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Clinical Question
Is givosiran a safe and effective treatment for acute intermittent porphyria?
Bottom line
Givosiran is an effective treatment for acute intermittent porphyria, resulting in a large reduction in the number of attacks. However, it has potentially serious adverse effects in some patients that must be balanced against the benefit. This drug was recently approved by the US Food and Drug Administration, with Phase 4 trials underway. 1b
Reference
Study design: Randomized controlled trial (double-blinded)
Funding: Industry
Setting: Outpatient (any)
Synopsis
Givosiran is a drug that targets messenger RNA and prevents synthesis of delta aminolevulinic acid and porphobilinogen, which are central to causing attacks of acute intermittent porphyria. In this trial, 94 patients, 12 years and older, with acute hepatic porphyria were randomized to once-monthly subcutaneous injections with givosiran 2.5 mg/kg or matching placebo. Randomization was stratified by subtype of porphyria, previous use of hemin prophylaxis (which was discontinued during the trial), and high frequency versus low frequency of attacks. Allocation concealment is not mentioned. The mean age of participants was 39 years, 90% were women, approximately 40% were using prophylactic hemin, and participants were evenly split between those with high versus low numbers of attacks per year. Patients were followed up for 6 months, and all patients completed follow-up. Results are only reported for the 89 of 94 patients with the subtype of acute intermittent porphyria: the annualized attack rate was significantly lower in this group (3.2 vs 12.5 attacks per year; P < .001). Presumably because attacks were not normally distributed, the authors also report the median number of attacks, which were similarly reduced (1.0 vs 10.7). The percentage of patients who reported no attacks was also higher in the girovisan group (50% vs 17%; number needed to treat = 3; statistical significance not reported). A variety of secondary measures, such as quality of life and treatment satisfaction, were also improved. Serious adverse events, including worsening chronic kidney disease and elevation of hepatic transaminases levels, were more common in the treatment group (21% vs 9%). Injection site reactions (25% vs 0%) and nausea (27% vs 11%) were also more common in the givosiran group. This Phase 3 trial was funded, designed, analyzed, and written by the pharmaceutical company.
Reviewer
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA