Disrupting the Cell Cycle to Treat AML, MDS and other Cancers

Transcription

1 CYC 682 Disrupting the Cell Cycle to Treat AML, MDS and other Cancers February 2015

2 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 The information in this presentation is current as of this date. Cyclacel does not take any responsibility to update such information Cyclacel Pharmaceuticals, Inc. Released FEB

3 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 Cyclacel Pharmaceuticals, Inc. Released FEB

4 Sapacitabine for AML Cyclacel Pharmaceuticals, Inc. Released FEB

5 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% Cyclacel Pharmaceuticals, Inc. Released FEB

6 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 Kantarjian et al, JCO, Cyclacel Pharmaceuticals, Inc. Released FEB

7 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) Cyclacel Pharmaceuticals, Inc. Released FEB

8 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% FEB Cyclacel Pharmaceuticals, Inc. Released FEB

9 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., Springer-Verlag, New York, Cyclacel Pharmaceuticals, Inc. Released FEB

10 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., Springer-Verlag, New York, # ProschanMA, Lan KKG, Wittes JT, Statistical Monitoring of Clinical Trials: A Unified Approach, New York: Springer, Cyclacel Pharmaceuticals, Inc. Released FEB

11 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, Cyclacel Pharmaceuticals, Inc. Released FEB

12 Possible SEAMLESS Outcomes Superior Equivalent Inferior Cyclacel Pharmaceuticals, Inc. Released FEB

13 * Source: FDA Briefing Document, Dacogen ODAC, February 9, Of 242 treated with decitabine 39% were aged 75 years or older Cyclacel Pharmaceuticals, Inc. Released FEB

14 SEAMLESS Pilot/Lead-in Study Kaplan-Meier Survival Plot All Patients (n=46) CYC Pilot (25) CYC 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 # Cyclacel Pharmaceuticals, Inc. Released FEB

15 Sapacitabine for MDS Cyclacel Pharmaceuticals, Inc. Released FEB

16 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 months Source: PrebetT, Gore S, et al, JCO 2011; Jabbour E, Garcia-Manero G, et al, Cancer Cyclacel Pharmaceuticals, Inc. Released FEB

17 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 PrebetT, Gore S, et al, JCO 2011 (95% CI, 14% to 26%on best supportive care; 29% on investigational Garcia- Manero G et al, American Society of Hematology Annual Meeting Dec. 2013, Abstract #2752 (Arm G 1-year survival) Cyclacel Pharmaceuticals, Inc. Released FEB

18 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 Cyclacel Pharmaceuticals, Inc. Released FEB

19 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 Cyclacel Pharmaceuticals, Inc. Released FEB

20 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 Cyclacel Pharmaceuticals, Inc. Released FEB

21 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 - BAY pan CDK (BAY) P2 * Source: Cyclacel data on file Cyclacel Pharmaceuticals, Inc. Released FEB

22 CYC065 Modulates Trastuzumab Resistance in HER2 + Breast Cancer incl. Regression Control Trastuzumab CDK2i. CYC065 T+CDK2i. CYC065 Tumor volume (mm3) 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 Cyclacel Pharmaceuticals, Inc. Released FEB

23 CYC065 eradication of AML and MLL-r xenograft models Vehicle 55 mg/kg CYC065 vehicle CYC mg/kg po 5d on/2d off x mg/kg CYC065 Mean tumour volume (mm3) mg/kg AraC Mean tumour volume (mm3) Days Days after start of treatment EOL xenograft (AML with MLL translocation) treated with CYC065 poqd days 1-5 & 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 Median TGI day 11 90%. Source: Frame et al., AACR, 2010, Abs 3886; Frame et al, SOHO, 2014, Abs Cyclacel Pharmaceuticals, Inc. Released FEB

24 Financial Position & Capitalization SEAMLESS data read-out: 2H H 2016 YE 2014 Est. cash & cash equivalents: ~$24.0m 1 Operating cash burn (excludes non-cash items) 2013: ~ $18.2m annual Est.: ~ $19.2m annual Est.: ~ $15.0m annual (~$3.7m / quarter) 1 Fully diluted shares: ~ 25.6 million 3 No debt 1. Est.= estimated. Co. guidance K filings Q September 30, Common stock outstanding: 23.0 m. Includes 1.1 m warrants and options with an exercise price higher than $10 per share Cyclacel Pharmaceuticals, Inc. Released FEB

25 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 Cyclacel Pharmaceuticals, Inc. Released FEB

26 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 Cyclacel Pharmaceuticals, Inc. Released FEB

27 Cyclacel Pharmaceuticals Cell cycle pioneers Improving patient lives With orally-available Innovative medicines Cyclacel Pharmaceuticals, Inc. Released FEB