First human PI trial for Inhibitor of Bcl-2 proteins

Gemin X Biotechnologies from Montreal, Canda, has initiated a Phase I clinical trial for GX15-070, the first small-molecule inhibitor of Bcl-2 proteins to be tested in humans.

The clinical trial is an open-label, dose-escalation study being conducted at the Lombardi Comprehensive Cancer Center at Georgetown University, and is designed to evaluate the safety and tolerability of multiple doses of GX15-070 in solid tumours. The protocol will include extensive pharmacokinetic sampling and pharmacodynamic evaluation.

Gemin X is the first company to develop a small molecule designed to target the Bcl-2 proteins and to test it in human clinical trials. Small molecules are considered the 'holy grail' of drug development because they are often easier to administer and cause fewer toxicities than other types of drugs.

'The start of clinical trials for GX15-070 represents a major step forward in Gemin X's mission of developing a portfolio of novel cancer treatments based on the modulation of apoptosis,' said Dan Giampuzzi, president and ceo of Gemin X. 'GX15-070 has shown remarkable safety and activity as a single agent in preclinical trials. Given its unique profile, we believe it has significant potential as a treatment for many types of cancers, both as a stand-alone therapy and in combination with existing therapies.'

In preclinical studies, GX15-070 administered as a single agent inhibited tumour growth in mouse models of melanoma as well as of breast, cervical, prostate and colon cancers. 'GX15-070 has shown strong activity at levels well below the maximum tolerated dose, which indicates that such a targeted therapy could potentially avoid the toxicities associated with less specific cancer treatments such as chemotherapy and radiation,' said Dr Jean Viallet, vice president of Clinical Development at Gemin X. 'If reflected in clinical studies, such a profile would make GX15-070 a very attractive alternative to burdensome combination therapies.'

In addition to the Phase I trial for solid tumour indications, the company expects to begin separate Phase I trials in Chronic Lymphocytic Leukemia (CLL) both in the US and Canada.

Apoptosis

Apoptosis is the natural process by which the body destroys diseased or damaged cells and is often inhibited in cancer cells, allowing them to accumulate and spread. GX15-070 induces apoptosis in cancer cells without damaging normal cells by inhibiting members of the Bcl-2 protein family. When over-expressed in cancer cells, Bcl-2 proteins stop apoptosis by blocking Bax and Bak, two key elements of the cell-death pathway. This over-expression of Bcl-2 proteins has been observed in a wide range of cancers, including those of the lymph, breast, lung, prostate and colon. Scientists believe that, because of the redundancy in the Bcl-2 family, inhibition of a single protein in this group is unlikely to result in a therapeutic effect. Instead, inhibition of all proteins in the family is needed to allow the cell death program to proceed. To address this issue, Gemin X has designed GX15-070 to target the entire group, instead of a single member, by exploiting the structural similarity of Bcl-2 proteins. "Bcl-2 is one of the most validated and well-studied targets in cancer research, so a compound that can inhibit not just one, but multiple members of this class is very exciting," said Dr John Marshall, an associate professor at Georgetown University. "Given the novelty of the mechanism and the practical nature of small molecule therapeutics, I am especially interested in exploring the potential of GX15-070 in this clinical trial."