Alnylam shores up enthusiasm for givosiran with early dataset ahead of crucial PhIII readout

In the run-up to top-line results from a crucial Phase III for its second RNAi drug, Alnylam has solidified an early set of safety and efficacy numbers for givosiran’s data package — part of a rolling submission at the FDA.

Results from the Phase I, which we first heard about last April, suggest that monthly injections of givosiran reduced the number of attacks in patients with acute hepatic porphyria by up to 79%, according to a new paper in the New England Journal of Medicine. The usage of hemin, an infusion currently used to treat these attacks, also dropped by 83% compared to placebo, the company added.

Source: NEJM

The key target here is the ALAS1 messenger RNA, or delta aminolevulinic acid synthase 1, which leads to accumulation of the toxic metabolites aminolevulinic acid (ALA) — believed to be the primary disease trigger — and porphobilinogen (PBG). That leads to “acute debilitating neurovisceral attacks and, in some patients, disabling chronic symptoms.”

Givosiran brought all of them to normal levels and kept it there, with a mean maximum reduction of over 90%.

While promising, these results will have to be borne out by the ongoing PhI/II open-label extension and Phase III studies, especially considering that the attack reduction data are based on 6 patients assigned to givosiran in one of three parts of this 40-patient study.

Part C of the trial also zeroed in on acute intermittent porphyria, “the most common subtype of AHP where patients experience recurrent, incapacitating, neurovisceral attacks requiring hospitalization or urgent medical attention,” according to Eliane Sardh of the Karolinska Institutet, the lead author of the NEJM paper.

In terms of safety — a historic concern for Alnylam’s RNAi drugs — investigators documented serious adverse events in 6 patients who received givosiran throughout the trial, including a fatal case of hemorrhagic pancreatitis considered unlikely related to the drug. Other common adverse effects include nasopharyngitis, abdominal pain and diarrhea.

“There was no clear difference in the proportion of patients who reported adverse events and severe adverse events between the placebo group and the givosiran group, and there was no clear relationship between givosiran dose and the incidence of adverse events,” the NEJM paper noted.

Assuming positive results in the Phase III, Alnylam aims to submit full clinical sections in mid-2019 for its rolling NDA after dropping earlier plans for an accelerated approval.

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Recursion Pharmaceuticals Salt Lake City, UT
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Atlas Venture Cambridge, MA

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