Intravenous hemin for prevention of frequent attacks of acute hepatic porphyria - a double-blind placebo controlled pilot study.

INTRODUCTION: Hepatic heme production is deficient in the acute hepatic porphyrias (AHPs) due to partial deficiencies of specific enzymes in the heme biosynthetic pathway. Attacks of severe neurological symptoms of AHP may recur frequently during adult life and are accompanied by induction of hepatic δ-aminolevulinic acid (ALA) synthase 1 (ALAS1, the initial and rate-limiting enzyme of this pathway) and marked elevations of ALA, porphobilinogen (PBG) and porphyrins. These levels decrease rapidly after intravenous heme replenishment, but verification of clinical benefit of this treatment approach remains elusive because design of blinded, placebo-controlled studies is especially difficult during potentially life-threatening acute attacks often lasting for many days. We considered that a study of attack prevention rather than treatment might have fewer constraints.

DESIGN: This double-blind placebo-controlled pilot study enrolled 13 patients with acute intermittent porphyria (AIP, n = 8) or variegate porphyria (VP, n = 5) as documented by pathogenic HMBS or PPOX mutations and elevations in ALA, PBG and porphyrins. All were receiving evidently beneficial prophylactic treatment with hemin for prior frequent attacks despite avoidance of known predisposing factors, and consented to receive a single scheduled blinded intravenous dose of either hemin (Panhematin™, Recordati Rare Diseases) 4 mg/kg body weight, or placebo, with provisions for timely rescue treatment of an attack if such occurred within 7 days.

RESULTS: Attacks occurred within 7 days after blinded treatment with hemin in only 1 of 7 patients and in 5 of 6 patients who received placebo (p = 0.029, 2-sided Fisher's Exact Test). Symptoms started within a few hours in the hemin-treated patient who had an attack, which suggests that a longer interval may be required for attack prevention. Attacks in 6 patients which were treated promptly were the only serious adverse events.

CONCLUSIONS: This study in AHP patients already on hemin prophylaxis is, to our knowledge, the first randomized, placebo-controlled, blinded trial to provide statistically significant evidence for clinical benefit of hemin in AHP. Hemin treatment of attacks already in progress would likely address the same underlying hepatic and neuropathic mechanisms, but their study remains more challenging.