Background Acute hepatic porphyria (AHP) is a group of rare genetic diseases that affect the haem biosynthesis pathway. Overproduction and accumulation of haem intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) cause acute attacks and chronic complications in multiple organ systems, severely affecting patients’ quality of life. Givosiran is a small interfering RNA molecule approved for the treatment of adults (USA) and adults and adolescents (≥12 years old; EU) with AHP.

Methods ELEVATE (NCT04883905), started in April 2021, is an international, prospective, observational registry. The primary objective is to characterize the long-term real-world safety of givosiran in patients with AHP. The secondary objectives focus on characterizing long-term real-world effectiveness of givosiran treatment and describing the natural history and clinical management of patients with AHP. Currently, there are 23 active sites in 6 countries in Europe and North America, with 2 sites in Asia to join. Data from routine clinical assessments of registry patients are collected at least once annually.

Results As of March 6, 2024, 166 patients with AHP (135 females [81.3%]) were enrolled in ELEVATE, with equal distribution between North American and European sites (n=83 in each). The median age (range) of patients at enrolment was 43 (12–77) years, with 54.2% in the 18–45 years age category. Most patients were white (71.1%), with a median (range) body mass index of 24.6 (15.9–53.1) kg/m2. Median age at diagnosis and/or testing (based on family history), as per the treating healthcare provider determination, was 29 (4–70) years. Among those with symptoms (n=151), median age of symptom onset was 29 (6–69) years. Of the 166 patients, 104 (62.7%) had at least one relative with known or suspected AHP. A total of 139 patients (83.7%) had acute intermittent porphyria, 20 (12.0%) had variegate porphyria, 4 (2.4%) had hereditary coproporphyria and 1 (0.6%) had ALA dehydratase-deficient porphyria; AHP type was not reported for 2 patients (1.2%). The majority of patients had unique mutations. A total of 117 patients (70.5%) reported ever having received treatment for AHP with any AHP medication. A total of 109 patients (65.7%) reported receiving treatment for AHP at the time of enrolment: 104 (95.4%) were treated with givosiran, 15 (13.8%) with hemin prophylaxis, 13 (11.9%) with intravenous glucose/dextrose, 6 (5.5%) with carbohydrate intake and 4 (3.7%) with other medications.

Conclusions The demographic and clinical characteristics of the patients enrolled in ELEVATE underscore the heterogeneous nature of AHP. The registry data collected will provide real-world evidence on the natural history and treatment of patients, helping to improve the clinical management of AHP. Safety and effectiveness endpoints will be analyzed in the future, during ongoing data collection as part of a post-authorization commitment. This study is funded by Alnylam Pharmaceuticals.