analyst and investor event...2018/12/10 · azra raza, m.d. chan soon-shiong professor of medicine...

Analyst and Investor Event

December 10, 2018

Forward-Looking Statements

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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 1995. 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 plan to initiate screening and enrollment of the Phase 3 portion of IMerge by mid-2019; (iv) that Geron expects top-line results for the Phase 3 portion of IMerge by mid-year 2022; (v) that Geron will outline a decision regarding late-stage development in myelofibrosis by the end of the third quarter 2019; (vi) that imetelstat for MDS would be prescribed before or in lieu of lenalidomide, hypomethylating agents and/or luspatercept; (vii) financial or operating projections or requirements of Geron; and (viii) 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 both the start of the Phase 3 portion of IMerge by mid-year 2019 and top-line results by mid-year 2022; (ii) whether regulatory authorities permit the further development of imetelstat for MF or MDS 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 opportunity of imetelstat; (vi) whether imetelstat’s benefit-risk profile for MDS is better than lenalidomide, hypomethylating agents and/or luspatercept; 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, 2018. Undue reliance should not be placed on forward-looking 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.

Agenda

8:00 am Welcome Suzanne Messere Investor Relations

8:05 am Geron Overview and Introductions John A. Scarlett, M.D. President and Chief Executive Officer

8:15 am An Introduction to Myelofibrosis

Imetelstat in Int-2 to High-risk MFData from IMbark Phase 2 Clinical Trial Presented at the 60th American Society of Hematology Annual Meeting

Q&A

John Mascarenhas, M.D. Associate Professor of Medicine in the Myeloproliferative Disorders Program of the Tisch Cancer Institute, Division of Hematology/Oncology at the Icahn School of Medicine at Mount Sinai, New York

8:45 am An Introduction to Myelodysplastic Syndromes

Imetelstat in Lower Risk MDSData from IMerge Part 1 Clinical Trial Presented at the 60th American Society of Hematology Annual Meeting

Q&A

Azra Raza, M.D. Chan Soon-Shiong Professor of Medicine and Director of the MDS Center at New York-Presbyterian/Columbia University Medical Center, New York

9:15 am Closing Remarks John A. Scarlett, M.D.

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Geron Overview and Introductions

John A. Scarlett, M.D.

President & CEO

Geron Overview

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Imetelstat• 100% ownership of global rights• Clinical evidence of potential disease-modifying activity in three myeloid malignancies: essential thrombocythemia (ET),

myelofibrosis (MF) and myelodysplastic syndromes (MDS)• Two ongoing Phase 2 clinical trials: IMerge, a Phase 2/3 trial in lower risk MDS and IMbark, a Phase 2 trial in Intermediate-2 or

High-risk MF, both indications represent large unmet needs with limited available treatments• Granted Fast Track designation by FDA for treatment of lower risk MDS patients

Company• Founded with the vision of creating innovative oncology treatments by applying advances in telomere biology• Cloned the catalytic and RNA template components of human telomerase• Focused on the development and commercialization of potential treatments for hematologic myeloid malignancies• Entering Phase 3 clinical development with lead product candidate, imetelstat, a first-in-class telomerase inhibitor discovered

and developed by Geron

Future Plans• Sufficient cash ($185M as of 9/30/18) to move imetelstat forward into Phase 3• Plan to build on organizational strength with addition of experienced development personnel in hematologic malignancies• 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 2019

John Mascarenhas, M.D.

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Current • Associate Professor of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

• Director, Adult Leukemia Program, Icahn School of Medicine at Mount Sinai, New York, NY

• Teaching Faculty, Graduate School of Biomedical Sciences of the Icahn School of Medicine at Mount Sinai, New York, NY

Medical Training • New York Medical College, Valhalla, NY

• Internal Medicine Resident, Brown University School of Medicine, Providence, RI

• Hematology-Oncology Fellow, Mount Sinai School of Medicine, New York, NY

• Clinical Research, Master of Science Program, Mount Sinai Graduate School in Biological Sciences

Expertise • Translational research in malignant hematology and the development of investigator-initiated clinical trials in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML)

An Introduction toMyelofibrosis


Tisch Cancer Institute

Myelofibrosis (MF)Disease characteristics

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• 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; 23:8520-8530Tefferi, Mayo Clin Proc 2012; 87:25-33 Gangat et al, JCO 2011; 29:392-397

MF Patient Population in the U.S.Addressing an underserved market

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~70%of MF patients have Intermediate-2 or

High-risk MF

13,000MF patients in the U.S.

3,000Cases diagnosed annually in the U.S.

Mehta et al, Leuk Lymphoma 2014; 55:595-600Gangat et al, JCO 2011; 29:392-397

75%5-year ruxolitinib

discontinuation rate

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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 2016Newberry et al, Blood 2017; 130:1125-1131Kuykendall et al, Ann Hematol 2018; 97:435-441Spiegel et al, Blood Advances 2017; 1:1729-1738

Treatment Landscape for Int-2/High-Risk MFNo approved drug for patients relapsed/refractory to ruxolitinib

Primary reasons:• Suboptimal response• Loss of therapeutic

effect

Median Overall Survival is ~14-16 months

After discontinuation of ruxolitinib

Investigational Agents

(e.g., imetelstat)

Data from IMbark Phase 2Presented at the 60th ASH Annual Meeting



John Mascarenhas, MD1, Rami S. Komrokji2, Michele Cavo, MD3, Bruno Martino, MD4, Dietger Niederwieser, MD5, Andreas Reiter, MD6, Bart L Scott, MD7, Maria R. Baer, MD8, Ronald Hoffman, MD9, Olatoyosi Odenike, MD10, Jacqueline Bussolari, PhD11, Eugene Zhu, PhD11, Fei Huang, PhD11, Esther Rose, MD11, Laurie Sherman, BSN11,

Souria Dougherty, BS, MBA11, Faye M. Feller, MD11 and Jean-Jacques Kiladjian, MD, PhD12

1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; MPN-RC (US), 2H Lee Moffitt Cancer Center (US), 3”Seràgnoli” Institute of Hematology, University of Bologna (IT), 4Grande Ospedale Metropolitano-G.O.M. Bianchi-Melacrino-Morelli (IT),

5University Hospital Leipzig (DE), 6University Hospital Mannheim (DE), 7Fred Hutchinson Cancer Research Center (US), 8University of Maryland Greenebaum Comprehensive Cancer Center (US), 9Tisch Cancer Institute, Mount Sinai School of Medicine (US),

10University of Chicago (US), 11Janssen Research & Development, LLC (US), 12Hôpital Saint-Louis, Université Paris (FR)

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

Mascarenhas et al. ASH 2018 Oral Presentation

Funded by Janssen Research & Development and Geron Corporation Abstract #685


Background

Imetelstat, a 13-mer oligonucleotide that specifically targets the RNA template of human telomerase, is a potent competitive inhibitor of telomerase enzymatic activity1,2

Clinical activity and an acceptable safety profile were reported in a 33-patient pilot study in intermediate-2 (int-2) or high-risk myelofibrosis (MF)

o 48% of patients had been previously treated with a Janus Kinase inhibitor (JAKi)3

Currently, JAKi is the only approved therapy for MF, with failure leading to poor outcomes

Here, we report the results of a phase 2 clinical study of imetelstat at two dose levels in patients with MF who have relapsed after or are refractory to JAKi therapy (MYF2001, NCT02426086)

1Asai, et al. Cancer Res 2003;63:3931-3939. 2Herbert, et al. Oncogene 2005;24:5262-5268. 3Tefferi, et al. N Engl J Med 2015;373:908-919.

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Patient Population

Int-2/high-risk MF per DIPSS criteria

Relapsed or refractory to JAKi defined as documented progressive disease during or after JAKi:

o Patients must have worsening of splenomegaly-related abdominal pain at any time after the start of JAKi therapy and EITHER:

▪ No reduction in spleen volume or size after 12 weeks of JAKi therapy, OR

▪ Worsening splenomegaly* at any time after the start of JAKi therapy documented by:

✓ Increase in spleen volume from nadir by 25% measured by MRI or CT, or

✓ Increase in spleen size by palpation

Active symptoms of MF

Baseline measurable splenomegaly (palpable spleen ≥ 5 cm below LCM or ≥ 450 cm3

by MRI)

* Adapted from IWG-MRT response criteria definition of progressive disease.

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Study Design

Randomized to 2 doses

9.4 mg/kg q3w

4.7 mg/kgq3w

Enrollment Suspended

Closed; escalation permitted

n = 59 n = 48

Follow for overall survival

Interim analysis after 20 patients in each arm reached

disease assessment at 12-wks

Disease assessment at 24-wks included in Primary analysis

Co-primary endpoints at Week 24

o Spleen response rate: proportion of patients achieving ≥ 35% reduction in spleen volume by MRI at 24 weeks

o Symptom response rate: proportion of patients achieving ≥ 50% reduction in total symptom score per modified MFSAF v2.0 at 24 weeks

Key secondary endpoints: safety, overall survival (OS), treatment response, and pharmacokinetic and pharmacodynamic relationships

Stratification

o Spleen size ≥ 15 cm (yes/no)

o Platelets 75K – 150K vs ≥ 150K

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Treatment Exposure

107 patients were enrolled at 55 institutions

Clinical cutoffs for analyses:

o April 26, 2018 – Primary analysis of efficacy and safety, with a median follow-up of 22.6 (0.2-27.4) months

o October 22, 2018 – Overall survival, with a median follow-up of 27.4 (0.2-33.0) months

Median treatment duration: 26.9 (0.1-118.1) weeks

o Median duration on treatment was 33.3 weeks on the 9.4 mg/kg arm and 23.9 weeks on the 4.7 mg/kg arm

o The 4.7 mg/kg arm had been closed early, influencing duration of treatment

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Baseline Demographics and Disease Characteristics

4.7 mg/kg(n = 48)

9.4 mg/kg(n = 59)

Total(N = 107)

Median age (range), years 68.5 (44, 84) 67 (31, 86) 68.0 (31, 86)Male, n (%) 32 (67) 35 (59) 67 (63)Myelofibrosis subtype, n (%)

PrimaryPost-ETPost-PV

27 (56)9 (19)

12 (25)

36 (61)10 (17)13 (22)

63 (59)19 (18)25 (23)

DIPSS risk status, n (%)Intermediate-1 riskIntermediate-2 riskHigh Risk

1a (2)28 (58)19 (40)

034 (58)25 (42)

1 (1)62 (58)44 (41)

Spleen length (palpation) – Median (range), cm≥ 15cm, n (%)

18 (4, 35)31 (65)

18 (3, 32)35 (59)

18 (3, 35)66 (62)

Spleen volume (MRI) – Median, IRC (range), cm3 3353 (726, 7243) 2998 (890, 7607) 3167 (726, 7607)

Total Symptom Score – Median (range) 22 (7, 58) 24 (3, 57) 23 (3, 58)

RBC transfusion dependentb, n (%) 14 (29) 12 (20) 26 (24)

Platelet count – Median (range), x109/L 153 (74, 1097) 146 (65, 798) 147 (65, 1097)

Time since initial diagnosis – Median (range), months 49 (2, 227) 43 (7, 201) 44 (2, 227)

Time since last JAKi Tx – Median (range), months 1.4 (1, 31) 1.7 (1, 38) 1.7 (1, 38)

Duration of prior JAKi Tx – Median (range), months 22 (3, 90) 25 (1, 73) 23 (1, 90)a Indicated in eCRF comments, but does not appear in statistical output. This is a protocol deviation.b Received 6 units PRBC in 12 weeks prior to enrollment.

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Patients Disposition

n (%)4.7 mg/kg

(n = 48)9.4 mg/kg

(n = 59)Total

(N = 107)

Discontinued study treatmentAdverse Event a

DeathLack of EfficacyPhysician DecisionProtocol ViolationWithdrawal by Patient / Refused Study TreatmentProgressive DiseaseOther

47 (98)12 (25)

07 (15)7 (15)1 (2)

12 (25)8 (17)

0

53 (90)15 (25)

1 (2)10 (17)

4 (7)1 (2)

11 (19)9 (15)2 (3)

100 (93)27 (25)

1 (1)17 (16)11 (10)

2 (2)23 (21)17 (16)

2 (2)

Ongoing study participation 17 (35) 33 (56) 50 (47)

Terminated study participationDeathLost to Follow-upWithdrawal by Patient

31 (65)24 (50)

1 (2)6 (13)

26 (44)21 (36)

05 (8)

57 (53)45 (42)

1 (1)11 (10)

a Discontinuations from study treatment due to fatal adverse events occurred in 4 patients on 4.7 mg/kg and 3 patients on 9.4 mg/kg. The patient who discontinued treatment due to death had a primary reason for death recorded as progressive disease (adverse event not reported).

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n (%) 4.7 mg/kg 9.4 mg/kg Total

Biomarker population, n 48 57 105

With ≥ 1 mutation 48 (100) 55 (96.5) 103 (98)

≥ 3 mutations 40 (83) 38 (67) 78 (74)

Triple Negative 10 (21) 16 (28) 26 (25)

JAK2 V617F 32 (67) 32 (56) 64 (61)

CALR 2 (4) 7 (12) 9 (9)

MPL 4 (8) 2 (4) 6 (6)

HMRa 36 (75) 35 (61) 71 (68)

ASXL1 24 (50) 25 (44) 49 (47)

EZH2 10 (21) 18 (32) 28 (27)

SRSF2 5 (10) 2 (4) 7 (7)

IDH1 2 (4) 2 (4) 4 (4)

IDH2 4 (8) 5 (9) 9 (9)

Baseline Mutation Summary on Selected Genes

aHMR, high molecular risk; ie, 1 or more mutations in ASXL1, EZH2, SRSF2, IDH1, or IDH2.

