Oral Ciclopirox Treatment for Congenital Erythropoietic Porphyria.

ABSTRACT To address the unmet need for an effective treatment for the ultra-rare porphyria, Congenital Erythropoietic Porphyria (CEP), we propose a phase 1/2 clinical trial to be conducted by a team of porphyria experts experienced in successful clinical trials for other porphyrias. CEP is an autosomal recessive inborn error of heme biosynthesis resulting from mostly missense mutations that markedly reduce the activity of the heme biosynthetic enzyme, uroporphyrinogen synthase (UROS), resulting in the massive accumulation of the non- physiologic and phototoxic porphyrins, uroporphyrin and coproporphyrin I isomers. Pathophysiologically, the pathogenic porphyrins accumulate in erythroid cells, leading to hemolysis, with the resultant severe clinical manifestations of transfusion-dependency, splenomegaly, and phototoxic cutaneous blistering on sun-exposed skin that often become infected, causing disfiguring photomutilation. Although bone marrow/hematopoietic stem cell transplantation has been curative in transfusion-dependent children, the limitations of match, ablation damage, graft rejection, graft vs. host disease, expert availability, etc. limit its use in clinical practice. Chronic erythrocyte transfusions and iron chelation do not treat the underlying disease pathogenesis. Therefore, the recent discovery of a pharmacologic chaperone, ciclopirox, previously FDA-approved as a topical fungicide, has been modified for oral administration. This repurposed oral form, ciclopirox olamine, has been shown in in vitro studies to increase the stability and activity of most known UROS missense mutations present in over 80% of known CEP patients. In the knock-in murine CEP model, it increased residual enzymatic stability and activity, thereby reducing accumulated porphyrins, splenomegaly, and cutaneous phototoxic damage. Importantly, this oral drug would treat the pathogenesis of the disease as has been successfully accomplished with specific chaperone therapies for Cystic Fibrosis and Fabry disease. A recent toxicity study in 34 normal adults found the oral drug well tolerated. As the severity of CEP varies from hydrops fetalis to later-onset transfusion-independent patients with severe phototoxicity, a phase 1/2 “N-of-1” study is proposed to evaluate the safety and efficacy in adult patients. The proposed clinical trial involves a six-month run-in, a three-month open-label treatment period with 2mg/kg of ciclopirox olamine, followed by nine months of 4mg/kg. As proof-of-concept endpoints, patients will be evaluated to determine the drug's effect on blood hemoglobin levels and symptoms of anemia, sunlight tolerance, porphyrins, hematologic measures including percentage of fluorocytes and reticulocytes, and quality of life measures.