FWP 1 t1701721_fwp.htm FREE WRITING PROSPECTUS

Filed pursuant to Rule 433
Registration No. 333-218305
July 10, 2017

CYC 682 Translating cancer biology into medicines NASDAQ:CYCC | July 2017

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. For a further list and description of the risks and uncertainties the Company faces, please refer to our 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. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 2

Statement about Free Writing Prospectus • This presentation highlights basic information about us and the offering. Because it is a summary that has been prepared solely for informational purposes, it does not contain all of the information that you should consider before investing in our company. Except as otherwise indicated, this presentation speaks only as of the date hereof. • This presentation does not constitute an offer to sell, nor a solicitation of an offer to buy, any securities by any person in any jurisdiction in which it is unlawful for such person to make such an offering or solicitation. • Neither the Securities and Exchange Commission (the “SEC”) nor any other regulatory body has approved or disapproved of our securities or passed upon the accuracy or adequacy of this presentation. Any representation to the contrary is a criminal offense. • This presentation includes industry and market data that we obtained from industry publications and journals, third-party studies and surveys, internal company studies and surveys, and other publicly available information. Industry publications and surveys generally state that the information contained therein has been obtained from sources believed to be reliable. Although we believe the industry and market data to be reliable as of the date of this presentation, this information could prove to be inaccurate. Industry and market data could be wrong because of the method by which sources obtained their data and because information cannot always be verified with complete certainty due to the limits on the availability and reliability of raw data, the voluntary nature of the data gathering process and other limitations and uncertainties. In addition, we do not know all of the assumptions that were used in preparing the forecasts from the sources relied upon or cited herein. • We have filed a Registration Statement on Form S-1 with the SEC, including a preliminary prospectus dated May 26, 2017 (the “Preliminary Prospectus”) and subsequent amendments S-1/A dated June 30, 2017 and July 7, 2017, with respect to the offering of our securities to which this communication relates. Before you invest, you should read the Preliminary Prospectus (including the risk factors described therein) and, when available, the final prospectus relating to the offering, and the other documents filed with the SEC and incorporated by reference into the Preliminary Prospectus, for more complete information about us and the offering. You may obtain these documents, including the Preliminary Prospectus, for free by visiting EDGAR on the SEC website at http://sec.gov. • Alternatively, we or any underwriter participating in the offering will arrange to send you the prospectus if you request it by contacting Ladenburg Thalmann & Co. Inc., 277 Park Ave, 26th Floor, New York, NY 10172 or by email at prospectus@ladenburg.com. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 3

Overview § Mission: exploit cell cycle biology to disrupt cancer cell immortality § Pioneer in Cyclin Dependent Kinase inhibitors § Focus on genetically-defined patient populations § Rationally designed single agents/combinations in liquid & solid cancers § CDK inhibitor and DNA Damage Response clinical stage programs § Experienced management, estimated capital through YE 2018 © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 4

Cyclin Dependent Kinase inhibitors (CDKi) 2001 Nobel Prize for Physiology & Medicine culminating in approved Rx Paradigm-shift in breast cancer: CDK4/6i-based combinations with AI § IBRANCE® (palbociclib, PFE, approved 2015, ~$2.1bn 2016 sales) § KISQALI® (ribociclib, NVS, approved 2017) CYCC’s CDK2/9i portfolio strategy: address key issue of resistance • Seliciclib 1st Gen, signals of anticancer activity (Ph 2) • CYC065 2nd Gen, more potent, better profile than seliciclib (Ph 1) © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 5

Pipeline Program Target/Indication Preclinical Phase 1/1b Phase 2 Pivotal Rights Solid tumors (FIH) Mcl-1 CLL Mcl-1 /Cyclin E solid tumors MYCN / Mcl-1 NB / MLL-r leukemias DDR*: HRD+ve Breast, ovarian,pancreatic DDR*: HRP+ve Breast, ovarian Sapacitabine AML CYC140 (PLK1 inhibitor) Solid & liquid cancers Seliciclib (CDKi) Cushings disease, cystic fibrosis, RA CYC065 (CDKi) Worldwide Worldwide RP2D Data Analysis Investigator Sponsored Trials (IST) CYC065 + venetoclax RR CLL CYC065 Ovarian CYC065 IST CDKi + sapacitabine + PARPi IND-ready Ph1 FIH *DDR=DNA Damage Response Current status Future studies Data Dependent © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 6

