Piper Jaffray Healthcare Conference

Transcription

1 Piper Jaffray Healthcare Conference John Scarlett, M.D. President and CEO, Geron Corporation November 2018

2 Forward-Looking Statements Except for statements of historical fact, the statements contained in this presentation are forward-looking statements made pursuant to the Safe Harbor provisions of the Private Securities Litigation Reform Act of These include, without limitation, statements regarding the expectations, plans, timelines and prospects for imetelstat and Geron, including without limitation: (i) that the imetelstat IND transfers from Janssen to Geron in the second quarter of 2019; (ii) that IMbark and IMerge will continue; (iii) Geron s plans to initiate the Phase 3 portion of IMerge in mid-2019; (iv) that Geron will outline a decision for myelofibrosis development by the end of the third quarter 2019; (v) that imetelstat for MDS would be prescribed before or in lieu of lenalidomide and/or hypomethylating agents; (vi) financial or operating projections or requirements of Geron; and (vii) other statements that are not historical facts, constitute forward-looking statements. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. These risks and uncertainties, include, without limitation: (i) whether contingencies delay or prevent the start of the Phase 3 portion of IMerge by mid-year 2019; (ii) whether regulatory authorities permit the further development of imetelstat on a timely basis, or at all; (iii) whether Geron decides for any reason not to develop imetelstat for myelofibrosis; (iv) whether any circumstances arise that prevent a timely transition of the imetelstat program from Janssen; (v) whether Geron s patents protect the commercial value of imetelstat; (vi) whether imetelstat s benefit-risk profile for MDS is better than lenalidomide and/or hypomethylating agents; and (vii) whether Geron can obtain sufficient funding to support further development of imetelstat. Additional information and factors that could cause actual results to differ materially from those in the forward-looking statements are contained in Geron's periodic reports filed with the Securities and Exchange Commission under the heading Risk Factors, including Geron's quarterly report on Form 10-Q for the quarter ending September 30, Undue reliance should not be placed on forwardlooking statements, which speak only as of the date they are made, and the facts and assumptions underlying the forward-looking statements may change. Except as required by law, Geron disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances. 2

3 Geron Overview Company A late-stage clinical development biopharmaceutical company with 100% ownership of imetelstat, a Phase 3-ready asset Sufficient cash ($185M as of 9/30/18) to move imetelstat forward into Phase 3 Imetelstat A first-in-class telomerase inhibitor, focused on hematologic myeloid malignancies Clinical evidence of potential disease-modifying activity in three myeloid malignancies: essential thrombocythemia (ET), myelofibrosis (MF) and myelodysplastic syndromes (MDS) Granted Fast Track designation by FDA for treatment of lower risk MDS patients Current Clinical Trials IMerge: Phase 2/3 trial in lower risk MDS IMbark: Phase 2 trial in Intermediate-2 or High-risk MF Oral presentations of updated data for both trials scheduled at American Society of Hematology (ASH) Annual Meeting Future Plans Screening and enrollment for Phase 3 portion of IMerge planned to begin by mid-year 2019 Exploring potential for late-stage development in MF, expect decision by end of third quarter

4 Telomerase A novel molecular target in oncology Telomerase enzyme Comprised of an RNA template component (htr) and a reverse transcriptase catalytic protein subunit (htert) In 2009, three Geron collaborators won the Nobel Prize for Medicine for discovery of telomerase and its relationship with telomeres Malignant Progenitor Cells Telomerase highly upregulated, in over 90% of cancers, enabling continued and uncontrolled proliferation Normal Progenitor Cells Telomerase transiently upregulated to support controlled proliferation telomeric DNA catalytic subunit (htert) RNA template (htr) Somatic Cells Telomerase inactive 4

5 Imetelstat A first-in-class telomerase inhibitor lipid tail imetelstat X NPS oligonucleotide Imetelstat binds to RNA template of telomerase Target: malignant progenitor cell clonal proliferation Structure: 13-mer thio-phosphoramidate (NPS) oligonucleotide complementary to htr, with covalently-bound lipid tail to increase cell permeability/tissue distribution Long tissue residence time in bone marrow, spleen, liver Potent competitive inhibitor of telomerase Clinical experience: more than 600 patients treated in Phase 1 and 2 trials telomere Prevents binding by and maintenance of telomeres 5

