Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study

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.