CDK inhibitor landscape CDK4/6 isoform - palbociclib (NYSE:PFE); ribociclib (SWX:NOVN) - Approved in combination with letrozole for ER +ve Her2 -ve advanced or met BC - abemaciclib (NYSE:LLY) Ph3 - trilaciclib (NASDAQ:GTHX) Ph1/2 CDK2/9 transcriptional isoform - CYC065 (CYCC 2Gen) Ph1 - seliciclib (CYCC 1Gen) Ph2 - dinaciclib (pan CDK, MRK) Ph3 - BAY1143572 (CDK9, BAY) Ph1 * Source: Cyclacel data on file. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 7

CYC065 CDK2/9 inhibitor summary Second generation, available by i.v. and oral route Unique kinase selectivity • CDK2 (cell cycle control) • CDK9 (regulation of transcription & survival) Differentiation vs. CDK4/6 or pan-CDK inhibitors • Selective pro-apoptotic, p53-independent MoA Completed Ph 1, FIH study, i.v. in advanced patients with solid tumors • Established safety, target engagement, RP2D Robust IP position; exclusivity beyond 2030 Addressing cancers: • dependent on Mcl-1 pro-survival protein • or addicted to Oncogenes © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 8

CYC065 Genetically-Defined Patient Populations 1. Mcl-1 or MYC dependent (↑) liquid & solid cancers A. Venetoclax (Bcl-2i) treated CLL* with Mcl-1 ↑ B. Selected Mcl-1 amplified solid tumors, i.e. ovarian C. Cancers addicted to MYCN, i.e. neuroblastoma 2. Cyclin E amplified (↑) solid cancers A. HGSOC (BRCA mutually exclusive, PARPi not option) B. Selected Cyclin E ↑ solid tumors, i.e. breast HER2+ C. CDK4/6i resistant breast cancer * Also MLL-r leukemias, lymphoma, and multiple myeloma. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 9

CYC065 First in Human Phase 1 Study n=23 heavily pretreated patients with various advanced solid tumors § Determined safety, DLT, PK in 7 DL, established RP2D § Treated n=10 in total at DL6 cohort; DL7 MTD neutropenia § Demonstrated target engagement and consistent Mcl-1 suppression over 24h after single dose in 7/9 DL6 patients § Anticancer activity observed in patients with: Ø Mcl-1 ↑ (ovarian), Ø Myc ↑ (larynx) and Ø cyclin E / Mcl-1 ↑ (ovarian) amplified tumors Similar CDK2/9 CYC065 CDK selectivity vs. seliciclib but 40x higher potency & improved pharmaceutical properties. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 10

Phase 1 patient durable target inhibition Source: Cyclacel data on file. Observations are representative for the cohort. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 11

CYC065 mechanism of action Inhibits CDK9-mediated oncogenic transcription • Rapidly induces apoptosis; preferentially kills cancer cells over non-cancerous cells • ↓ an -apoptotic proteins (Mcl-1, XIAP) & oncogenes (MYC, cyclins) Inhibits CDK2 (cell cycle control) • Targets cyclin E addicted, drug resistant tumors Potentiates effects of DNA damaging agents • ↓ expression of HR DNA repair genes (BRCA1 and BRCA2) Mcl-1 MYC Cyclins Cyclin E BRCA1 BRCA2 Cyclacel data on file. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 12

CYC065 response in cancer vs. normal cells 13 -10 -5 0 5 10 15 Change in % G1 cells to control Cell cycle arrest 1 Mcf10a 0 0.5 MDA-MB-468 0 0.5 1 Breast Cancer 0 1 Cal51 0.5 0 1 HCC1954 0.5 μM 0 2 4 6 8 10 12 % Sub G1 cells Cell death 1 Mcf10a 0 0.5 MDA-MB-468 0 0.5 1 Normal Breast Normal Breast Breast Cancer 0 1 Cal51 0.5 0 1 HCC1954 0.5 μM § CYC065-dependent apoptosis induction in cancer cells but not in non-cancer Mcf10a § CYC065 caused G1 arrest in non-cancer Mcf10a cells § Similar trend observed in other cancer and non-cancer cell lines MacKay et al. SABCS 2015 © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017

