Molecular Genetics and Metabolism

In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. To describe the efficacy and safety of givosiran based on a personalized medical approach. We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient. • Givosiran sustained activity allows to reduce dosing frequency • Reduced dosing does not impair clinical or biological response to treatment • Givosiran is most effective when given early in the disease course • Givosiran is associated with severe hyperhomocysteinemia that responds to B6

Givosiran in acute intermittent porphyria: A personalized medicine approach