A Phase 1 Clinical Study of the Retinoid X Receptor (RXR) Selective Agonist IRX4204 in Patients with Early Parkinson’s Disease (PD) (P2.342)

Objective: To evaluate the safety, tolerability, and effects on dopamine transporter binding (DAT), UPDRS Total and Motor Score, of short term administration of IRX4204 to patients with early PD. Background: IRX4204 is a highly selective and potent agonist of the RXR nuclear receptors, and of RXR-Nurr1 and RXR-Nur77 heterodimers. IRX4204 and other RXR agonists previously have been reported to promote dopaminergic neuron survival and functions in vitro, and to be effective in vivo in a 6-OH induced rat model of PD. Design: This study was a single center, open-label clinical trial. IRX4204 was administered orally, once daily, at 5, 10, or 20 mg/day, for up to 30 days. Three cohorts of 5 early PD patients were enrolled. Patients were evaluated for safety, UPDRS, and DAT binding using [123I]β-CIT SPECT. Results: Few adverse events, all non-serious, were observed. Safety laboratory side effects, including known RXR agonist class related reductions in TSH, T4, and circulating leukocytes; and elevations of circulating triglycerides, occurred at all dose levels. Treatment was suspended in the 20 mg/day cohort for decreased leukocytes; and in one patient in the 10 mg/day cohort for elevated triglycerides. No effect on DAT expression was observed by SPECT. There was a trend toward reduction of UPDRS total scores by 4.6 (SD 3.9). Conclusions: IRX4204 was safe and well tolerated by early PD patients at 5 and 10 mg/day for 30 days. No short-term effect on DAT binding was observed by SPECT. There was a trend towards improvements in UPDRS in this open label study. More definitive assessment of UPDRS change after treatment with IRX4204, will require future blinded, controlled clinical trials. These are the first human clinical data to support RXR agonists may be effective for treatment of PD. Disclosure: Dr. Sanders has received personal compensation for activities with Io Therapeutics, Inc., as an employee. Dr. Rosh Chandraratna has received personal compensation for activities with Io Therapeutics, Inc. as the President and Chief Scientific Officer. Dr Merak received compensation for activities with Molecular Neuroimaging, GE healthcare, Piramal, Eli Lilly, Merck, Roche, Pronetha, Novartis, US World Meds, and nLife as a consultant. Dr. Jennings has nothing to disclose.