FDA Approves Phase 1/2 Clinical Trial with ABX196 in Patients with Liver Cancer

ABX196 to be tested in combination with checkpoint inhibitor nivolumab to treat hepatocellular carcinoma

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The U.S. Food and Drug Administration has approved an investigational new drug (IND) application for a phase 1/2 clinical trial of ABX196, a liver cancer therapy developed in the laboratory of Scripps Research Professor Luc Teyton, MD, PhD, and licensed to French pharmaceutical company Abivax.

The FDA approval allows Abivax testing of ABX196 in patients with hepatocellular carcinoma (HCC), the most common form of liver cancer. ABX196 showed potent efficacy against HCC in preclinical testing.

“The translation of basic research discoveries to the clinic is the greatest achievement we can hope for as clinician scientists.” says Teyton, who is also a member of Abivax’s Scientific Advisory Board.“The use of ABX196 in the context of immunotherapy has been shown to be beneficial in multiple animal models of cancer, but the results with hepatocellular carcinoma are spectacular. We are looking forward to impacting the disease in patients, especially given the limitations of current therapies.”

The open IND allows Abivax to test ABX196 in combination with nivolumab (Opdivo, Bristol-Myers Squibb), a checkpoint inhibitor, in a first phase 1/2 clinical trial to treat patients with HCC. The initial dose-escalation phase of the study will be conducted at the Scripps MD Anderson Cancer Center in San Diego, California, USA; additional leading cancer centers in the U.S. will be involved in the subsequent expansion phase of the study. The first patient is expected to be enrolled this summer.

“We are thrilled to have been given the green light by FDA for our U.S. study.” says Hartmut J. Ehrlich, MD, chief executive officer of Abivax. “This open IND allows Abivax, in collaboration with leading key opinion leaders at internationally renowned U.S. cancer centers of excellence, to explore the clinical potential of our iNKT agonist ABX196 to broaden and potentiate the activity of the checkpoint inhibitor nivolumab. Based on its unique mechanism of action and exciting preclinical data in several cancer models, we believe ABX196 is a promising immunotherapeutic product candidate for patients with liver cancer that may also have potential in other cancers.”

ABX196 is a synthetic glycolipid agonist of invariant natural killer T cells (iNKT) in a liposomal formulation. A phase 1 clinical trial conducted by Abivax in healthy volunteers has been completed and demonstrated safety and tolerability as well as a potent activation of iNKT cells. ABX196, both alone and in combination with a checkpoint inhibitor, showed a statistically highly significant therapeutic effect in reducing tumor growth as measured by MRI and increasing survival in mice with HCC. Abivax holds exclusive rights to ABX196 from Scripps Research, the University of Chicago, and Brigham Young University.

“Despite the recent introduction of checkpoint inhibitors, hepatocellular carcinoma continues to be a substantial therapeutic challenge, as only about 20 percent of the treated patients show a response to these new drugs” says Darren Sigal, MD, program director of GI Oncology at Scripps Clinic and Scripps MD Anderson Cancer Center in San Diego, and principal investigator of the study. “While checkpoint inhibitors block a ‘do not attack me’ signal on cancer cells, ABX196 activates iNKT cells, a subpopulation of lymphocytes that is critical for mounting an effective immune response. The synergy between these two molecules carries substantial promise for improved outcomes for patients with this deadly cancer.”

Checkpoint inhibitors like nivolumab are a leading class of therapeutic monoclonal antibodies that block certain endogenous proteins (PD-1/PDL-1) made by immune cells, such as T cells, as well as some cancer cells. These proteins effectively hijack the immune system, causing it to keep immune responses in check and preventing T cells from killing cancer cells. When these proteins are blocked, the “brakes” on the immune system are released and T cells are able to kill cancer cells much more efficiently. In some cancers, treatment with checkpoint inhibitors has been highly efficacious. However, due to the tumor micro-environment in other cancers, such as HCC, checkpoint inhibitors can have difficulties exerting their effects. ABX196 is intended as a drug that will potentiate the efficacy of checkpoint inhibitors by activating iNKT cells to kill tumor cells.

HCC is the most common form (75 to 90 percent) of primary liver cancer in adults. It typically occurs in the setting of chronic liver inflammation and/or cirrhosis and is closely linked to chronic viral infection such as hepatitis B or C, exposure to toxins such as alcohol, and to certain diseases such as non-alcoholic steatohepatitis (NASH).

The incidence of and deaths related to HCC are increasing in the United States and globally due to hepatitis B and C virus infections, as well as NASH. Prevalence data from 2018 show a total of 79,000 cases of HCC in the U.S. and G5 Europe (Germany, France, Italy, Spain and the UK), with 67,000 new cases, and a total of 260,000 cases in China with 338,000 new cases. Globally, there were 841,000 new cases of liver cancer (ranking it sixth of all reported cancers) and 782,000 fatalities (ranking it fourth) in 2018.

Currently, the American Cancer Society reports five-year survival rates in the U.S. of 31 percent for localized HCC, 11 percent for regional, and 2 percent for distant or metastatic, indicating a clear unmet medical need for improved therapies for HCC.