Cyclacel Announces In-Licensing Of Phase I Anticancer Drug From Sankyo

CYC682 Nucleoside Analogue Is Second Clinical Stage Compound in Cyclacel’s Portfolio

Dundee, UK and Tokyo, Japan - 5 December 2003 - Cyclacel Limited, the UK-based biopharmaceutical company, and Sankyo Co., Ltd, one of Japan’s top pharmaceutical companies, announced today that Cyclacel acquired exclusive rights in nearly all world territories to a Sankyo anticancer drug code-named CYC682. CYC682 is an oral small molecule nucleoside analogue that completed two Phase I studies involving 88 cancer patients in US hospitals under a US IND. Cyclacel plans to begin Phase I/II clinical studies with CYC682 in 2004.

Sankyo received an upfront payment and will receive milestones and royalties from Cyclacel. In addition, Sankyo has retained a right of first negotiation to market the compound in Japan. Specific financial terms were not disclosed.

Spiro Rombotis, CEO of Cyclacel said, “CYC682 provides Cyclacel with a second, clinical stage compound in oncology. CYC682 is complementary to and potentially synergistic with CYC202, which is currently in Phase II clinical trials for non-small cell lung and breast cancers. This asset has good strategic fit with our in-house assets, builds on our existing biomarker know how and clinical trial networks and broadens our oncology franchise.”

A Sankyo spokesperson said, “Cyclacel was selected among potential licensees because of its expertise in cancer cell cycle biology, its innovative use of biomarkers in clinical development of oncology drugs and its focus on similar projects which have a potential synergistic value with the CYC682 program. We look forward to the development of this promising anticancer agent and working with Cyclacel to bring it to market.”

CYC682 is an antimetabolite prodrug of the novel nucleoside CNDAC. Sankyo selected CYC682 for development because of its oral availability and its improved activity over gemcitabine (the leading marketed nucleoside analogue) and 5-FU (a widely-used antimetabolite drug) based on preclinical data in solid tumours. Recently investigators from Roswell Park Cancer Institute (Buffalo, New York) reported that CYC682 exhibited strong anticancer activity in a model of colon cancer. In the same model CYC682 was found to be superior to either gemcitabine or 5-FU in terms of increasing survival and also preventing the spread of colon cancer metastases to the liver.

Phase I data from eighty-eight (88) patients with a variety of cancers suggest that CYC682 is well tolerated in man. The dose limiting toxicity was myelosuppression. Stable disease was observed in seventeen (17) patients after CYC682 treatment, including one patient with ovarian cancer who experienced a minimal response and one patient with a gastrointestinal stromal sarcoma tumour (GIST) who remains on study for over 90 weeks with stable disease after failing multiple therapies.

Dr Bob Jackson, Cyclacel's Executive Director of R&D, said: “CYC682 has the potential to be an active anticancer drug. This nucleoside analogue appears under certain conditions to be superior to gemcitabine with the added advantage of oral bioavailability. CYC682 maybe particularly active in tumours with a low ratio of cytidine deaminase to deoxycytidine kinase, two enzymes involved in inactivating and activating respectively the mechanism by which CYC682 acts. This observation suggests the possibility of targeting clinical trials through the use of biomarker analysis to those patients most likely to benefit from the drug. In addition our in-house preclinical data suggested a synergistic effect between our lead CDK inhibitor CYC202 and the nucleoside analogue gemcitabine. We are now testing this combination in a Phase IIa clinical trial.”

Cyclacel's lead drug (CYC202, R-roscovitine) is presently in two Phase IIa trials in combination with gemcitabine and cisplatinum in patients with Non-Small Cell Lung (NSCLC) cancer and with capecitabine (a 5-FU prodrug) in breast cancer. It is thought that CYC202 acts mainly on the G1/S or early checkpoint of the cell cycle inducing cancer cells to die by committing suicide via apoptosis. CYC682 appears to exert its anticancer activity both by delaying cell cycle progression during S phase and inducing arrest at the G2 phase of the cell cycle. The potential therefore exists for combinations of G1/S or early cell cycle inhibitors and drugs acting on the S and G2 phases to work in synergy and kill more cancer cells than either drug alone.

