Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study
Publication Details
Orphanet Journal of Rare Diseases
August 2022
Author(s)
Bruce Wang1, Paolo Ventura2, Kei-Ichiro Takase3, Manish Thapar4, David Cassiman5, Ilja Kubisch6, Shangbin Liu7, Marianne T Sweetser7, Manisha Balwani8
Affiliations
1Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA; 2University of Modena and Reggio Emilia, Modena, Italy; 3Iizuka Hospital, Iizuka, Japan; 4Thomas Jefferson University, Philadelphia, PA, USA; 5University Hospital Leuven, Leuven, Belgium; 6Klinikum Chemnitz, Chemnitz, Germany; 7Alnylam Pharmaceuticals, Cambridge, MA, USA; 8Icahn School of Medicine at Mount Sinai, New York, NY, USA
Abstract
Background:
Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks.
Results:
Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0–46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo.
Conclusions:
Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.
PMID
36028858
DOI
10.1186/s13023-022-02463-x
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