CYCLACEL'S CYC202 INDUCES CANCER CELLS TO COMMIT SUICIDE.

Cyclacel Limited, the UK-based biopharmaceutical company, has demonstrated through state-of-the-art biomarker technology that CYC202 (R-roscovitine), its lead CDK inhibitor drug candidate, appears to induce cancer cell suicide or apoptosis in patients receiving the drug.

Biomarker technology is used to understand the molecular mechanism of action of novel drugs in humans, provide insights into their pharmacological properties, measure their biological effect (e.g. induce cancer cells to commit suicide) and determine susceptibility or resistance to the treatment. In the long-term biomarker analysis of tumor blood and tissues may allow selective treatment with CYC202 of those patients identified as likely to benefit from the drug based on the specific genetic profile of their tumor.

Biomarker analysis of blood samples from patients with cancer treated with CYC202 demonstrated that 54% (14 of 26 analyzed) tested positive for cancer cell death or apoptosis following single agent treatment with the drug. In addition, seven CYC202 Phase I patients with various tumors, including pancreas and lung cancer, experienced long lasting tumor stabilization. These patients received CYC202 capsules taken by mouth after exhausting other treatment options. CYC202 is presently being tested in two international, multicentre Phase IIa clinical trials for the treatment of breast and lung cancer in combination with standard chemotherapy.

Cyclacel's Biomarker Team used a novel assay technique to calculate the extent by which cancer cells are committing suicide (or apoptotic index) in different patients on the drug. An advantage of this test is that it measures cellular material released into the circulation by dying or dead cancer cells as a result of apoptosis. In this manner small blood samples can be readily obtained from patients with solid tumors rather than tissue pathology samples obtained through biopsies. Another approach taken by Cyclacel's Biomarker Team is the study of plasma proteomic profiles allowing the precise comparison of the proteins present in a patient's plasma before and after treatment with CYC202. Using this approach markers were detected that are only present in plasma following CYC202 treatment.

Phase I trials are not designed to detect efficacy of experimental drugs. Patients enrolled in Phase I studies suffer from many different types of cancer, have typically exhausted other therapeutic alternatives and usually experience low survival. In order to assess their prognosis it is necessary to wait for approximately six months post treatment to determine whether their cancer has continued to grow. The seven patients in the CYC202 Phase I study reported with stable disease included patients with adenocarcinoma, adrenal, lung, ovarian, pancreatic, parotid gland and thymus cancers. All seven showed long Times-To-Progression ("TTP") of their cancer, ranging between 7 and more than 11 months, and have been on drug for several months, ranging between 6 and more than 15 cycles each involving 3 weeks of treatment.

Dr Athos Gianella-Borradori, Cyclacel's medical director commented, "It is encouraging to see validation of the presumed mechanism by which CYC202 is causing the death of cancer cells through biomarker technology. It is also encouraging to see Phase I patients with poor prognosis experience long periods of stable disease after single therapy with CYC202. One should nevertheless be cautious about not over interpreting early indications of effectiveness from unscheduled efficacy assessments. Now that we have established a baseline for quantifying apoptosis in patients undergoing CYC202 monotherapy, we can use such biomarker techniques to assess the effects of the drug on patients receiving CYC202 in combination with chemotherapy."

"The results presented at AACR confirm Cyclacel's technological leadership in the emerging field of biomarkers," said Spiro Rombotis, CEO. "This is a strategic technology facilitating more efficient investments in drug development programs. Biomarkers help determine clinical go/no go decisions very early in clinical development and are also proving invaluable in demonstrating early proof of concept in humans. We believe that biomarkers will be a source of competitive advantage in pivotal trials and market positioning by helping identify responder patients based on their genetic profile. We are excited about the work of our talented Biomarker Team and our goal of converting our understanding of biological pathways into patient treatment guidelines. We expect to use our Biomarker technology in additional drug programs as they progress into clinical trials."

About Cyclacel Cyclacel is a biopharmaceutical company that designs and develops small molecule drugs that act on key cell cycle regulators to stop uncontrolled cell division in cancer and other diseases involving abnormal cell proliferation. The company's discovery engines integrate cell cycle biology expertise with a large library of gene-based targets, state-of-the-art RNAi functional genomics, chemogenomics and clinical biomarker technologies to rapidly deliver new drugs. Cyclacel has six research and development programs underway. Most advanced is CYC202, a Cyclin Dependent Kinase (CDK) inhibitor, in Phase II trials for breast and lung cancer. CYC202 has also completed a Phase I trial in healthy volunteers and is being explored for use in glomerulonephritis, a disease of renal cell proliferation. Cyclacel has entered into corporate alliances with AstraZeneca, CV Therapeutics and a top 5 pharmaceutical major all in the oncology field.

Background

CYC202 (R-roscovitine) is a novel cell cycle drug belonging to the Cyclin Dependent Kinase (CDK) inhibitor class (US Patent 6,316,456). CDK inhibition is an important new approach in the quest for drugs that target the molecular mechanism of the body's own cancer stopping genes. In preclinical studies CYC202 demonstrated high specificity against CDK targets. CYC202 is supplied in capsules and is the first drug in its class that is available by mouth. Phase I clinical trials suggested that CYC202 appears to be well tolerated without the typical side effects associated with current chemotherapy and may induce lengthening of Time-To-Progression in patients with various cancers. Biomarker data showed that CYC202 is inducing cancer cell suicide or apoptosis in 54% (14/26 analyzed) of patients with solid tumors. CYC202 is currently in Phase IIa trials for breast and lung cancer. CYC202 has also completed a Phase I trial in healthy volunteers and is being explored for use in glomerulonephritis, a disease of renal cell proliferation.

Because CDK inhibitors act at a different part of the cell cycle than current chemotherapies, giving these drugs in combination to patients may work synergistically to improve anti-tumor activity compared to standard therapies. It is thought that the drug acts on the G1/S or early checkpoint of the cell cycle via CDK inhibition and induces cancer cells to die by committing suicide via apoptosis. Certain conventional chemotherapies, such as the antimetabolite gemcitabine, exert their anticancer activity at the S-phase of the cell cycle. The potential therefore exists for combinations of G1/S or early cell cycle inhibitors and S-phase active drugs to act in synergy and kill more cancer cells than either drug alone.

Dr Athos Gianella-Borradori, 47, joined October 2000. Previously Director Preclinical Development, Manufacturing, Clinical & Regulatory Affairs, Bavarian Nordic Research Institute GmbH; vice president Clinical Affairs, CruCell BV; and Head, Oncology & Hematology Clinical R&D, senior adviser Genetic Therapy and Stem Cell Technologies, Novartis Pharma Ltd. MD University of Bern; fellow Charing Cross Hospital, London; Children's Hospital, Los Angeles; University of Glasgow Royal Infirmary; University of Lausanne; University of Zurich. Board certified in Pediatrics Hematology and Oncology.

Spiro Rombotis, 45, joined August 1997. Has 21 years of experience with pharmaceutical and biotech companies. Previously vice president, International Operations & Business Development, managing director, Europe and director Japanese joint venture, The Liposome Company, Inc.; vice president, Pharmaceuticals, Central & Eastern Europe and director International Marketing, Bristol-Myers Squibb Company; head European Marketing and Sales, head Corporate Development, Centocor, Inc.; Business Development, Novartis AG. BA, Williams College, USA. MBA and Master's degree in Hospital Management with honours, Kellogg Graduate School of Management, where he serves on the Advisory Board, Kellogg Center for Biotechnology.

For more information, visit http://www.cyclacel.com.