Copper Histidinate Treatment for Menkes Disease (Kinky Hair Syndrome)

Background: Menkes disease (MD) is a X-linked recessive disorder caused by mutations in the copper transport gene, ATP7A. Although MD patients appear asymptomatic at birth, they develop significant symptoms such as seizures, hypotonia, and failure to thrive 6-10 weeks after birth. Without treatment, death by age three years is the typical outcome in MD. Copper histidinate (CUTX-101) is being investigated for the treatment of Menkes disease. Methods: We treated MD subjects with 1450 mcg of CUTX-101 (250 mcg elemental copper) administered subcutaneously twice daily until 12 months of age, and once daily thereafter, for a total duration of three years. Subjects born after 1999 and with severe loss-of-function ATP7A mutations from two open-label, single-arm, single-site studies were combined and categorized into an Early Treatment cohort (CuHis-ET; treatment initiated within 4 weeks of birth, corrected for prematurity) and a Late Treatment cohort (CuHis-LT; treatment initiated after 4 weeks of birth). Untreated historical control (HC) MD patients were enrolled under an amendment to one of the studies. The safety profile of CUTX-101 was assessed in all MD patients treated with at least one dose. Efficacy of CUTX-101 was assessed by comparing CuHis-ET to untreated HC-ET, and CuHis-LT to untreated HC-LT. The primary efficacy endpoint was overall survival (OS) comparing CuHis-ET to HC-ET. The secondary efficacy endpoint was OS comparing CuHis-LT to HC-LT. Results: There were 31 CuHis-ET, 35 CuHis-LT, 18 HC-ET, and 17 HC-LT subjects. A 79% reduction in risk of death was observed in CuHis-ET subjects compared with HC-ET subjects: median OS was 177.1 and 16.1 months, respectively; HR (95% CI) = 0.208 (0.094, 0.463); p<0.0001. A 75% reduction in the risk of death was observed in CuHis-LT subjects compared with HC-LT subjects: median OS was 62.4 and 17.6 months, respectively; HR (95% CI) = 0.253 (0.119, 0.537); p<0.0001. Sensitivity analyses demonstrated that these results were consistent regardless of severe ATP7A mutation type or prematurity. Generally, CuHis-ET subjects who completed three years of treatment attend(ed) school and remain active and engaged. Most surviving CuHis-LT subjects resided with their families; some require respiratory and feeding support. In CuHis-ET and CuHis-LT cohorts, TEAEs were reported in 61 subjects (92.4%) with none considered related to study treatment. In CuHis-ET and CuHis-LT cohorts, the most common TEAEs were pneumonia (30.3%), seizures (21.2%), dehydration (18.2%), failure to thrive (16.7%), and respiratory distress (15.2%). Conclusion: CUTX-101 was safe and well tolerated. In pre-specified primary and secondary efficacy analyses, OS was significantly improved in Menkes disease subjects treated with CUTX-101 compared to untreated subjects. Clinical benefit for CuHis-ET was greater than for CuHis-LT, underscoring the importance of early identification, including newborn screening, and prompt initiation of treatment. An expanded access program for newly diagnosed MD patients is ongoing.