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SVR Per IRC at Week 24

At time of cut-off, 20 patients in the 4.7 mg/kg and 44 patients in the 9.4 mg/kg had Week 24 MRI, however, ITT is used as denominator for percentages.

6 (10%) patients in the 9.4 mg/kg arm had ≥ 35% SVR at Week 24

23 (37%) patients in the 9.4 mg/kg arm had ≥ 10% SVR at Week 24

0 SVR responder in4.7 mg/kg 6 SVR responders in 9.4 mg/kg

IRC, Independent Review Committee; SVR, spleen volume reduction.

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Symptom Response based on TSS at Week 24

19 (32%) patients in the 9.4 mg/kg arm had ≥ 50% symptom response at Week 24

At time of cut-off, 20 patients in the 4.7 mg/kg and 43 patients in the 9.4 mg/kg had Week 24 TSS e-diary entries, however, ITT is used as denominator for percentages.

3 symptom responders in 4.7 mg/kg

19 symptom responders in 9.4 mg/kg

TSS, total symptom score.

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Change in Bone Marrow Fibrosis

19 (18%) patients had an improvement in bone marrow fibrosis per central assessment

Shift in Central Bone Marrow Fibrosis from Baseline to Best Fibrosis Grading

n (%)4.7 mg/kg

(n = 48)9.4 mg/kg

(n = 59)

Completed baseline and post-baseline BM assessment, n

20 37

Improvement 4 (8) 15 (25)

Stable 15 (31) 15 (25)

Worsening 1 (2) 7 (12)

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BM, bone marrow.


Overall Survival (ITT) for Imetelstat at Different Dose Levels

Median follow-up: 27.4 months

Median survival:

o 19.9 months (95% CI, 17.1, NE) in

4.7 mg/kg

o 29.9 months (95% CI, 22.8, NE) in

9.4 mg/kg

Multiple sensitivity analyses were performed (including data censoring at time of dose escalation, censoring at subsequent JAKior stem cell transplant and excluding patients who were dose escalated or randomized

after closure of the 4.7 mg/kg arm), all generating similar results

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OS in Triple Negative Disease

In 9.4 mg/kg arm, lower death rate seen in Triple Negative (TN) group compared to Non-TN group

TN

Non-TN

Patients at risk

10 9 7 1

38 30 16 2

TN

Non-TN

Patients at risk

16 16 14 3

41 33 20 4

4.7 mg/kg Death RateMedian Survival

(months)

TN 60% 23.1 (17.0, NE)

Non-TN 55% 19.4 (17.1, NE)

9.4 mg/kg Death RateMedian Survival

(months)

TN 25% NE (NE, NE)

Non-TN 51% 24.6 (20.7, NE)

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Most Frequent Hematologic* and Non-Hematologic AEs

4.7 mg/kg (n = 48) 9.4 mg/kg (n = 59)

n (%) All Grades Grade ≥ 3 All Grades Grade ≥ 3

Hematologic (≥ 10% in either arm)

Thrombocytopenia 11 (23) 11 (23) 29 (49) 24 (41)

Anemia 15 (31) 15 (31) 26 (44) 23 (39)

Neutropenia 5 (10) 5 (10) 21 (36) 19 (32)

Leukopenia 3 (6) 3 (6) 8 (14) 8 (14)

Non-hematologic (≥ 20% in either arm)

Nausea 15 (31) 1 (2) 20 (34) 2 (3)

Vomiting 10 (21) 1 (2) 8 (14) 1 (2)

Diarrhea 18 (38) 2 (4) 18 (31) 0

Fatigue 10 (21) 3 (6) 16 (27) 4 (7)

Cough 11 (23) 0 9 (15) 0

Dyspnea 9 (19) 6 (13) 14 (24) 3 (5)

Abdominal Pain 10 (21) 2 (4) 14 (24) 3 (5)

Asthenia 9 (19) 3 (6) 14 (24) 6 (10)

Pyrexia 8 (17) 1 (2) 13 (22) 3 (5)

Edema peripheral 13 (27) 0 11 (19) 0*Treatment emergent, per reported AEs (not laboratory values). Frequency of reported Grade 3/4 hematologic AEs were consistent with cytopenias reported through lab values.

