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GMX1777

R&D Pipeline GX15-070 (obatoclax) Oral GX15-070 Telomere Capping Mechanism p53 Independent Mechanism

Status  GMX1777 is a water soluble intravenously-administered prodrug of GMX1778, in-licensed from LEO Pharma (LEO numbers: EB1627 and CHS828, respectively). Although the mechanism of action of LEO's CHS828 was not known, it exhibited highly potent toxicity in cancer cells, including those with a loss of the p53 tumor suppressor. Gemin X has discovered that the cytotoxicity of GMX1778 occurs exclusively through its ability to selectively inhibit nicotinamide phosphoribosyl transferase (NAMPRT). GMX1777 exhibits unusually potent anti-tumor activity in preclinical animal models. Gemin X completed IND-enabling studies of GMX1777 in late 2006, and has initiated Phase 1 dose-escalation clinical trials in relapsed patients with solid tumor and lymphoma malignancies.

Mechanism of Action   Gemin X performed extensive preclinical studies to optimize the therapeutic potential of GMX1777. The ability to deliver the prodrug by prolonged intravenous infusion overcomes the limiting acute toxicities previously encountered with the orally administered CHS828. GMX1777 is rapidly converted to GMX1778 in vivo through hydrolytic cleavage of an ester carbonate bond.

Tumor cells have elevated NAMPRT, an enzyme involved in the biosynthesis of oxidized nicotinamide adenine dinucleotide (NAD+). These cells have a high rate of NAD+ turnover due to elevated glycolysis and high ADP-ribosylation activity required for DNA repair, genome stability and telomere maintenance. These latter characteristics make cancer cells more susceptible to NAMPRT inhibition than normal cells. Although the mechanism of action of GMX1778 was initially believed to include NF-κB inhibition, a transcriptional factor that plays a role in cancer cell survival, NF-κB inhibition occurs as a consequence of ATP loss following NAMPRT inhibition and NAD+ decline.

The novel mechanism of action of GMX1778 supports the clinical use of GMX1777 as an anti-cancer agent. Moreover, the strong dependency of cancer cells on NAD+ to support DNA repair suggests a strong rationale for the use of GMX1777 in combination with DNA damaging agents for future trials.