the ALAS1-targeted RNAi drug was able to cut urinary aminolevulinic acid levels, which Alnylam reckons is a predictor of clinical benefit, but it looks like the FDA wants to see hard evidence before it will start a regulatory review, setting the program back by a few months. There was also one case of elevated liver enzymes in the initial data set, which could also explain the agency’s caution.

Nevertheless—assuming the attack data turn out as hoped—Alnylam could still be looking at U.S. approval in the first half of 2020 for givosiran, which has a breakthrough designation and so will have an expedited review. Shares dipped only marginally in premarket trading after news of the new plan emerged.

“The AHPs are devastating diseases and our goal is to help address the significant unmet need that exists today for people living with AHP,” says Akin Akinc, Ph.D., who heads up the givosiran program at Alnylam. “This filing plan creates the potential to achieve full approval as rapidly as possible and aligns with our strategy in all other countries.”

AHPs are a collection of rare diseases that affect the liver, causing the accumulation of neurotoxic compounds that in turn precipitate debilitating attacks that can be disabling and in some cases life-threatening. There are no approved treatments, and Alnylam estimates there are about 1,000 patients with regular, severe attacks in the U.S., plus another few thousand with less severe forms.

Alnylam is still riding high after claiming the first-ever FDA approval for an RNAi drug, getting a green light for hereditary ATTR amyloidosis therapy Onpattro (patisiran) and, despite the delay, givosiran is still on course to become the next product to emerge from its late-stage pipeline.

Alnylam said after it reported the interim data last month that it was possible the FDA would hold off for primary endpoint data, and in an earlier research note analysts at Cowen suggested this would not change givosiran’s “approvability or its chances of commercial success.”