Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria

RCT (n=94) found givosiran, an RNA interference therapy that inhibits ALAS1 expression, linked to lower rate of porphyria attacks (3.2 vs. 12.5/yr; p<0.001); and better results for other disease manifestations vs. placebo, but higher frequency of hepatic and renal adverse events.

SPS commentary:

According to an editorial, despite the striking findings, some limitations remain, such as short follow-up of 6 months, considering this is a chronic disease, and the higher frequency of adverse events in the givosiran group is worrisome. It notes that the interpretation of the safety data is complicated by the fact that chronic kidney disease and liver damage are common coexisting illnesses and long-term complications of acute hepatic porphyria and these disorders may have been exacerbated by givosiran treatment. Other remaining questions include whether it will it be possible to predict which patients with this disorder will have serious adverse events and whether givosiran treatment should be restricted to patients with no previous history of chronic kidney disease or elevated liver-enzyme levels. It adds however that given the limited treatment options for patients with acute hepatic porphyria and the excellent therapeutic efficacy data observed in this trial, subcutaneous monthly administration of givosiran represents a very attractive option to replace intravenous hemin administration to reduce ALAS1 activity, but the collection and analysis of long-term data, together with a better understanding of givosiran-related toxic effects, are essential.


Both the Food and Drug Administration and the European Medicines Agency have recently approved givosiran for adults with acute hepatic porphyria, and the European Medicines Agency has approved the drug for adolescents 12 years of age or older.


New England Journal of Medicine

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