Effect of Oral Cimetidine in the Protoporphyrias (IND 153247 submitted 9/2/2020)

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PROJECT SUMMARY/ABSTRACT Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are a genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. EPP and XLP, collectively called the protoporphyrias, result in the accumulation of the light-sensitive molecule protoporphyrin IX (PPIX) in erythrocytes and secondarily in the plasma and the liver. In addition to photosensitivity, protoporphyria can also result in anemia, gallstones, and chronic liver disease, and in 2-5% of cases it results in rapidly progressive cholestatic liver failure that is fatal without liver transplantation. Because patients are sensitive to visible light and not UV light, sunscreen is not effective in EPP. Afamelanotide, which increases cutaneous melanin, was recently approved by the FDA for the prevention of photosensitivity in EPP. Additional therapies besides afamelanotide are necessary because afamelanotide is does not change PPIX level and therefore does not prevent the life-threatening complications of EPP. Cimetidine has gained attention as a possible treatment for human porphyrias because of a potential off-target effect of inhibition of ALAS, the first enzyme of heme biosynthesis. This inhibition was first described in vitro. Later case reports suggested that cimetidine was beneficial for the treatment of acute intermittent porphyria and porphyria cutanea tarda. Subsequently, case reports also described a potential effect in EPP. However, these reports are anecdotal and uncontrolled. Some patients also had pre-existing hepatic damage from EPP, which complicates the observations of drug effects in EPP. Communications in the porphyria community indicate that a large number of patients, including children, have used cimetidine without oversight and without a systematic record of dosage or symptomatic improvement. The considerable interest in the larger porphyria community to assess with care its possible benefit as a treatment approach has therefore neither been addressed nor satisfied. Therefore, the objective of this study is to determine the efficacy and safety of oral cimetidine administration in the protoporphyrias. The study design is a multicenter, prospective, randomized, double-blind, placebo-controlled, crossover trial, and efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. If the results are positive, this would be the first study providing quality evidence for an agent acting as a disease-modifying therapy for protoporphyria.