1. Among patients with acute intermittent porphyria (AIP), there was no difference in the proportion of any and serious adverse events reported between those treated with the RNA interference (RNAi) therapeutic agent givosiran and placebo, and no relationship between the dose of givosiran and adverse events.
2. In an exploratory analysis, givosiran reduced the neurotoxic intermediates (delta aminolevulinic acid [ALA] and porphobilinogen [PBG]) of heme biosynthesis and lowered rates of porphyria attacks.
Evidence Rating Level: 3 (Average)
Study Rundown: AIP is a life-threatening condition caused by a hydroxymethylbilane synthase (HMBS) gene mutation, which results in accumulation of neurotoxic intermediates of heme synthesis and leads to neurovisceral attacks. While no medications are approved for attack prevention, animal studies of the RNAi agent givosiran have demonstrated reductions in delta aminolevulinic acid synthase (ALAS1) messenger RNA (mRNA) – an enzyme in heme synthesis upstream from HMBS. This phase I trial was conducted to assess the safety, pharmacokinetic, and pharmacodynamic profiles of givosiran in patients with mutation-confirmed AIP. The authors found no significant difference in adverse events between patients treated with givosiran versus placebo, and no association between adverse events and givosiran dose. Pharmacokinetic results demonstrated dose-proportional efficacy of givosiran in reducing levels of ALAS1 mRNA, urinary ALA, and urinary PBG. As an exploratory end point, givosiran was associated with a lower annualized attack rate and need for hemin therapy. This trial supports the safety and potential efficacy of givosiran in acute intermittent porphyria and will lead to larger efficacy trials.
This was a phase I, multicenter, randomized, placebo-controlled trial that used dose escalation and multiple frequencies of drug administration to determine adverse events. The primary limitations of the study were its short duration and small sample population. Though an association between givosiran and a reduction in the frequency of attack rates was found, the trial was not designed to draw conclusions on efficacy and larger confirmation studies are required.
Click to read the study in NEJM
Relevant Reading: RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria in mice
In-Depth [randomized controlled trial]: This was a phase I trial conducted in three parts. Parts A and B enrolled 23 patients with confirmed HMBS mutations and urinary PBG levels greater than 4 mmol/mole of creatinine, and part B enrolled 17 patients with recurrent attacks. Part A randomized patients in a 3:1 ratio to a single subcutaneous injection of one of five ascending doses (0.035, 0.1, 0.35, 1.0, and 2.5 mg/kg) of givosiran or placebo. Part B randomized patients in a 3:1 ratio to once-monthly injections of one of two doses (0.35 or 1.0 mg/kg) of givosiran or placebo. After the run-in period, part C randomized patients in a 3:1 ratio to one of two doses of givosiran (n=13; 2.5 or 5.0 mg/kg) or placebo (n=4) once monthly or once quarterly during a 12-week period. The primary end points were adverse events, pharmacodynamic, and pharmacokinetic measurements. The effect of givosiran on rates of attacks and hemin in part C were exploratory end points.
The most common adverse events across parts A through C were abdominal pain, nausea, diarrhea, and nasopharyngitis. All adverse events were mild-to-moderate in parts A and B and similar between givosiran and placebo. In part C, all patients (givosiran and placebo) reported an adverse event and the rate of severe adverse events was similar in the placebo and combined givosiran groups. Five serious adverse events in three patients were reported in part C. Pharmacokinetic profiles demonstrated dose-proportional characteristics for givosiran. In part A, a single 2.5 mg/kg dose of givosiran reduced baseline ALAS1 mRNA by a maximum of 86±8%, ALA by a maximum of 91±3%, and PBG by a maximum of 96±1%. Reductions were similar in part B and sustained at day 70 in both cohorts. In part C, two once-quarterly injections of givosiran resulted in a maximum reduction of ALAS1 mRNA of 49±3% and 53±7% in the 2.5 mg/kg and 5.0 mg/kg groups, respectively, and four once-monthly injections resulted in maximum reductions of 67±3% and 74±6%, respectively. Regarding the exploratory end point, the mean annualized attack rate among patients receiving givosiran was 7.2 vs. 16.7 with placebo (57% difference) and the annualized number of hemin doses was 12.1 vs. 23.4 (48% difference).
Image: PD
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