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Item 1. Business

2022-03-30 compared with 2021-03-01 · 209 added, 203 removed, 272 unchanged (60% of the section changed)

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In this report, “Cyclacel,” the “Company,” “we,” “us,” and “our” refer to Cyclacel Pharmaceuticals, Inc.

Cyclacel is a clinical-stage biopharmaceutical company developing innovative cancer medicines based on cell cycle, transcriptional regulation and mitosis control biology.

Cyclacel is a pioneer company in the field of cancer cell cycle biology with a vision to improve patient healthcare by translating insights in cancer biology into medicines that can overcome resistance and ultimately increase a patient’s overall survival.

We are a clinical-stage biopharmaceutical company working to develop innovative cancer medicines based on cell cycle, transcriptional regulation and mitosis control biology.

We are a pioneer company in the field of cancer cell cycle biology with a vision to improve patient healthcare by translating insights in cancer biology into medicines that can overcome resistance and ultimately increase a patient’s overall survival.

The transcriptional regulation program is evaluating fadraciclib, a CDK2/9 inhibitor, in solid tumors and hematological malignancies.

The anti-mitotic program is evaluating CYC140, a PLK1 inhibitor, in advanced cancers.

Cyclacel's strategy is to build a diversified biopharmaceutical business based on a pipeline of novel drug candidates addressing oncology and hematology indications.

Our strategy is to build a diversified biopharmaceutical business based on a pipeline of novel drug candidates addressing oncology and hematology indications.

We have retained rights to commercialize our clinical development candidates and our business objective is to enter into selective partnership arrangements with these programs.

Substantially all efforts of the Company to date have been devoted to performing research and development, conducting clinical trials, developing and acquiring intellectual property, raising capital and recruiting and training personnel.

Substantially all our efforts to date have been devoted to performing research and development, conducting clinical trials, developing and acquiring intellectual property, raising capital and recruiting and training personnel.

Cell Cycle Control Biology

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This process also includes mechanisms known as cell cycle checkpoints, to ensure all necessary events of each cell cycle phase are completed before beginning the next phase.

If the events are not completed correctly, the cells may commit suicide by a process of programmed cell death called apoptosis.

Cyclin dependent kinases, or CDKs, and Polo-like Kinases, or PLKs, are key regulators among the numerous genes and proteins involved in cell cycle control processes.

CDKs connect with proteins called cyclins to regulate cell cycle checkpoints and control transcription, DNA repair and metastatic spread.

Specific isoforms of cyclin dependent kinases, or CDKs, and Polo-like Kinases, or PLKs, are some of the key regulators among the numerous genes and proteins involved in cell cycle checkpoints.

If checkpoint control events are not completed correctly, the cancer cells may commit suicide by a process of programmed cell death called apoptosis.

We seek to enhance and facilitate apoptotic outcomes in cancer cells with the objective of containing the disease and benefitting patients with various cancers.

CDKs interact with proteins called cyclins to regulate cell cycle checkpoints and control transcription, DNA repair and metastatic spread.

The discovery of CDKs and cyclins and their regulation of cell cycle checkpoint control were cited in the 2001 Nobel Prize in Physiology or Medicine.

Cyclacel’s founder, Professor Sir David Lane, PhD, first identified CDK2/9 inhibition as the optimal target profile for transcriptionally active CDK inhibitors.

Our founder, Professor Sir David Lane, PhD, an internationally recognized authority in cell cycle biology who discovered p53, a key tumor suppressor that malfunctions in about two-thirds of human cancers, first identified CDK2/9 inhibition as an optimal target profile for transcriptionally active CDK inhibitors.

The lead drug in our transcriptional regulation program is fadraciclib (also known as CYC065), a CDK2/9 inhibitor.

Polo Kinases and other mitotic kinases were first discovered in fruit flies by Cyclacel’s former Chief Scientist, Professor David Glover, PhD.

Polo Kinases and other mitotic kinases were first discovered in fruit flies by our former Chief Scientist, Professor David Glover, PhD.

PLK1 is a serine/threonine kinase playing a central role in cell division, or mitosis.

In particular, PLK1 regulates mitotic entry, spindle formation, mitotic exit, cytokinesis and is an important regulator of the DNA damage checkpoint.

Cancer cells are much more sensitive to PLK1 depletion than normal cells with intact checkpoints.

Cancer cells are much more sensitive to PLK1 depletion than normal cells with intact cell cycle checkpoints.

Inhibiting PLK1 blocks proliferation by prolonged mitotic arrest followed by onset of cancer cell death.

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Clinical Development Pipeline

The following table summarizes our development pipeline:

Our pipeline of innovative medicines aims to provide safe and effective anticancer treatment options to patients combined with the convenience of oral administration.

Although we initially evaluated both fadraciclib and CYC140 using intravenous, or i.v., administration our recent and planned Phase 1/2 clinical studies use oral administration.

During the pandemic, hospitals severely restricted access for patients to clinical studies which in particular impacted those receiving i.v.

Empirical data from our clinical studies also suggested that daily dosing by the oral route is a preferred strategy for both our drugs.

We thus moved quickly to switch our studies from i.v.

to oral administration of fadraciclib and CYC140.

The aim of the current streamlined studies is to assess safety and identify signals of clinical activity which may lead to registration-enabling outcomes.

The following table summarizes our current development programs:

Transcriptional Regulation

Fadraciclib CDK inhibitor (oral)

Solid tumors – multiple cohorts defined by cancer histology

Phase 1/2 to achieve proof of concept (in planning)

Leukemias – multiple cohorts defined by cancer histology

Phase 1/2 to achieve proof of concept (in planning)

Phase 1 (ongoing) incl.

part 3 oral bioequivalence study

Fadraciclib CDK inhibitor (i.v.)

Solid Tumors incl.

MCL1, MYC family, Cyclin E amplification

CLL combination with venetoclax, BCL2 inhibitor

AML/MDS combination with

venetoclax, BCL2 inhibitor

Phase 1 (ongoing)

Solid tumors – multiple cohorts defined by cancer histology and a basket cohort

Phase 1/2 to achieve proof of concept (in progress)

Fadraciclib CDK inhibitor

Leukemias – multiple cohorts defined by cancer histology and a

Phase 1/2 to achieve proof of concept (in progress)

basket cohort

Mitosis Regulation

CYC140 PLK inhibitor (oral)

Solid tumors – multiple cohorts defined by cancer histology

Solid tumors – multiple cohorts defined by cancer histology and a basket cohort

Phase 1/2 to achieve proof of concept (in progress)

CYC140 PLK inhibitor (oral)

Leukemias – multiple cohorts defined by cancer histology and a basket cohort

Phase 1/2 to achieve proof of concept (in planning)

CYC140 PLK inhibitor (i.v.)

Advanced leukemias

Phase 1 (ongoing)

DNA Damage Response

Sapacitabine (oral)

BRCA mutated breast cancer combination with Olaparib, PARP inhibitor

Phase 1 (ongoing investigator-sponsored trial)

Sapacitabine (oral)

AML/MDS combination with venetoclax, BCL2 inhibitor

Phase 1/2 (ongoing)

Cyclacel currently retains all global marketing rights to the compounds associated with our clinical-stage drug programs with the exception of Japan in the case of sapacitabine.

Phase 1/2 (completed recruitment)

acute myeloid leukemia;

cyclin-dependent kinase;

chronic lymphocytic leukemia;

myelodysplastic syndrome;

polo-like kinase.

We currently retain all global marketing rights to the compounds associated with our clinical-stage drug programs with the exception of Japan in the case of sapacitabine.

