Translating Cancer Biology Into Medicines

Translating cancer biology into medicines

February 2021 Disclaimer This presentation contains forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995 about financial results and estimates, business strategy, clinical trial plans and research and development programs of Cyclacel Pharmaceuticals, Inc. By their nature, forward- looking statements and forecasts involve risks and uncertainties because they relate to events and depend on circumstances that will occur in the future and are generally preceded by terms such as “may,” “will,” “should,” “could,” “would,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “projects,” “predicts,” “potential,” and similar expressions (including the negative thereof). For a further list and description of the risks and uncertainties the Company faces, please refer to our most recent registration statement on Form S-1, most recent Annual Report on Form 10-K and other periodic and current filings that have been filed with the Securities and Exchange Commission and are available at www.sec.gov. The information in this presentation is current as of this date. Cyclacel does not take any responsibility to update such information.

Fadraciclib (CYC065) CDK2/9 inhibitor (i.v. and oral) Clinical proof of mechanism i.v. (durable MCL1 / cyclin E downregulation; tumor shrinkage; durable PR) 1st Rx to show durable MCL1 suppression and anticancer activity in humans Combination with BCL2 inhibitor venetoclax in R/R AML, CLL Phase 1b/2 oral in registration enabling, multiple cohorts to start 1H 21 CYC140 PLK1 inhibitor (i.v. and oral) Compelling preclinical data in liquid & solid cancers; first-in-human study in progress Phase 1b/2 oral in registration enabling, multiple cohorts in planning

CDK2/9 inhibitor

© 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 4 CDK Inhibitors Targeting Different Isoforms CDK9 → transcriptional regulation of anti-apoptotic proteins MCL1, MYC … CDK2 → cell cycle checkpoint regulation of cyclin E (CCNE) Aim: restore apoptosis (CDK2 inh. enhances apoptosis by CDK9 inhibition) @

CDK4/6 → cancer cell senescence • $5 bn class (palbociclib, abemaciclib, ribociclib) • Palbociclib failure stat sig correlated with cyclin E ↑ (PALOMA-3)*

Pan CDK → active but off target effects & toxicities (flavopiridol, etc.)

Source: @Roghani, ASCO 2020 Abs e16056. Poon E et al, JCI 2020_doi.org10.1172JCI134132. *Turner NC et al; JCO 2019 . © 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 5 Fadraciclib Early to Mid-stage Development

 Low intensity schedules (single agent i.v. once q3 wk; 4x q3 wk)  tolerability i.v., PK/PD markers relevant to CDK2/9 MoA, durable PR and SD  r/r CLL: ↓ lymph nodes; MRD +ve to –ve conversion (with venetoclax)  r/r AML/MDS: ↓ peripheral blast counts (with venetoclax)  After showing oral bioavailability at ENA (Triple Meeting) 2020: . High intensity schedules (single agent, Ph 1b/2 to start in 1H 21) . Prespecified statistical success rules, registration enabling design . Expansion cohorts to explore activity across solid tumors & leukemias . Combinability with relevant MoA drugs

Source: Do, Khanh T., et al, AACR Annual Meeting 2018. RP2D = 192mg/m2

Summary: . 20/26 patients evaluable for response per RECIST 1.1 . 11/20 patients achieved stable disease (SD) . 6/11 patients achieved SD for 4+ cycles

Source: Do, Khanh T., et al, AACR Annual Meeting 2018.

Part 2 i.v. n=25; 1h, d1, 2, 8, 9; 3wk

20 At 213 mg, 1 confirmed PR

0 and 2 SD were observed # -20 . PR at 4 cycles (MCL1 amplified endometrial; -40 CCNE deepening response; -60 90mg (DL1) >96% shrinkage at C24) 160mg (DL3)

% Change From Baseline From Change % 213mg (DL4) -80 . SD >4 cycles (Cyclin E -100 MCL1 amplified ovarian) # Cycles: 4 9 4 5 >23 Source: Data on file. # Non-measurable target tumor lesion © 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 9 PR in MCL1 Amplified Endometrial Patient

Baseline 4 cycles 20 cycles Do, KT, et al, 2nd EORTC/AACR/NCI © 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 10 Virtual Symposium 24-25 October 2020. Fadraciclib Most Efficacious Treatment (endometrial adenocarcinoma patient with MCL1 amplification) Best response Fadraciclib PR

Carboplatin/taxol SD PD

Metabolic inhibitor SD PD

Wnt/beta-catenin modulator/taxol PD PD

Everolimus/letrozole PD PD

PD-1 inhibitor PD PD

DNA damage repair inhibitor PD PD

Liposomal doxorubicin PD PD

0 2 4 6 8 10 12 14 16 Duration on treatment (months) Source: Do, KT, et al, 2nd EORTC/AACR/NCI Virtual Symposium 24-25 October 2020. PD=progressive disease.

