Pioglitazone (pio) is a drug approved for the treatment of type 2 diabetes mellitus. Because of its superior efficacy for NASH demonstrated in multiple clinical trials, it is currently the only drug recommended off-label for the treatment of this silent, but highly prevalent liver disease. However, its use is limited due to PPARγ agonism-related side effects, including weight gain and edema. Pio is a racemic mixture of (R)- and (S)-enantiomers that rapidly interconvert, which has prevented the characterization of their individual pharmacokinetic and pharmacodynamic properties. Substituting the hydrogen at the chiral center of pio with deuterium stabilized the enantiomers and allowed their full characterization and evaluation as distinct molecular entities. Herein, we show that, through mitochondrial function modulation, DRX-065, the deuterated (R)-enantiomer of pio, is responsible for the NASH efficacy of pio while the (S)-enantiomer shows strong PPARγ agonist activity and the related side effects of weight gain and fluid retention found in the racemate. The superior efficacy of DRX-065 in rodent models and the observed absence of PPARγ-driven side effects prompted our advancement of DRX-065 for NASH and adrenomyeloneuropathy (AMN), a rare monogenic CNS disease. Herein, we show that, in a Phase 1 single dose study of 22.5 mg DRX-065 compared to 45 mg Actos® (pio), DRX-065 demonstrates good safety and tolerability. Furthermore, dosing of DRX-065 provides selective exposure to the (R)-enantiomer and is predicted to have efficacy equivalent to 45 mg pio at a significantly lower dose without the PPARγ-related side effects of weight gain and edema.

DRX-065, the deuterated (R)-enantiomer of pioglitazone, as a nonalcoholic steatohepatitis (NASH) drug candidate: Preclinical and phase 1 results

256th National Meeting (2018)

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