ELESCLOMOL
Mitochondria Metabolism Inhibitor

Program Overview

About Elesclomol

Elesclomol is a first-in-class, investigational drug candidate that triggers programmed cell death (apoptosis), in cancer cells through a novel mechanism: disrupting cancer cell energy metabolism by selectively targeting the electron transport chain in cancer cell mitochondria.

Upon infusion, elesclomol binds copper in plasma, causing a change in conformation that enables its uptake through membranes and into cells. Elesclomol binds copper in an oxidative, positively charged, state called Cu(II). Once inside mitochondria, the elesclomol-Cu(II) complex interacts with the energy production mechanism of the cell, or the electron transport chain. This interaction reduces the copper from Cu(II) to Cu(I), resulting in a cascade of reduction-oxidation, or redox, reactions, that causes a rapid increase of oxidative stress, disruption of mitochondrial energy production, and ultimately, triggering of the mitochondrial apoptosis pathway.

Mitochondria generate energy for cells, but also can drive apoptosis under certain conditions, such as a high level of oxidative stress. By increasing oxidative stress inside mitochondria and inducing apoptosis, elesclomol may provide a means to overcome resistance to traditional chemotherapy or targeted therapy. Elesclomol has shown potent cancer-cell killing activity against a broad range of cancers in vitro, and synergistic anti-cancer activity with paclitaxel and other agents in animal models of cancer.

LDH: predictive biomarker for activity

LDH is an enzyme that plays a key role in cancer cell energy metabolism. Under normal oxygen, or normoxic, conditions, energy in tumors is primarily generated by conversion of nutrients to adenosine triphosphate, or ATP, in the mitochondria, with oxygen as a key component of this process. Levels of LDH generally remain in the normal range in this state. Under low oxygen, or hypoxic conditions, energy in tumors is primarily generated by glycolysis in the cytoplasm, and levels of LDH may increase. Accordingly, LDH can be used as a marker of mitochondrial activity, or tumor cell metabolic state.

Elesclomol kills cancer cells in which the mitochondrial ETC is the dominant source of energy production. This occurs under normal oxygen (normoxic) conditions. When cells are under low oxygen (hypoxic) conditions, energy production shifts to glycolysis in the cytoplasm, producing energy from the conversion of glucose into other byproducts; mitochondrial energy production is reduced or absent. Under these conditions, elesclomol loses anti-cancer activity.

Glycolysis under hypoxic conditions is reflected in an increase in the levels of the enzyme lactate deyhdrogenase (LDH). This suggests that level of LDH may be a predictive biomarker for elesclomol activity. Evidence that elesclomol anti-cancer activity correlates with metabolic state – oxygen conditions and level of LDH – includes:

• elesclomol shows potent activity, with IC50<10 nM in over 150 different cancer lines, against cells grown under normal oxygen conditions, but little to no activity against cells grown under hypoxic conditions;
• elesclomol shows little to no activity against cells treated with CoCl2, a chemical mimetic of hypoxia;
• treating hypoxic cells with the LDH inhibitor oxamate, which induces a shift from glycolysis back to mitochondria-driven oxidative phosphorylation, restores elesclomol anti-cancer activity; and
• within the same cancer type, elesclomol is less active in cell lines with high levels of HIF1a (hypoxia inducible factor 1 alpha) and LDH, markers of hypoxic conditions; and more active in cells with low levels of HIF1a and LDH.

Clinical observations have been consistent with the preclinical findings that elesclomol activity depends on metabolic state at the cellular level. In three randomized trials, in a total of over 800 patients, elesclomol showed clinical activity that correlated with baseline level of LDH. Benefit was seen only in patients with the low to normal levels of LDH associated with normoxic conditions. In our ongoing and planned studies with elesclomol, we anticipate enrolling only patients with low to normal LDH levels, as these are the patients we believe are most likely to derive benefit from treatment with elesclomol.

Clinical Trials

Phase 2 in Combination with Paclitaxel in Ovarian Cancer

This Phase 2 single-arm, open-label study will recruit up to approximately 50 patients who have progressed on platinum-based therapy. The primary objectives of the trial are to assess activity, based on objective response rate, and safety of the combination in this patient population. Secondary objectives include assessing progression-free survival and overall survival. Elesclomol sodium 200 mg/m2 and paclitaxel 80 mg/m2 will be given as separate 1 hour IV infusions weekly for three weeks followed by one week rest, comprising a four-week cycle. Treatment may continue until disease progression. Click here for further information.

Phase 1 Trial in Acute Myeloid Leukemia (AML)

This is a Phase 1 dose-escalation study of elesclomol sodium in patients with relapsed or refractory acute myeloid leukemia (AML). The primary objectives of study are to characterize safety, tolerability, and pharmacokinetics. Additional objectives are to identify the phase 2 dose and characterize signs of biologic and clinical activity. Click here for more information on this trial.

Elesclomol Presentations

Elesclomol Publications

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References

Oxidative Stress and Cancer

• Fulda, S., Galluzzi, L., Kroemer, G.: Targeting mitochondria for cancer therapy. Nature Reviews Drug Discovery. (9) June 2010, 447-64.
• Georg T. Wondrak. Antioxidants & Redox Signaling. December 2009, 11(12): 3013-3069.
• Hersey, P., et. al.: Small molecules and targeted therapies in distant metastitic disease. Annals of Oncology. 20(6) August 2009, 35-40.
• J.P., Trapp, V: Reactive oxygen species: an Achilles' heel of melanoma? Expert Review of Anticancer Therapy. 8(11) November 2008, 1751-1757.
• Toogood, P.: Mitochondrial drugs. Current Opinion in Chemical Biology. (12) July 2008, 457-63.
• Tuma, R.: Reactive oxygen species may have antitumor activity in metastitic melanoma. Journal of National Cancer Institute. 100(1) January 2008, 11-12.
• Fruehauf, J.P., Meyskens, FL: Reactive Oxygen Species: A Breath of Life or Death? Clinical Cancer Research; 13(3) February 2007, 789-794.
• Schumacker, P.T.: Reactive oxygen species in cancer cells: Live by the sword, die by the sword, Cancer Cell, September 2006, 175-176.
• Ramanathan, B., et al: Resistance to Paclitaxel is Proportional to Cellular Total Antioxidant Capacity, Cancer Research 65: (18), September 2005, 8455-8460.
• Pelicano, H., et al: ROS stress in cancer cells and therapeutic implications, Drug Resistance Updates 7 (2004) 97-110.

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