Transcriptional Regulation Program

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The best characterized CDK enzymes include CDK2, -4, -6 and -9.

Cyclacel’s CDK inhibitors, fadraciclib and seliciclib, target CDKs 2 and 9.

CDK2/9 inhibition may also overcome aberrant cell cycle control in certain non-malignant diseases of proliferation.

Following Professor Sir David Lane’s insights, our drug discovery and development programs concentrated on the CDK2/9 isoforms, which operate as key components of the p53 pathway.

Pharmacological inhibition of the CDK2/9 isoforms, by medicines like fadraciclib, has been shown to have potent anticancer effects in preclinical and clinical studies against certain cancer types, including some that are resistant to approved treatments.

It is hoped that treatment with fadraciclib will result in clinically relevant, tumor cell death in patients with selected cancer types.

Fadraciclib inhibits CDK2, which is activated by Cyclin E, an oncogene to which cancer cells become addicted.

CDK2/9 inhibitors may be able to overcome cyclin E-dependent resistance to CDK4/6 inhibitor plus hormone therapy regimens when given in combination with one or more of these agents.

The FDA approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, represent an important therapeutic advance and are associated with clinically meaningful survival advantages with good tolerability when combined with hormone therapy versus hormone therapy alone in patients with hormone receptor positive, HER2-negative breast cancer.

CDK4/6 inhibitors induce senescence or dormancy of cancer cells, which may be associated with the emergence of resistance.

If clinical manifestation of resistance becomes common, the therapeutic utility of CDK4/6 inhibitors could be hampered.

Cyclacel’s founding scientist, Professor Sir David Lane, is an internationally recognized authority in cell cycle biology who discovered p53, a key tumor suppressor 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, a first-generation CDK inhibitor, and fadraciclib, a second-generation CDK inhibitor, which has benefited from the Company’s clinical experience with seliciclib.

Pharmacological inhibition of the CDK2/9 isoforms has been shown to have potent anticancer effects in certain cancer types, including some that are resistant to approved treatments.

CDK2/9 inhibitors have been shown to induce apoptosis of cancer cells.

It is hoped that treatment with CDK2/9 inhibitors will result in clinically relevant, tumor cell death in patients with selected cancer types.

Similar to the approved CDK 4/6 inhibitors, CDK2/9 inhibitors will likely be given in combination with other available anticancer agents.

For example, a potential use of CDK2/9 inhibitors may be to overcome cyclin E dependent resistance to CDK4/6 inhibitors and hormone therapy when given in combination with one or more of these agents.

Recent clinical data show that treatment failure after CDK4/6 inhibitors is associated with amplification of cyclin E (Turner NC et al, JCO, 2019).

Treatment of patients failing CDK4/6 inhibitors with CDK2/9 inhibitors, such as fadraciclib, may provide extended benefit to these patients.

Preclinical data suggest that treatment of HER2-positive breast cancer cells resistant to standard of care trastuzumab with a combination of trastuzumab and fadraciclib results in regression of these difficult to treat cancer cells (Scaltriti M et al, PNAS , 2011).

Different CDKs are responsible for controlling different aspects of proliferation which, when dysregulated, can be drivers of particular cancer sub-sets.

Our CDK clinical candidates target:

● CDK2, which drives cell cycle transition and

● CDK9, which regulates transcription of certain genes, including cyclins, MCL1, MYC family and DNA double-strand break repair pathway components, through phosphorylation of RNA polymerase II.

CDK2 and CDK9 inhibitors have been shown to induce apoptosis of cancer cells.

CDK2/9 inhibition may also overcome aberrant cell cycle control in certain non-malignant diseases of proliferation.

Fadraciclib targets:

● CDK2, which drives cell cycle transition and is activated by Cyclin E.

● CDK9, which regulates transcription of certain genes through phosphorylation of RNA polymerase II c-terminal domain Ser2., MCL1 mRNA and protein are labile (and turn over rapidly).

Blocking CDK9-dependent transcription quickly leads to loss of MCL1 protein, resulting in apoptosis in MCL1-dependent cancer cells.

Labile proteins rapidly depleted by short CDK9 inhibitor exposure include MCL1, MYCN, MYC, MYB, BCL2A1 and MDM2.

o MCL1 is overexpressed in many types of cancer acting as a survival and drug resistance mechanism.

Multiple studies show that knockdown of MCL1 leads to cancer cell death and resensitization to drug treatment.

o MYC proto-oncogenes encode MYC family proteins which are overexpressed in over 50% of human cancers often via gene amplification.

MYC proteins are transcriptional regulators which promote cancer cell growth and survival by increasing the expression of target genes involved in cell metabolism and growth.

MYCN gene amplification is found in 45% of high-risk neuroblastomas, or NB, a childhood cancer with poor long-term survival.

o Multiple studies show that knockdown of MCL1 and/or MYC lead to cancer cell death and resensitization to drug treatment.

Fadraciclib is a selective, second-generation inhibitor of CDK2/9 that causes apoptotic death of cancer cells at sub-micromolar concentrations and is bioavailable via oral and intravenous routes.

Antitumor efficacy has been achieved in preclinical models with once-a-day oral dosing at well tolerated doses.

Fadraciclib is mechanistically similar to seliciclib, Cyclacel’s first-generation CDK2/9 inhibitor, but has much higher potency in vitro and in vivo, improved metabolic stability and longer patent protection.

Translational biology data support development of fadraciclib in MCL1 dependent cancers.

In a Phase 1, first-in-human study of fadraciclib, prolonged reduction of MCL1 for at least 24 hours was achieved and preliminary anticancer activity observed.

In a Phase 1, first-in-human study of fadraciclib, prolonged reduction of MCL1 for at least 24 hours was achieved and anticancer activity observed.

Fadraciclib has been shown to inhibit CDK9-dependent oncogenic and leukemogenic pathways, including MYCN and mixed lineage leukemia rearrangements, or MLL-r.

Fadraciclib and seliciclib both suppress the MCL1-mediated survival pathway in cancer cells, leading to rapid induction of apoptosis in MCL1 dependent cancer cells, and can reverse drug resistance associated with the addiction of cancer cells to cyclin E, a partner protein of CDK2.

Fadraciclib suppresses the MCL1-mediated survival pathway in cancer cells, leading to rapid induction of apoptosis in MCL1 dependent cancer cells, and can reverse drug resistance associated with the addiction of cancer cells to cyclin E, a partner protein of CDK2.

Clinical development

Fadraciclib has been evaluated in a first-in-human, single agent, ascending dose, Phase 1 trial to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in patients with advanced solid tumors (065-01, NCT02552953) .

The results of part 1 of the study were reported in an oral presentation at the 2018 Annual Meeting of the American Association of Cancer Research.

26 patients were treated with fadraciclib as a 4-hour infusion once every 3 weeks and a recommended Phase 2 dose, or RP2D, established.

Durable MCL1 suppression was observed in 11 of 13 patients treated at the RP2D.

Stable disease lasting at least six cycles was observed in six patients of which three had molecular features associated with fadraciclib’s mechanism, including MCL1, MYC or cyclin E.

Advanced cancers (CYC065-01, i.v., NCT02552953)

Fadraciclib, using i.v.

administration, has been evaluated in a first-in-human, single agent, ascending dose, Phase 1 trial to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in patients with advanced solid tumors.

In part 1 of the study 26 patients were treated with fadraciclib as a 4-hour infusion once every 3 weeks.

Part 2 tested a more intensive dosing regimen with 24 patients treated with fadraciclib as a 1-hour infusion or orally on days 1, 2, 8 and 9 every 3 weeks .

