ELESCLOMOL

Program Overview

About Elesclomol

Elesclomol is a first-in-class, investigational drug candidate that triggers apoptosis (programmed cell death) in cancer cells. Cancer cells operate at high levels of reactive oxygen species (ROS), or oxidative stress. Elesclomol is believed to act by increasing the level of oxidative stress in cancer cells even further, beyond sustainable levels, inducing apoptosis. This mechanism of action, called oxidative stress induction, represents a novel way of selectively targeting and killing cancer cells.

In preclinical models elesclomol showed potent anti-cancer activity against a broad range of cancer cell types, as well as an ability to enhance the efficacy of certain chemotherapy agents with minimal additional toxicity. Cancers with elevated levels of reactive oxygen species (ROS) may be the most vulnerable to the oxidative stress induction mechanism of elesclomol. Tumor types with high ROS include melanoma, prostate, breast, ovarian, pancreatic, hematologic, and others.

In a 21-center, double-blind, randomized, controlled Phase 2b clinical trial in 81 patients with metastatic melanoma, elesclomol in combination with paclitaxel met the primary endpoint – doubling the median time patients survived without their disease progressing – compared to paclitaxel alone.

In November 2007, Synta announced that it had initiated a global, pivotal Phase 3 clinical trial in patients with metastatic melanoma. In February 2009, the trial was suspended 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.

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 in cancer cells. 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.

In December 2009, results presented at the American Society for Hematology showed that elesclomol was highly active against acute myeloid leukemia (AML) cell lines and primary blast cells from AML patients.

In March 2010, Synta announced that the FDA approved resuming clinical development with elesclomol.

Plans for future clinical trials with elesclomol will be announced later in 2010.

Elesclomol Presentations

Elesclomol Publications

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References

Oxidative Stress and Cancer

• Fruehauf, J.P., Meyskens, FL: Reactive Oxygen Species: A Breath of Life or Death? Clinical Cancer Research; 13(3) February 2007, 789-794.
• Fruehauf, J.P., Trapp, V: Reactive oxygen species: an Achilles' heel of melanoma? Expert Review of Anticancer Therapy. 8(11) November 2008, 1751-1757.
• Gastpar, R., Gehrmann, M., et.al.: Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res, 2005; 65 (12).
• Massa, C., et.al.: Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70. Cancer Res, 2004; 64:1502-1508.
• Noessner, E., et.al.: Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells. J of Immunology, 2002; 169:5424-5432.
• O'Day, S., et.al.: A Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma. J Clin Oncol. 2009 Oct 13. [Epub ahead of print].
• Pelicano, H., et al: ROS stress in cancer cells and therapeutic implications, Drug Resistance Updates 7 (2004) 97-110.
• Ramanathan, B., et al: Resistance to Paclitaxel is Proportional to Cellular Total Antioxidant Capacity, Cancer Research 65: (18), September 2005, 8455-8460.
• Schmitt, E., et.al.: Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J of Leukocyte Biology, 2007; Vol 81 (published as DOI 10.1189/jlb.0306167, Aug 2006).
• Schumacker, P.T.: Reactive oxygen species in cancer cells: Live by the sword, die by the sword, Cancer Cell, September 2006, 175-176.

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