6 Imetelstat Key differentiating features Unique Mechanism of Action Targeting telomerase to tackle the underlying disease Telomerase activity is high in patients with myeloproliferative neoplasms Inhibiting telomerase expression limits the proliferation of malignant progenitor cell clones that drive the disease Challenging Patient Populations Tested Trial eligibility criteria emphasizes difficult-to-treat patients IMerge open to all MDS subtypes, minimum transfusion burden of 4.0 units/8 weeks, pretransfusion hemoglobin 9.0 g/dl IMbark must show objective evidence of disease progression during or after treatment with a JAK inhibitor (JAKi) or never responded to JAKi treatment plus active symptoms of MF Broad Clinical Activity Activity within multiple outcome measures suggest clinical benefit IMerge 8-week red blood cell (RBC) transfusion independence (TI) achieved across MDS subtypes (ring-sideroblast, RS +/-) and erythropoietin (EPO) levels, reductions in transfusion burden in all patients IMbark range of reductions in Total Symptom Score, potential improvement in overall survival for 9.4 mg/kg arm, including patients with at least one high-risk mutation and triple negative mutation patients 6

7 Hematologic Myeloid Malignancies Clinical evidence of potential disease modifying activity All arise from malignant progenitor cell clones in the bone marrow Baerlocher et al, NEJM 2015; 373: telomerase Steensma et al, 2018 ASH Abstract #463 Tefferi Pilot Study, unpublished Tefferi et al, NEJM 2015; 373:

8 Myelodysplastic Syndromes (MDS) Disease characteristics telomerase Sekeres, Natl Compr Canc Netw 2011; 9:57-63 Bejar & Steensma, Blood 2014; 124: Greenberg et al, Blood 1997; 89: Malcovati et al, JCO 2007; 25: MDS is a diverse group of clonal hematologic malignancies Comprised of numerous subtypes, including refractory anemia with ring-sideroblasts (RARS) and refractory cytopenia with multi-lineage dysplasia-rs (RCMD-RS) RS+ MDS associated with lower risk of AML transformation and better survival than RS- patients Median age at diagnosis is 70 Up to 30% of patients progress to acute leukemia (AML) Lower Risk MDS Median overall-survival is years Chronic anemia is the predominant clinical problem, many patients are dependent on RBC transfusions Transfusion dependency is associated with iron overload, and shorter survival - 2 units of RBC monthly may reduce life expectancy by 50% and increase risk of progression to AML 8

9 MDS Patient Population in the U.S. Addressing a large unmet need 60,000 MDS patients in the U.S. 16,000 Cases diagnosed annually in the U.S. ~70% of MDS patients have Lower Risk MDS Cogle, Curr Hematol Malig Rep; 2015, Greenberg et al, Blood 1997; 89:

10 Treatment Landscape for Lower Risk MDS Chronic anemia remains an unmet need Erythropoiesis Stimulating Agents (ESAs) Improvement in anemia in ~50% of patients Median treatment duration: ~2 years Patients refractory to ESAs become dependent on red blood cell transfusions Lenalidomide Not approved in U.S. or Europe for non-del(5q) patients 8-week RBC-TI: 27% Hypomethylating Agents (HMAs) Approved in U.S. for all patients, including del(5q) and non-del(5q) Not approved in Europe 8-week RBC-TI: ~17% Fenaux and Adès, Blood 2013; 121: Santini et al, J Clin Oncol 2016; 34: Tobiasson et al, BCJ 2014; 4: e189 10

11 Treatment Landscape for Lower Risk MDS Opportunity to sequence imetelstat ahead of available therapies Erythropoiesis Stimulating Agents (ESAs) Improvement in anemia in ~50% of patients Median treatment duration: ~2 years Patients refractory to ESAs become dependent on red blood cell transfusions Imetelstat 8-week RBC-TI: 37% potential to sequence ahead of lenalidomide and HMAs ASH 2018 Abstract #463: Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naïve; Steensma D, et.al. Lenalidomide Not approved in U.S. or Europe for non-del(5q) patients 8-week RBC-TI: 27% Hypomethylating Agents (HMAs) Approved in U.S. for all patients, including del(5q) and non-del(5q) Not approved in Europe 8-week RBC-TI: ~17% Fenaux and Adès, Blood 2013; 121: Santini et al, J Clin Oncol 2016; 34: Tobiasson et al, BCJ 2014; 4: e189 11

