ANDOVER, Mass.—The FDA has completed its review of DeuteRx’s investigational new drug 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. DeuteRx, an R&D-focused biotechnology company dedicated to improving racemic small-molecule marketed drugs and drug candidates, recently presented preclinical results at the American Chemical Society National Meeting, indicating that DRX-065 exhibited a superior therapeutic index compared to pioglitazone for the treatment of nonalcoholic steatohepatitis (NASH) and adrenomyeloneuropathy (AMN).
NASH, a common and often “silent” liver disease, resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. AMN, a form of X-linked adrenoleukodystrophy, often causes spinal cord dysfunction, which leads to the initial symptoms that include difficulties in walking or a change in the walking pattern. No drugs have received FDA approval for either condition.
DeuteRx has pioneered deuterium-enabled chiral switching (DECS) to improve racemic (a mixture of two mirror-image compounds or enantiomers) small-molecule marketed drugs and drug candidates intended for patients across multiple therapeutic indications. While enantiomers are chemically unstable and rapidly interconvert in vivo, DeuteRx has demonstrated the use of DECS to stabilize the enantiomers of many racemic active ingredients. DeuteRx is a spin-out company from Deuteria Pharmaceuticals Inc., where the original patent application originated.
According to Dr. Sheila DeWitt, president and CEO of DeuteRx, “We have discovered and are developing stabilized enantiomers for several classes of compounds by replacing the exchangeable hydrogen at the chiral center with deuterium.” DeWitt, an organic chemist, has been in the pharmaceutical and biotechnology industries for 30 years and has been involved in the startup or turnaround of eight different companies.
DeWitt explained that DRX-065 exhibits a superior therapeutic index compared to pioglitazone for the treatment of NASH and AMN because it reduces side effects, including weight gain, edema and bone loss. DRX-065 is an anti-inflammatory and a mitochondrial function modulator that reduces glucose.
AMN, also known as Lorenzo’s disease, is a “gut-wrenching” condition with onset usually before age 5, according to DeWitt. People with the disease are generally dysfunctional by their early teens, and the condition is often misdiagnosed as multiple sclerosis or fibromyalgia. AMN, which affects one in 17,000 people, involves myelin breakdown around the spinal column.
NASH, which could account for a $20-billion market by 2025, affects 5 to 30 percent of the population, DeWitt said. She attributed the nonalcoholic fatty liver disease to dietary habits in western society and related that 31 percent of diabetics have the disease.
According to Dr. Scott Friedman, dean for therapeutic discovery and chief of the Division of Liver Diseases at Mount Sinai School of Medicine, “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). I believe that there is great potential for DRX-065 to provide superior efficacy to pioglitazone without the undesired 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 six subjects each will compare 22.5 mg of DRX-065 to 45 mg of Actos, the highest approved dose of marketed racemic pioglitazone. Dosing was 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,” noted Dr. Lex Van der Ploeg, advisor to DeuteRx. “The treatment of AMN with DRX-065 is supported by the profound effects observed with racemic pioglitazone in rodent models of ALD and AMN.”