kol event...2020/06/17 · eha presentation #s183 meaningful and durable transfusion independence...
TRANSCRIPT
Geron CorporationNasdaq: GERN
KOL EventJune 17, 2020
Forward Looking Statements
©2020, Geron Corporation | Nasdaq: GERN | 2
Except for the historical information contained herein, this presentation contains forward-looking statements made pursuant tothe “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that such forward-looking statements, include, without limitation, those regarding: (i) that imetelstat has potential disease-modifying activity, and (ii)that Geron has a plan to open for enrollment a Phase 3 clinical trial in Intermediate-2 or High-risk myelofibrosis in the first quarterof 2021. These statements involve risks and uncertainties that can cause actual results to differ materially from those in suchforward-looking statements. These risks and uncertainties, include, without limitation, risks and uncertainties related to: (a)whether the COVID-19 pandemic slows or prohibits the Company’s ability to open for enrollment in the first quarter of 2021 theplanned Phase 3 clinical trial in Intermediate-2 or High-risk myelofibrosis; (b) whether regulatory authorities permit the furtherdevelopment of imetelstat on a timely basis, or at all, without any clinical holds; (c) whether imetelstat is safe and efficacious; (d)whether any future efficacy or safety results may cause the benefit-risk profile of imetelstat to become unacceptable; and (e)whether imetelstat demonstrates disease-modifying activity in clinical trials. Additional information on the above risks anduncertainties and additional risks, uncertainties and factors that could cause actual results to differ materially from those in theforward-looking statements are contained under the heading “Risk Factors” in Geron’s Quarterly Report on Form 10-Q for thequarter ended March 31, 2020 filed with the Securities and Exchange Commission (the “SEC”). Undue reliance should not beplaced on forward-looking statements, which speak only as of the date they are made, and the facts and assumptions underlyingthe 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.
©2020, Geron Corporation | Nasdaq: GERN | 3
Today’s Agenda8:00 am Welcome Suzanne Messere Investor Relations
8:05 am Introduction Aleksandra Rizo, M.D., Ph.D. Chief Medical Officer
8:10 am Imetelstat in Lower Risk Myelodysplastic Syndromes (MDS)at 25th Annual European Hematology Association Annual Congress
Imetelstat to address significant unmet medical need
EHA Presentation #S183Meaningful and Durable Transfusion Independence
Q&A
Valeria Santini, M.D. Associate Professor of Hematology, University of Florence, Italy
Imetelstat in Intermediate-2 or High-risk Myelofibrosis (MF) at 25th Annual European Hematology Association Annual Congress
8:30 am Imetelstat to address significant unmet medical need
EHA Poster #EP1098Telomerase Activity, Telomere Length and hTERT Expression Correlate with Clinical Outcomes
Q&A
John Mascarenhas, M.D. Associate Professor in Myeloproliferative Disorders Program of the Tisch Cancer Institute, Division of Hematology/Oncology at the Icahn School of Medicine at Mount Sinai, New York
8:50 am EHA Poster #EP1101Longer OS in Patients with Higher Risk Triple Negative MF
Q&A
Rami Komrokji, M.D. Vice Chair, Malignant Hematology Department, Moffitt Cancer Center, Tampa, Florida
9:10 am EHA Poster #EP1107Favorable Overall Survival Correlates with Other Clinical Benefits
Q&A
John Mascarenhas, M.D. Associate Professor in Myeloproliferative Disorders Program of the Tisch Cancer Institute, Division of Hematology/Oncology at the Icahn School of Medicine at Mount Sinai, New York
9:30 am Planned Phase 3 Clinical Trial in Refractory MF Aleksandra Rizo, M.D., Ph.D. Chief Medical Officer
9:40 am Closing Remarks John Scarlett, M.D. Chairman and CEO
Introduction
Aleksandra Rizo, M.D., Ph.D.
Chief Medical Officer
Geron
Valeria Santini, M.D.
©2020, Geron Corporation | Nasdaq: GERN | 5
Current • Associate Professor of Hematology at the University of Florence Medical School, Florence, Italy
• Responsible for the MDS Unit of the Hematology/Clinical and Experimental Medicine Department, AOU Careggi, University of Florence, Italy
Medical Training • University of Florence Medical School, Florence, Italy
• Fellow in Experimental Hematology, Dr. den Hoed Kliniek, Erasmus University, Rotterdam, Netherlands
• Visiting Physician Scientist, Department of Leukemia, M.D. Anderson Cancer Center, University of Texas, Houston, TX
Expertise • Scientific interests and publications are focused on maturation induction and therapeutic targeting of epigenetics modifications in MDS and AML
Imetelstat in Lower Risk
Myelodysplastic Syndromes (MDS)
at 25th Annual European Hematology
Association Annual Congress
Meaningful and Durable Transfusion Independence
Lower Risk Myelodysplastic Syndromes (LR MDS)
©2020, Geron Corporation | Nasdaq: GERN | 7
Imetelstat to address significant unmet need with a large market opportunity
Disease Characteristics• Ineffective production of RBCs, WBCs, and platelets (hematopoiesis)
• Chronic anemia
• Patient subgroups include Ring Sideroblast Positive (RS+) and Ring Sideroblast Negative (RS-)
Current Treatment Paradigm• Treated initially with erythropoiesis stimulating agents (ESAs)
• Patients relapsed/refractory to ESAs are frequently RBC transfusion dependent
• Serial RBC transfusions result in lower quality of life, significant costs, lengthy office visits, iron overload, shorter survival and higher risk of transformation to AML
Patient Population~70% of all MDS patients are lower risk
>100,000 LR MDS worldwide
>40,000 LR MDS patients in the U.S.
>10,000 LR MDS patients diagnosed each year in the U.S.
