BioWorld International Correspondent

LONDON - Cyclacel Ltd. said it is starting two Phase IIa trials of CYC202 in cancer, the first orally available small-molecule inhibitor of cyclin dependent kinase (CDK) to reach this stage of development.

CEO Spiro Rombotis told BioWorld International, "This is the first orally available CDK inhibitor to go into Phase II, and not only that, but it is the first CDK2-specific inhibitor. We still have a long way to go in the clinic [but] initiation of CYC202 trials in cancer is a very important milestone for our young company."

The trials will test CYC202 in combination with standard chemotherapy. In the first, in non-small-cell lung cancer, the drug will be administered with gemcitabine and cisplatinum. The second trial will evaluate CYC202 in the treatment of advanced breast cancer in combination with capecitabine. The open-label, multicenter studies each will recruit 30 patients.

CYC202 acts on the same CDK enzyme targets as tumor suppressor genes such as p53 and p21. These genes stop cancer cells at cell cycle checkpoints, causing them to commit suicide. While there are several CDK enzymes, Cyclacel believes CDK2 is the key target for initiating apoptosis. In the Phase I program, 78 subjects received CYC202 without any of the major side effects associated with standard cancer chemotherapy.

Cyclacel, based in Dundee, has set up a team of experts to assess and identify protein biomarkers that may be used to monitor susceptibility, or resistance, to the treatment. In particular, the company is working on detecting apoptotic nuclei of cancer cells in the patient's bloodstream.

Rombotis hopes this will allow Cyclacel to avoid the problem that British Biotech plc encountered in assessing the efficacy of its oral cancer treatment, marimastat, a matrix metalloproteinase inhibitor (MMPI). British Biotech relied on tumor antigen levels as proof of efficacy in Phase II, but that marker did not translate into a significant improvement in life expectancy in any of the nine Phase III trials of marimastat, all of which failed.

Rombotis said, "We are not arrogant, but there are two important differences. First, MMPIs do not achieve tumor kill; CDK inhibitors do. So looking for apoptopic nuclei is a far more pertinent marker of what we are trying to do. Second, we intend to match diagnostic tests with subtypes of patients on the basis of tumor types and genetic phenotypes."

In the longer term, biomarker analysis of tumors may allow selective treatment with CYC202 of those patients identified as likely to benefit based on the specific profile of their tumor.

The Phase II trials in cancer are expected to report in about one year. Within the next few weeks Cyclacel expects CYC202 to enter Phase II for the treatment of glomerulonephritis, an inflammatory disease of the kidney.