CYC065-venetoclax rational combination CLL § CLL unmet medical need • 30% all adult leukemias; 70% mortality rate; 70% aged > 65 years § Venetoclax ORR: 71-79%; CR: ~20% (R/R CLL with 17p del)1 § Tumor microenvironment ↑ Mcl-1 diminishing venetoclax effect2,3 § Mcl-1 ↓ overcomes venetoclax resistance (stimulated CLL)3 § CYC065 ↓ Mcl-1 effectively & durably (>24h) in Phase 1 patients at well tolerated doses § CYC065 and venetoclax synergistic in CLL (incl. 17p del), multiple leukemia & lymphoma cell line models4,5 ABT-263 ABT-737 CYC065 venetoclax Anti-apoptotic Pro-apoptotic Bak Bax APOPTOSIS Bcl-xL Bcl-w A1 Bcl-2 Mcl-1 Adapted from: Adams & Cory, Oncogene 2007 1 Roberts et al. 2016. 2 Smith et al. 2007; 3 Oppermann et al. Blood 2016, 4 Frame et al. AACR 2014, 5 Zheleva et al. SOHO 2015. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 14

CYC065 & venetoclax synergy in AML & ALL cells Example Fa:CI plots & median CI values for THP-1 (AML) cell line. Combination Index (CI) values calculated using Chou & Talalay method. CI of 0.9 to 1.1 indicate additivity, below 0.9 synergy. Median CI: 0.76 Median CI: 0.74 Median CI: 0.57 • CYC065 synergy with venetoclax (ABT-199) in AML & ALL cell lines • CYC065 synergy with Bcl-2/Bcl-xL/Bcl-w inhibitors ABT-263 or ABT-737 • CYC065 synergies demonstrated in several acute leukemia cell lines (AML: THP-1, HEL; ALL: Jurkat, SEM) Source: Frame et al, SOHO, 2014, Abs 209 © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 15

CYC065 transcriptional regulation of MYC Very common genomic alteration in aggressive tumors 0.1 1 10 100 GI50 (μM) CYC065 p = 0.016 No MYCN expression MYCN expression DMSO 1 μM CYC065 MYCN ↑ neuroblastoma highly sensitive § Amplification of MYC family oncogenes: poor clinical outcome in neuroblastoma (NB), SCLC, breast, prostate § No therapeutics against MYCN or MYC reported § CDK9 involved in MYCN transcriptional regulation § MYCN ↑ NB cells highly sensi ve to CYC065 § CYC065 inhibits NB cell proliferation, induces apoptosis and ↓ MYCN protein § CYC065 causes tumor regression & prolongs survival in MYCN-amplified NB models Potent in vitro and in vivo anti-tumor activity suggest that CYC065 may have therapeutic potential in NB with MYCN oncogene amplification. Poon et al. 4th Neuroblastoma Society Symposium 2015. 8 h treatment. SRB colony formation assay after 72 h. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 16

CYC065 in MYCN↑ NB: regression & ↑ survival Kelly xenograft (MYCN amplified) Poon et al. 4th Neuroblastoma Society Symposium 2015, 25-27 Nov, Newcastle. Treatment regimen: CYC065 – po, dq x 5/week x2 Th-MYCN GEMM of NB Cyclacel data on file. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 17

Overcoming resistance in cyclin E amplified tumors 18 200 400 600 800 1000 1200 0 5 10 15 20 Tumor volume (mm3) Days of treatment Control Trastuzumab CYDCK026i.5 T+CCYDCK026i.5 CYC065 alone or in combination with trastuzumab causes very effective in vivo tumor growth inhibition of BT474R trastuzumab resistant HER2+ BC cell line, and increased apoptosis in vitro. Source: Scaltriti et al 2011 PNAS 108 3761 Trastuzumab resistant Her2+ breast cancer Drug-resistant Uterine Serous Carcinoma CYC065 active as a single agent and in combination (p<0.03) in ARK-1 (trastuzumab-resistant, PI3K mutant) xenograft model with without CCNE1 amplification CCNE1 amplified USC primary cell lines show increased CYC065 sensitivity Source: Cocco et al., AACR, 2015, Abs 3103; Cocco et al, BJC, 2016 © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017

Overcoming resistance to CDK4/6 inhibitors + AI CDK4/6i+AI inhibit proliferation; but senescence → emergence of resistance, i.e. CDK2/cycE ↑ CDK2 activation or cyclin E amplifica on/overexpression → acquired/intrinsic resistance to CDK4/6i in breast and ovarian cancer and AML models* Higher CCNE1 gene expression observed in BC resistant to neoadjuvant palbociclib + anastrozole* Cyclin E mediated resistance to letrozole in HR+ breast cancer is reversed by seliciclib* CDK4/6i + AI resistance CDK4/6 cyclin D CDK2 cyclin E Rb E2F E2F Rb P P Rb P E2F inactive active G1 S palbociclib ribociclib abemaciclib CYC065 estrogen signalling aromatase inhibitors fulvestrant proliferation cell cycle *Source: Herrera-Abreu et al. Cancer Res. 2016; Konecny & Slamon Clin. Cancer Res. 2011; Taylor-Harding et al. Oncotarget 2015; Caldon et al. Mol. Cancer Ther. 2012 ; Wang et al. Blood 2007; Ma et al. Clin Cancer Res. 2017; Akli et al, Clin Cancer Res. 2010. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 19