*Lower risk MDS patients without chromosomal 5q deletion (non-del(5q)), relapsed/refractory to ESAs prior to being treated with lenalidomide or hypomethylating agents (HMAs)
The Unmet NeedHigher rate of transfusion independence than currently available options
Durable transfusion independence
Ability to treat both RS+ and RS- patients
Disease-modifying therapy
RBCs, red blood cells; WBCs, white blood cells; AML, acute myeloid leukemia
TREATMENT WITH IMETELSTAT PROVIDES DURABLE TRANSFUSION INDEPENDENCE (TI) IN HEAVILY TRANSFUSED NON-DEL(5Q) LOWER RISK
MDS (LR-MDS) RELAPSED/REFRACTORY (R/R) TO ERYTHROPOIESIS STIMULATING AGENTS (ESAs)
Uwe Platzbecker1, Pierre Fenaux2, David P. Steensma3, Koen Van Eygen4, Azra Raza5, Ulrich Germing6, Patricia Font7, Maria Diez-Campelo8, Sylvain Thepot9, Edo Vellenga10, Mrinal M. Patnaik11, Jun Ho Jang12, Helen Varsos13, Esther Rose13, Jacqueline Bussolari13, Fei Huang14, Laurie Sherman14, Faye
Feller14, Souria Dougherty14, Libo Sun14, Ying Wan14, Aleksandra Rizo14, Valeria Santini15
1Department of Hematology and Cell Therapy, University Clinic Leipzig, Leipzig, Germany, 2Hospital Saint-Louis, Universiteƴ Paris Diderot, Paris, France, 3Dana-Farber Cancer Institute, Boston, United States, 4Algemeen Ziekenhuis Groeninge, Kortrijk, Belgium, 5Columbia University Medical Center, New York, United States, 6Klinik für Hämatologie, Onkologie and Klinische lmmunologie, Universitätsklinik Düsseldorf, Heinrich-Heine-
Universität, Düsseldorf, Germany, 7Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, 8Hematology Department, The University Hospital of Salamanca, Salamanca, Spain, 9CHU Angers, Angers, France, 10Department of Hematology, University Medical Center
Groningen, Groningen, Netherlands, 11Division of Hematology, Mayo Clinic, Department of Internal Medicine, Rochester, MN, United States, 12Department of Hematology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic Of, 13Janssen Research &
Development, LLC, Raritan, NJ, 14Geron Corporation, Menlo Park, CA, United States, 15MOS Unit, AOU Careggi-University of Florence, Florence, Italy
8Funded by Geron Corporation and Janssen Research & Development Abstract code S183
Telomerase Upregulation
Apoptosis of malignant cells
Recovery of normal RBCs, WBCs,
platelets enabled
X
Mechanism of Action
• Potent competitive inhibitor of telomerase activity
• Structure: Proprietary 13-mer thio-phosphoramidate (NPS) oligonucleotide, with covalently-bound lipid tail to increase cell permeability/tissue distribution
• Disease-modifying potential: selective killing of malignant stem and progenitor cells enabling normal blood cell production
Malignant progenitor
cell
Malignant hematopoietic
stem cells
Imetelstat binds to RNA template,preventing maintenance of telomeres
(hTR)
(hTERT)
Imetelstatinhibits telomerase
activity
Imetelstat: First-in-Class Telomerase Inhibitor with Disease-Modifying Potential
9
RBCs, red blood cells; WBCs, white blood cells
Phase 2/3 Study Design
Imetelstat (n~115)7.5 mg/kg IV q4w
R
A
N
D
O
M
I
Z
E
2:1
Placebo (n~55)
Stratification: - Transfusion burden (≤6 vs. >6 units) - IPSS risk category (low vs intermediate-1)
Phase 2single arm, open label
LR MDS R/R to ESA
Phase 3double-blind, placebo-controlled
N~170
• LR MDS patients:o Non-del(5q), IPSS Low or Int-1o Relapsed/Refractory to ESA or EPO >500 mU/ml; HMA/Len naïve o Transfusion dependent: ≥ 4 units RBC/8 weeks over 16 week pre-study period
• Primary Endpoint: 8-week RBC Transfusion Independence (TI)
• Key Secondary Endpoints: 24-week RBC TI/Duration of TI/HI-E
Enrollment Complete Currently Enrolling
EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; HI-E, hematologic improvement-erythroid; HMA, hypomethylating agents; IPSS, International Prognostic Scoring System; Len, lenalidomide; LR, low risk; RBC, red blood cell; R/R, relapsed/refractory
Imetelstat (n=38)7.5 mg/kg IV q4w
10
• 38 patients with non-del(5q) LR MDS R/R to ESA
• Clinical cutoff for analyses: 4 Feb 2020
Treatment Exposure
Parameters N = 38
Median follow-up, months (range) 24.0 (5.6 – 45.5)
Median treatment duration, months (range) 8.5 (0.02 – 38.7)
Median treatment cycles (range) 9 (1 – 40)
Median dose intensity*, % 100
*Median dose intensity of the assigned dose
11
Baseline Patient Characteristics
Parameters N = 38Age, years, median (range) 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)
RBC transfusion burden, units/8 weeks, median (range) 8 (4 – 14)
4-5 units / 8 weeks at baseline, n (%) 6 (16)
≥ 6 units / 8 weeks at baseline, n (%) 32 (84)
WHO 2001 category, n (%)
RARS or RCMD-RS
RA, RCMD or RAEB-1
27 (71)
11 (29)
Prior ESA use, n (%) 34 (89)
sEPO > 500 mU/mL, n (%)12 (32)
(from 37 patients with baseline sEPO levels)
ECOG PS, Eastern Cooperative Oncology Group Performance Status; ESA, erythropoiesis-stimulating agent; IPSS, International Prognostic Scoring System; sEPO, serum erythropoietin;RA, refractory anemia; RAEB1, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; RBC, red blood cell; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; WHO, World Health Organization
12
Patient Disposition
Parameters N = 38 n (%)
Ongoing on treatment 9 (24)
Discontinued study treatmentLack of EfficacyAdverse EventProgressive DiseaseWithdrawal by Patient DeathPhysician DecisionDisease Relapse
29 (76)12 (32)8 (21)4 (10)2 (5)1 (3)1 (3)1 (3)
Ongoing study participation * 27 (71)
Terminated study participationDeathWithdrawal by Patient
11 (29)8 (21)3 (8)
