Better understanding of fibrosis spurs drug development

Nonalcoholic fatty liver disease (NAFLD) — a spectrum of disorders associated with lipid deposition in hepatocytes — is the leading cause of liver disease in the Western world. Strongly associated with metabolic syndrome, NAFLD may progress to fibrosis, cirrhosis and liver failure and increase the risk of hepatocellular carcinoma.

Although regimens for hepatitis B and C have reduced the burden of viral-related liver cirrhosis, treatments to reverse or prevent progression of fibrosis from other causes are limited. Current treatment options for NAFLD include general lifestyle changes such as diet, exercise and weight loss, which are difficult for many patients to undertake long term. Thus, progressive fibrosis and cirrhosis represent one of the largest areas of unmet medical need for these patients.

Mechanism of fibrosis and anti-fibrotics

Fibrosis is a wound-healing response to acute or chronic liver injury that starts with hepatocyte necrosis. This initiates inflammatory signaling by chemokines and cytokines, activation of fibrogenic cells, especially hepatic stellate cells, and ultimately, the deposition of extracellular matrix. Each step in the cascade of signaling and transcriptional events in stellate cells is a potential target for anti-fibrotics, but most efforts to develop such therapies haven't proved successful, says Bashar A. Aqel, M.D., a hepatologist at Mayo Clinic's campus in Arizona.

"Liver fibrosis is a complex process involving multiple pathways in the liver, some of which are not fully understood, which is why attempts to identify an effective anti-fibrotic have been unsuccessful so far. But recent advances in understanding fibrosis, combined with improved technologies for assessment, now allow the development of anti-fibrotics and their analysis in clinical trials," he says.

One agent currently in clinical trials is simtuzumab, a monoclonal antibody that is selective for lysyl oxidase-like 2 (LOXL2), an enzyme that modifies the extracellular matrix by promoting cross-linking of collagen fibers.

"Studies have demonstrated that cross-linking of collagen and elastin is the final step in the fibrotic pathway, which causes tissue stiffness and further enhances transforming growth factor-β tissue remodeling," Dr. Aqel explains. "Lysyl oxidase activity has long been linked to fibrosis, but until recently, there hasn't been much success in finding inhibitors for it."

Mayo Clinic investigators are currently participating in a multi-site phase II trial of simtuzumab for patients with nonalcoholic steatohepatitis and various stages of fibrosis.

"So far, the drug has been well-tolerated, and we have not seen any serious adverse events in patients. In terms of reversal of fibrosis, it's too early to tell. Most patients have been enrolled an average of 18 months, and it will be a few years before we start seeing results," Dr. Aqel says. "It's true the drug may be costly and the infusion may add to the cost, but if we can reverse fibrosis and avoid a liver transplant, which is very expensive, simtuzumab may be cost-effective."

In the pipeline is a small-molecule LOXL-2 inhibitor with the potential for daily oral dosing. If proved effective, it would likely be less expensive than infused agents.

Cenicriviroc

Dr. Aqel is also currently recruiting patients for a phase II study of cenicriviroc, a dual CC chemokine receptor type 2 (CCR2) and type 5 (CCR5) antagonist. CCR2 and CCR5 are known to play a role in the pathogenesis of liver fibrosis by promoting the recruitment of monocytes and macrophages as well as hepatic stellate cell migration and have been shown to promote hepatic fibrosis in mouse models.

Cenicriviroc has already demonstrated safety and efficacy for the treatment of HIV. In January 2015, the Food and Drug Administration granted fast-track designation to cenicriviroc for treating nonalcoholic steatohepatitis in patients with liver fibrosis.

"Mayo is participating in multiple studies of new anti-fibrotics," Dr. Aqel says. "These are still in the development stage and their safety and efficacy is yet to be proved, but the search is ongoing."

For more information

For clinical trial information, contact Kelly Clark, CCRP, study coordinator, at Clark.Kelly2@mayo.edu.