Acute hepatic porphyrias are rare diseases. They are due to a deficiency of one of the enzymes involved in haem synthesis. Accumulation of neurotoxic haem precursors triggers serious attacks, with severe abdominal pain, often accompanied by neurological and psychiatric disorders. These attacks are a medical emergency and, without treatment, are sometimes fatal. The long-term complications are mainly renal, hepatic and neurological. The standard treatment for an attack is administration of hemin (in the form of haem arginate). Givosiran (Givlaari0, Alnylam), an interfering ribonucleic acid (RNA), reduces the synthesis of ALA synthase 1, an enzyme which produces haem precursors whose accumulation is toxic. The aim of treatment with this medication is to prevent accumulation of substrates of the deficient enzyme, and hence attacks of acute hepatic porphyria. A double-blind randomised trial compared givosiran versus placebo in 94 patients who had had at least two attacks of acute hepatic porphyria in the preceding six months. The trial lasted six months. The estimated mean annualised attack rate leading to hospitalisation, urgent medical consultation or administration of hemin was 3 attacks per patient in the givosiran group versus 12 attacks per patient in the placebo group (p<0.0001). 50 of patients in the givosiran group had no attacks during the trial, versus 17 of patients in the placebo group. It is not known whether givosiran prevents longterm complications. During the course of the trial, a serious adverse event was reported in 21 of patients in the givosiran group versus 9 of those in the placebo group.The most frequent adverse effects of givosiran were injection site reactions and hypersensitivity reactions. Givosiran also carries a risk of hepatic and renal disorders, including renal failure. Givosiran has a moderate inhibitory effect on some cytochrome P450 isoenzymes, notably CYP1A2 and CYP2D6. It is liable to increase the effects of substrates of these isoenzymes such as caffeine or dextromethorphan. No teratogenic action of givosiran was observed in studies of rats and rabbits. Fetal loss and fetal skeletal anomalies were reported following administration of givosiran to pregnant rabbits at toxic doses. No data are available on pregnant women. Before giving givosiran to a woman who is, or could become, pregnant, this information should be taken into account and weighed against the expected benefits. Givosiran is given by monthly subcutaneous injection. Its route and frequency of administration are simpler than those of hemin, which when used (off-label) to prevent porphyria attacks, requires one or several intravenous infusions per month.
展开▼