One patient with MCL1 amplified endometrial cancer has experienced a confirmed partial response after 4 cycles and remains on fadraciclib monotherapy for more than two years with 100% reduction in target tumor lesions and a negative PET scan.

Another patient with cyclin E amplified ovarian cancer has achieved cancer shrinkage of target tumor lesions of 29% after 4 cycles.

In part 3 of the study high bioequivalence of an oral formulation of fadraciclib was reported at the 32 nd EORTC-NCI-AACR (ENA) Symposium in October 2020 .

Dose limiting toxicities were reversible neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, hypomagnesemia, white blood cell lysis syndrome and its associated electrolyte abnormalities and liver enzyme elevations.

Part 2 of this study tested a more intensive dosing regimen with 24 patients treated with fadraciclib as a 1-hour infusion or orally on days 1, 2, 8 and 9 every 3 weeks .

One patient with MCL1 amplified endometrial cancer has experienced a confirmed partial response after 4 cycles and remains on fadraciblib monotherapy for 18 months with 96% reduction in target tumor lesions.

Another patient with cyclin E amplified ovarian cancer has achieved cancer shrinkage of target tumor lesions of 29%.

In part 3 of the trial high bioequivalence of an oral formulation of fadraciblib was observed.

These data were reported at the Plenary Session of the 32 nd EORTC-NCI-AACR (ENA) Symposium in October 2020 .

Supported by strong preclinical activity, the observation of durable suppression of MCL1 in patients and preliminary evidence of anticancer activity from the ongoing Phase 1 first-in-human (FIH) study we are preparing to commence a streamlined Phase 1/2 clinical studies in a broad range of solid tumors and leukemias.

The study will evaluate oral fadraciclib in multiple cohorts defined by cancer histology and biospecimens will be collected for translational analysis.

The aim of these streamlined studies is to identify clinical activity which may lead to registration-enabling outcomes.

Chronic lymphocytic leukemia (fadraciclib-02, NCT03739554)

We are enrolling a Phase 1 study to evaluate fadraciclib in combination with venetoclax in patients with relapsed or refractory CLL.

The study design and preliminary data from the study were presented at a poster presentation during the 61 st American Society of Hematology 2019 Annual Meeting and Exposition.

fadraciclib is being administered intravenously via four-hour infusion on days 1 and 15 in combination with daily oral venetoclax.

Supported by strong preclinical activity, the observation of durable suppression of MCL1 in patients and preliminary evidence of anticancer activity from this study, we have commenced a Phase 1/2 clinical study in a broad range of solid tumors.

Advanced solid tumors and lymphomas (CYC065-101, dosed orally, NCT04983810 )

The Phase 1/2 registration-directed trial uses a streamlined design and will first determine the recommended Phase 2 dose (RP2D) for single-agent, oral fadraciclib.

Once RP2D has been established, the trial will immediately enter proof-of-concept, cohort stage, using a Simon 2-stage design, where single agent fadraciclib will be administered to patients in up to eight cohorts defined by histology thought to be sensitive to the drug’s mechanism of action and informed by the clinical activity of fadraciclib in previous studies.

The cohorts will include patients with breast cancer (selected for metastatic, hormone receptor positive, HER-2 negative, post-CDK4/6 inhibitor;

HER-2 refractory;

or triple negative), colorectal (including KRAS mutant), endometrial, hepatobiliary and ovarian cancers, and certain lymphomas.

An additional basket cohort will enroll patients with mechanistically relevant biomarkers, including MCL1, MYC and cyclin E, regardless of histology.

The protocol allows for expansion of a cohort based on response which may allow acceleration of the clinical development and registration plan for fadraciclib.

Twelve patients have been dosed to date.

Chronic lymphocytic leukemia (CYC065-02, i.v., NCT03739554)

CLL cell survival depends on the expression of anti-apoptotic proteins, including MCL1 and BCL2.

In this context, targeting MCL1 or BCL2 releases pro-death signals and commits CLL cells to apoptosis.

In preclinical studies, rapid cell death was induced in CLL and multiple myeloma patient-derived cell lines after short exposure to fadraciclib, even in the presence of stromal cells which confer protection from standard treatments.

MCL1 down-regulation was observed,

consistent with the pro-apoptotic mechanism of fadraciclib.

Fadraciclib synergizes with venetoclax in preclinical models at clinically achievable concentrations, supporting the clinical investigation of combination regimens of fadraciclib and venetoclax.

In a Phase 1 study, i.v.

fadraciclib was evaluated in combination with venetoclax in patients with relapsed or refractory CLL.

The study design and preliminary data were presented at a poster during the 2019 Annual Meeting of the American Society of Hematology .

Fadraciclib was administered intravenously via four-hour infusion on days 1 and 15 in combination with daily oral venetoclax.

Initial dose escalation is 33% and upon occurrence of the first dose limiting toxicity, or DLT, 25%.

The primary objective is determination of a recommended Phase 2 dose, or RP2D, defined as the highest dose level at which less than one-third of at least six patients experience a DLT during the first treatment cycle.

Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment.

Laboratory tests and CT scans will be performed regularly to assess response according to standard criteria.

Treatment continued until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment.

Laboratory tests and CT scans were performed regularly to assess response according to standard criteria.

Of the five R/R CLL patients enrolled in CYC065-02 all had failed ibrutinib and one had also failed CAR-T cell treatment.

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The patient who failed CAR-T cell therapy and two additional patients achieved MRD negative status on the combination.

CLL cell survival depends on the expression of anti-apoptotic proteins, including MCL1 and BCL2.

In this context, targeting MCL1 or BCL2 releases pro-death signals and commits CLL cells to apoptosis.

Venetoclax was recently approved as a second line treatment of relapsed/refractory CLL with or without 17p deletion after at least one prior therapy.

The pan-CDK inhibitors flavopiridol and dinaciclib have shown efficacy in CLL clinical trials providing clinical proof-of-concept for the targeting of anti-apoptotic pathways in such leukemias.

MCL1 expression can modulate resistance to BCL2 inhibition and is known to be upregulated in lymph node CLL cells, possibly leading to resistance to venetoclax.

Rapid cell death was induced in CLL and multiple myeloma cell lines after short exposure to fadraciclib, even in the presence of stromal cells which confer protection from standard treatments.

MCL1 down-regulation was observed, consistent with the pro-apoptotic mechanism of fadraciclib.

fadraciclib synergizes with venetoclax in preclinical models at clinically achievable concentrations, supporting the clinical investigation of combination regimens of fadraciclib and venetoclax.

Acute myeloid leukemia, or AML (CYC065-03, NCT04017546)

Acute myeloid leukemia, or AML (CYC065-03, i.v., NCT04017546)

Drug resistance in AML has been attributed among others to high levels of MCL1.

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In leukemia cells harboring the rearranged Mixed Lineage Leukemia gene (MLLr), fadraciclib reduced both MCL1 expression and CDK9 dependent transcription of MLL-regulated leukemogenic genes.

We are enrolling a Phase 1 study evaluating fadraciclib in combination with venetoclax in patients with relapsed or refractory AML or MDS.

The study design and preliminary data from the study was presented at a poster presentation during the 61 st American Society of Hematology 2019 Annual Meeting and Exposition.

We completed enrolment in a Phase 1 study evaluating i.v.

fadraciclib in combination with venetoclax in patients with relapsed or refractory AML or MDS.

The study design and preliminary data were presented at a poster during the 2019 Annual Meeting of the American Society of Hematology .

Fadraciclib is being administered intravenously via four-hour infusion on days 1 and 15 in combination with daily venetoclax on days 1 to 15.