Oral dosing regimen: qd on days Fadraciclib plasma levels after oral and 1h-IV infusion 1, 2, 8 and 9 every 3 weeks; ongoing

3000

150 mg (oral) Day 1 2500 Cohort 2000 154.8 mg (IV) Half-life Cmax AUCinf 1500 (mg) (h) (ng/ml) (h*ng/ml) 1000

150 Free Base 500 equivalent (oral) 3.97 2080 6250 Plasma levels (ng/ml) 0 0 10 20 30 40 50 60 154.8 Free base 3.51 2460 8190 equivalent (IV) Time (h)

Source: Do, KT, et al, 2nd EORTC/AACR/NCI Virtual Symposium 24-25 October 2020.

© 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 12 Fadraciclib Clinical Safety Summary Dosing: . 192mg/m2 (~ 350-400mg) RP2D i.v. once q3wk . 213mg (i.v. 4x q3wk): some creatinine ↑, neutropenia . 150mg (p.o. daily schedules) Toxicity: . Solid tumors: ↓ WBC, renal observations . Hem. Malignancies (AML/MDS): ↓ WBC, TLS (200mg/m2 i.v. day 1, 15)

Source: Cyclacel data on file.

. Initially single agent based on biomarker

. Add combinations with appropriate SoC

. Depending on signal expand or drop cohort

Efficient use of patient and capital resources

HGSOC 2L • 27k US incidence; ~79k prevalence • CCNE1 is 35% of US BRCA1/2 wt CCNE1 and BRCA1/2 m CCNE1 amplified Endometrial/Uterine 2L • 5k US incidence; ~77k prevalence • CCNE1 is 20% of high grade serous which is 50% of total Breast HR+ 2L • 56k US incidence; ~735k prevalence • CCNE1 is 30% of HR+ which is 73% of total Breast Cancer BRCA1/2+ • 18k US incidence; ~238k prevalence • CCNE1 is 40% of BRCA+ which is 17% of total

CDK2/9 transcriptional isoforms enabling apoptosis: MCL1 inhibitors: CYC065 (CDK2/9, CYCC) Ph1 data AMG176 i.v. Ph 1; murizatoclax AMG397 BAY1251152; atuveciclib BAY’572 (CDK9, BAY) Ph1 data oral paused; AMG176+ven suspended AZD4573 (CDK9, AZN) Ph1 S64315 i.v. (Servier, Ph1b +ven AML) (FiH Ph 1) Other (pan CDK or selective): AZD5991 AZ poster AACR 2019: CDK9i targeting flavopiridol/alvocidib (pan CDK, SUM) Ph2 MCL1: Antitumor responses with AZD4573 dinaciclib (pan CDK, MRK) Ph3 terminated strongly correlate with selective MCL1 voruciclib (CDK4/6/9, MEIP) Ph1 data inhibitors, such as AZD5991. CDK9i targets SY-5609 (CDK7, SYRS) Ph1 (SY-1365 Ph1 data) other labile pro-survival proteins beyond MCL1 such as Bfl-1 (a.k.a. BCL2A1).

CDK2 inhibitors: Selective estrogen receptor degraders (SERDs): Fadra (CYCC, CYC065, CDK2/9) Ph 1 data; P1b/2a to SAR439859 (Sanofi Ph 3) start RG6171 (Roche Ph 3) PF-06873600 (CDK2/4/6, Pfizer) Ph 1 Rintodestrant /G1T48 (G1 Tx Ph 1) Elacestrant /RAD1901 (Radius Pharma Ph 1)

CDK4/6 inhibitors: Lerociclib (G1 Tx Ph 1)

PLK1 inhibitor

Oncogene with key role in regulation of — mitotic entry and exit — spindle formation — cytokinesis Cancer cells are very sensitive to PLK1 depletion, esp. — mutated KRAS — blocks proliferation by prolonged mitotic arrest — onset of cell death in cancer cells Medema RH et al. (2011) Clin Can Res 17(20):6459-66 — normal cells with intact checkpoints less sensitive

© 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 19 PLK Inhibitors  Volasertib  BTD in AML Ph2 data; but Ph3 POLO-1 in AML imbalance of deaths  Dose intensity led to single agent activity; long terminal half-life ~110h . Onvansertib (selectivity mainly PLK1, secondarily CDK9, etc.)

