Alnylam’s givosiran met its primary endpoint in a phase 3 study in the rare liver disease acute hepatic porphyria. In addition to reducing the rate of porphyria attacks over placebo, the ALAS1-targeting RNAi treatment also hit the majority of its secondary endpoints. The company will file a rolling NDA for givosiran in mid-2019.
The study enrolled 94 patients with acute hepatic porphyria (AHP), half of whom randomized to receive givosiran, with the other half on placebo, the company said in a statement. Specifically, givosiran outperformed placebo at reducing the annualized rate of composite porphyria attacks, that is, those that required hospitalization, an urgent healthcare visit, or an administration of hemin, which is used to treat porphyria attacks.
Givosiran also met five of its nine secondary endpoints, including several specific to patients with acute intermittent porphyria, the most common subset of AHP. It did not meet statistical significance for the remaining secondary endpoints: daily worst fatigue, daily worst nausea, daily worst fatigue and the physical health component of a quality-of-life survey.
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Though givosiran’s efficacy looked “robust,” its safety profile was “materially worse than expected,” wrote Leerink analysts Mani Foroohar and Rick Bienkowski. Adverse events occurred at roughly the same rate in both groups—90% of givosiran patients and 80% of placebo patients—but serious adverse events affected the givosiran group at nearly double the rate of the placebo group: 21% versus 9%.
“While these patients have baseline liver disease, and can be attributable to some of the underlying safety events, the more than double SAEs exhibited in the treatment arm compared to placebo could be signs of a safety signal,” the analysts wrote.
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Alnylam once set its sights on filing an accelerated approval for givosiran, thanks to strong interim data unveiled late last year. But a month later, the company revised its schedule, deciding to wait for final results before filing the NDA.
“Assuming favorable regulatory review, we very much look forward to adding givosiran as the second product in our global commercialization efforts. Indeed, we believe today’s news brings us one important step closer to meeting our Alnylam 2020 goals of building a multi-product, global commercial company with a deep clinical pipeline for continued growth and a robust product engine for sustainable innovation,” said Alnylam CEO John Maraganore, in the statement.