Givosiran delivers safe, sustained improvements in acute hepatic porphyria

Long-term monthly treatment with givosiran has good tolerability and offers continuous improvements to patients with acute hepatic porphyria (AHP), results of the phase III ENVISION trial have shown.

“AHP is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms,” the investigators said. “In [the primary analysis] of ENVISION, givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo.”

The results of the 36-month final analysis were reported in this study of 94 AHP patients (aged ≥12 years) with recurrent attacks who were randomly assigned to monthly subcutaneous givosiran 2.5 mg/kg (n=48) or placebo (n=46) for 6 months. In the open-label extension (OLE) phase, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg.

The median annualized attack rate (AAR) during treatment with givosiran was very low at 0.4. Annualized days of hemin use through month 36 remained low in patients on continuous givosiran (median, 0.0‒0.4) and decreased among those who transitioned to givosiran from placebo (median, 16.2‒0.4). [J Hepatol 2023;79:1150-1158]

At the end of the OLE period, 86 percent of patients in the continuous givosiran group and 92 percent of those in the placebo crossover group had zero attacks. Post hoc analysis revealed a lower AAR than historical AAR in 98 percent and 100 percent of patients, with 0 days of hemin use in 88 percent and 90 percent, respectively.

An increase was also noted in the 12-item short-form health survey physical and mental component summary scores: 8.6 and 8.1, respectively, in the continuous givosiran group; 9.4 and 3.2, respectively, in the placebo crossover group. Scores in the EQ-5D health-related questionnaire also increased by 18.9 in patients on continuous givosiran treatment and 9.9 in those who transitioned from placebo.

Lower levels of urinary delta-aminolevulinic acid and porphobilinogen were sustained. In terms of safety, givosiran demonstrated a continued positive risk/benefit profile.

“Consistent with the results from the ENVISION primary analysis, these final 36-month results of ENVISION show that long-term monthly treatment with givosiran leads to continuous and sustained reductions in AAR and use of hemin over time in patients with AHP and recurrent attacks,” the investigators said. [N Engl J Med 2020;382:2289-2301]

“Patients receiving long-term monthly treatment with givosiran reported improved patient quality of life assessment scores, including assessments of physical functioning, activities of daily living, and overall health status,” they added.

The study was limited by the small sample size, which was expected because AHP is a rare disease. To date, however, ENVISION is the largest interventional study in AHP patients.

“Patients with AHP have debilitating, potentially life-threatening acute attacks, chronic symptoms, and a high disease burden (beyond attacks) that affect their physical, emotional, social, and financial well-being,” the investigators said. [Mol Genet Metab 2019;128:219-227; Hepatology 2020;71:1546-1558; Patient 2018;11:527-537; JIMD Rep 2023;64:104-113; Orphanet J Rare Dis 2021;16:106]