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Rodents to the rescue
RENSSELAER, N.Y.—There's good news on the preclinical front from Taconic Biosciences and Edison, N.J.-based ContraVir Pharmaceuticals Inc. The companies recently reported promising strides toward a much-needed treatment for nonalcoholic steatohepatitis (NASH), a life-threatening disease that affects up to 12 percent of the U.S. population—with numbers on the rise.
Aimed at saving precious time to find the solution to liver disease, Taconic Biosciences launched the first commercially available diet-induced NASH rodent model. For its part, ContraVir reported results from its first study with human precision cut liver slice (PCLS) cultures and findings from a preclinical study where CRV431, a novel cyclophilin inhibitor, significantly decreased the extent of fibrosis in a second animal model of liver fibrosis.
Fibrosis, or scarring of the liver, is a hallmark symptom of NASH, resulting in impaired liver function. Obeticholic acid (OCA), a semi-synthetic bile acid analogue drug approved for the treatment of primary biliary cholangitis (PBC), was evaluated in Phase 3 trials by another company whose results were used as a comparator drug in a study conducted by ContraVir. The study found that OCA did not decrease the extent of fibrosis.
NASH, a dangerous subtype of nonalcoholic fatty liver disease (NAFLD), has recently gained attention in the biomedical community due to its growing prevalence in the population. The National Institute of Diabetes and Digestive and Kidney Diseases estimates that in the U.S., between 30 and 40 percent of adults have NAFLD, with about 3 to 12 percent of adults diagnosed with NASH.
People with NASH have an increased chance of dying from liver-related causes, the National Institutes of Health (NIH) states. If NASH leads to cirrhosis, and cirrhosis leads to liver failure, a liver transplant is necessary to survive. Individuals can also develop liver cancer as a result of NASH.
The rise in NASH patients over the years has led to a national demand for a NASH animal model, reports Taconic. However, “some diet-induced models require up to 26 weeks to be ready for study, and time delays are a serious problem for drug discovery. Additionally, the absence of a commercial product forces researchers to use their precious vivarium space to condition animals for months, displacing other important projects.”
“Prior to this product, researchers lacked access to preconditioned NASH mice, slowing critical research,” says Dr. Michael Seiler, vice president of Taconic’s commercial model portfolio. “This forced researchers to plan studies months in advance, and left little flexibility as new compounds were discovered along the way.”
To address this unmet need, Taconic came up with its diet-induced NASH rodent model for commercial use.
On the clinical end of things, ContraVir reported compelling positive results from human liver experiments with its NASH drug candidate CRV431, which decreases fibrosis and key biomarkers of liver disease in a pivotal experimental model with human PCLS.
The study was conducted by FibroFind, a spin-out contract research company from the Fibrosis Research Group at Newcastle University that spent two years optimizing this experimental model using PCLS.
Researchers simulated liver disease in this experimental model by application of the potent, profibrotic molecules TGFβ and PDGF. Co-administration of ContraVir’s clinical-phase drug candidate, CRV431, was found to be 100 percent effective at preventing fibrosis induction beyond baseline levels. CRV431, at clinically relevant concentrations, also partially or completely blocked several genetic and protein biomarkers of inflammation. The compound was more effective at preventing fibrosis than elafibranor, a dual PPAR α/δ agonist, and OCA, an FXR agonist. Both Phase 3 NASH drug candidates were tested simultaneously with CRV431.
The study found that Elafibranor was 62 percent effective and OCA was 9 percent effective at preventing fibrosis, which was measured by Picrosirius red staining. The beneficial effects of CRV431 on biomarkers of inflammation and fibrosis were similar to those of elafibranor and greater than those of OCA. CRV431 exerted its therapeutic activities at lower concentrations than the other two late-stage drugs, suggesting that CRV431 is a highly potent pharmaceutical agent, the study indicated. At the same time, CRV431 did not demonstrate any negative effects on liver biomarkers, further supporting its safety profile.
Dr. Robert Foster, CEO of ContraVir, notes that, “The results from this study are highly meaningful because they come from fully intact samples of human livers. The closer the experimental models are to replicating what happens in the human body, the greater the likelihood that the therapeutic effects observed in the models will translate to human diseases.”
“This is the second animal model, and the fifth study overall, in which CRV431 consistently demonstrated a statistically significant reduction in fibrosis,” he adds. “In addition, this study showed that CRV431 reduced fibrosis where OCA, a drug approved for PBC with potential to treat additional liver diseases such as NASH, did not.”
ContraVir is developing CRV431 for NASH, fibrosis and other liver diseases such as viral hepatitis and hepatocellular carcinoma. A Phase 1, single ascending dose study previously showed CRV431 to be safe and well tolerated in humans. CRV431 was also administered in a 28-day, multiple ascending dose study. According to the company, CRV431 shows the potential to play an important role in the overall treatment of liver disease - from triggering events through to end-stage disease.