12 IMerge: 2-Part Phase 2/3 Trial Part 1 Phase 2 portion ClinicalTrials.gov (NCT ) single arm, open label (n = 57); target patient population (n=38) IMerge Part 1: Phase 2 Portion Imetelstat 7.5mg/kg every 4 weeks 1 Efficacy: Red Blood Cell (RBC) Transfusion Independence (TI) 8 weeks 2 Efficacy: RBC TI 24 weeks; time to and duration of RBC TI; hematologic improvement (HI); reduction in RBC burden Transfusion dependent is defined as an RBC transfusion requirement of 4 units over 8 weeks prior to trial entry ESA R/R following 8 weeks of weekly epoetin alfa 40,000 U or darbepoetin alfa 150 mcg (or equivalent) or serum erythropoietin (sepo) >500 mu/ml Supportive care permitted in both arms: RBC transfusions, myeloid growth factors per investigator discretion as clinically needed and local guidelines Clinical Trial Conduct and Status Initial enrollment: transfusion dependent patients with IPSS Low or Intermediate-1 Risk MDS that is relapsed or refractory (R/R) to erythropoiesis stimulating agent (ESA) treatment Results from initial enrollment presented at ASH in December 2017 and the European Hematology Association (EHA) in June 2018 Starting dose confirmed Target patient population defined: no del(5q) chromosomal abnormality or non-del(5q), naïve to lenalidomide or HMA treatment Fast Track designation by FDA for treatment of lower risk MDS patients More mature data for target patient population (n=38) to be presented at ASH in December Treatment and follow-up continuing as per protocol 12

13 Lower Risk MDS Trials Targeting different patient populations IMerge MEDALIST Geron Company Acceleron/Celgene Imetelstat Drug name Luspatercept Telomerase inhibitor Mechanism of action TGF-b inhibitor Phase 2 (n=38) Phase of development Phase 3 (n=229) active (n=153), placebo (n=76) RS+ or RS- 4 units/8 weeks MDS subtype Ring-sideroblasts (RS) Minimum transfusion burden for enrollment 8 (4-14) Median baseline transfusion burden # units/8 weeks (range) RS+ only Required RBC transfusions 5 (1-20) 29% < 4 units IMerge focused on high transfusion burden patients and open to all MDS subtypes ASH 2018 Abstract #463: Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis- Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naïve; Steensma D, et.al. ASH 2018 Abstract #1: The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate- Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions 13

14 IMerge Part 1: Target Patient Population Results from ASH abstract ClinicalTrials.gov (NCT ) IMerge Target Patient Population* (n=38) Baseline median RBC transfusion burden 8.0 units/8 weeks; range week RBC-TI 37% (14/38) 8-week RBC-TI observed across MDS subtypes RARS/RCMD-RS (RS+) 33% Other Patients (RS-) 27% 8-week RBC-TI consistent across baseline EPO levels EPO >500 mu/ml 33% EPO 500 mu/ml 32% Safety Safety profile consistent with previous imetelstat clinical trials in hematologic myeloid malignancies Adverse events such as cytopenias, gastrointestinal or constitutional symptoms and hepatic biochemistry abnormalities No new safety signals reported Myelosuppression is dose-limiting toxicity observed (managed through dose holds and modification rules) Most cytopenias resolved within 4 weeks *Transfusion dependent patients with IPSS Low or Intermediate-1 Risk MDS, who are non-del(5q), R/R to ESAs and naïve to lenalidomide and HMA treatment More mature data expected in oral presentation at ASH on December 2, 2018 ASH 2018 Abstract #463: Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis- Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naïve; Steensma D, et.al. 14

15 Randomize (2:1) Double-blind IMerge: 2-Part Phase 2/3 Trial Part 2 Phase 3 portion ClinicalTrials.gov (NCT ) Data from Part 1 for target patient population support moving forward with Part 2 Patient screening and enrollment planned to begin mid-year 2019* Current Clinical Trial Design for IMerge Part 2: Phase 3 Portion Transfusion Dependent, Low or Intermediate-1 Risk MDS, Non-del(5q), R/R ESAs, Naïve to Lenalidomide and HMA (n = ~170) Imetelstat (n = ~115) 7.5mg/kg every 4 weeks Placebo (n = ~55) 1 Efficacy: Red Blood Cell (RBC) Transfusion Independence (TI) 8 weeks 2 Efficacy: RBC TI 24 weeks; time to and duration of RBC TI; hematologic improvement (HI); reduction in RBC burden Transfusion dependent is defined as an RBC transfusion requirement of 4 units over 8 weeks prior to clinical trial entry ESA R/R following 8 weeks of weekly epoetin alfa 40,000 U or darbepoetin alfa 150 mcg (or equivalent) or serum erythropoietin (sepo) >500 mu/ml Supportive care permitted in both arms: RBC transfusions, myeloid growth factors per investigator discretion as clinically needed and local guidelines *Timing dependent upon transfer of imetelstat investigational new drug (IND) sponsorship from Janssen to Geron. 15

