CYC 682 Disrupting the Cell Cycle to Treat AML, MDS and other Cancers February 2015
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,pleaserefertoourmostrecentannualreportonform10- Kandotherperiodic andcurrentfilingsthathavebeen 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. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 2
Cyclacel Highlights Sapacitabine front-line AML in the elderly: SEAMLESS Phase 3 Oral agent for elderly AML patients; minimal options today Fully enrolled 2H14; futility cross but DSMB recommended to continue follow-up; top-line data readout 2H15/1H16 Sapacitabine other indications & earlier-stage pipeline Impressive survival data in 2 nd /3 rd Line hi-risk MDS (Phase 2) Sapacitabine/seliciclib in solid tumors (Phase 1) CDK inhibitors: CYC065 (IND-ready) and seliciclib (Phase 2) PLK inhibitor CYC140 (IND-directed development) Strong financial position Est. capital to late 2016 beyond Phase 3 data readout * Source: Cyclacel press releases and data on file. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 3
Sapacitabine for AML 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 4
Predicament of 70+ year old AML Patient Newly diagnosed AML: multigenetic, heterogeneous disease Old age, frailty and comorbid conditions Options: 45-year old intensive chemotherapy regimen Investigational agent(s) in a clinical trial Hospice or terminal care at home Expected median survival of 3-6 months Mortality in first 60 days of ~ 20-36% 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 5
Sapacitabine for AML in the elderly Elderly AML key challenge: control leukemic cell growth but not worsen immunity & quality of life Sapacitabine-based regimen results in ~ half 60-day mortality vs. reported with control regimen * Sapacitabine 8 mos. median OS in Phase 1/2 * Based on DSMB recommendation study follow-up continues to final analysis Regulatory submission activities in progress * Source: ASH 2012. Kantarjian et al, JCO, 2012. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 6
SEAMLESS Phase 3 Design (Untreated AML: front line; 70 years; n=485; p=0.05; HR=0.725) In consultation with FDA under SPA Fully enrolled at 110 US & European hospitals Final analysis after 424 events (interim ~ 50% of events) 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 7
SEAMLESS Phase 3 Assumptions & Events * 27.5% reduction in risk of death Median OS of: 8 months for experimental arm versus 6 months for control arm Final analysis after 424 events (interim ~ 50%) % of Events Remaining until Mature Data * Source: Cyclacel data on file. 31% FEB15 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 8
Futility Analyses in Randomized Trials Formulaic Interpretations of Interim Analyses for Futility may be Misleading * * Source: HersonJ, BuyseM, WittesJ, On stopping a randomized trial for futility, Design for Clinical Trials Perspectives on Current Issues, Harrington D ed., 109-138 Springer-Verlag, New York, 2011. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 9
Reasons for DSMB Recommendation to Continue Despite Futility Outcome * # No safety concerns Data may exhibit favorable trend and/or consideration of late treatment effect Confidence that experimental arm is not inferior to control Enrollment nearly or fully completed Data can be used for approval in other countries * Source: HersonJ, BuyseM, WittesJ, On stopping a randomized trial for futility, Design for Clinical Trials Perspectives on Current Issues, Harrington D ed., 109-138 Springer-Verlag, New York, 2011. # ProschanMA, Lan KKG, Wittes JT, Statistical Monitoring of Clinical Trials: A Unified Approach, New York: Springer, 2006. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 10
SEAMLESS DSMB Recommendations * After 247 events No safety concerns 173/247 events (70%) occurred in first 6 months Complete follow-up so that any treatment effect beyond 6 months is not missed Saw no reasons to discontinue treatment and recommended that recruited patients stay on treatment Similar response rates between arms and no adverse outcomes for experimental arm * Source: Cyclacel press release December 16, 2014. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 11
Possible SEAMLESS Outcomes Superior Equivalent Inferior 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 12
* Source: FDA Briefing Document, Dacogen ODAC, February 9, 2012. Of 242 treated with decitabine 39% were aged 75 years or older. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 13
SEAMLESS Pilot/Lead-in Study Kaplan-Meier Survival Plot All Patients (n=46) CYC682-11 Pilot (25) CYC682-12 Lead-in (21) Median O.S. (n=46) ~ 8 months 72% > 75 yrs(n=33) ~ 9 months No. at risk 3M 6M 12M 18M 24M 38(83%) 30 (65%) 16 (35%) 12 (26%) not reached * Source: Ravandi F, et al, American Society of Hematology Annual Meeting Dec. 2012, Abstract #2630. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 14
Sapacitabine for MDS 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 15
