DeuteRx LLC announced that the US Food and Drug Administration (FDA) has completed its review of the company's investigational new drug (IND) application for DRX-065 (the deuterium-stabilized (R)-enantiomer of pioglitazone) and has determined that a phase 1 clinical study in healthy volunteers can be initiated. Development of DRX-065 will be pursued via a 505(b)(2) regulatory pathway.
The presentation of preclinical data supporting the advancement of DRX-065 for both AMN and NASH will be presented during the ‘First-Time Disclosures’ symposium at the ACS National Meeting in Philadelphia, PA. Based on these preclinical results, DRX-065, is expected to exhibit a superior therapeutic index compared to pioglitazone for the treatment of AMN and NASH.
“The preclinical results with DRX-065 align with the benefits observed in several clinical trials of pioglitazone in NASH patients, most notably the recent publication by Dr. Kenneth Cusi (Ann Intern Med. 2016 doi:10.7326/M15-1774),” says Dr. Scott Friedman, Dean for Therapeutic Discovery, Professor of Medicine and Pharmacologic Sciences and Chief, Division of Liver Diseases at Mount Sinai School of Medicine. “I believe that there is great potential for DRX-065 to provide superior efficacy to pioglitazone without the undesired PPAR? related side effects for NASH patients.”
The phase 1a open-label study of DRX-065 in healthy adult volunteers will assess the safety, tolerability and pharmacokinetics of DRX-065 versus Actos. The first two cohorts of 6 subjects each will compare 22.5 mg of DRX-065 to 45 mg of Actos, the highest approved dose of marketed racemic pioglitazone. Dosing is expected to be completed in September 2016. Pending review of the safety, tolerability, and PK, a third cohort will receive a single additional 7.5 mg dose of DRX-065 to assess the dose proportionality of DRX-065 exposure.
“There is a significant unmet need for men and women afflicted with AMN, the adult form of adrenoleukodystrophy (ALD), a rare X-linked neurological disease,” says Dr. Lex Van der Ploeg, Advisor to DeuteRx. “ALD and AMN are characterized by a complex pathophysiology, which includes oxidative stress, mitochondrial dysfunction, and neuroinflammation. The treatment of AMN with DRX-065 is supported by the profound effects observed with racemic pioglitazone in rodent models of ALD & AMN where DRX-065 is predicted to represent the therapeutically active enantiomer.”
Pioglitazone, is a 1:1 mixture of two interconverting enantiomers. By stabilizing the enantiomers with deuterium, DeuteRx discovered that each enantiomer has dramatically different mechanistic properties. The (S)-enantiomer is a PPAR? agonist with the associated side effects of weight gain and edema. By contrast, the (R)-enantiomer exhibits mitochondrial function modulation and anti-inflammatory effects, likely due to mitochondrial pyruvate carrier (MPC) inhibition. The (R)-enantiomer is also devoid of the weight gain observed with racemic pioglitazone and the (S)-enantiomer in a rodent model of weight gain. Therefore, the (R)-enantiomer is likely responsible for the benefits of pioglitazone seen in animal and/or human studies for indications including Alzheimer's disease, NASH, ALD/AMN, and chronic obstructive pulmonary disease (COPD). The predicted beneficial effects of DRX-065 have been demonstrated by DeuteRx in two rodent models of NASH where DRX-065 exhibited equivalent or better activity than pioglitazone in the liver for measures of steatosis, inflammation, triglycerides, free fatty acids, and cholesterol.
DeuteRx is a Boston-based biotechnology company founded in December 2012 as a spin-out company from Deuteria Pharmaceuticals Inc.