HPP593 is a functionally selective peroxisome proliferator-activated receptor delta (“PPAR-delta”) agonist that is to begin a Phase 2 trial for the prevention of muscle weakness associated with PMV and critical injury.
PPAR-delta, a member of the nuclear regulatory superfamily of ligand-activating transcriptional regulators, is expressed in most metabolically active tissues throughout the body, particularly in muscle, where it has been shown to be important for the proper function of skeletal muscle in gain- and loss-of-function studies. PPAR-delta is associated with increased muscle endurance in mice and humans. Increases in the percentage of slow-twitch fibers and increased fatty acid oxidation and transport have been observed with overexpression of PPAR-delta in mice. Studies in mice have shown that PPAR-delta agonists induce genes related to mitochondrial biogenesis in muscle. PPAR-delta activation by agonists also reduces blood glucose and improves insulin insensitivity. PPAR-delta also has anti-inflammatory properties. All of these properties are potentially beneficial to PMV recipients. Preservation of skeletal muscle function during the period of sedation and mechanical ventilation, enhanced glucose control, and anti-inflammatory properties can reverse or limit the multi-organ failure and prolonged hospitalization that characterizes these conditions.
HPP593 is a potent selective PPAR-delta agonist that does not exhibit off-target activity. HPP593 has demonstrated a lowering of low-density lipoprotein cholesterol and triglycerides in animal models and humans, with a significant increase in high-density lipoprotein cholesterol. HPP593 has also demonstrated an antidiabetic effect in several animal models of type 2 diabetes. In a 28-day randomized, double-blind, placebo controlled Phase 1b study, HPP593 showed a statistically significant effect on maintaining muscle strength during limb immobilization and regaining improving muscle strength after removal of limb immobilization. These data suggest that HPP593 would be a good treatment option for the prevention of muscle weakness associated with PMV and critical injury.