Clinical Pearls & Morning Reports
Acute hepatic porphyria is a family of rare genetic disorders that is caused by defects in heme biosynthesis enzymes. Acute intermittent porphyria is the most common subtype of this disorder and accounts for approximately 80% of all symptomatic cases. Balwani et al. conducted ENVISION, a double-blind, placebo-controlled, phase 3 trial that evaluated givosiran in patients with acute hepatic porphyria with ongoing attacks. Read the NEJM Original Article here.
Q: Describe characteristic features of the attacks associated with acute hepatic porphyria.
A: Attacks that occur in acute hepatic porphyria are more commonly seen in females and are characterized by severe, diffuse abdominal pain, along with muscle weakness, autonomic neuropathy (e.g., hypertension, tachycardia, nausea, vomiting, and constipation), and changes in mental status. Attacks typically warrant urgent medical attention and sometimes prolonged hospitalization and rehabilitation. Most symptomatic patients have only a few attacks in their lifetime, but up to 8% have recurrent attacks (defined in some cases as four or more attacks per year).
Q: What is the mechanism of action of givosiran?
A: In patients with acute hepatic porphyria, induction of hepatic delta-aminolevulinic acid synthase 1 (ALAS1) results in the accumulation of neurotoxic heme intermediates, including delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). The accumulation of ALA and possibly PBG causes injury to the nervous system and other organs, resulting in potentially life-threatening acute attacks and chronic disease manifestations. Givosiran is a subcutaneously administered RNA interference therapeutic targeting hepatic ALAS1 messenger RNA, thereby preventing the accumulation of ALA and PBG.
A: Of the 94 patients in the trial, 89 had acute intermittent porphyria. In patients with acute intermittent porphyria, the mean annualized rate of composite porphyria attacks over 6 months (the primary end point) was 3.2 (95% confidence interval [CI], 2.3 to 4.6) in the givosiran group and 12.5 (95% CI, 9.4 to 16.8) in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001). Levels of urinary ALA (at 3 and 6 months) and PBG (at 6 months) were significantly lower in the givosiran group than in the placebo group (P<0.001). The mean annualized number of days of hemin use was significantly lower in the givosiran group than in the placebo group at 6 months (6.8 days vs. 29.7 days, representing a 77% lower number in the givosiran group) (P<0.001). The worst daily pain score was significantly lower in the givosiran group than in the placebo group. There were no significant between-group differences in the worst daily scores for fatigue or nausea. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.
A: The authors state that their findings suggest that patients with all subtypes of acute hepatic porphyria would probably derive similar clinical benefits from givosiran, since the subtypes have common pathophysiological features and treatment, along with the reduced levels of ALA and PBG seen in ENVISION in the givosiran-treated patients with hereditary coproporphyria and variegate porphyria. They are currently evaluating the long-term efficacy and safety of givosiran during the open-label extension period of the ENVISION trial involving patients with all subtypes of acute hepatic porphyria.