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Cytopenias and LFTs

Most grade 3/4 cytopenias were reversible within 4 weeks

Clinical consequences of cytopenias

Grade 3/4 LFT elevations were observed in 7 patients on study

o An independent Hepatic Review Committee reviewed all LFT and hepatic data

o Imetelstat-related hepatic toxicities were not observed

n (%)4.7 mg/kg

(n = 48)9.4 mg/kg

(n = 59)

Grade 3 Febrile Neutropenia 1 (2) 1 (2)

Grade ≥ 3 Hemorrhagic events 2 (4) 3 (5)

Grade ≥ 3 Infections 10 (21) 6 (10)

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Conclusions

Imetelstat at 9.4 mg/kg IV every 3 weeks has demonstrated clinical activity in int-2 or high-risk MF patients who are relapsed/refractory to JAKi, notably in observed median OS that approached 30 months

Though no formal study has reported survival for patients who are truly relapsed/refractory to JAKi, median OS of patients who were previously treated with JAKi has been reported to be 12-14 months1,2

The safety profile for imetelstat was considered acceptable for this poor-prognosis population

Imetelstat at 9.4 mg/kg IV every 3 weeks is a promising agent for JAKi failure MF patients and warrants further testing in clinical trials

1Kuykendall, et al. Ann Hematol 2018;97:435-441. 2Newberry, et al. Blood 2017;130:1125-1131.

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Acknowledgements

The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment

of all investigators and their staff

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Q&A



Azra Raza, M.D.

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Current • Chan Soon-Shiong Professor of Medicine and Director of the MDS Center at New York-Presbyterian/Columbia University in New York, NY

Previous Positions • Professor at the University of Massachusetts and Director of Hematology and Oncology

• Professor at the University of Chicago and the first Director of the Department of Medicine’s Division of Myeloid Diseases

• Professor at Rush University in Chicago

Medical Training • Internal medicine at the University of Maryland, Franklin Square Hospital, and Georgetown/VA Medical Center in Washington, D.C.

• Fellowship in Medical Oncology at Roswell Park Cancer Institute in Buffalo, NY

Expertise • Basic and clinical research in acute myeloid leukemia and MDS since the early 1980’s, studying the biology and pathology of myeloid malignancies

An Introduction to Myelodysplastic Syndromes

Azra Raza, M.D.

Columbia University Medical Center

Normal Blood Formation

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Normal and Malignant Blood Formation

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MD

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AnemiaNeutropenia

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Myelodysplastic Syndromes (MDS)Disease characteristics

37

telomerase

• 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 3.5-5.7 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

Sekeres, Natl Compr Canc Netw 2011; 9:57-63 Bejar & Steensma, Blood 2014; 124:2793-2803Greenberg et al, Blood 1997; 89:2079-2088 Malcovati et al, JCO 2007; 25:3503-3510www.cancer.org/cancer/myelodysplastic-syndromes

Cogle, Curr Hematol Malig Rep; 2015, 10272-10281Greenberg et al, Blood 1997; 89:2079-2088

~70%of MDS patients have

Lower Risk MDS

60,000MDS patients in the U.S.

16,000Cases diagnosed annually in the U.S.

MDS Patient Population in the U.S.Addressing a large unmet need

38

Treatment Landscape for Lower Risk MDSChronic anemia remains an unmet need

39

Fenaux and Adès, Blood 2013; 121:4280-4286Santini et al, J Clin Oncol 2016; 34:2988-2996Tobiasson et al, BCJ 2014; 4: e189

Patients refractory to ESAs become dependent on red blood cell transfusions

Erythropoiesis Stimulating Agents (ESAs)

• Improvement in anemia in ~50% of patients

• Median treatment duration: ~2 years

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%

LenalidomideNot approved in U.S. or Europe for non-del(5q) patients• ≥8-week RBC-TI: 27%

Data from Part 1 of IMerge Presented at the 60th ASH Annual Meeting

Azra Raza, M.D.


Steensma et al. ASH 2018 Oral Presentation

Imetelstat Treatment Leads to Durable Transfusion Independence in RBC Transfusion-Dependent,

Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent Who Are

Lenalidomide and HMA Naive

David P. Steensma, MD1, Uwe Platzbecker, MD2, Koen Van Eygen, MD3, Azra Raza, MD4, Valeria Santini, MD5, Ulrich Germing, MD, PhD6, Patricia Font, MD7, Irina Samarina, MD8, Maria Díez-Campelo, MD, PhD9, Sylvain Thepot, MD10, Edo Vellenga, MD11, Mrinal M. Patnaik, MD, MBBS12, Jun Ho Jang, MD, PhD13,

Jacqueline Bussolari, PhD14, Laurie Sherman, BSN14, Libo Sun, PhD14, Helen Varsos, MS, RPh14, Esther Rose, MD14 and Pierre Fenaux, MD, PhD15