Initial dose escalation is 33% and 25% upon occurrence of the DLT.

Initial dose escalation is 33% and 25% upon occurrence of DLT.

The primary objective is determination of RP2D defined as the highest dose level at which less than one-third of at least six patients experience a DLT during the first treatment cycle.

Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment.

Laboratory tests and bone marrow aspirate/biopsy will be performed to assess response according to standard criteria.

Treatment continued until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment.

Four of twelve patients in CYC065-03 achieved decreases in leukemia blast cells in their peripheral blood as reported by investigators.

Similar to our clinical development strategy for fadraciclib in solid tumors we plan to commence a streamlined Phase 1/2 clinical studies in a broad range of leukemias.

The study will evaluate oral fadraciclib in multiple cohorts defined by cancer histology and collection of biospecimens for translational analysis.

The aim of these studies is to identify clinical activity which may lead to registration-enabling studies.

Leukemia or myelodysplastic syndromes (CYC065-102, dosed orally, NCT05168904)

This Phase 1/2 registration-directed trial uses a streamlined design and will first determine the recommended Phase 2 dose (RP2D) for single-agent, oral fadraciclib.

Once RP2D has been established, the trial will immediately enter proof-of-concept, cohort stage, using a Simon 2-stage design.

Oral fadraciclib, both as a single agent and in combinations, will be administered to patients in up to seven cohorts relevant to the drug’s mechanism of action and informed by the clinical activity of fadraciclib in previous studies.

Single-agent cohorts will include patients with acute myeloid leukemia (AML) or MDS who have an inadequate response or have progressed on venetoclax combinations with hypomethylating agent (HMA) or low dose Ara C;

relapsed/refractory AML or MDS patients with FLT3, KIT or MAPK pathways (including N and K RAS, BRAF, PTPN11, NF1).

The trial will also include patients with chronic lymphocytic leukemia (CLL) who have progressed after at least two lines of therapy including a BTK inhibitor and venetoclax.

Combination cohorts for patients with AML or MDS are:

fadraciclib and azacitidine for patients with AML or MDS who progressed with hypomethylating (HMA) treatments and also fadraciclib and venetoclax for patients that have progressed after venetoclax therapy.

A further combination cohort of fadraciclib and venetoclax will enroll patients with CLL or small lymphocytic lymphoma (SLL) who have progressed after venetoclax therapy.

An additional basket cohort will evaluate patients with biomarkers relevant to the drug’s mechanism, including MCL1 and MYC.

The protocol allows for expansion of a cohort based on response which may allow acceleration of the clinical development and registration plan for fadraciclib.

Two patients have been dosed on the study to date.

Published preclinical data

Preclinical data suggest that fadraciclib may benefit adults and children with hematological malignancies, including AML, acute lymphocytic leukemias, or ALL, and in particular leukemias with rearrangement of the Mixed Lineage Leukemia gene (MLL-r), CLL, B-cell lymphomas, multiple myelomas, and patients with certain solid tumors, including breast and uterine cancers, and neuroblastomas.

Published preclinical data with respect to fadraciclib has yielded the following results:

● Induces cancer cell death and can combine beneficially with other anti-cancer drugs

● Prolonged survival and reduced tumor burden in MYCN-addicted neuroblastoma

The MYCN oncogene is over-expressed in several types of cancer, most notably neuroblastoma, and also rhabdomyosarcoma, medulloblastoma, astrocytoma, Wilms’ tumor and small cell lung cancer.

Amplification of MYCN is the most common genomic alteration in aggressive neuroblastoma and is associated with poor clinical outcome.

Preclinical data presented at the 2016 Childhood Cancer Meeting demonstrated that fadraciclib prolonged survival in MYCN-addicted neuroblastoma models.

Neuroblastoma cells with MYCN amplification and overexpression were found to be particularly sensitive.

Treatment with fadraciclib was associated with inhibition of MYCN transcription, downregulation of MYCN protein, blocking neuroblastoma cell proliferation and induction of apoptosis.

There are no approved drugs that directly target MYCN, prompting investigation of indirect approaches such as suppression of MYCN gene expression via CDK9 inhibition, or exploitation of a synthetic lethal relationship between MYCN amplification/overexpression and inhibition of CDK2.

● May reverse drug resistance associated with addiction of cancer cells to cyclin E, the partner protein of CDK2

Fadraciclib as a single agent can induce tumor growth delay in HER2-positive breast cancer cells addicted to cyclin E and resistant to trastuzumab, while administration of fadraciclib in combination with trastuzumab resulted in regression or sustained tumor growth inhibition.

● May have activity in KRAS-mutated cancers

Researchers led by Frank McCormick , PhD of University of California San Francisco and NCI’s Frederick National Lab for Cancer Research reported that overactive KRAS mutants are impeded by CDK9 inhibition ( Pui Lai L , et al, SLAS Discovery I-II 2021) .

These data expand on previous publications which report that dual CDK2/9 inhibition is an optimal strategy to treat colorectal cancer ( Somarelli JA, et al, Mol Cancer Ther , 2020) , that KRAS mutant pancreatic cancer is sensitive to CDK9 inhibition ( Blake DR, et al, Science Signalling , 2019) , and that fadraciclib showed efficacy against KRAS mutant lung cancer in preclinical PDX models ( Kawakami M, et al J Natl Cancer Inst, 2017) .

Collectively these publications suggest the potential for the therapeutic use of fadraciclib in KRAS-mutated cancers, including colorectal, lung and pancreatic.

● Induces leukemia cell death and can combine beneficially with other anti-cancer drugs

Fadraciclib targets key CDK9-dependent oncogenic and leukemogenic survival pathways.

Data presented at the 2018 Annual Meeting of the American Association of Cancer Research demonstrated strong synergy between, fadraciclib, and the BCL2 inhibitor, venetoclax in primary CLL, cells obtained from patients, including those with 17p deletions.

Data presented at the 2018 Annual Meeting of the American Association of Cancer Research demonstrated strong synergy between,

fadraciclib, and venetoclax in primary CLL, cells obtained from patients, including those with 17p deletions.

In addition, the combination was active in two CLL samples which were resistant to either agent alone.

Data presented at the 2016 Annual Meeting of the American Association of Cancer Research demonstrated that fadraciclib can induce cell death and combined beneficially with anti-cancer drugs from the BCL2 and BET (Bromodomain and Extra-Terminal domain) inhibitor classes, in in vitro models of B-cell lymphoma, including double-hit lymphomas.

Combinations of fadraciclib with the BCL2 inhibitor, venetoclax (ABT-199), or BET inhibitors were both synergistic.

Short exposure to fadraciclib was sufficient to downregulate MYC, an oncogene product aberrantly expressed in many cancers, and MCL1, an anti-apoptotic member of the BCL2 family, and to induce cell death.

Data presented at the 2016 Annual Meeting of the American Association of Cancer Research demonstrated that fadraciclib can induce cell death and combine beneficially with anti-cancer drugs from the BCL2 and BET (Bromodomain and Extra-Terminal domain) inhibitor classes, in in vitro models of B-cell lymphoma, including double-hit lymphomas.

Combinations of fadraciclib with the BCL2 inhibitor venetoclax, or BET inhibitors were both synergistic.

Short exposure to fadraciclib was sufficient to downregulate MYC and MCL1 and induce cell death.

Fadraciclib treatment had no impact on BCL2 levels.

These findings support the hypothesis that dual targeting of the MCL1- and BCL2-dependent mechanisms could induce synergistic cell death by apoptosis and highlight an opportunity to rationally disrupt the pathways promoting the survival of CLL cells.

