EXPLORE: A prospective, multinational natural history study of acute hepatic porphyria patients with recurrent attacks

The acute hepatic porphyrias (AHP), including acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), are due to a deficiency in the liver of one of the eight enzymes required for heme biosynthesis. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) by triggers such as fasting or drug exposure can lead to accumulation of neurotoxic heme intermediates that result in acute life threatening neurovisceral attacks. Methods: We are currently performing a prospective, multinational, observational study to characterize the natural history and clinical management of patients with AHP who experience recurrent attacks (> 3 attacks per year) or receive prophylactic treatment to prevent attacks. Patient porphyria disease activity questionnaires, physical examinations, plasma and urinary porphyrin precursors, circulating ALAS1 mRNA and health care utilization data are collected at pre-specified intervals throughout the 6 month study. In addition, porphyria attack assessments and porphyrin precursor levels are collected during attacks. Interim Results: Enrollment is complete, but the study is ongoing. A total of 112 patients have been enrolled from 20 centers in 13 countries. The mean patient age is 39 years old, with the majority being female (99F; 13M) and having a diagnosis of AIP (AIP=104; HCP=3; and VP=5) for a mean of 11.4 years. Most patients (85%) reported being treated previously with heme during an attack, while less than half (43%) reported taking heme prophylactically to prevent attacks. Patients reported a mean of 9.44 attacks (median 6; range 0-54) in the prior year, of which approximately 70% required treatment in a healthcare setting. The most common acute attack symptoms included abdominal pain (92%), nausea or vomiting (80%) and weakness (79%). Symptoms similar in character to those occurring in attacks were reported chronically (i.e. all the time) in 46% of the patients. The baseline urinary porphobilinogen and aminolevulinic acid levels while patients were not having an acute attack were elevated at 34.9 mmol/mol Cr and 26.7 mmol/mol Cr respectively (upper limit of normal: PBG < 1.2 mmol/mol Cr; ALA < 3.1 mmol/mol Cr). Summary: This ongoing study should provide important information about the full spectrum of disease in AHP patients with recurrent attacks, as well as provide insights into AHP pathophysiology and disease management. The fact that close to half the patients have porphyria symptoms all the time, even when not in the setting of an acute attack, suggests the disease is more chronic than previously appreciated. Additional 6-month data from this study will be reported.