Synta Pharmaceuticals receives FDA approval for resuming elesclomol clinical development

"The collected clinical and preclinical data presented to the FDA and to our external scientific advisory board provided compelling evidence for resuming clinical development with elesclomol,” said Vojo Vukovic, M.D., Ph.D., Chief Medical Officer, Synta. “The action by the FDA will allow us to further evaluate the potential of elesclomol in treating patients with cancer, incorporating the clinical experience and scientific understanding gained through a full analysis of the most recent data. Based on these results, we expect to initiate one or more clinical trials for elesclomol in the second half of this year. Further details will be announced over the coming months.”

The Phase 3 SYMMETRY^(SM) trial of elesclomol in metastatic melanoma was suspended in February 2009 based on an interim analysis that identified possible safety concerns. Preliminary results from the trial were presented at ASCO in May 2009 and Perspectives in Melanoma XIII in October 2009. These results showed a differential response to treatment with elesclomol based on level of baseline lactate dehydrogenase (LDH), an established prognostic biomarker in melanoma and a pre-specified stratification variable in the trial. The primary endpoint of progression-free survival was achieved in the normal LDH population, 68% of enrolled patients, with an acceptable safety profile. In the elevated LDH population, 32% of patients, no difference was observed between the two arms of the trial for the primary endpoint, and a negative impact was observed for the survival endpoint.

Results presented at the NCI-AACR-EORTC meeting in November 2009 demonstrated that elesclomol binds copper in plasma, facilitating its uptake into cells and enabling a transition between copper oxidation states inside the cell. Additional research by Synta and by external collaborators has shown that this reaction disrupts the metabolic properties of cancer cell mitochondria and generates the oxidative stress that triggers programmed cell death. Under normal oxygen conditions elesclomol exhibits potent anti-cancer activity. Under hypoxic (low oxygen) conditions, which are often associated with elevated LDH levels, cancer cell metabolism shifts away from the mitochondria and elesclomol anti-cancer activity is reduced. These results, together with the results observed in the SYMMETRY trial, suggest excluding patients with elevated LDH from future trials with elesclomol.

The application to the FDA to resume development focused on a specific clinical trial protocol that excluded patients with elevated LDH. Additional clinical trial protocols will require additional review by the FDA.