About Cyclacel ( www.cyclacel.com )
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. Cyclacel’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. The Company has seven 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 completed Phase I trials in Europe with evidence of potential clinical benefit and is also being explored for use in glomerulonephritis, an inflammatory disease associated with kidney cell proliferation. CYC682, a nucleoside analogue, has completed Phase I trials in the USA with evidence of potential clinical benefit and was shown in preclinical tests to be superior to the leading nucleoside analogue gemcitabine. Cyclacel has entered into corporate alliances with AstraZeneca, CV Therapeutics, Lorus, Sankyo and a top 5 pharmaceutical major all in the oncology field.

About Sankyo
Sankyo Co. Ltd. is one of Japan's largest pharmaceutical companies with worldwide annual sales of $5 billion. Sankyo has a long history of discovering new classes of drugs, including the statin class of lipid-lowering drugs, with its discovery of the first statin, which was mevastatin (compactin, ML236B). Sankyo also discovered, co-developed and manufactures pravastatin sodium. Currently Sankyo’s research has been generating an innovative and attractive pipeline of anticancer drugs.

Notes to Editors: CYC202 (R-roscovitine) is a novel cell cycle drug belonging to the Cyclin Dependent Kinase (CDK) inhibitor class. 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 multiple CDKs. It is supplied in capsules and is the first drug in its class that is available by mouth. Results of Phase I trials in about 80 patients with different types of cancer suggest that CYC202 is well tolerated with evidence of potential clinical benefit in terms of response or stable disease. CYC202 has completed a Phase I trial in 24 healthy volunteers and is also being explored for use in glomerulonephritis, an inflammatory disease associated with kidney cell proliferation. CYC202 is currently in Phase IIa trials for breast and lung cancer.

CYC682 (1-(2-C-cyano-2-deoxy-ß-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine)⁴
CYC682 (or CS-682) is an oral prodrug and a novel derivative of 2’-deoxycytidine analogue CNDAC (1-(2-C-cyano-2-deoxy-ß-D-arabino-pentofuranosyl)-cytosine). CYC682’s availability by mouth is a feature of few new anticancer drugs increasingly favoured by patients. Knowledge of CYC682’s metabolic pathway and its effects on tumour growth offer the possibility of patient specific therapy. Studying appropriate biomarkers affected by CYC682 could aid selection of optimal dose and schedule and could eventually predict treatment outcome. Phase I data from eighty-eight (88) patients with a variety of cancers suggest that CYC682 is well tolerated in man with myelosuppression as dose limiting toxicity. Stable disease was observed in seventeen (17) patients after CYC682 treatment, including one patient with ovarian cancer who experienced a minor response and one patient with a gastrointestinal stromal sarcoma tumour (GIST) who remains on study for over 90 weeks with stable disease after failing multiple therapies.

Dr Robert Jackson, 60, joined January 2001. Has 21 years of experience with pharmaceutical and biotech companies and 14 as an academic investigator. Previously Research and Development Director and a member of the Board of Directors at Celltech Group plc; Executive Director, Research and Development and Chief Operating Officer and a member of the Board of Directors at Chiroscience Group plc, which was acquired by Celltech in 1999. Before these appointments, he was Vice President, Research and Development at Agouron Pharmaceuticals, Inc., and headed cancer research at DuPont Pharmaceuticals and Warner-Lambert Company. During his distinguished career, he has been instrumental in the discovery and development of several marketed drugs used to treat cancer, HIV and other serious diseases. BA, University of Cambridge; PhD University of London, Institute of Cancer Research.

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 honors, Kellogg Graduate School of Management, where he serves on the Advisory Board, Kellogg Center for Biotechnology.

© 2003 - Cyclacel Limited. Cyclacel®, Fluorescience®, Penetratin® and Polgen® are registered trademarks.

⁴ SELECTED ADDITIONAL REFERENCES (in chronological order):
Hanaoka, K., et al, Int. J. Cancer, 1999:82:226-236.
Donehower R, et al, Proc Am Soc Clin Oncol, 2000: abstract 764.
Burch, PA, et al, Proc Am Soc Clin Oncol, 2001: abstract 364.