16 Myelofibrosis (MF) Disease characteristics Malignant clonal proliferation and atypical megakaryocytic hyperplasia leads to bone marrow fibrosis and impaired hematopoiesis Fibrosis thought to be induced by inflammatory cytokines produced by megakaryocytes originating from the malignant progenitor cell clone Constitutional symptoms (e.g., fever, weight loss, night sweats, pruritus) present in approximately 35% of patients also thought to be due to cytokines produced by malignant megakaryocytes Impaired bone marrow hematopoiesis shifts blood production to spleen and liver (palpable splenomegaly in approximately 80% of patients) Serious and life-threatening illness Leukemic transformation to AML (blast-phase MF) Thrombohemorrhagic complications associated with dysfunctional hematopoiesis Median survival: ~1-3 years for intermediate-2 or high-risk disease telomerase Tefferi, JCO 2005; 23: Tefferi, Mayo Clin Proc 2012; 87:25-33 Gangat et al, JCO 2011; 29:

17 MF Patient Population in the U.S. Addressing an underserved market 13,000 MF patients in the U.S. 3,000 Cases diagnosed annually in the U.S. ~70% of MF patients have Intermediate-2 or High-risk MF Mehta et al, Leuk Lymphoma 2014; 55: Gangat et al, JCO 2011; 29:

18 Current Treatments for Int-2/High-Risk MF No approved drug for patients relapsed/refractory to ruxolitinib Ruxolitinib Primarily for symptoms or splenomegaly Oral JAK1/JAK2 inhibitor Only approved product for MF in U.S./Europe Stay on drug as long as tolerated Conventional drugs viewed as ineffective, especially in advanced disease Harrison et al, ASH 2015; Gupta et al, ASCO 2016 Newberry et al, Blood 2017; 130: Kuykendall et al, Ann Hematol 2018; 97: Spiegel et al, Blood Advances 2017; 1: % 5-year ruxolitinib discontinuation rate Primary reasons: Suboptimal response Loss of therapeutic effect After discontinuation of ruxolitinib Median Overall Survival is ~14-16 months Investigational Agents (e.g., imetelstat) 18

19 Randomize (1:1) IMbark Phase 2 Trial Rigorously defined relapsed/refractory MF patients ClincialTrials.gov (NCT ) Trial Population: Patients with Intermediate-2 or High-risk MF Relapsed or refractory (R/R) to JAKi treatment Key Goals: Define appropriate dosing (9.4 or 4.7 mg/kg every 3 weeks) Confirm safety and clinical benefit in this high unmet need population Intermediate-2 or High-risk MF R/R to JAKi treatment Imetelstat 9.4 mg/kg every 3 weeks Imetelstat 4.7 mg/kg every 3 weeks Co-1 Efficacy: Spleen response rate and symptom response rate 2 Efficacy: CR, PR and CI, anemia response per 2013 IWG-MRT criteria, duration of responses, overall survival (OS) Exploratory: Cytogenetic and molecular responses, leukemia free survival 19

20 IMbark Results from ASH Abstract Eligibility criteria yields poor-prognosis MF patient population First trial requiring patients to meet rigorous definition of relapsed/refractory to JAKi Objective evidence of disease progression during or after treatment with a JAKi through worsening splenomegaly or never responded to JAKi treatment through no reduction in spleen size after 12 weeks of JAKi therapy Active symptoms of MF with minimum symptom score of 5 out of 10 Patient demographic highlights: 1) Considerable proportion of DIPSS high-risk MF 41% (44/107) These patients have a high risk for leukemic transformation 2) Sizeable triple negative patient population 25% (26/105) Triple negative means an absence of JAK2, MPL or CALR mutations Triple negative patients have poor overall survival, an increased risk of leukemic transformation and do not respond well to existing therapies 3) Significant number of high molecular risk patients 68% (71/105) Presence of at least 1 mutation in high-molecular risk genes, ASXL1, EZH2, IDH1/2 and SRSF2 These genes have been associated with inferior prognosis ClincialTrials.gov (NCT ) ASH 2018 Abstract #685: Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels; Mascarhenas, J., et al. 20

