Introduction: The acute hepatic porphyrias (AHP) are inherited metabolic disorders caused by deficiencies of specific enzymes in the heme biosynthetic pathway. Of the four AHP, the most common is acute intermittent porphyria (AIP), an autosomal dominant disease due to the half-normal activity of porphobilinogen deaminase (PBGD). These diseases are characterized by life-threatening acute neurovisceral attacks that involve the autonomic, peripheral and central nervous systems, and often require urgent medical care and/or hospitalization. Acute attacks are triggered by a number of factors, including cytochrome P450-inducing drugs, dieting, and hormonal fluctuations, all of which result in the increased expression of hepatic 5-aminolevulinic acid synthase (ALAS1), the first and rate-limiting enzyme of the heme biosynthetic pathway. When ALAS1 activity is induced, the inherited enzyme deficiency becomes limiting and results in the increased hepatic production of the upstream neurotoxic porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which accumulate in the plasma and urine.

Methods: EXPLORE (ClinicalTrials.gov Identifier: NCT02240784) is an on-going, prospective, international, observational study characterizing the natural history and clinical management of patients with AHP with recurrent attacks (> 3 attacks/year) or who receive hemin prophylaxis to prevent attacks. Patient medical history, physical examination and porphyrin precursors, along with questionnaires on porphyria activity, quality of life and healthcare utilization were collected.

Results: A total of 112 patients with AHP were enrolled from 13 countries, and have been followed for 6 to 12 months. The mean patient age is 39 years, with 89% female, and 93% with AIP, 4% variegate porphyria (VP), and 3% hereditary coproporphyria (HCP). The most common associated medical conditions were hypertension (23%), headaches/migraine (11%), depression (17%) and insomnia (12%). Patients reported a mean of 9.3 attacks in the 12 months prior to enrolling in the study, with pain being the most common symptom in 99% of attacks. Chronic symptoms in between attacks were also reported by 65% of patients, with pain being the most frequent symptom. Overall, 46% of patients experienced symptoms daily. While on study, the annualized attack rate was 4.9 attacks/person, with a mean duration of 7 days. In patients that were not being treated with hemin prophylactically, attack rate was 5.5 attacks/person and in patients being treated with hemin prophylactically, attack rate was 4.0 attacks/person. Seventy-seven percent of attacks required treatment at a healthcare facility or with intravenous hemin. Patients reported diminished quality of life (EQ-5D-5L), with the greatest impact seen in the domains of pain/discomfort, usual activities and anxiety/depression. Asymptomatic patients have induced ALAS1 and high urinary ALA/PBG compared to normal healthy individuals, which increase further during attacks.

Conclusions: EXPLORE is the first international, natural history study in patients with AHP. Results from this study demonstrate that patients suffer from both acute and chronic symptoms (most commonly pain), during and in between attacks, which collectively result in a diminished quality of life. Furthermore, in patients treated with hemin prophylactically, attacks continued to occur. Given the continued morbidity and mortality, there remains an unmet need for an efficacious, simple, fast-acting and better tolerated treatment for patients with AIP.


Windyga: Baxalta: Honoraria, Research Funding; Biogen Idec: Honoraria, Research Funding; Baxter Healthcare: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire: Honoraria, Research Funding. Cappellini: Sanofi-Genzyme: Honoraria, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Celgene: Honoraria; Vifor: Honoraria. Rock: Alnylam: Employment. Chan: Alnylam: Employment. Soh: Alnylam: Employment. McCarthy: Alnylam: Employment. Querbes: Alnylam: Employment. Penz: Alnylam: Employment. Simon: Alnylam: Employment.

Author notes


Asterisk with author names denotes non-ASH members.