Cyclacel has opened for enrolment a Phase 1 clinical study to evaluate fadraciclib in combination with venetoclax in patients with relapsed/refractory CLL.

Potent anticancer activity of fadraciclib has been demonstrated in vivo in AML xenograft models resulting in over 90% inhibition of tumor growth.

● Prolonged survival and reduced tumor burden in MYCN-addicted neuroblastoma

The MYCN oncogene is over-expressed in a number of different types of cancer, most notably neuroblastoma, but also rhabdomyosarcoma, medulloblastoma, astrocytoma, Wilms’ tumor and small cell lung cancer.

Amplification of the MYCN oncogene is the most common genomic alteration in aggressive neuroblastomas and is associated with poor clinical outcome.

Preclinical data presented at the 2016 Childhood Cancer Meeting demonstrated that fadraciclib prolonged survival in MYCN-addicted neuroblastoma models, and neuroblastoma cells with MYCN amplification and overexpression were found to be particularly sensitive.

The mechanism of action of fadraciclib included inhibition of MYCN transcription, downregulation of MYCN protein, blocking neuroblastoma cell proliferation and inducing apoptosis.

There are no approved drugs that directly target MYCN, prompting the investigation of indirect approaches such as suppression of MYCN gene expression via CDK9 inhibition, or exploitation of a synthetic lethal relationship between MYCN amplification/ overexpression and inhibition of CDK2.

● May reverse drug resistance associated with addiction of cancer cells to cyclin E, the partner protein of CDK2

In 2011, independent investigators published preclinical evidence that fadraciclib as a single agent can induce tumor growth delay in HER2-positive breast cancer cells addicted to cyclin E and resistant to trastuzumab, while administration of fadraciclib in combination with trastuzumab resulted in regression or sustained tumor growth inhibition.

● May have activity in triple-negative breast cancer

Data presented at the 2015 San Antonio Breast Cancer Symposium demonstrated in particular the mechanistic rationale for clinical development of fadraciclib in basal-like triple negative breast cancer, or TNBC, a cancer with poor prognosis frequently associated with BRCA mutations.

Molecular characteristics of TNBC include amplification or overexpression of Cyclin E, the partner protein of CDK2, and MYC.

Fadraciclib directs a pro-apoptotic mechanism in breast cancer cell lines, which includes transcriptional down regulation of key pro-survival and oncogenic regulators, including MCL1 and MYC.

Like seliciclib, fadraciclib combined effectively with sapacitabine in breast cancer cell lines.

We anticipate that fadraciclib will likely be best used in combination with available anti-cancer agents, as is the case for recently approved CDK4/6 inhibitors.

We have retained worldwide rights to commercialize fadraciclib.

Seliciclib, our first-generation CDK inhibitor, is a novel, orally available, CDK2/7/9 inhibitor that has been evaluated in over 500 patients.

As fadraciclib has improved potency and pharmacological properties compared to seliciclib, we would expect to advance fadraciclib in lieu of seliciclib.

Mitosis Regulation Program

Polo-Like-Kinase inhibitor — CYC140

In our Polo-like Kinase, or PLK, inhibitor program, we have discovered potent and selective small molecule inhibitors of PLK1, a kinase active during cell division, which target the mitotic phase of the cell cycle.

In our Polo-like Kinase, or PLK, inhibitor program, we have discovered potent and selective small molecule inhibitors of PLK1.

Polo Kinase was discovered by Professor David Glover, our former Chief Scientist.

CYC140 is a novel, small molecule, selective, PLK1 inhibitor It has demonstrated potent and selective target inhibition (PLK1 IC 50 ~ 3 nM) and impressive efficacy in human tumor xenografts at non-toxic doses.

The pharmaceutical properties of CYC140 are improved over earlier clinical stage PLK inhibitors.

PLK1 is a serine/threonine kinase with a central role in cell division, or mitosis, and is an important regulator of the DNA damage checkpoint.

PLK1 over-expressing tumors with levels correlating with patient prognosis include esophageal, gastric, leukemia, NSCLC, ovarian and squamous cell cancers as well as MYC amplified cancers.

PLK1 is a serine/threonine kinase with a central role in cell division, or the mitotic phase of the cell cycle, and is an important regulator of the DNA damage checkpoint.

PLK1 over-expressing tumors include colorectal, esophageal, gastric, leukemia, lung, lymphoma, ovarian and squamous cell cancers, as well as MYC amplified cancers including breast.

Recent data with another PLK1 inhibitor in clinical development, suggest that PLK1 inhibition may be effective in KRAS-mutated metastatic colorectal cancer.

Cyclacel’s translational biology program supports the development of CYC140 in acute leukemias and solid tumors.

CYC140 is a novel, small molecule, selective, PLK1 inhibitor which has demonstrated potent and selective target inhibition (PLK1 IC50 ~ 3 nM) and impressive efficacy in human tumor xenografts at non-toxic doses.

CYC140 has improved pharmaceutical properties over earlier, clinical stage, PLK inhibitors.

Our translational biology program supports the development of CYC140 in acute leukemias and solid tumors.

Clinical development

CYC140 is undergoing safety/tolerability evaluation in a Phase 1 first-in-human trial (NCT03884829) in patients with advanced leukemias.

Seven patients with advanced leukemias have been recruited so far to this first-in-human, single agent, dose escalation study of CYC140 given intravenously.

No dose-limiting toxicities have been observed thus far.

Supported by strong preclinical activity we plan to commence a streamlined Phase 1/2 clinical studies in a broad range of solid tumors.

The study will evaluate oral CYC140 in multiple cohorts defined by cancer histology and collection of biospecimens for translational analysis.

This will be followed by a similar study to evaluate oral CYC140 in hematological malignancies.

Advanced leukemias and MDS (140-01, i.v., NCT03884829)

Seven patients with advanced leukemias have been recruited in this first-in-human, single agent, dose escalation study of CYC140 given intravenously, and enrollment is completed.

No dose-limiting toxicities have been observed.

Advanced solid tumors and lymphomas (CYC140-101, orally dosed)

Supported by strong preclinical activity we have opened a streamlined Phase 1/2 clinical study in a broad range of solid tumors.

This Phase 1/2 registration-directed trial will determine in dose escalation the recommended Phase 2 dose (RP2D) for single-agent oral CYC140.

Once RP2D has been established, the trial will immediately enter proof-of-concept, cohort stage, using a Simon 2-stage design.

In this stage CYC140 will be administered to patients in up to seven mechanistically relevant cohorts plus a basket cohort which will enroll patients with biomarkers relevant to the drug’s mechanism.

This study is planned to be followed by a similar study to evaluate oral CYC140 in hematological malignancies.

The aim of these studies is to identify clinical activity which may lead to registration-enabling studies.

Published preclinical data

Preclinical data presented at the 2016 28th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium demonstrated the therapeutic potential of CYC140 as a targeted anti-cancer agent.

The data demonstrated

that CYC140 is a selective PLK1 inhibitor which preferentially induces growth inhibition and cell death in malignant versus non-malignant cells.

Preclinical data presented at the 2016 28th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium and at the 2017 Annual Meeting of the American Association of Cancer Research demonstrated the therapeutic potential of CYC140 as a targeted anti-cancer agent.

The data demonstrated that CYC140 is a selective PLK1 inhibitor which is highly active against both solid and liquid cancer models, preferentially induces growth inhibition and cell death in malignant versus non-malignant cells.

Treatment of proliferating cells with CYC140 resulted in reduced phosphorylation of the PLK1 substrate phospho-nucleophosmin, accumulation of cells in mitosis and an increase in the proportion of mitotic cells with monopolar spindles, which are all features consistent with PLK1 inhibition.