* Median follow up time: 24 months (5.6 – 45.5)13
a Kaplan Meier method; b Cumulative Duration of TI ≥ 8 weeks is defined as the sum of all periods of TI ≥ 8 weeks during the treatment; c Maximum Hb rise of ≥ 3g/dL from pretreatment level (pretreatment level defined as mean Hb / 8 weeks).CI, confidence interval; Hb, hemoglobin
*Longest TI > 2.7 years
Meaningful and Durable Transfusion Independence (TI) with Imetelstat Treatment
Parameters N = 38
8-week TI, n (%)Time to onset of 8-week TI, weeks, median (range)Duration of TI, weeks, median (95% CI)a
Cumulative duration of TI ≥ 8 weeksb, median (95% CI)a
Hb rise ≥ 3.0 g/dL during TIc, n (%)
16 (42)8.3 (0.1 – 40.7)
88.0 (23.1 – 140.9*)92.3 (42.9 – 140.9)
12 (32)
24-week TI, n (%)Hb rise ≥ 3.0 g/dL during TIc, n (%)
12 (32)11 (29)
1-year TI, n (%) 11 (29)
14
a All patients also achieved 8-week TI b Kaplan Meier methodCI, confidence interval; CR, complete remission; Hb, hemoglobin; HI-E, hematologic improvement-erythroid; IWG 2006, International Working Group Response Criteria 2006; International Working Group Major and Minor Response Criteria 2018; TI, Transfusion Independence
Hematologic Improvement and IWG Response with Imetelstat Treatment
Parameters N = 38
HI-E per IWG 2006, n (%)≥1.5 g/dL increase in Hb lasting ≥ 8 weeksa, n (%)Transfusion reduction by ≥ 4 units/8 weeks, n (%)Duration of HI-E, weeks, median (95% CI)b
26 (68)13 (34)26 (68)
92.7 (37.1 – 149.4)
Major and Minor Response per IWG 2018Major response: 16-week TI, n (%)Minor response: ≥ 50% transfusion reduction/16 weeks, n (%)
14 (37)21 (55)
CR + marrow CR, n (%)CR, n (%)marrow CR, n (%)
9 (24)4 (11)5 (13)
15
Potential Disease-Modifying Activity with Imetelstat Treatment: Durable TI and Substantial Increase in Hb
• 29% of the patients transfusion-free for at least one year• Longest transfusion-free period 2.7 years• 75% of TI responders had a maximum Hb rise of ≥ 3g/dL from pretreatment level
(pretreatment level defined as mean Hb / 8 weeks) 16
Clinical Benefit Observed Across Different Patient Subgroups
Similar HI-E responses across different patient subgroups
• RS Subgroups:
RS+ (RARS/RCMD- RS) vs. RS- (Other)
• Baseline transfusion burden:
High (4-6 units) vs. Very High (>6 units)
• Serum EPO level:
≤ 500 mU/mL vs. > 500 mU/mL
All 8-week TIs (16 patients, 42%) are also HI-E responders in this study
17
Reversible Grade 3/4 Cytopenias without Significant Clinical Consequences
AEAll Grades
N=38n (%)
Grade 3/4N=38 n (%)
Thrombocytopenia 25 (66) 23 (61)Neutropenia 22 (58) 21 (55)Anemia 11 (29) 8 (21)
Frequency of Hematologic AEs
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Neutrophils Platelets
Resolved within 4weeks
Did not resolve within4 weeks**
87%90%
* Resolve to Grade 2 or lower by laboratory assessment** Resolved ≥4 weeks or ongoing at cutoff date
Reversibility of Grade 3/4 Cytopenias*
• 2/38 pts (5%) had febrile neutropenia (Gr3)• 3/38 pts (8%) had Grade 3/4 bleeding
18
Most Frequently Reported Non-Hematologic AEs:no new clinically significant events
TEAE All GradesN=38 n (%)
Grade 3/4N=38n (%)
Back pain 9 (24) 2 (5)
Pyrexia 8 (21) 0
Diarrhea 7 (18) 0
Nasopharyngitis 7 (18) 0
ALT increased 7 (18) 2 (5)*
AST increased 6 (16) 3 (8)*
Bronchitis 6 (16) 3 (8)
Asthenia 6 (16) 1 (3)
Headache 6 (16) 1 (3)
Urinary tract infection 6 (16) 1 (3)
Constipation 6 (16) 0
Edema peripheral 6 (16) 0
Fatigue 6 (16) 0
ALT, alanine aminotransferase; AST, aspartate aminotransferase
*Grade ≥3 AST and ALT were reversible
19
Reduction in hTERT expression correlates with 8- and 24-week TI
On-Target Activity of Imetelstat Correlates with Transfusion Independence
On-Target* activity demonstrated by reduction
in Telomerase Activity (TA) and hTERT expression
*Optimal target activity/PD effect defined as ≥ 50% reduction in TA or hTERT expression based on pre-clinical PK/PD/efficacy experiments PK, pharmacokinetic; PD, pharmacodynamic
80.0%
35.0%
91.7%
34.8%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Yes No Yes No
8-wk TI 24-wk TI
% o
f p
ts a
chie
ve
d >
=5
0%
hT
ER
T
red
uct
ion
Correlation between on-target activity and clinical responses
p=0.002p=0.016
23.1%
54.3%
0%
10%
20%
30%
40%
50%
60%
TA hTERT
% o
f p
ts a
chie
ved
>=5
0%
re
du
ctio
n
in T
A o
r h
TER
T%
pts
wit
h ≥
50
% r
ed
uct
ion
in T
A o
r h
TER
T
% p
ts w
ith
≥5
0%
re
du
ctio
n i
n h
TER
T
20
11 patients had SF3B1 mutations detected at baseline and had paired post-treatment mutation data available:
A. 10/11 had reduction (ranging 10-93%) in SF3B1 variant allele frequency (VAF)
B. The greater reduction of SF3B1 VAF, the longer TI duration patients maintained
C. Significant correlation between greater reduction of SF3B1 VAF and shorter onset time to achieve the longest TI interval (Pearson correlation coefficient r=0.646, p=0.032)
Potential Disease-Modifying Activity with Imetelstat Treatment:Reduction of Malignant Clones Associated with Treatment Response
0%
10%
20%
30%
40%
50%
60%
Baseline Post-imetelstat
% o
f SF
3B1
vari
ant
alle
le f
req
uen
cy (V
AF)
Reduction of SF3B1 VAF by Imetelstat Treatment
# 088-K700E
# 086-H662Q
# 006-E622D
# 095-R625C
# 093-R625L
# 102-K700E
# 080-K700E
# 079-K666R
# 081-R625C
# 078-K700E
# 083-K700E
A
% S
F3B
1 V
AF
Reduction of SF3B1 VAF with Imetelstat treatment A.
-100%
-80%
-60%
-40%
-20%
0%
20%
0 50 100 150
%V
AF
red
uct
ion
of
SF3B
1
Longest transfusion free interval (weeks)
% SF3B1 VAF Reduction vs the Longest TI DurationB
% S
F3B
1 V
AF
Reduction of SF3B1 VAF vs the longest TI durationB.