1Dana-Farber Cancer Institute (US), 2University Hospital Carl Gustav Carus, Dresden (DE), 3Algemeen Ziekenhuis Groeninge, Kortrijk (BE), 4Columbia University Medical Center (US), 5MDS Unit, AOU Careggi-University of Florence (IT), 6Heinrich-Heine-Universität, Düsseldorf (DE),

7Hospital General Universitario Gregorio Marañon, Madrid (ES), 8Emergency Hospital of Dzerzhinsk, Nizhny Novgorod (RU), 9The University Hospital of Salamanca (ES), 10CHU Angers (FR), 11University Medical Center Groningen (NE), 12Mayo Clinic, Rochester (US),

13Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (KO), 14Janssen Research & Development, LLC (US), 15Hôpital Saint-Louis, Université Paris (FR)

Funded by Janssen Research & Development and Geron Corporation Abstract #463


Patients with TD LR-MDS that has relapsed or is refractory to ESA therapy have limited treatment options

Higher telomerase activity, expression of hTERT and shorter telomeres predict for shorter overall survival in lower risk MDS

Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase and has clinical activity in myeloid malignancies1-3

o FDA granted Fast-Track designation for LR-MDS (Oct 2017)

IMerge is an ongoing global phase 2/3 study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1)4

1. Baerlocher GM, et al. N Engl J Med 2015;373:920-9282. Tefferi A, et al. N Engl J Med 2015;373:908-9193. Tefferi A, et al. Blood Cancer J 2016;6:e4054. Fenaux P, et al. HemaSphere 2018;2(S1):S1557

[oral presentation]

ESA, erythropoiesis-stimulating agent; hTERT, human telomerase reverse transcriptase; IPSS, International Prognostic Scoring System; Int-1, Intermediate-1; LR, lower risk; RBC, red blood cell; TD, transfusion dependent.

Background: Myelodysplastic Syndromes (MDS) and Imetelstat

42


single arm

open label

Background: IMerge/NCT02598661 (Part 1) Study Design1

1o Endpoint: 8-Week RBC TI2o Endpoints: 24-Week RBC TI / Time to TI / TI duration / TR (HI-E: Transfusion Reduction by ≥ 4 RBC units over 8 weeks) / MDS response per IWG / Overall survival / Incidence of AML / SafetyExploratory: telomerase activity / hTERT / telomere length / genetic mutations

Pre-medication: diphenhydramine, hydrocortisone 100-200 mg (or equivalent)

Supportive care: RBC transfusions, myeloid growth factors per local guidelines

1. Fenaux P, et al. HemaSphere 2018;2(S1):S1557 [oral presentation]

Patients with MDS

• IPSS Low or Int-1• Relapsed / refractory to ESA or ineligible for

ESA• Transfusion dependent (≥ 4u RBC/8 weeks)• ANC ≥ 1.5 x 109/L • Platelets ≥ 75 x 109/L

Imetelstat Treatment

7.5 mg/kg IV q4w (2-hr infusion)

AML, acute myeloid leukemia; ANC, absolute neutrophil count; HI-E, hematologic improvement-erythroid; IWG, International Working Group; TI, transfusion independence; TR, transfusion reduction.

43


Background: Key Efficacy and Safety Outcomes from IMerge (Part 1)1

Most grade ≥ 3 cytopenias were reversible in < 4 weeks

1Fenaux P, et al. HemaSphere 2018;2(S1):S1557 [oral presentation]HI-E, hematologic improvement-erythroid; HMA, hypomethylating agents; TI, transfusion independence.

ParametersAll Treated

(N=32)

Rate of 8-week TI, n (%) 11 (34)


Rate of transfusion reduction (HI-E), n (%) 19 (59)

Most common adverse events, n (%)

Neutropenia 23 (72)

Grade 3 / 4 8 (25) / 13 (41)

Thrombocytopenia 18 (56)

Grade 3 / 4 10 (31) / 8 (25)

Lenalidomide and HMA naïve and Non-del (5q)

(n=13)

7 (54)

4 (31)

9 (69)

7 (54)

2 (15) / 5 (38)

8 (62)

5 (38) / 3 (23)

44


An additional 25 lenalidomide and HMA naïve patients without del(5q) were enrolled

Here we report updated results for 38 patients

Clinical Cutoff: 26-Oct-2018

Median number of treatment cycles: 8.0 (range: 1‒34) cycles

o Mean dose intensity was 6.9 mg/kg/cycle

IMerge: Patients and Treatment Exposure

Median Follow-up

Initial 13 lenalidomide and HMA naïve patients without del(5q)

29.1 mo

25 patients meeting the same criteria 8.7 mo

45


IMerge: Baseline Characteristics

Parameters N=38

Median age (range), years 71.5 (46-83)

Male, n (%) 25 (66)

ECOG PS 0-1, n (%) 34 (89)

IPSS risk, n (%)Low

Intermediate-1

24 (63)

14 (37)

Baseline median (range) RBC transfusion burden, units/8 weeks 8 (4–14)

WHO 2001 category, n (%)

RARS or RCMD-RS

All others

27 (71)

11 (29)

Prior ESA use, n (%) 34 (89)

sEPO > 500 mU/mL, n (%) 12a (32)

aOf the 37 patients with sEPO levels reported.