. Signal in KRASm mCRC with bevacizumab/FOLFIRI; terminal t1/2 ~24h . Ph 1b studies in AML with chemo; prostate with abiraterone . CYC140 (selectivity mainly PLK1, secondarily PLK2, PLK3 family)

. Preclinical activity in multiple solid tumors and leukemias; terminal t1/2 ~11h . Unremarkable toxicity i.v. thus far . Aim: oral, dose intense, Ph 1b/2 in multiple solid tumors and leukemia cohorts Source: data on file and Valsasina B et al Mol Can Ther 2012 11 1106-1016; https://mct.aacrjournals.org/content/11/4/1006.figures-only. © 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 20 PLK1 Inhibitor Landscape

Onvansertib oral (CRDF PLK1, CDK9) Ph 1b signal in Discontinued: KRASmut mCRC Volasertib (BI6727; Boehringer I Ph 3 failed) CYC140 (CYCC PLK1, -2, -3) Ph 1 FIH i.v. in progress; oral GSK 461364 (GSK Ph 2 terminated) to start TAK-960 (Takeda Ph 1 terminated)

Source: data on file and Valsasina B et al Mol Can Ther 2012 11 1106-1016; https://mct.aacrjournals.org/content/11/4/1006.figures-only.

Potent and selective inhibitor (PLK1 IC50 ~ 3 nM)

Source: Cyclacel data on file. FiH=First in human.

© 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 22 CYC140 Summary Optimized oral PLK inhibitor with short half life Improved kinase selectivity Favorable PK: minimize toxicity, increase dosing flexibility Broad single agent preclinical activity – Supports potential single agent clinical activity Streamlined, registration-directed development strategy

● Up to 170 patients with single agent or combinations of: CYC065, CYC140, sapacitabine ● Risk Sharing: MD Anderson assumes patient costs; Cyclacel supplies drugs and limited support ● Payments to MD Anderson upon First Commercial Sale in indications studied ● We are sponsor of the studies

Rx Candidate Phase 1 Phase 1b - Phase 2 Phase 3 MoA / Rights

065-01 parts 1, 2 i.v. Streamlined multi cohort oral CDK2/9; w/w Fadraciclib oral part 3 oral solid tumors study to PoC in solid tumors

065-02 i.v. + venetoclax Streamlined multi cohort oral CDK2/9; w/w Fadraciclib oral R/R CLL; 03 AML/MDS M study to PoC in leukemias

140-01 part 1 i.v. R/R Streamlined multi cohort oral PLK1; w/w CYC140 oral AML/MDS M study to PoC in solid tumors

140-01 part 1 i.v. R/R Streamlined multi cohort oral PLK1; w/w CYC140 oral AML/MDS M study to PoC in leukemias

IST sapacitabine + olaparib BRCA mutant Sapacitabine oral w/w exc. Japan breast CA

682-11 sapacitabine + venetoclax R/R Sapacitabine oral w/w exc. Japan AML/MDS M

M MD Anderson alliance programs. w/w = worldwide. IST=investigator sponsored study. In planning IST

Proforma cash & cash equivalents September 30, 2020: $30.0m 1 Operating cash burn (annual; excludes non-cash items) ✔2016: ~ $10.1m 2 ✔2017: ~ $ 7.5m 2 ✔2018: ~ $ 6.7m 2 ✔2019: ~ $ 9.4m 2 Fully diluted shares: 12.2 million3. No debt 1. $23.1m (10Q) + $6.9m (RD December 2020) 2. 10K Estimated capital to early 2023 3. Common stock outstanding 5.4m, preferred stock 1.2m, common stock warrants 5.0m, stock options 0.6m © 2021 Cyclacel Pharmaceuticals, Inc. Released FEB2021 26 Key Milestones

• FPI orally-administered fadra in Ph 1/2 advanced solid tumor study;

• Initial safety, antileukemic activity data from fadra-venetoclax Ph 1 in R/R AML & CLL;

• Initial safety, PK data from Ph 1 study of fadra oral formulation;

• Initial data from CYC140 Ph 1 First-in-Human study in R/R leukemias;

• Initial data from sapacitabine-venetoclax Ph 1/2 study in R/R AML/MDS; and

• Data from Phase 1b/2 sapacitabine-olaparib IST in BRCA mutant metastatic breast cancer when reported by the investigators.

Clinical stage, state-of the-art oncology programs

Targeting molecularly-defined patient populations

Overcome cancer cell resistance & DNA repair

CDK inhibitors: validated drug class

Competitively positioned

Significant market opportunities

Cyclacel Pharmaceuticals, Inc. 200 Connell Drive #1500 Berkeley Heights, NJ 07922 +1 (908) 517 7330 Contact: [email protected]