Elesclomol is a first-in-class investigational drug, believed to work by exploiting a fundamental vulnerability of many cancer cells – their elevated level of reactive oxygen species (ROS) and diminished anti-oxidant capacity. By further elevating ROS levels in cancer cells, elesclomol increases oxidative stress, triggering programmed cell death (apoptosis) while leaving normal cells relatively unaffected. Elesclomol is not approved for marketing by any regulatory body in any country.
"This is the first clinical trial that will study the potential
anti-cancer activity of elesclomol as a single agent," said
The open-label, dose-escalation study of elesclomol in up to 30 subjects with advanced metastatic or unresectable solid tumors is designed to identify the maximum tolerated dose of elesclomol sodium based on a weekly infusion dosing schedule. Pharmacokinetic, safety and efficacy endpoints, including tumor response and durability of response will also be evaluated. This study uses a water soluble (sodium salt) formulation, allowing flexible administration, either as monotherapy or in combination with other anti-cancer agents.
Elesclomol is a novel, injectable, investigational drug candidate that triggers apoptosis (programmed cell death) in cancer cells. Cancer cells operate at high levels of reactive oxygen species, 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 a double-blind, randomized, controlled Phase 2b clinical trial in 81 patients with stage IV 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 (p = 0.035). The most common adverse events in the elesclomol plus paclitaxel group seen in at least 20% of patients included fatigue, alopecia, constipation, nausea, hypoaesthesia, arthralgia, insomnia, diarrhea, and anemia.
Ongoing Clinical Trials
A global, pivotal Phase 3 clinical trial of elesclomol in combination with paclitaxel in patients with stage IV metastatic melanoma (the SYMMETRY trial) has completed enrollment. Elesclomol is also being studied in an open-label Phase 1/2 study of elesclomol in combination with docetaxel in approximately 34 patients with advanced metastatic, hormone refractory prostate cancer. Additional trials to evaluate elesclomol as a therapy for other cancers are planned.
About Oxidative Stress
Oxidative stress in cells is the presence of elevated levels of reactive oxygen species (ROS) such as oxygen radicals and hydrogen peroxide. ROS can be generated by many processes and stimuli, including ordinary cell metabolism, exposure to heat or radiation, or attack by bacteria or viruses. Because ROS can react chemically with different proteins and other elements of a cell, altering their normal function, prolonged exposure to elevated levels of ROS can cause serious damage to a cell. To protect against this damage, cells have natural defense mechanisms – anti-oxidant abilities – to clear excessive levels of ROS and to repair the disruption they cause.
Normal, non-cancer cells typically function at a low, steady-state level of oxidative stress. Their strong anti-oxidant capacity guards against prolonged, excessive levels of ROS. Cancer cells, however, typically operate at a much higher level of oxidative stress than normal cells, and have a greatly diminished anti-oxidant capacity. This diminished capacity to clear ROS leaves them vulnerable to further increases in oxidative stress. In particular, when ROS levels exceed a natural breaking point, continued survival of the cell becomes unsustainable. At levels of ROS above this breaking point, a switch inside the mitochondria is triggered that causes the cell to initiate programmed cell death, also known as apoptosis.
By elevating ROS, an oxidative stress inducer such as elesclomol exploits this difference between cancer cells and normal cells. Elesclomol has been observed to have little to no effect in vitro on most normal cells. In contrast, elesclomol has been observed to potently induce apoptosis in 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.
Oxidative stress induction represents a novel approach to treating cancer. It is distinct from chemotherapy, from "targeted" agents such as kinase inhibitors and antibodies, and from angiogenesis inhibitors in that OS inducers exploit a fundamentally different vulnerability of cancer cells – the elevated levels of reactive oxygen species.
For more on oxidative stress and cancer see for example J. Fruehauf et
Synta and GSK are working closely together to further the clinical development of elesclomol as well as prepare for the manufacture and commercial launch of elesclomol.
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This media release may contain forward-looking statements about
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125
MacDougall Biomedical Communications
Doug MacDougall, 781-235-3060