Cyclacel Pharmaceuticals recently announced the first patient dosed in its Phase 1/2 study of oral fadraciclib in patients with advanced solid tumors and aggressive lymphomas. The trial used a streamlined study design and will determine the recommended Phase 2 dose. Once established, the trial will immediately enter a proof of concept, cohort stage trial with several cohorts.
I spoke to Spiro Rombotis, CEO of Cyclacel, to learn about the treatment, the importance of an oral cancer treatment in the time of COVID, and what the news will mean for patients with cancer tumors and leukemia.
Ed Miseta: Cyclacel Pharmaceuticals is developing therapies that target various phases of cell cycle control for the treatment of cancer and other diseases. Can you explain what that means?
Spiro Rombotis: Cyclin-dependent kinases (CDKs) are the “master regulators” of the cell cycle. Through phosphorylation and the binding of cyclin proteins, CDKs become activated and control cell cycle progression. CDK2 is responsible for regulating progression of the cell cycle while CDK9 regulates gene transcriptional activity, the mechanism by which normal cells transmit genetic instructions to their daughter cells. When CDKs become dysregulated, cancer cells experience unfettered growth and proliferation, transcription is disrupted and the program by which the body disposes of cancer cells, or apoptosis, is blocked. By selectively interfering with CDK2 and CDK9 activity through the use of inhibitors such as fadraciclib, apoptosis can be reactivated resulting in cancer cell death and normal cell cycle and transcriptional activity can resume.
Miseta: Can you tell us about the programs you have under way and where they stand?
Rombotis: Cyclacel is a clinical-stage biopharmaceutical company developing innovative oral, small-molecule drugs based on cell cycle biology to address the unmet needs of cancer patients. Both our most advanced medicines were designed in-house by our scientific teams. Our lead candidate, fadraciclib (formerly CYC065), is a highly selective and potent CDK2/9 inhibitor which enables cancer cell death by apoptosis in solid tumors and lymphomas. Preclinical models have demonstrated antitumor efficacy with daily oral dosing. Fadraciclib has recently entered into a potentially registration-enabling, Phase 1/2 trial in patients with 8 different types of advanced solid tumors with a similar study in leukemia soon to follow. Our second small-molecule drug candidate, CYC140, is a highly selective and potent, polo-like kinase 1 (PLK1) inhibitor. PLK1 is overexpressed in cancer cells and by interfering with cell division in the last stage of the cell cycle, or mitosis, it overrides DNA damage checkpoints ultimately leading to cancer growth. CYC140 specifically targets mitosis in cancer cells by inhibiting PLK1. When PLK1 is suppressed, cancer cells become more vulnerable to undergo apoptosis than normal cells. CYC140 showed promising preclinical activity in both liquid and solid cancer animal models. It is currently undergoing Phase 1 studies and will soon enter potentially registration-enabling, Phase 1/2 trials in patients with multiple types of advanced solid tumors and leukemias.
Miseta: Your ongoing Phase 1/2 trial with oral fadraciclib is in patients with solid tumors and lymphomas utilizes a streamlined trial design. Why did Cyclacel decide on a streamlined design for this study?
Rombotis: A streamlined trial design allows a sponsor company to advance from a Phase 1 stage aiming to define a recommended Phase 2 dose (RP2D) straight into a Phase 2 proof-of-concept stage aiming to identify activity in multiple cancer types initially as a single agent and later in combinations. If properly designed, a streamlined study may enable a sponsor to generate registration-enabling data facilitating accelerated registration and early market entry. This design represents an efficient use of capital and human resources and speeds patient access to innovative medicines.
Miseta: What types of cancer will you target with these treatments?
Rombotis: This trial is the first of four planned, streamlined Phase 1/2 studies to evaluate the potential of fadraciclib and CYC140 in multiple groups of patients, or cohorts, with solid tumors and later in leukemias. The Phase 2 portion of the fadraciclib solid tumor study includes 8 different cancer types, including bile duct, colorectal, liver, several women’s cancers, and lymphomas. Together with the soon to start leukemia study of oral fadraciclib which includes 6 different blood cancer types, they represent 14 chances to find registration-enabling outcomes or “shots on goal”.
This trial design also includes an innovative feature of a “basket” cohort in which patients can be enrolled regardless of where their cancer originated so long as they were found prior to enrolment to overexpress relevant proteins to the drugs’ mechanism of action. In the case of fadraciclib, such proteins include: MCL1, MYC and cyclin E.
Miseta: Where does Cyclacel go from here and what should we expect to see over the next several years?
Rombotis: We expect to be generating multiple outcomes in the 4 mid-stage trials we discussed over the next 18-24 months. At this point an estimated 25 “shots on goal” in solid tumors and leukemias with both of our drugs will read out over this period. It is very exciting to watch these in-house discovered medicines reach this stage in drug development. The future is bright for the biopharmaceutical industry as a continuous stream of innovative, small-molecule and biologic medicines are reaching the market in the years to come. Orally available small molecule drugs may hold particular promise in the war against cancer in these pandemic years as they spare patients from exposure to viral infections while receiving intravenous treatments. They can also increase quality of life for elderly and unfit patients who can be treated at home. This is our commitment to the cancer patients we serve and the reason for our efforts over many years to harness the power of cell cycle biology.