Phase 2 Study of Hemin for Treatment and Prevention of Porphyria Attacks

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PROJECT ABSTRACT/SUMMARY Hemin for injection (Panhematin", Lundbeck) was the first drug approved under the Orphan Drug Act. Its approval in 1971 for the amelioration of acute attacks of acute intermittent porphyria was based on published reports of biochemical efficacy and evident benefit in numerous individual cases and case series rather than adequately powered, randomized, controlled studies. Therefore its efficacy has remained in question especially in an era of evidence-based medicine. Moreover, the narrow approved indications (only women with cyclic attacks), a requirement for an initial trial of glucose loading, a wide dose range of 1-4 mg/kg, and a method for reconstitution of the lyophilized product with sterile water have impaired its clinical usefullness. It is increasingly recognized that additional clinical studies are needed to address these longstanding issues and considerable disparities between product labeling and current expert recommendations. A Phase 2 study to be conducted by at least 5 centers in the Porphyrias Consortium (supported by NIDDK and part of the NIH Rare Diseases Clinical Research Network - RDCRN) aims to improve the evidence base for this treatment for acute porphyric attacks. This randomized, blinded placebo-controlled study will compare treatment with Panhematin" 4 mg/kg daily plus glucose for 4 days to treatment with glucose alone in 30-40 patients with acute attacks of porphyria. The consortium investigators have experience in conducting controlled studies in porphyrias, including studies in patients with acute attacks. The RDCRN supports development of study materials, web-based data entry, data warehousing, and monitoring at multiple study sites, and has established a data and safety monitoring board. The manufacturer has committed drug for the study. The American Porphyria Foundation, a longstanding and effective patient support group that is also part of the Consortium, will assist with patient recruitment. Infrastructure at all sites will include facilities of NIH-funded Clinical and Translational Science Awards. An investigator IND application (IND#13,929) has been approved. An analgous study is being developed to assess the use of Panhematin" for prevention of porphyric attacks, since there is even less evidence for this use of the drug. Additionally, single-patient controlled crossover studies are planned to address the problem that response to a preventive regimen is variable, unpredictable and difficult to assess for individual patients. This project will provide the first high quality evidence for efficacy and safety of the drug viewed as the most important available treatment for acute attacks of porphyria.