IO strategy: modulate antitumor immune response CDK2/9i synergy with IO agents § Dinaciclib synergistic with anti-PD-1 in mouse syngeneic tumor models § Dinaciclib induces immunogenic cell death (ICD) with evidence of ↑ T cell infiltra on and dendritic cell activation in tumors1 § MC38 mouse colorectal carcinoma in C57BL/6 mice, 12 per group, dinaciclib 40 mg/kg, anti-PD-1 5 mg/kg each dosed once daily for 25 days2 § Phase 1 open-label study evaluating safety and efficacy of pembrolizumab + dinaciclib in relapsed or refractory CLL, MM, DLBCL3 (1) Hossain et al., Cancer Res, 2015 (2) US20160193334A (3) NCT02684617 © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 20

CYC065 CDK2/9i investment highlights § CDKis: validated drug class § Targeting genetically-defined patient populations § Significant market potential § Potential to treat difficult cancers and overcome cancer cell resistance § Single agent and combination opportunity © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 21

DNA Damage Response (DDR) Clinical Program © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 22

Modulation of DNA Damage Response (DDR) Cyclacel’s CDK inhibitor-based DDR strategies: • Modulate DNA repair via HR, NHEJ, etc. pathways • ↓ expression of HR DNA repair genes, i.e. BRCA1 / BRCA2 • ↓ an -apoptotic survival signalling , i.e. Mcl-1 Cyclacel’s oral sapacitabine may work best in HR-deficient tumors: Clinical utility observed in combination with CDK inhibitor; future options • Combinations with SoC, i.e. PARP inhibitors • Single agent treatment in sensitive cancers © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 23

DDR sapacitabine/seliciclib in HR-repair deficient tumors* § Oral combo of complementary mechanisms: sapacitabine’s unique, MoA (DNA SSBs# & cell cycle arrest) combined with CDKi modulation § Parts 1 & 2: durable clinical benefit (PRs & prolonged SD) in patients with BRCA +ve: breast, ovarian, pancreatic cancers § Part 3 to start: revised schedule including BRCA +ve ovarian, pancreatic cancer patients … Plan to substitute seliciclib with CYC065 ... * Source: Tolaney S et al, J Clin Oncol 34, 2016 (suppl; abstr 2503); Shapiro et al, AACR Proceedings, 2013, LB-202. HR=homologous recombination. # single-strand breaks © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 24

DDR: sapacitabine/seliciclib Ph 1 best responses* * Source: Tolaney S et al, J Clin Oncol 34, 2016 (suppl; abstr 2503). © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 25

Sapacitabine/seliciclib Phase 1 BRCA +ve benefit* A * Source: Tolaney S et al, J Clin Oncol 34, 2016 (suppl; abstr 2503). © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 26

Sapacitabine/seliciclib Phase 1 BRCA +ve benefit* B * Source: Tolaney S et al, J Clin Oncol 34, 2016 (suppl; abstr 2503). © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 27

Financials © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 28

Financial position & capitalization Mar. 31 2017 Pro Forma Cash & cash equivalents: $15.7m1 Current Operating cash burn (excludes non-cash items) ü 2014: ~ $18.7m annual 2 ü 2015: ~ $14.5m annual 2 ü 2016: ~ $10.1m annual 2 ü 2017: ~ $ 8.0m annual 3 Fully diluted shares: ~ 4.6 million4,5 No debt 1. Cyclacel press release 2. 10-K. 3. Company estimate 4. 10Q - 31 March 2017 5. Common stock outstanding: 4.3m. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 29

Key milestones § CYC065 First-in-Human, Phase 1 data solid tumors § Start CYC065 Phase 1, Part 2 in solid tumors § Start CYC065 Ph 1b in R/R CLL combo with venetoclax § Sapacitabine/seliciclib update BRCA+ve breast cancer § CYC140 (PLKi) IND submission © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 30

Cyclacel Highlights § Transcriptional CDKi and DNA Damage Response clinical stage oncology programs § Treat difficult cancers and overcome resistance § Competitive positioning § Large markets Contact: ir@cyclacel.com. Thank you. © 1997-2017 Cyclacel Pharmaceuticals, Inc. Released JUL 2017 31