*Remain on treatment as of 4 Feb 2020
Reduction of SF3B1 VAF vs time to the longest TI
Patient ID
The longest TI
interval (weeks)
Time to the longest
TI interval start
(weeks)
% SF3B1 VAF
reduction
200088* 98.9 6.6 -93.3%
200086* 104 4.3 -91.8%
200006 140.9 9.9 -86.4%
200095 92.4 5.4 -71.9%
200093* 64.6 40.7 -45.5%
200102* 4 32.9 -31.2%
200080 79.9 44.1 -21.9%
200079 3.6 20.7 -11.6%
200081* 76.3 12.1 -10.9%
200078* 89.7 23.1 -9.8%
200083* 68.9 37.1 2.0%
C.
21
• Imetelstat treatment shows meaningful and durable transfusion independence:
• High rates of TI and HI-E: 42% 8-week TI rate and 68% HI-E rate
• Durable TI and HI-E: Median duration of TI is 20 months and median duration of HI-E is 21 months
• TI across multiple patient subtypes: RS+ and RS-, high and very high transfusion burden
• Potential disease-modifying activity:
• 29% of patients transfusion free for ≥1 year
• 75% of TI responders had hemoglobin rise of ≥ 3g/dL from pretreatment level
• Reduction in SF3B1 mutation correlated with shorter onset time to achieve TI
• No new safety signal identified; reversable cytopenias were most frequent AEs, without significant clinical consequences
• Phase 3 trial ongoing: double-blind, placebo-controlled, 2:1 randomization
Imetelstat in LR MDS Key Conclusions
22
Phase 2/3 Study Design
Imetelstat (n~115)7.5 mg/kg IV q4w
R
A
N
D
O
M
I
Z
E
2:1
Placebo (n~55)
Stratification: - Transfusion burden (≤6 vs. >6 units) - IPSS risk category (low vs intermediate-1)
Phase 2single arm, open label
LR MDS R/R to ESA
Phase 3double-blind, placebo-controlled
N~170
• LR MDS patients:o Non-del(5q), IPSS Low or Int-1o Relapsed/Refractory to ESA or EPO >500 mU/ml; HMA/Len naïve o Transfusion dependent: ≥ 4 units RBC/8 weeks over 16 week pre-study period
• Primary Endpoint: 8-week RBC Transfusion Independence (TI)
• Key Secondary Endpoints: 24-week RBC TI/Duration of TI/HI-E
Enrollment Complete Currently Enrolling
EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; HI-E, hematologic improvement-erythroid; HMA, hypomethylating agents; IPSS, International Prognostic Scoring System; RBC, red blood cell; Len, lenalidomide.
Imetelstat (n=38)7.5 mg/kg IV q4w
• Key Elements Same as Phase 2:
▪ Dose and schedule
▪ Primary/secondary endpoints
▪ Patient population as n=38
▪ Continuity of most of the clinical sites
• Current Status/Progress:
▪ First patient dosed in October 2019
▪ Currently enrolling
23
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
24
Q&A
Valeria Santini, M.D.
University of Florence
Introduction
Aleksandra Rizo, M.D., Ph.D.
Chief Medical Officer
Geron
John Mascarenhas, M.D.
©2020, Geron Corporation | Nasdaq: GERN | 27
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)
Imetelstat in Intermediate-2 or
High-risk Myelofibrosis (MF)
at 25th Annual European Hematology
Association Annual Congress
Telomerase Activity, Telomere Length and hTERT Expression Correlate with Clinical Outcomes
Int-2/High-Risk Myelofibrosis
©2020, Geron Corporation | Nasdaq: GERN | 29
Imetelstat to address significant unmet need with a large market opportunity
Patient Population*
~70% of all MF patients are Int-2 or HR
>35,000 Int-HR MF patients worldwide
>12,500 Int-2/HR MF patients in the U.S.
>2,100 Int-2/HR MF patients diagnosed each year in the U.S.
The Unmet NeedTherapies that can extend survival
Treatment options for patients who are refractory to JAKi therapy
Disease-modifying therapy
Non-JAKi mechanism of action
Disease Characteristics• Malignant stem and progenitor cell proliferation give rise to malignant
megakaryocytes, bone marrow fibrosis and impaired hematopoiesis
• Splenomegaly: normal blood production shifts to other organs, such as the spleen, which can cause the spleen to enlarge
• Symptoms: fever, weight loss, night sweats)
• Fibrosis: thought to be induced by inflammatory cytokines produced by megakaryocytes originating from malignant progenitor cell clones
Current Treatment Paradigm for Int-2/HR MF• Only approved therapies in the U.S. are JAKi (ruxolitinib and fedratinib)
• Most patients lose response to ruxolitinib
• ~50% patients discontinue ruxolitinib within 3 years and 75% within 5 years
• Poor survival of 14-16a months for patients who discontinue ruxolitinib
* Int-2/HR MF patients who are refractory to JAKi treatment
aKuykendall et al, Ann Hematol 2018; Newberry et al, Blood 2017; 130:1125-1131; 97:435-441; Spiegel et al, Blood Advances 2017; 1:1729-1738
TELOMERASE ACTIVITY, TELOMERE LENGTH AND hTERT EXPRESSION CORRELATE WITH CLINICAL OUTCOMES IN HIGHER-RISK MYELOFIBROSIS (MF)
RELAPSED/REFRACTORY (R/R) TO JANUS KINASE INHIBITOR TREATED WITH IMETELSTAT
Mascarenhas1, R. Komrokji2, M. Cavo3, B. Martino4, D. Niederwieser5, A. Reiter6, B. Scott7, M. Baer8, R. Hoffman9, O. Odenike10, J. Bussolari11, E. Zhu11, E. Rose11, L. Sherman12, S. Dougherty12, F. Feller12, L. Sun12, Y. Wan12, A. Rizo12, F. Huang12, and J. Kiladjian13
1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; MPN-RC (US), 2H Lee Moffitt Cancer Center (US), 3”Seràgnoli” Institute ofHematology, 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 GreenebaumComprehensive Cancer Center (US), 9Tisch Cancer Institute, Mount Sinai School of Medicine (US), 10University of Chicago (US), 11JanssenResearch & Development, LLC (US), 12Geron Corporation (US), 13Hôpital Saint-Louis, Université Paris (FR)
30EHA 25 l EP1098
ClincialTrials.gov (NCT02426086)
IMbark Phase 2 Trial
©2020, Geron Corporation | Nasdaq: GERN | 31
Clinical activity in relapsed/refractory MF patients
Trial Population:
• Patients with Intermediate-2 or High-risk MF (Int-2/High-risk) patients who have relapsed after or are refractory to prior treatment with a janus kinase inhibitor (JAKi)
• 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
Intermediate-2 or High-risk MF
R/R to JAKi treatment
Ran
do
miz
e(1
:1) Imetelstat
9.4 mg/kgevery 3 weeksn=59
Imetelstat4.7 mg/kgevery 3 weeksn=48
Co-primary endpoints:Spleen response rate and symptom response rate
Secondary endpoints:CR, PR and CI, anemia response per 2013 IWG-MRTcriteria, duration of responses,and overall survival (OS)
Exploratory endpoints:Cytogenetic and molecular responses, leukemia free survival
* Adapted from IWG-MRT response criteria definition of progressive disease.