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We hold the worldwide rights to commercialize sapacitabine, except for Japan, for which Daiichi Sankyo Co., Ltd., or Daiichi Sankyo, has a right of first negotiation.

In 2008, sapacitabine received orphan drug designation for the treatment of AML and MDS from the European Medicines Agency, or EMA, which confers a range of benefits, including market exclusivity for a period of 10 years following approval for either indication.

In 2010, FDA granted orphan drug designation to sapacitabine for the treatment of AML and MDS, which confers a range of benefits, including market exclusivity for a period of seven years from approval.

Clinical development

Sapacitabine and venetoclax

We have dosed 12 patients in a Phase 1/2 study (NCT01211457) evaluating the safety and effectiveness of sapacitabine, in an oral regimen in combination with venetoclax in patients with relapsed or refractory AML or MDS.

The Phase 1/2 study is intended to enroll patients with relapsed or refractory AML or MDS with the objective of determining the safety and efficacy of the combination.

Secondary objectives include duration of response, CR, CRp, PR, or major HI, transfusion requirements, number of hospitalized days and overall survival.

Phase 1/2 clinical trial of sapacitabine and olaparib in patients BRCA mutant breast cancer (investigator sponsored)

Approved treatment for advanced ovarian cancer, including but not limited to BRCA-mutated (germline and/or somatic) associated advanced ovarian cancer, include the poly ADP-ribose polymerase, or PARP, inhibitors, olaparib, niraparib and rucaparib.

We believe that sapacitabine, possibly administered alongside a PARP or CDK inhibitor, may offer an alternative or complementary approach to PARP inhibitors in this area of unmet medical need.

As a result of findings in a Phase 1/2 of sapacitabine and an expansion cohort in patients with metastatic breast cancer, a combination regimen of sapacitabine and olaparib, a PARP inhibitor, is now being evaluated in an investigator-sponsored trial with sponsor Dana-Farber Cancer Institute and supported by the Company and Astra Zeneca in approximately 64 patients with PARP inhibitor-naïve, metastatic HER2-negative breast cancer with germline BRCA1/2 mutation (NCT03641755 ) .

Seven patients have been enrolled to date with two partial responses and prolonged stable diseases observed.

We have dosed 13 patients in a Phase 1/2 study (NCT01211457) evaluating sapacitabine in an oral combination regimen with venetoclax in patients with relapsed or refractory AML or MDS.

This study is enrolling patients with relapsed or refractory AML or MDS with the primary objective of determining safety and efficacy of the combination.

Secondary objectives include CR, CRp, PR, or major HI, duration of response, transfusion requirements, number of hospitalized days and overall survival.

Investigator sponsored Phase 1/2 trial of sapacitabine and olaparib in patients with BRCA mutant breast cancer

Approved treatments for advanced breast and ovarian cancer, including BRCA-mutated, include poly ADP-ribose polymerase, or PARP, inhibitors olaparib, niraparib, rucaparib and talazoparib.

We believe that sapacitabine, possibly administered alongside a PARP or CDK inhibitor, may offer a complementary approach in this area of unmet medical need.

Supported by data from a Phase 1/2 study and expansion cohort of sapacitabine in patients with metastatic breast cancer, a combination regimen of sapacitabine and olaparib is being evaluated in an investigator-sponsored trial by Dana-Farber Cancer Institute.

The trial is supported by us in terms of clinical supply of sapacitabine and AstraZeneca and will enroll approximately 64 patients with PARP inhibitor-naïve, metastatic HER2-negative breast cancer with germline BRCA1/2 mutation (NCT03641755 ).

Seven patients have been enrolled to date with two achieving partial response and five prolonged stable disease.

The sponsor has notified us that they have decided to close this study for low enrollment.

Sapacitabine in AML

SEAMLESS, randomized Phase 3, pivotal trial of sapacitabine in elderly patients with AML

On February 23, 2017, we announced that the trial did not meet its primary endpoint of demonstrating statistically significant improvement in overall survival, or OS, for the experimental arm versus an active control arm.

SEAMLESS was a multicenter, randomized, Phase 3 study of sapacitabine as a front-line treatment in 482 elderly patients aged 70 years or older with newly diagnosed AML who are not candidates for or have refused intensive induction chemotherapy.

An investigational arm of oral sapacitabine administered in alternating cycles with intravenous decitabine was compared with a control arm of intravenous decitabine administered alone.

Stratification factors at randomization were antecedent hematological disorders, baseline bone marrow blasts and baseline peripheral white blood cell counts.

The study was chaired by Hagop M.

Kantarjian, M.D., Chairman and Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center.

On February 23, 2017, we announced that the trial did not meet its primary endpoint of demonstrating statistically significant improvement in overall survival, or OS.

An improved rate of complete remission, or CR, a secondary endpoint, was observed in patients who had discontinued therapy at the time of analysis.

Other endpoints and safety were similar between the arms.

In the stratified subgroup of patients with low baseline peripheral white blood cell count, comprising approximately two-thirds of the study’s population, a trend toward improvement in OS was observed for the experimental arm.

Other secondary endpoints and safety were similar between the arms.

In the stratified subgroup of patients with low baseline peripheral white blood cell count, comprising approximately two-thirds of the population, a trend toward improvement in OS was observed for the experimental arm.

The opposite was true for patients with high white blood cell count.

Full results from the SEAMLESS study were presented at the 59 th American Society of Hematology, or ASH Annual Meeting in December 2017.

The study is chaired by Hagop M.

Kantarjian, M.D., Chairman and Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center.

SEAMLESS is a multicenter, randomized, Phase 3 study of sapacitabine as a front-line treatment in 482 elderly patients aged 70 years or older with newly diagnosed AML who are not candidates for or have refused intensive induction chemotherapy.

In SEAMLESS, an investigational arm of oral sapacitabine administered in alternating cycles with intravenous decitabine is compared with a control arm of intravenous decitabine administered alone.

The primary efficacy endpoint is overall survival.

Stratification factors at randomization were antecedent hematological disorders, baseline peripheral white blood cells and baseline bone marrow blasts.

SEAMLESS completed enrollment in December 2014 with approximately 110 centers participating in the United States and Europe.

In December 2014, the study’s independent Data Safety Monitoring Board, or DSMB, conducted a planned interim analysis for futility after 247 events, or patient deaths, and the final safety review of 470 randomized patients.

The DSMB found no safety concerns.

However, the planned futility boundary had been crossed and the DSMB determined that, based on available interim data, it would be unlikely for the study to reach statistically significant improvement in survival.

The DSMB saw no reasons why patients should discontinue treatment on their assigned arm and recommended that recruited patients stay on treatment.

In accordance with the DSMB’s recommendations, we followed-up patients as per the study protocol until the prespecified 424 events had been observed.

Stratified and exploratory subgroup analyses have been completed and have defined a patient population who may benefit from treatment with the experimental arm.

We have met and received consistent guidance from three European regulatory authorities regarding a potential approval pathway for sapacitabine.

SEAMLESS results were presented at the 2017 American Society of Hematology Annual Meeting and subsequently published in a peer-reviewed journal (Kantarjian HM et al, Results of a Randomized Phase 3 Study of Oral Sapacitabine in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia (SEAMLESS), Cancer 2021) .

SEAMLESS completed enrollment in December 2014 with approximately 110 centers in the U.S.

In December 2014, the independent Data Safety Monitoring Board, or DSMB, conducted a planned interim analysis for futility after 247 events, or patient deaths, and reviewed safety of 470 randomized patients.