46


IMerge: Longest Transfusion-Free Interval

Parameters N=38


Rate of 24-week TI, n (%) 10 (26)

Median time to onset of TI (range), weeks 8.1 (0.1-33.1)

Median duration of TI (range), weeks NE (17.0-NE)

Among the patients achieving durable TI, all showed a Hb rise of ≥ 3.0 g/dL compared to baseline during the transfusion-free interval

Hb, hemoglobin; HI-E, hematologic improvement-erythroid; TI, transfusion independence; TR, transfusion reduction.

150

125

75

50

25

0Patients

24-week TI 8-week TI HI-E (TR) No response

24

8

Treatment Group: Imetelstat (N=38)

100

Lo

ng

es

t T

ran

sfu

sio

n F

ree

In

terv

al (W

ee

ks

)

47


Hemoglobin Levels (g/L)

IMerge: Hemoglobin and Imetelstat Dosing Among Patients with Durable TI

48

Pri

or

RB

C T

ran

sfu

sio

n

Bu

rde

n (

un

its/

8 w

ee

ks)

6

-2 3 7 11 15 19 23 27 31 35 39 43 47 51 55 59 63 67 71 75 79 83 87 91 95 99 103 107 111 115

0

50

100

Hgb( g

/ L)

6

-2 3 7 11 15 19 23 27 31 35 39 43 47 51 55 59 63 67 71 75 79 83 87 91 95 99 103 107 111 115

0

50

100

Hgb( g

/ L)

4

-2 2 5 8 11 14 17 20 23 26 29 32 35 38 41 44 47 50 53 56 59 62 65 68 71

0

50

100

Hgb( g

/ L)

11

-3 2 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 94 98

0

50

100

150

Hgb( g

/ L)


IMerge: Absolute Change in Transfusion Amount in the Best 8-Week Interval

Parameters N=38


Mean relative reduction of RBC transfusion burden from baseline, %

-68

HI-E, hematologic improvement-erythroid; RBC, red blood cell; TI, transfusion independence; TR, transfusion reduction.

4

2

0

-2

-4

-6

-8

-10

-12

Treatment Group: Imetelstat (N=38)

24-week TI 8-week TI HI-E (TR) No response

Patients

Ab

so

lute

Ch

an

ge

in

Tra

ns

fus

ion

Am

ou

nt

in t

he

Be

st

8-w

ee

k in

terv

al

49


IMerge: Key Efficacy Outcomes

Parameters N=38


Rate of 24-week TI, n (%) 10 (26)

Median time to onset of TI (range), weeks 8.1 (0.1-33.1)

Median duration of TI (range), weeks NE (17.0-NE)


Mean relative reduction of RBC transfusion burden from baseline, %

-68

CR + marrow CR + PR (per IWG), n (%) 8 (21)

CR, complete remission; HI-E, hematologic improvement-erythroid; IWG, International Working Group; NE, not estimable; PR, partial remission; RBC, red blood cell; TI, transfusion independence.

50


IMerge: Efficacy Results in EPO and RS Subgroups

Similar efficacy was observed across these subgroups

EPO, erythropoietin; RARS, refractory anemia with ringed sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; RS, ring sideroblast; TI, transfusion independence.

0 10 20 30 40

EPO > 500 mU/mL (n=12)

EPO ≤ 500 mU/mL (n=25)

Other (n=11)

RARS/RCMD-RS (n=27)

8-week TI rate

% of Patients

37%

36%

40%

33%

51


IMerge: Most Common Treatment-Emergent Adverse Events

19 patients (50%) had dose reductions and 26 patients (68%) had cycle delays

Reversible grade 3 LFT elevations were observed in 3 (8%) patients on study

o Independent Hepatic Review Committee considered these not drug-related

ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; TEAE, treatment-emergent adverse event.