32
Imetelstat Mechanism of ActionOn-target pharmacodynamic (PD) effects and clinical benefits
Source: EHA 2020 Poster: Mascarenhas J, et al
• Imetelstat• A potent, first-in-class competitive inhibitor of telomerase enzymatic activity.• Selectively targets malignant cells with continuously upregulated telomerase, inducing their apoptosis and
thereby enabling potential recovery of normal hematopoiesis.• Currently in clinical development for hematologic malignancies.
• Background• Nonclinical studies demonstrated that imetelstat reduces telomerase activity (TA), human telomerase reverse
transcriptase (hTERT) expression level, and JAK2V617 hematopoietic progenitor cells in MF patient samples,indicative of mechanism based on-target activity.
• Short telomere length (TL), high levels of TA and high expression of hTERT correlated with higher risk, diseaseprogression and shorter OS in patients with myeloid malignancies.
• Cells with short TL, high levels of TA and hTERT represent best target for treatment with telomerase inhibitor.• Optimal PD effect of imetelstat was defined as ≥50% reduction in TA or hTERT from baseline as it correlated
with antitumor activity in preclinical PK/PD/efficacy studies.
• Objectives• Evaluate on-target PD effect of imetelstat and relationship to dose and exposure levels in MF patients.• Assess the correlation of the optimal PD effect with symptom or spleen response and overall survival (OS).• Explore the association between baseline telomere length and hTERT expression level and clinical benefits.• Evaluate the change in allele burden of driver mutation, such as JAK2, CALR, MPL, by imetelstat treatment to
assess disease-modifying activity.
Significantly higher % of pts in 9.4mg/kg arm achieved optimal PD effect* compared to 4.7mg/kg arm
*Optimal PD effect defined as >=50% reduction in telomerase activity (TA) or hTERT expression level.**28 pts had serial (intense) PK samples collected during C1D1; Cmax and AUC0-24h were determined for exposure.
Dose-dependent and Exposure-dependent PD EffectsOn-target activity
Significantly higher % pts with high imetelstat exposure** achieved ≥50% hTERT reduction
33Source: EHA 2020 Poster: Mascarenhas J, et al
p=0.049p=0.033
30.3%
41.7%
57.5%62.5%
0%
10%
20%
30%
40%
50%
60%
70%
≥50% TA reduction ≥50% hTERT reduction
% o
f p
atie
nts
ach
ieve
d >
=50
%
red
uct
ion
in T
A o
r h
TER
T
4.7 mg/kg 9.4 mg/kg
Optimal PD Effects Correlated with Clinical Responses and Longer OS
34
*Optimal PD effect defined as >=50% reduction in telomerase activity (TA) or hTERT expression level.
Source: EHA 2020 Poster: Mascarenhas J, et al
100.0%
76.1%
93.8%
72.7%
0%
20%
40%
60%
80%
100%
120%
Yes No Yes No
Spleen Response Symptom Response
% o
f p
ts a
chie
ved
op
tim
al P
D e
ffe
ct
AOptimal PD
Median OS (mo)
(95% CI)
HR
(95% CI)
Yes 27.2 (22.2, 34.1)0.54 (0.28, 1.06)
No 18.3 (4.2, 31.6)
B
Patients who achieved optimal PD effect had better OS
Higher % of patients achieved optimal PD effect in responders [spleen response
(SVR ≥35%) or symptom response (TSS reduction ≥50%)] at week 24 than in
non-responders
35
Potential Disease-Modifying Activity
Reduction in malignant clones with imetelstat treatment
0.0%
50.0%
0.0%5.6%
31.3%
100.0% 100.0%
42.1%
0%
20%
40%
60%
80%
100%
120%
JAK2 CALR MPL Any of 3 genes
% p
ts h
ad >
=25
% V
AF
red
uct
ion
4.7 mg/kg 9.4 mg/kg
p=0.019
4.7 mg/kg 9.4 mg/kg
JAK2 N=15 N=16
>=25% Decrease 0 (0%) 5 (31.3%)
CALR N=2 N=2
>=25% Decrease 1 (50%) 2 (100%)
MPL N=1 N=1
>=25% Decrease 0 (0%) 1 (100%)
Any of 3 genes N= 18 N=19
>=25% Decrease 1 (5.6%) 8 (42.1%)
Imetelstat resulted in dose-dependent reduction in variant allele frequency (VAF) of JAK2V617F, CALR and MPL mutations
Source: EHA 2020 Poster: Mascarenhas J, et al
36
Patients with Short Telomere Length (TL) or Higher hTERT Expression
Improved clinical outcomes when treated with 9.4 mg/kg
Patients with short baseline TL (<=median) had higher rate of responses in 9.4 mg/kg arm
BA
0.0% 0.0%
5.6% 4.5%
17.3%
4.2%
37.9%
25.0%
0%
5%
10%
15%
20%
25%
30%
35%
40%
Shorter TL Longer TL Shorter TL Longer TL
Spleen Response Symptom Response
% p
ts a
chie
ve
d r
esp
on
se
Baseline telomere length (TL) vs responses
4.7 mg/kg 9.4 mg/kg
0.0% 0.0%
12.0%
0.0%
7.1%
13.8%
28.6%
37.9%
0%
5%
10%
15%
20%
25%
30%
35%
40%
Lower hTERT Higher hTERT Lower hTERT Higher hTERT
Spleen Response Symptom Response
% p
ts a
chie
ve
d r
esp
on
se
Baseline hTERT level vs responses
4.7 mg/kg 9.4 mg/kg
Source: EHA 2020 Poster: Mascarenhas J, et al
Patients with high baseline hTERT level (>median) had higher rate of responses in 9.4 mg/kg arm
37
Patients with Short Telomere Length (TL) or Higher hTERT Expression
Longer OS when treated with 9.4 mg/kg
9.4 mg/kg4.7 mg/kg
Baseline TLMedian OS (mo)
(95% CI)
HR
(95% CI)
<= Median 20.3 (17.2, 36.6) 0.88 (0.41, 1.88)
> Median 28.6 (16.6, 33.9)
Baseline TLMedian OS (mo)
(95% CI)
HR
(95% CI)
<= Median 30.1 (23.2, NE) 0.70 (0.35, 1.41)
> Median 27.1 (16.2, 33.8)
Patients with shorter baseline TL had a trend of better OS compared to patients with longer TL when treated with 9.4 mg/kg of imetelstat
Source: EHA 2020 Poster: Mascarenhas J, et al
Conclusions
38
• Imetelstat achieved dose- and exposure-dependent reduction of telomerase activity and hTERT expressionlevel, demonstrating on-target mechanism of action.
