Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial
Publication Details
Journal of Hepatology
July 2023
Author(s)
David J Kuter1, Herbert L Bonkovsky2, Susana Monroy3, Gayle Ross4, Encarna Guillén-Navarro5, Maria Domenica Cappellini6, Anna-Elisabeth Minder7, Ole Hother-Nielsen8, Paolo Ventura9, Gang Jia10, Marianne T Sweetser10, Manish Thapar11; ENVISION Investigators
Affiliations
1Hematology Division, Massachusetts General Hospital, Boston, MA, USA. Electronic address; 2Atrium Wake Forest Baptist Health, Winston-Salem, NC, USA; 3Instituto Nacional de Pediatría, Mexico City, Mexico; 4Royal Melbourne Hospital, Melbourne, Victoria, Australia; 5Medical Genetics Section, Virgen de la Arrixaca University Hospital, IMIB Pascual Parrilla, University of Murcia (UMU), Murcia, Spain; CIBERER-ISCIII, Madrid, Spain; 6University of Milan, Fondazione IRCCS Ca' Granda Policlinico, Milan, Italy; 7Division of Endocrinology, Diabetes and Porphyria, Stadtspital Zürich, Triemli, Zürich, Switzerland; 8Odense University Hospital, Odense, Denmark; 9Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy; 10Alnylam Pharmaceuticals, Cambridge, MA, USA; 11Thomas Jefferson University, Philadelphia, PA, USA;
Abstract
Background & Aims:
Acute hepatic porphyria (AHP) is caused by defects in hepatic heme biosynthesis, leading to disabling acute neurovisceral attacks and chronic symptoms. In ENVISION (NCT03338816), givosiran treatment for 6 months reduced attacks and other disease manifestations compared with placebo. Herein, we report data from the 36-month final analysis of ENVISION.
Methods:
Ninety-four patients with AHP (age ≥12 years) and recurrent attacks were randomized 1:1 to monthly double-blind subcutaneous givosiran 2.5 mg/kg (n = 48) or placebo (n = 46) for 6 months. In the open-label extension (OLE) period, 93 patients received givosiran 2.5 or 1.25 mg/kg for 6 months or more before transitioning to 2.5 mg/kg. Endpoints were exploratory unless otherwise noted.
Results:
During givosiran treatment, the median annualized attack rate (AAR) was 0.4. Through Month 36, annualized days of hemin use remained low in the continuous givosiran group (median, 0.0 to 0.4) and decreased in the placebo crossover group (16.2 to 0.4). At end of OLE, in the continuous givosiran and placebo crossover groups, 86% and 92%, respectively, had 0 attacks. AAR was lower than historical AAR in 98% and 100%, respectively (post hoc analysis), and there were 0 days of hemin use in 88% and 90%, respectively. The 12-item short-form health survey physical and mental component summary scores increased by 8.6 and 8.1, respectively (continuous givosiran) and 9.4 and 3.2, respectively (placebo crossover). EQ-5D health-related questionnaire scores increased by 18.9 (continuous givosiran) and 9.9 (placebo crossover). Lower urinary delta-aminolevulinic acid and porphobilinogen levels were sustained. Safety findings demonstrated a continued positive risk/benefit profile for givosiran.
Conclusions:
Long-term monthly givosiran treatment provides sustained and continued improvement in clinical manifestations of AHP.
PMID
37479139
DOI
10.1016/j.jhep.2023.06.013
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