Predicament of 60+ year old High-Risk MDS Patient High risk MDS after failure of front-line drugs Already failed 1 st line hypomethylating agents (HMAs): azacitidine (Vidaza ) and/or decitabine (Dacogen ) Higher risk from infections; transformation into AML Multigenetic, heterogeneous disease Options: Investigational agent(s) in a clinical trial Hospice or terminal care at home Expected median survival of 4.3-5.6 months Source: PrebetT, Gore S, et al, JCO 2011; Jabbour E, Garcia-Manero G, et al, Cancer 2010. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 16
MDS HMA Failures: Key Benchmarks MDS int-2 & high-risk IPSS experimental Standard of Care after frontline failure Treatment m OS 1 year survival Azacitidine2 nd line ~6 months - Decitabine2 nd line ~ 4 months - Best SupportiveCare ~ 4 months 17% Sapacitabine: Phase 2 study 2 nd, 3 rd, 4 th line ~ 9 months @ 38% @ PrebetT, Gore S, et al, JCO 2011 (95% CI, 14% to 26%on best supportive care; 29% on investigational agents). @ Garcia- Manero G et al, American Society of Hematology Annual Meeting Dec. 2013, Abstract #2752 (Arm G 1-year survival). 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 17
Rationale for Randomized Phase 2b RCT Limited knowledge Genetic heterogeneity & treatment complexity Sapacitabine Phase 2 clinical data encouraging Cyclacel approach Review recent MDS trials Confer with MDS KOLs Conduct feasibility assessment Goal: determine path that may Add to understanding of sapacitabine s role in the indication If RCT data exceptional, discuss with regulators 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 18
Cyclacel Early-stage Pipeline Candidate MOA Use Preclinical Phase 1 Phase 2 Phase 3 Sapacitabine + seliciclib DNA synthesis inhibitor+ CDK2/9 inhibitor HR repairdeficient solid tumors CYC065 CDK2/9 inhibitor Blood & solid tumors* CYC140 PLK1 inhibitor Blood & solid tumors* *Both mainly funded by government grants. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 19
CDKs Lift-Off after ~20 years on Runway Two major isoform profiles: CDK4/6 and CDK2/9 Goal: Block phosphorylation by CDK enzyme of its cyclin subunit protein substrate; not inhibit signaling like TKIs 4/6: delay cell transit through G1 Phase > senescence 2/9: checkpoint control depending on amount of DNA damage > apoptosis of malignant clone Secondary mechanisms of action: (2) reverse cyclin E/CDK2 addiction & resistance (9) MCL-1 protein expression in CDK9-driven cancers 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 20
CDK Inhibitor Landscape * CDK4/6 isoform - palbociclib (PFE) Approved for ER +ve letrozole resistant breast cancer (P2) - abemaciclib (LLY) P3 - LEE011 (NVS) P3 CDK2/9 isoform - dinaciclib(mrk) P3 - seliciclib (CYCC) P2 - CYC065 (CYCC) IND - BAY1000394 pan CDK (BAY) P2 * Source: Cyclacel data on file. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 21
CYC065 Modulates Trastuzumab Resistance in HER2 + Breast Cancer incl. Regression Control Trastuzumab CDK2i. CYC065 T+CDK2i. CYC065 Tumor volume (mm3) 1200 1000 800 600 400 200 0 5 10 15 20 Days of treatment CYC065 single agent and in combination with trastuzumab in vivo tumorgrowth inhibition and regression (combination) of BT474R trastuzumab resistant HER2 + BC cell line. Source: Scaltriti et al 2011 PNAS 108 3761 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 22
CYC065 eradication of AML and MLL-r xenograft models Vehicle 55 mg/kg CYC065 vehicle CYC065 70 mg/kg po 5d on/2d off x 2 2500 40 mg/kg CYC065 Mean tumour volume (mm3) 3500 3000 2500 2000 1500 1000 100 mg/kg AraC Mean tumour volume (mm3) 2000 1500 1000 500 500 0 0 5 10 15 20 25 30 Days 0 0 5 10 15 20 Days after start of treatment EOL xenograft (AML with MLL translocation) treated with CYC065 poqd days 1-5 & 8-12. Median TGI day 19 97% for 40 mg/kg and 95% for 29 mg/kg CYC065. HL60 xenograft model (MLL WT) treated with CYC065 poqd on days 1-5 and 8-12. Median TGI day 11 90%. Source: Frame et al., AACR, 2010, Abs 3886; Frame et al, SOHO, 2014, Abs 209 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 23
Financial Position & Capitalization SEAMLESS data read-out: 2H 2015-1H 2016 YE 2014 Est. cash & cash equivalents: ~$24.0m 1 Operating cash burn (excludes non-cash items) 2013: ~ $18.2m annual 2 2014 Est.: ~ $19.2m annual 1 2015 Est.: ~ $15.0m annual (~$3.7m / quarter) 1 Fully diluted shares: ~ 25.6 million 3 No debt 1. Est.= estimated. Co. guidance. 2. 10-K filings. 3. 10-Q September 30, 2014. Common stock outstanding: 23.0 m. Includes 1.1 m warrants and options with an exercise price higher than $10 per share. 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 24
Key Milestones Sapacitabine SEAMLESS: interim analysis for futility SEAMLESS: complete enrollment SEAMLESS: topline data readout MDS: open enrollment of Phase 2b after HMA failure Sapacitabine & seliciclib in patients with solid tumors: update Phase 1 data Other Advance early-stage pipeline 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 25
Summary Sapacitabine opportunity in front line AML: SEAMLESS approaching topline data readout Sapacitabine in MDS: Phase 2 data, high-reward Financial position: sufficient capital through SEAMLESS data read-out Early-stage pipeline addressing high-interest targets & mechanisms of action 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 26
Cyclacel Pharmaceuticals Cell cycle pioneers Improving patient lives With orally-available Innovative medicines 1997-2015 Cyclacel Pharmaceuticals, Inc. Released FEB 2015 27