• Achieving optimal PD effect (≥50% reduction of telomerase activity or hTERT level) in patients treated withimetelstat is correlated with clinical responses and longer OS. This validates the pre-clinical PD findings.
• Significant, dose-dependent, reduction in VAF of JAK2, CALR and MPL mutations were observed, indicatingthat imetelstat has disease-modifying activity by targeting the underlying MF malignant clones.
• Treatment with 9.4mg/kg imetelstat improved clinical outcomes in patients with short telomeres or highhTERT expression level at baseline. The results are consistent with telomere biology in cancer cells andprovide evidence for on-target mechanism of action of imetelstat through telomerase inhibition.
• This is the first clinical report to systematically evaluate the mechanism of action based PD effect ofimetelstat, and its relationship to exposure and clinical benefits.
Source: EHA 2020 Poster: Mascarenhas J, et al
Q&A
John Mascarenhas, M.D.
Icahn School of Medicine at Mount Sinai
Introduction
Aleksandra Rizo, M.D., Ph.D.
Chief Medical Officer
Geron
Rami Komrokji, M.D.
©2020, Geron Corporation | Nasdaq: GERN | 41
Current • Section Head – Leukemia and MDS, Moffitt Cancer Center, Tampa, Florida• Vice Chair, Malignant Hematology Department, Moffitt Cancer Center, Tampa,
Florida• Senior Member and Professor of Oncologic Services, Moffitt Cancer Center, Tampa,
FL
Previous • Clinical Director, Malignant Hematology Department Lead Clinical Investigator, Moffitt Cancer Center, Tampa, Florida
• Director Leukemia & Lymphoma Program, University of Cincinnati, Cincinnati, Ohio
Medical Training • Jordan University School of Medicine, Amman, Jordan
• Internal Medicine Resident, Case Western University, St. Vincent Program, Cleveland, Ohio
• Hematology-Oncology Fellow, Strong Memorial Hospital, University of Rochester, Rochester, New York
Expertise • Clinical trials in hematologic malignancies with a focus on myelodysplastic syndromes, myeloproliferative neoplasms and acute myeloid leukemia
Imetelstat in Intermediate-2 or
High-risk Myelofibrosis (MF)
at 25th Annual European Hematology
Association Annual Congress
Longer OS in Patients with Higher Risk Triple Negative MF
IMETELSTAT TREATMENT RESULTS IN CLINICAL BENEFITS, INCLUDING IMPROVED OVERALL SURVIVAL, IN PATIENTS WITH HIGHER-RISK TRIPLE-NEGATIVE
MYELOFIBROSIS RELAPSED/REFRACTORY TO JANUS KINASE INHIBITORS (JAKI)
J. Kiladjian1, J. Mascarenhas2, R. Komrokji3, M. Cavo4, B. Martino5, D. Niederwieser6, A. Reiter7, B. Scott8, M. Baer9, R. Hoffman10, O. Odenike11, J. Bussolari12, E. Zhu12, E. Rose12, L. Sherman13,
S. Dougherty13, F. Feller13, L. Sun13, Y. Wan13, A. Rizo13, F. Huang13, and A. Vannucchi14
1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; MPN-RC (US), 2H Lee Moffitt Cancer Center (US), 3”Seràgnoli” Institute ofHematology, 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 GreenebaumComprehensive Cancer Center (US), 9Tisch Cancer Institute, Mount Sinai School of Medicine (US), 10University of Chicago (US), 11JanssenResearch & Development, LLC (US), 12Geron Corporation (US), 13Hôpital Saint-Louis, Université Paris (FR)
43EHA 25 l EP1101
Imetelstat in Triple Negative Patients
44Source: EHA 2020 Poster: Kiladjian J, et al
• Imetelstat• Imetelstat is a telomerase inhibitor that selectively targets malignant cells with continuously upregulated
telomerase, inducing their apoptosis and thereby enabling potential recovery of normal hematopoiesis.
• Background• Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm. JAK2, MPL, and CALR
mutations are considered "driver mutations" and directly contribute to the myeloproliferative phenotypethrough convergent activation of intracellular JAK-STAT signaling, which led to the development of JAKinhibitors (JAKi).
• MF patients negative for JAK2, CALR and MPL mutations are termed Triple Negative (TN), a subpopulationassociated with a higher incidence of leukemic transformation and shorter overall survival (OS) ~2.5-3 yearsfrom diagnosis compared to pts carrying a mutation in JAK2, CALR or MPL gene.
• Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment forMF, but TN MF patients also have worse prognosis and non-relapse mortality vs. non-TN pts after alloHSCT.
• New agents with novel mechanisms of action beyond JAKi are needed to treat TN MF pts.• Reported at ASH 2018, IMbark showed a 32% symptom response rate and median OS of 29.9 months in the
overall population on the 9.4 mg/kg arm, with acceptable safety.
• Objective• To evaluate TN patients enrolled in the IMbark clinical trial for spleen response [spleen volume reduction
(SVR) ≥35%] and symptom response [total symptom score (TSS) reduction ≥50%] at Week 24, fibrosisimprovement and OS to determine if this molecularly defined subset, associated with poor prognosis,benefits from imetelstat treatment.
ClincialTrials.gov (NCT02426086)
IMbark Phase 2 Trial
©2020, Geron Corporation | Nasdaq: GERN | 45
Clinical activity in relapsed/refractory MF patients
Trial Population:
• Patients with Intermediate-2 or High-risk MF (Int-2/High-risk) patients who have relapsed after or are refractory to prior treatment with a janus kinase inhibitor (JAKi)
• 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
Intermediate-2 or High-risk MF
R/R to JAKi treatment
Ran
do
miz
e(1
:1) Imetelstat
9.4 mg/kgevery 3 weeksn=59
Imetelstat4.7 mg/kgevery 3 weeksn=48
Co-primary endpoints:Spleen response rate and symptom response rate
Secondary endpoints:CR, PR and CI, anemia response per 2013 IWG-MRTcriteria, duration of responses,and overall survival (OS)
Exploratory endpoints:Cytogenetic and molecular responses, leukemia free survival
* Adapted from IWG-MRT response criteria definition of progressive disease.
