Syndax Moves Closer to Pivotal Trials of Selective Lung Cancer Treatment

7/5/11Follow @arleneweintraub

Executives from Syndax Pharmaceuticals are spending their post-holiday week in Amsterdam, where they’ll be presenting three sets of data on the company’s lung cancer drug at the International Association for the Study of Lung Cancer conference. The drug, called entinostat, is in Phase 2 clinical testing, the results of which will be critical to advancing Syndax’s plan to move into Phase 3 next year.

Syndax, based in Waltham, MA, is one of several Boston-area companies pursuing drugs designed around epigenetics—the molecular changes in cells that can activate or de-activate genes without affecting the underlying DNA. Entinostat is a selective histone deacetylase inhibitor. It acts against certain enzymes that influence specific epigenetic alterations that drive cancer growth and drug tolerance. Syndax’s strategy is to test the drug in combination with other cancer therapies, so as to boost the receptiveness of a patient’s tumor to drugs to which it might not normally respond.

In previous studies, Syndax showed that in non-small cell lung cancer patients with high levels of a specific protein called e-cadherin, entinostat plus the blockbuster drug erlotinib (Tarceva) produced a survival benefit over entinostat plus placebo. The e-cadherin biomarker is found in about 40 percent of patients with the disease. On July 6 in Amsterdam, researchers for the company will present data further defining the e-cadherin biomarker and showing that some patients with resistance to erlotinib benefitted from the addition of Syndax’s drug.

Syndax CEO Joanna Horobin says the further definition of the e-cadherin biomarker, as described in the data being presented, will allow the company to better design an effective Phase 3 program. “The most important thing is that this gives us a robust way to select patients” who are most likely to benefit from entinostat, she says. “We can identify the right patients to treat and monitor them while they’re being treated.”

Horobin says the company aims to start a Phase 3 study of entinostat plus erlotinib in the first half of next year. She adds that if the study succeeds, the drug will most likely be able to be marketed with a companion diagnostic to identify patients whose tumors have high levels of e-cadherin.

As the field of epigenetics continues to evolve, the cancer community is starting to explore the potential of combination epigenetic approaches. Towards that end, Syndax and the National Cancer Institute are studying entinostat in combination with 5-azacitidine (Vidaza), a drug marketed by Summit, NJ-based Celgene (NASDAQ: CELG). The Celgene product, which is what’s known as a “demethylation” agent,” destroys abnormal cells in the bone marrow and helps generate normal blood cells But it is also believed to reverse DNA methylation, thereby reactivating tumor-suppressor genes that have been silenced in the course of the disease.

Data from a Phase 2 trial of the combination in advanced non-small cell lung cancer will be presented in Amsterdam today. The study, which included 27 patients, showed a median overall survival of eight months. One patient, whose cancer spread to the liver despite previous therapies, responded so well to the experimental treatment that his liver disease resolved. And, says Horobin, “To our surprise, one patient had a complete tumor shrinkage. We often see stabilization, but not shrinkage.”

The entinostat-azacitidine combination is being tested in conjunction with Johns Hopkins University and Stand Up to Cancer—a Hollywood-funded initiative that’s aimed at encouraging research collaborations across companies and academic institutions. Horobin calls the project’s leaders “a dream team in epigenetics,” which includes Stephen Baylin, Hopkins researcher and Syndax advisor.

The next milestone for Syndax will come in the fall, when it present data from a Phase 2 study of entinostat plus aromatase inhibitors in breast cancer patients. The company is also planning a Phase 3 program for that combination. All in all, says Horobin, “We’re very excited. The whole premise of Syndax was to take the promise of epigenetics into solid tumors. This is very cool science.”

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