Although no safety concerns were found, the planned futility boundary had been crossed and the DSMB determined that the study would be unlikely to reach statistically significant improvement in OS, but saw no reasons why recruited patients should discontinue and recommended that they stay on treatment.

We therefore followed-up patients as per protocol until the prespecified 424 events had been observed.

Stratified and exploratory subgroup analyses have defined a patient population who may benefit from treatment with the experimental arm.

We have received consistent scientific advice guidance from three European regulatory authorities regarding a potential approval pathway for sapacitabine.

The discussions followed submission of statistical and exploratory analyses demonstrating sapacitabine’s potential clinical benefit in a subgroup of patients for whom the sapacitabine regimen may represent an improvement over low intensity treatment by decitabine alone.

We previously submitted, and have received validation of, a Pediatric Investigation Plan, or PIP, to the European Medicines Agency, or EMA.

Orphan Designation

In 2008, sapacitabine received orphan drug designation for the treatment of both AML and MDS from the EMA, which confers a range of benefits to sponsor companies, including market exclusivity for a period of 10 years following a product’s approval for either of these indications in Europe.

In 2010, the FDA granted orphan drug designation to sapacitabine for the treatment of AML and MDS, which confers a range of benefits to sponsor companies, including market exclusivity for a period of seven years from the date of drug approval.

MD Anderson Cancer Center

In October 2018 we entered into a three-year strategic alliance agreement with The University of Texas MD Anderson Cancer Center that will enable clinical evaluation for safety and efficacy of three of our medicines in patients with hematological malignancies, including CLL, AML, MDS and other advanced leukemias.

MD Anderson will conduct four clinical studies with a total projected enrollment of up to 170 patients, which will investigate fadraciclib, CYC140 and sapacitabine either as single agents or in combination with approved drugs.

The collaboration leverages MD Anderson’s expertise in clinical development of drugs for hematological malignancies and our knowledge of cell cycle biology and mechanisms of cancer cell resistance to medicines.

Under the agreement, MD Anderson will assume the patient costs for all studies and we, as the sponsor, will provide investigational drugs and other limited support.

Upon first commercial sale in specific indications studied in the alliance, we will make certain payments to MD Anderson.

Investigator-Sponsored Trials

Preclinical results from several independent investigators suggest that cell cycle inhibitors, such as seliciclib and related molecules, arrest the progress of the cell cycle and may have therapeutic benefit in the treatment of patients with autoimmune and inflammatory diseases as well as in diseases characterized by uncontrolled cell proliferation.

Published data indicate potential benefit in glomerulonephritis, graft-versus-host disease, idiopathic pulmonary fibrosis, lupus nephritis, polycystic kidney disease and rheumatoid arthritis.

Based on these data, investigators have approached us to be provided with seliciclib so that they can evaluate it in various indications in clinical trials.

In this regard, there are ongoing investigator sponsored trials, or ISTs, evaluating oral seliciclib capsules in endocrinologic and inflammatory indications in patients who have failed prior treatments.

In an IST at Cedars-Sinai Medical Center, Los Angeles, supported in part by grants from The National Institute of Diabetes, Digestive and Kidney Diseases and the FDA, patients are being treated in an ongoing Phase 2 trial to evaluate seliciclib as a potential therapy for Cushing’s disease.

Cushing’s disease is characterized by abnormally high levels of cortisol, a stress hormone, associated with pituitary tumors, which are highly sensitive to cell cycle disruptions.

In a European IST, oral seliciclib capsules are being evaluated as a potential treatment for rheumatoid arthritis, or RA.

Investigators are evaluating whether seliciclib can benefit patients with RA by targeting proliferating fibroblasts.

If confirmed, this would be a novel approach compared to approved RA therapies.

This study is also being supported by an approximately $1.5 million grant from the United Kingdom’s Medical Research Council.

A preclinical collaboration with the MRC Centre for Inflammation Research at the University of Edinburgh is comparing fadraciclib to seliciclib as a potential treatment for COVID-19 pneumonia, acute lung injury or Acute Respiratory Distress Syndrome.

The study is based on extensive research carried out in Professor Adriano Rossi’s laboratory which demonstrated that MCL1 downregulation by seliciclib induced anti-inflammatory effects and promoted resolution of inflammation in relevant models.

Initial results from the comparative program confirmed the hypothesis that fadraciclib enabled overactive neutrophil apoptosis is more active in this setting than seliciclib in line with its higher dose potency.

The investigators consider that further research is merited to evaluate the potential therapeutic use of fadraciclib in COVID-19 pneumonia and other pulmonary diseases.

We have received validation of a Pediatric Investigation Plan submitted to EMA.

Investigator-Sponsored Trials (IST’s)

Preclinical data suggest that CDK2/9 inhibitors, such as fadraciclib and related molecules, arrest progress of the cell cycle and may benefit patients with autoimmune and inflammatory diseases as well as diseases of uncontrolled cell

proliferation.

Potential benefit was reported in glomerulonephritis, graft-versus-host disease, idiopathic pulmonary fibrosis, lupus nephritis, polycystic kidney disease and rheumatoid arthritis.

Based on the data, investigators have requested clinical supplies of oral seliciclib, a precursor to fadraciclib, for ISTs.

Two ISTs are ongoing evaluating seliciclib in advanced endocrinologic and inflammatory indications.

Cedars-Sinai Medical Center, Los Angeles, CA, with grant support from The National Institute of Diabetes, Digestive and Kidney Diseases and FDA, is evaluating seliciclib in a Phase 2 IST in Cushing’s disease, characterized by high levels of cortisol and associated with pituitary tumors.

In a Phase 1/2 IST, with grant support from the United Kingdom’s Medical Research Council, seliciclib is being evaluated as a treatment for advanced rheumatoid arthritis, or RA, by targeting proliferating fibroblasts.

If confirmed, this may be a novel approach compared to standard of care RA therapies.

Business Strategy

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In-license Agreement with Daiichi Sankyo

On September 10, 2003, we entered into a license agreement with Daiichi Sankyo Co., Ltd.

of Japan or Daiichi Sankyo, with respect to patents and patent applications covering sapacitabine.

Daiichi Sankyo filed patent applications claiming sapacitabine, certain crystalline forms and methods for its preparation and use which encompass our chosen commercial development form, as well as related know-how and materials.

On September 10, 2003, we entered into a license agreement with Daiichi Sankyo with respect to patents and patent applications covering sapacitabine.

Daiichi Sankyo filed patent applications claiming sapacitabine, certain crystalline forms and methods for its preparation and use which encompass our chosen commercial development form, as well as

related know-how and materials.

The license grants us the exclusive right to exploit and sublicense sapacitabine and any other products covered by the patents and patent applications owned by Daiichi Sankyo.

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If we wish to appoint a third-party to develop or commercialize a sapacitabine-based product in Japan, within certain limitations, Daiichi Sankyo must be notified and given a right of first refusal to develop and/or commercialize in Japan.

Effective July 11, 2011, the license was amended to irrevocably waive a termination right Daiichi Sankyo possessed under a provision of the agreement that required the Company to obtain regulatory approval to sell sapacitabine in at least one country by September 2011 and releases the Company from all claims and liability of any kind arising under such provision.

Effective July 11, 2011, the license was amended to irrevocably waive a termination right Daiichi Sankyo possessed under a provision of the agreement that required us to obtain regulatory approval to sell sapacitabine in at least one country by September 2011 and releases us from all claims and liability of any kind arising under such provision.

The amendment further provides that the royalty fee due from us to Daiichi Sankyo on future net sales of sapacitabine be increased by a percentage between 1.25% and 1.50%, depending on the level of net sales of sapacitabine realized.