46
IMbark Phase 2Baseline Frequency of JAK2, CALR, MPL Mutation and TN for Patients
Molecular Subtype4.7 MG/KG,
N=48 9.4 MG/KG,
N=57 Total
N=105
JAK2 V617F 32 (66.7%) 32 (56.1%) 64 (61%)
CALR 2 (4.2%) 7 (12.3%) 9 (8.5%)
MPL 4 (8.3%) 2 (3.5%) 6 (5.7%)
TN 10 (20.8%) 16 (28.1%) 26 (24.8%)
Source: EHA 2020 Poster: Kiladjian J, et al
47
Higher Rates of Spleen and Symptom Response in TN MF PatientsWhen treated with 9.4 mg/kg of imetelstat
0.0%
18.8%
10.0%
50.0%
0.0%
7.3%5.3%
24.4%
0%
10%
20%
30%
40%
50%
60%
4.7 mg/kg 9.4 mg/kg 4.7 mg/kg 9.4 mg/kg
Spleen Response Symptom Response
% o
f pat
ient
s ac
hive
d re
spon
se
Higher rates of clinical response in TN vs. Non-TN in 9.4mg/kg
TN Non-TN
Source: EHA 2020 Poster: Kiladjian J, et al
48
Longer OS in TN MF PatientsWhen treated with 9.4 mg/kg of imetelstat
4.7 mg/kg 9.4 mg/kg
Imetelstat Dose
(mg/kg)TN vs Non-TN
Percentage of Subjects
Who Died
Median Survival (months)
(95% CI)
HR
(95% CI)
P-value
(Log-rank)
4.7TN 8 / 10 (80.0%) 23.1 (4.2, 36.6) 1.01 (0.46, 2.23) 0.98
Non-TN 27 / 38 (71.1%) 19.4 (16.7, 33.9)
9.4TN 7 / 16 (43.8%) 35.9 (23.2, NE) 0.45 (0.19, 1.03) 0.05
Non-TN 28 / 41 (68.3%) 24.6 (19.6, 29.9)
Source: EHA 2020 Poster: Kiladjian J, et al
49
Higher Rate of Bone Marrow Fibrosis Improvement in TN MF Patients When treated with 9.4 mg/kg of imetelstat
0%6%
94%
13%21%
66%
0%
20%
40%
60%
80%
100%
Grade 1 Grade 2 Grade 3
Bone marrow fibrosis grade at baseline
% o
f p
atie
nts
Worse baseline fibrosis grade in TN
TN Non-TN
20.0%
50.0%
20.0%
39.1%
0%
10%
20%
30%
40%
50%
60%
4.7 mg/kg 9.4 mg/kg
% p
ts w
ith
fib
rosi
s im
pro
ven
t
Higher rate of BM fibrosis improvement in TN vs Non-TN in 9.4 mg/kg
TN Non-TN
Source: EHA 2020 Poster: Kiladjian J, et al
50
TN MF Patients had Shorter Telomeres and Higher Level of hTERT at Baseline
Representing a suitable target population for imetelstat treatment
79%
60%
46% 48%
0%
20%
40%
60%
80%
100%
Shorter TL Higher hTERT
% o
f p
atie
nts
Higher % of TN pts have shorter TL or higher level of hTERT at baseline compared to Non-TN pts
TN Non-TN
TN MF patients treated with 9.4 mg/kg of imetelstatSource: EHA 2020 Poster: Kiladjian J, et al
Conclusions
51
Overall, TN MF pts R/R to JAKi treated with 9.4 mg/kg imetelstat had better clinical outcomes and prolongedOS compared to non-TN pts, suggesting that imetelstat may improve the poor outcomes expected for TN pts.
• There were 20.8% TN patients in the 4.7 arm and 28.1% in the 9.4 arm, for a total of 24.8% TN patients on thestudy.
• With 9.4 mg/kg imetelstat treatment, clinical response rates were higher in TN vs non-TN patients: spleenresponse rate was 18.8% in TN vs 7.3% in non-TN; and symptom response was 50.0% in TN vs 24.4% in non-TNpatients.
• Imetelstat treatment at 9.4 mg/kg resulted in significantly longer median OS of 35.9 months for TN patients vs24.6 months for non-TN patients.
• Majority (94%) of the TN patients enrolled on the study had Grade 3 fibrosis. Higher rate of bone marrowfibrosis improvement was noted in the TN (50%) vs non-TN (39.1%) patients.
• TN patients enrolled on the study had short telomere length and high hTERT expression level at baseline,representing a suitable target population for imetelstat, a telomerase inhibitor.
These data warrant further investigation of imetelstat in a targeted clinical trial in TN MF patients who havepoor outcomes.
Source: EHA 2020 Poster: Kiladjian J, et al
Q&A
Rami Komrokji, M.D.
Moffitt Cancer Center
Imetelstat in Intermediate-2 or
High-risk Myelofibrosis (MF)
at 25th Annual European Hematology
Association Annual Congress
Favorable Overall Survival Correlates with Other Clinical Benefits
FAVORABLE OVERALL SURVIVAL WITH IMETELSTAT TREATMENT CORRELATES WITH OTHER CLINICAL BENEFITS IN INTERMEDIATE 2 OR HIGH RISK MYELOFIBROSIS
RELAPSED/REFRACTORY TO JANUS KINASE INHIBITOR
J. Mascarenhas1, R. Komrokji2, B. Martino3, D. Niederwieser4, A. Reiter5, B. Scott6, M. Baer7, R. Hoffman8, O. Odenike9, J. Bussolari10, E. Zhu10, E. Rose10, L. Sherman11, S. Dougherty11, F.
