CiVi 020 is a potent, selective peroxisome proliferator-activated receptor delta (PPARδ) agonist. PPARδ is a ligand activated transcription factor that exerts tissue specific control of genes involved in energy utilization.
PPARδ’s involvement in energy utilization results from mechanistic regulation of fatty acid uptake, transport, and fatty acid β-oxidation, insulin secretion and insulin sensitivity. These actions suggest therapeutic potential in metabolic-syndrome-related diseases, such as obesity, insulin resistance/type 2 diabetes dyslipidemia, hepatosteatosis, and atherosclerosis. Studies in several animal models of obesity demonstrate that PPARδ agonists can improve fasting glucose and insulin sensitivity/levels, enhance fatty acid β-oxidation, beneficially impact lipid parameters, reduce inflammatory markers, and limit weight gain.
Supportive Clinical Work
Proof-of-concept (POC) work conducted with CiVi 020 include the demonstration of hepatoprotective and antifibrotic effects in mouse models of liver injury and the reduction of fasting hyperglycemia and hyperinsulinemia, reduction of triglycerides and lipid accumulation in the liver and the induction of weight loss in a high fat diet (HFD) induced obesity (DIO) mouse model. In this latter model reductions in leptin, MCP-1, several markers of insulin resistance, liver transaminases, TGF-β, fibrosis, inflammation, steatosis and fat accumulation in skeletal muscle were also observed. Studies in the monkey have demonstrated that CiVi 020 possesses an expression profile consistent with that expected of a PPARδ agonist.
Pursuing Orphan Indications and Rare Diseases
The pleiotropic effects of PPARδ tentially also provide opportunities to treat multiple rare disease indications, where smaller clinical studies are required and Orphan Disease Designation can be achieved. These include diseases such as:
- PBC (Primary Biliary Cholangitis)
- Fatty Acid Oxidative Disorders
- Mitochondrial Myopathies
- Lupus Nephritis
- Duchenne Muscular Dystrophy
- Neurodegenerative disorders (i.e., Huntington’s disease)
CiVi Biopharma has also conducted CiVi 020 IND-enabling toxicology studies in rodent and non-human primates and scaled manufacturing to support a Phase 1 clinical study in healthy volunteers. The Company’s plan moving forward is to design and implement a Phase 1 SAD/MAD study and to rationalize and select potential rare disease indications.