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In addition, we have a license to 23 patents granted in the US, by the EPO or worldwide.

We have 1 patent application pending in the United States, 1 before the EPO, 11 pending patent applications in other countries and 4 pending PCT applications still in the international application phase.

We have 2 patent applications pending in the United States, 3 before the EPO, 24 pending patent applications in other countries and 2 pending PCT applications still in the international application phase.

No assurances can be given that any patents will be issued with respect to the pending applications, nor that the claims will provide equivalent coverage in all jurisdictions.

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Litigation would create substantial costs.

We are aware that other patents exist that claim substances, processes and techniques, which, if held valid, could potentially restrict the scope of our research, development or manufacturing operations.

We are aware that other patents exist that claim substances, processes, techniques and methods of use, which, if held valid, could potentially restrict the scope of our research, development or manufacturing operations.

If competitors prepare and file patent applications in the United States that claim technology that we also claim, we may have to participate in interference proceedings in the United States Patent and Trademark Office to determine which invention has priority.

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Issued patents for the fadraciclib compound cover the United States, EPO and eleven other countries.

Issued patents for CYC140 cover the United States, EPO and six other countries.

Issued patents for the sapacitabine compound expired in the United States in 2014 and elsewhere in 2012.

Patents for the crystalline forms issued in the United States, EPO, Japan and thirteen other countries.

These patents expire in 2022.

Separately, we own an issued United States patent with granted claims to a specified method of administration of sapacitabine, adding to the existing composition of matter patents and supporting market exclusivity out to 2030.

Issued patents for CYC140 cover the United States, EPO and seven other countries.

Manufacturing

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The FDA, EMA and comparable regulatory agencies in state and local jurisdictions impose substantial requirements upon the clinical development, manufacture, marketing and distribution of drugs.

These agencies and other federal, state and local entities regulate research and development activities and the testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion of our drug candidates and commercialized drugs.

For example, in the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act and implementing regulations.

These agencies and other federal, state and local entities regulate research and development activities and the testing, manufacture, quality control, safety, efficacy, labeling, storage, record keeping, approval, advertising and promotion of our drug candidates and commercialized drugs.

For example, in the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act and implement regulations.

The process required by the FDA before our drug candidates may be marketed in the United States generally involves the following:

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The NDA also must contain extensive manufacturing information.

Once the submission has been accepted for filing, by law the FDA has 180 days to review the application and respond to the applicant.

Once the submission has been accepted for filing, by law the FDA has six to ten months to review the application and respond to the applicant.

The review process is often significantly extended by FDA requests for additional information or clarification.

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The FDA’s fast track program is intended to facilitate the development and to expedite the review of drugs that are intended for the treatment of a serious or life-threatening condition for which there is no effective treatment and which demonstrate the potential to address unmet medical needs for the condition.

Under the fast-track program, the sponsor of a new drug candidate may request the FDA to designate the drug candidate for a specific indication as a fast-track drug concurrent with or after the submission of the IND for the drug candidate.

Under the fast-track program, the sponsor of a new drug candidate may request the FDA to designate the drug candidate for a specific indication as a fast-track for the drug candidate.

The FDA must determine if the drug candidate qualifies for fast track designation within 60 days of receipt of the sponsor’s request.

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This rolling review is available if the applicant provides, and the FDA approves, a schedule for the submission of the remaining information and the applicant pays applicable user fees.

Additionally, the fast-track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Additionally, the fast-track designation may be rescinded by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

In some cases, a drug candidate may also qualify for one or more of the following programs:

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A large number of drug candidates are in development for the treatment of leukemia and lymphomas, MDS, gastrointestinal, genitourinary, gynecological and thoracic cancers and other advanced solid tumors.

Several biopharmaceutical companies have CDK or MCL1 inhibitors in clinical trials including Adastra, Amgen, AstraZeneca, Dainippon Sumitomo, Eli Lilly, G1 Therapeutics, Kronos Bio, MEI Pharma, Merck, Novartis, Otsuka, Pfizer, Prelude, Servier, Syros, Tiziana and Vincera.

Several biopharmaceutical companies have CDK or MCL1 inhibitors in clinical trials including Amgen, AstraZeneca, Blueprint, Cothera, Dainippon Sumitomo, Eli Lilly, G1 Therapeutics, Kronos Bio, MEI Pharma, Merck, Novartis, Otsuka, Pfizer, Prelude, Servier, Syros, Tiziana and Vincerx.

Cardiff Oncology (formerly Trovagene) has a PLK1 inhibitor in clinical trials and we believe that Arbutus, Boehringer Ingelheim, GlaxoSmithKline, Merck, Onconova, and Takeda have been and may continue to be evaluating PLK inhibitors for hemato-oncology indications.

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Several companies are pursuing discovery and research activities in each of the other areas that are the subject of our research and drug development programs.

Environmental Social and Government (“ESG”) Matters

We recognize the importance of ESG matters, with a specific focus on Human Capital Management, as integral to creating a sustainable foundation for our long-term business strategy.

We support professional development at all levels.

We also take report of suspected violations of our codes of conduct and take seriously appropriate action.

As we do not operate laboratories or manufacture products, we believe that our environmental impact is relatively small.

We are involved in office waste reduction practices.

Our mostly remote workforce has further reduced our carbon footprint.

We strive to offer excellent benefits and long-term incentives to help retain our workforce.

Our human capital resources and objectives include identifying, recruiting, retaining and incentivizing our existing and additional employees.

The principal purposes of our equity incentive plans are to attract, retain and reward personnel through the granting of equity-based compensation awards in order to increase shareholder value and our success by motivating such individuals to perform to the best of their abilities to achieve our objectives.

We recognize that our industry is specialized and dynamic and a significant aspect of our success is our continued ability to execute our human capital strategy of attracting, engaging, developing and retaining highly skilled talent.

There is fierce competition both within our industry and in the geographic locations in which we have offices for highly skilled talent, and we offer a robust set of benefits, career-enhancing learning experiences and initiatives aligned with our mission, vision, and values in order to attract qualified prospective employees and to retain and motivate our employees.

We offer competitive compensation for our employees and strongly embrace a pay for performance philosophy in setting and adjusting compensation.

Our codes of conduct clearly outline our commitment to diversity and inclusion, where all employees are welcomed in an environment designed to make them feel comfortable, respected, and accepted regardless of their age, race, national origin, gender, religion, disability or sexual orientation.

We have a set of policies explicitly setting forth our expectations for nondiscrimination and a harassment-free work environment.

We are also a proud equal opportunity employer and cultivate a highly collaborative and entrepreneurial culture.

Legal Proceedings

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Our corporate headquarters are located at 200 Connell Drive, Suite 1500, Berkeley Heights, New Jersey 07922, and our telephone number is 908-517-7330.

This is also where our medical and regulatory functions are located.

Our research facility is located in Dundee, Scotland, UK which is also the center of our translational work and development programs.

Our employees are located in the United States and the United Kingdom.

Available information

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We will also provide copies of our current reports on Form 8-K, annual reports on Form 10-K, quarterly reports on Form 10-Q and proxy statements, and all amendments to those reports at no charge through our website at www.cyclacel.com as soon as reasonably practicable after such material is electronically filed with, or furnished to, the SEC.

We have not incorporated by reference in this Annual Report on Form 10-K the information on, or accessible through, our website.

We have not incorporated by reference in this Annual Report on Form 10-K the information on, or accessible

through, our website.

Copies are also available, without charge, from Cyclacel Pharmaceuticals, Inc., 200 Connell Drive, Suite 1500, Berkeley Heights, NJ 07922.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business