Cyclacel Pharmaceuticals
Cyclacel Pharmaceuticals (CYCC) Through the second quarter of 2017, its focus has been on its transcriptional regulation program where Cyclacel Pharmaceuticals is evaluating its cyclin dependent kinase, or CDK, inhibitor and its DNA damage response, or DDR, program, in which Cyclacel Pharmaceuticals is evaluating sapacitabine in combination with its CDK inhibitor seliciclib in solid tumors in a Phase1/2 study. Additionally, Cyclacel Pharmaceuticals is completing the analysis of data from SEAMLESS, the Phase 3 study in acute myeloid leukemia, (“AML”) and have closed the last remaining clinical trial sites.
Transcriptional Regulation Program, CDK inhibitors
Cyclacel Pharmaceuticals is progressing clinical development of its CDK inhibitor CYC065 in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors.1
CDKs are a family of enzymes first discovered as regulators of the cell cycle, but now understood to also provide pivotal functions in the regulation of transcription, DNA repair and metastatic spread. The precise selectivity of an individual CDK inhibitor molecule for specific CDKs is key to targeting particular tumor types and minimizing undesirable side effects through non-specific antiproliferative activity.
In general, cell cycle regulation is less well controlled in cancer cells than in normal cells, which explains in part why cancer cells divide uncontrollably. Different CDKs are responsible for control of different aspects of proliferation, and when dysregulated, can be drivers of particular cancer sub-sets. Modulating CDK activity with targeted therapies is an attractive strategy to reinforce cell cycle control and decrease the rate of abnormal proliferation of cancer cells. The first Food and Drug Administration (“FDA”) approval in March 2015 of a CDK inhibitor for palbociclib, and more recently in 2017, ribociclib, for a type of breast cancer, has led to great interest in the development of this class of drugs as oncology therapeutics.
Cyclacel’s founding scientist, Professor Sir David Lane, is a globally recognized authority in cell cycle biology, who discovered p53, a key tumor suppressor gene that malfunctions in about two-thirds of human cancers. Under his guidance, Cyclacel’s drug discovery and development programs concentrated on the CDK2/9 isoforms, which operate as key components of the p53 pathway. These efforts resulted in bringing two molecules into clinical trials: seliciclib, its first-generation CDK inhibitor, and CYC065, its second-generation CDK inhibitor, which has benefited from the Company’s clinical experience with seliciclib.
CYC065 is being evaluated in an on-going Phase 1 first-in-human clinical trial. The objective of Part 1 of the clinical trial was to assess the safety and recommended dosing for Phase 2 (RP2D) of CYC065 in advanced cancer patients, based on determination of the biologically effective dose through measurement of CYC065's effects on the Mcl-1 biomarker. Part 1 is now complete and the RP2D has been selected, Part 2 of the study will focus on patients with advanced solid tumors with amplification of cyclin E (CCNE). The trial is being conducted at the Dana Farber Cancer Institute in Boston.
Seliciclib, is being evaluated in an all-oral Phase 1/2 combination study with its sapacitabine in patients with BRCA mutations, and has been evaluated to date in approximately 450 patients.
Similar to the approved CDK inhibitors, palbociclib and ribociclib, CYC065 may be most useful in combination with other anticancer agents, but as a therapy for patients with both liquid and solid tumors, using combinations including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.
DNA Damage Response, or DDR, Program
In its DNA damage response program Cyclacel Pharmaceuticals is evaluating sapacitabine in combination with its first-generation CDK inhibitor seliciclib in solid tumors.
Many cancers have defects in the way in which cells monitor and repair damaged DNA, collectively termed DNA damage response, or DDR. These deficiencies in DDR pathways render cells more susceptible to DNA damage. Many traditional cancer treatments, such as DNA-damaging chemotherapy and radiotherapy, are based on this finding. However, such treatments are often accompanied by significant and unwanted side effects. Developing treatments which target specific DDR deficiencies to preferentially kill cancer cells, while minimizing the impact on normal cells, has potential for more selective, better tolerated therapies, to improve survival in multiple cancers.
Cyclacel Pharmaceuticals has focused on developing treatments targeting DNA damage pathways for several years. For example, drug candidate sapacitabine is an oral nucleoside analogue prodrug whose metabolite, CNDAC, generates single-strand DNA breaks, or SSB, either leading to arrest of the cell cycle at G2 phase or development of double-strand DNA breaks, or DSB. Repair of CNDAC-induced DSB is dependent on the homologous recombination, or HR repair pathway. BRCA mutations in cancer cells are a cause of HR deficiency, making such cancer cells susceptible to cell death induced by sapacitabine.
Cyclacel Pharmaceuticals is evaluating sapacitabine in a Phase 1/2 combination study with seliciclib in patients with BRCA mutations.
In addition to these development programs, Cyclacel Pharmaceuticals is completing the analysis of data from SEAMLESS, the Phase 3 study in AML, in the elderly, in an alternating schedule with decitabine and closing the last remaining clinical trial sites.
Cyclacel currently retains virtually all marketing rights worldwide to the compounds associated with the Company’s drug programs.
Subsequent Events
On July 19, 2017, the Company entered into an underwriting agreement with Ladenburg Thalmann & Co. Inc., acting as the representative of the several underwriters named therein, relating to the issuance and sale of 
3,154,000 Class A Units, each consisting of one share of the Company’s common stock, and a warrant to purchase one share of common stock, and (ii) 8,872 Class B Units, each consisting of one share of the Company’s Series A Preferred Stock, convertible into 500 shares of common stock at the initial conversion price, and a warrant to purchase a number of shares of common stock equal to $1,000.00 divided by the conversion price. The price to the public in the offering was $2.00 per Class A Unit and $1,000.00 per Class B Unit. The closing of the offering occurred on July 21, 2017, and the net proceeds to the Company were approximately $13,800,000 after deducting underwriting discounts and commissions and other estimated offering expenses, and including the full exercise of the underwriters’ option for a period of 45 days to purchase up to 990,000 additional shares of common stock and/or warrants to purchase up to 990,000 shares of common stock solely to cover any over-allotments.
Each share of Series A Preferred Stock is convertible at any time at the option of the holder thereof, into a number of shares of common stock determined by dividing $1,000 by the initial conversion price of $2.00 per share, subject to a 4.99% blocker provision, or, upon election by a holder prior to the issuance of shares of Series A Preferred Stock, 9.99%. The Series A Preferred Stock will have the same dividend rights as the common stock, and no voting rights except as provided for in the Certificate of Designation or as otherwise required by law. In the event of any liquidation or dissolution of the Company, the Series A Preferred Stock ranks senior to the common stock in the distribution of assets, to the extent legally available for distribution.
Subsequent to the closing of the offering, holders of 7,613 (86%) shares of the Series A Preferred Stock elected to convert their shares into 3,806,500 shares of common stock. Following such conversions, 11,400,447 shares of common stock and 1,259 (14%) shares of Series A Preferred Stock remain outstanding as of August 8, 2017.