2123

7 7

3 2 1 2 2

1

2

2

3 55 4 6 6 6 4

0

5

10

15

20

25

Nu

mb

er o

f p

atie

nts

wit

h ≥

1 T

EAE

Most common TEAEs

Grade ≥3

Grade 1-2

52


IMerge: Occurrence/Reversibility of Grade 3/4 Cytopenias

All events,n (%) of patients

(N=38)

Recovered in < 4 weeks, n (%) of patients

with an event

Neutrophils, n (%)

Grade 3 10 (26) 8 (80)

Grade 4 12 (32) 12 (100)

Platelets, n (%)

Grade 3 14 (37) 13 (93)

Grade 4 10 (26) 9 (90)

2 patients had febrile neutropenia

12 patients received G-CSF for neutropenia

7 patients received platelet transfusions

3 patients with Grade 1 bleeding events

53


IMerge: Change in Mutation Variant Frequency

6 patients had SF3B1 mutations at baseline, with reduction of variant frequency observed in patients 200088 and 200095, both of whom had durable TI

Patient 200088 also had reduction in DNMT3A mutation, and substantial reduction in bone marrow ringed sideroblasts (75% to 3%)

Longest TI Duration

(weeks)

25

3.6

24.1

4.6

33.7

34.9

TI, transfusion independence.

54


Conclusions: Overall Efficacy and Safety

In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to lenalidomide/HMA, single-agent imetelstat yielded:

o 8-week TI rate of 37%

o 24-week TI rate of 26%

o 24-week TI responses were accompanied by Hb rise of ≥ 3.0 g/dL

o Median duration of TI was not reached

o HI-E rate of 71%

Side effects were limited, mainly cytopenias that were predictable, manageable and reversible

55


Conclusions: Overall Efficacy and Safety (con’t)

Similar efficacy was seen in EPO high/low and RS+/RS- subgroups, supporting broad clinical activity

Reductions in mutation burden and RS noted among responding patients, suggesting potential disease modification

These results support the planned Phase 3 study, expected to start mid-2019

56


Acknowledgements

Mazure, DominiekMeers, StefBreems, Dimitri

The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment

of all investigators and their staff

Gourin, Marie-PierreGyan, EmmanuelLegros, LaurenceThepot, Sylvain

Kim, InhoLee, Je-hwan

Klein, SaskiaLangemeijer, Saskiavan de Loosdrecht, Arjan

Oliva, Esther

Pristupa, Alexander

Samoilova, Olga

Udovitsa, Dmitry

De Paz, RaquelEsteve, JordiValcarcel, DavidXicoy, Blanca

Boccia, RalphErba, Harry / DiStasi, AntonioGrunwald, MichaelJacoby, MeganMiller, CaroleSchiller, GarySilverman, LewisStevens, Don

57

Lower Risk MDS TrialsPresented at the 2018 ASH Annual Meeting


President and Chief Executive Officer

Lower Risk MDS TrialsTargeting different patient populations

IMerge Part 1 – Phase 2 MEDALIST – Phase 3

Imetelstat Luspatercept Placebo

38 No. of patients 153 76

RS+ and RS-MDS subtype

Ring-sideroblasts (RS)RS+ only

8 (4-14)Median baseline transfusion burden

# units/8 weeks (range)

5 (1-20)29% < 4 units

14 (36.8%) 8-week TI rate, n (%) 58 (37.9%) 10 (13.2%)

27 (71.1%) Rate of transfusion reduction (HI-E), n (%) 81 (52.9%) 9 (11.8%)

10 (26.3%) 24-week TI rate, n (%) Not assessed

14/38 (36.8%) 8-week TI rate, n (%)Baseline transfusion burden ≥4 units/8 weeks

21/107 (19.6%) 2/56 (3.6%)

59

ASH 2018 Presentation: 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

IMerge is focused on high transfusion burden patients and open to all MDS subtypes

Q&A

Azra Raza, M.D.


Future Plans


President & CEO

Upcoming Milestones

62

Clinical Development Plans

Discussions with MF experts and regulatory authorities to determine next stepsInitiate first quarter 2019

Imetelstat IND transfers from Janssen to GeronSecond quarter 2019

Initiate screening and enrollment for Phase 3 portion of IMerge By mid-year 2019 Expect top-line results by mid-year 2022

Outline decision regarding potential late-stage development in MFEnd of third quarter 2019

✓

Data Presentations

ASH abstracts published online November 1, 2018

IMerge Phase 2 data presentation at ASHDecember 2, 2018

IMbark Phase 2 data presentation at ASHDecember 3, 2018

Analyst and investor eventDecember 10, 2018

✓

✓

Thank you

If you have any questions, please contact us:[email protected]

analyst and investor event...2018/12/10 · azra raza, m.d. chan soon-shiong professor of medicine...

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