21 IMbark Results from ASH Abstract Efficacy results primary endpoints ClincialTrials.gov (NCT ) SVR Per IRC at Week 24 Symptom Response based on TSS at Week mg/kg (n=48) 9.4 mg/kg (n 59) Spleen Response 0% 10% (6/59) 4.7 mg/kg (n=48) 9.4 mg/kg (n 59) Symptom Response 6% (3/48) 32% (19/59) Spleen Response: proportion of patients who achieve a 35% reduction in spleen volume assessed by imaging at 24 weeks in comparison to baseline Symptom Response: proportion of patients who achieve a 50% reduction in Total Symptom Score at 24 weeks in comparison to baseline ASH 2018 Abstract #685: Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels; Mascarhenas, J., et al. 21

22 IMbark Results from ASH Abstract Efficacy results overall survival ClincialTrials.gov (NCT ) 4.7 mg/kg (n=48) 9.4 mg/kg (n 59) Median Overall Survival 20 mos not reached Median follow-up: 22.6 mos (range: ) Median Overall Survival: length of time from trial enrollment where half of the assessable patients in a group are still alive Additional Overall Survival Analyses: 1) Improvement in OS for the 9.4 mg/kg arm does not appear to be due to post-imetelstat intervention with either JAKi or allogeneic stem cell transplant A sensitivity analysis censoring patients at the time of subsequent JAKi therapy or stem cell transplant resulted in a median OS that had still not been reached 2) Triple negative patients in the 9.4 mg/kg dosing arm showed promising overall survival despite this subpopulation being difficult to treat using current available therapy ASH 2018 Abstract #685: Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels; Mascarhenas, J., et al. 22

23 IMbark Results from ASH Abstract Safety results ClincialTrials.gov (NCT ) Most Common Adverse Event on Treatment (all grades) 4.7 mg/kg (n=48) 9.4 mg/kg (n=59) Thrombocytopenia 23% 49% Anemia 31% 44% Neutropenia NR 36% Diarrhea 38% NR Nausea 31% 34% NR: not reported in abstract Grade 3/4 4.7 mg/kg (n=48) 9.4 mg/kg (n=59) Thrombocytopenia 29% 42% Neutropenia 13% 34% Safety Safety profile consistent with previous imetelstat clinical trials in hematologic myeloid malignancies Adverse events such as cytopenias, gastrointestinal or constitutional symptoms and hepatic biochemistry abnormalities No new safety signals reported Myelosuppression is dose-limiting toxicity observed (managed through dose holds and modification rules) Most cytopenias resolved within 4 weeks ASH 2018 Abstract #685: Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels; Mascarhenas, J., et al. 23

24 IMbark Results Key conclusions ClincialTrials.gov (NCT ) Clinical activity demonstrated in 9.4 mg/kg dosing arm No formal clinical trial conducted previously for patients R/R to JAKi Potential improvement in survival observed Median OS for previously treated JAKi patients reported to be mos (Kuykendall Ann Hematol 2018; Newberry Blood 2017) Safety profile considered acceptable for this poor-prognosis population Data warrant further exploration in future studies Geron s plan in MF Discuss IMbark results with MF experts and regulatory authorities to explore potential for late-stage development in MF Expect to outline a decision by end of third quarter of 2019 More mature data from extension phase of IMbark, including updated median overall survival for the 9.4 mg/kg arm, expected in oral presentation at ASH on December 3, 2018 ASH 2018 Abstract #685: Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels; Mascarhenas, J., et al. 24

25 Upcoming Milestones Data Presentations ASH abstracts published online November 1, 2018 IMerge Phase 2 data presentation at ASH December 2, 2018 IMbark Phase 2 data presentation at ASH December 3, 2018 Analyst and investor event December 10, 2018 Clinical Development Plans Discussions with MF experts and regulatory authorities to determine next steps Start of first quarter 2019 Imetelstat IND transfers from Janssen to Geron Second quarter 2019 Initiate screening and enrollment for Phase 3 portion of IMerge By mid-year 2019 Outline decision regarding potential latestage development in MF End of third quarter

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