Feller11, L. Sun11, Y. Wan11, A. Rizo11, F. Huang11, and J. Kiladjian12
1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; MPN-RC (US), 2H Lee Moffitt Cancer Center (US), 3Grande Ospedale Metropolitano-G.O.M.Bianchi-Melacrino-Morelli (IT), 4University Hospital Leipzig (DE), 5University Hospital Mannheim (DE), 6Fred Hutchinson Cancer Research Center (US),7University of Maryland Greenebaum Comprehensive Cancer Center (US), 8Tisch Cancer Institute, Mount Sinai School of Medicine (US), 9University ofChicago (US), 10Janssen Research & Development, LLC (US), 11Geron Corporation (US), 12Hôpital Saint-Louis, Université Paris (FR)
54EHA 25 l EP1107
ClincialTrials.gov (NCT02426086)
IMbark Phase 2 Trial
©2020, Geron Corporation | Nasdaq: GERN | 55
Clinical activity in relapsed/refractory MF patients
Trial Population:
• Patients with Intermediate-2 or High-risk MF (Int-2/High-risk) patients who have relapsed after or are refractory to prior treatment with a janus kinase inhibitor (JAKi)
• 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
Intermediate-2 or High-risk MF
R/R to JAKi treatment
Ran
do
miz
e(1
:1) Imetelstat
9.4 mg/kgevery 3 weeksn=59
Imetelstat4.7 mg/kgevery 3 weeksn=48
Co-primary endpoints:Spleen response rate and symptom response rate
Secondary endpoints:CR, PR and CI, anemia response per 2013 IWG-MRTcriteria, duration of responses,and overall survival (OS)
Exploratory endpoints:Cytogenetic and molecular responses, leukemia free survival
* Adapted from IWG-MRT response criteria definition of progressive disease.
56
Correlation of Overall Survival and Other Clinical BenefitsAnalysis of IMbark Phase 2 data
Source: EHA 2020 Poster: Mascarenhas J, et al
• Imetelstat• Imetelstat, a 13-mer oligonucleotide that specifically targets the RNA template of human
telomerase, is a potent competitive inhibitor of telomerase enzymatic activity.• Selectively targets malignant cells with continuously upregulated telomerase, inducing their
apoptosis and thereby enabling potential recovery of normal hematopoiesis.
• Background• Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm.• Patients who are relapsed after or refractory to (R/R) therapy with Janus kinase inhibitors (JAKi)
have dismal overall survival (OS) of 13-16 months.• Treatment with imetelstat has demonstrated dose-related clinical benefit, specifically in terms
of symptom response and improvement in OS in IMbark, a phase 2 study in MF patients R/R toa JAKi.
• The improvement in OS for patients treated with 9.4mg/kg imetelstat was further supported byanalyses of IMbark patients with closely matched real world controls.
• Objective• Evaluate the association between OS and spleen volume reduction (SVR) at Week 24, total
symptom score (TSS) reduction at Week 24, and fibrosis improvement.
57
Myelofibrosis Patients Relapsed/Refractory to JAKi OS improvement with 9.4 mg/kg imetelstat treatment
Similar results were observed when sensitivity analyses accounted for confounding factors of
subsequent therapies, including stem cell transplantation and dose escalation from
4.7 mg/kg to 9.4 mg/kg.
Source: EHA 2020 Poster: Mascarenhas J, et al
Median follow up of 41.7 months
Dose Related Clinical Benefits from Imetelstat Treatment
58
CALR = calreticulin gene, CI = confidence interval, JAK = Janus kinase, IWG-MRT = International Working Group – Myeloproliferative Neoplasms Research and Treatment, MPL = thrombopoietin receptor gene, OS = overall survival, PFS = progression free survival, SVR = spleen volume reduction, TSS = total symptom score, VAF = variant allele frequency
Source: EHA 2020 Poster: Mascarenhas J, et al
59
Trend of Longer OSCorrelated with reduction in fibrosis
Patients with ≥1 degree of bone marrow fibrosis improvement showed a significantly longer OS than those who had worsening bone marrow fibrosis.
A similar trend was seen in patients with stable vs. worsening fibrosis.
Source: EHA 2020 Poster: Mascarenhas J, et al
Hazard ratios (HR) and p-values are based on Cox regression models with Imetelstat treatment cohort and bone marrow degree of fibrosis as factors.N: Number of patients in each (reference or non-reference) category. Deaths: Number of deaths in each category.
60
Trend of Longer OS
Correlated with symptom response and spleen response
Patients who achieved symptom and spleen response at week 24 showed trend of longer OS compared to patients who did not achieve a response.
Hazard ratios (HR) and p-values are based on Cox regression models with Imetelstat treatment cohort and TSS reduction, or SVR reduction as factors.N: Number of patients in each (reference or non-reference) category. Deaths: Number of deaths in each category.
Source: EHA 2020 Poster: Mascarenhas J, et al
61
Prognostic Disease Characteristics for OSIrrespective of treatment dose
Source: EHA 2020 Poster: Mascarenhas J, et al
• Hazard ratios (HR) and p-values are based on Cox regression models with Imetelstat treatment cohort and demographic or baseline characteristic as factors.
• CI* = Clinical Improvement
Conclusions
62
Imetelstat showed dose-related improvement in OS in patients who are R/R to JAKi. The survival benefit observed with imetelstat was supported by the trend of correlation with other clinical benefits.
• With a median follow-up of 41.7 months, the median OS was 28.1 months for the 9.4 mg/kg arm and 19.9months for the 4.7 mg/kg arm.
• Among 57 patients across both treatment arms that had matching bone marrow samples, 20 patients(35%) had ≥1 degree of bone marrow fibrosis improvement while on study and had a significant longer OSthan those who had worsening bone marrow fibrosis. A similar trend was seen in 29 patients (51%) withstable vs. worsening fibrosis.
• Patients who achieved symptom and spleen response at week 24 showed trend of longer OS compared topatients who did not achieve response.
• Pretreatment DIPSS high risk, ECOG performance status, transfusion dependency, response to last JAKi,higher baseline neutrophils, lower baseline Hb and platelet values correlated with increased risk of death.
Source: EHA 2020 Poster: Mascarenhas J, et al
Q&A
John Mascarenhas, M.D.
Icahn School of Medicine at Mount Sinai
Planned Phase 3 in Refractory MF
Aleksandra Rizo, M.D., Ph.D.
Chief Medical Officer
Geron
Population: Int-2/High-risk MF refractory to a JAKi– Inadequate spleen or symptom response after treatment with JAKi for ≥ 6 months, including an optimal dose of JAKi for at least 2
months
Primary endpoint: Overall Survival (OS; HR=0.6)– Secondary endpoints include: symptom response, spleen response, progression free survival, complete response, partial
response, clinical improvement, duration of responses, safety, pharmacokinetics, patient reported outcomes
Statistical Design and Methods
Comparator arm: Best Available Therapy (BAT), excluding JAKi
Imetelstat treatment arm: 9.4 mg/kg every 3 weeks
Phase 3 Trial Design in Int-2/HR MF with OS as Primary Endpoint
©2020, Geron Corporation | Nasdaq: GERN | 65
Plan to open for enrollment 1Q 2021
Imetelstat(9.4 mg/kg q3 wks)
BAT (excl. JAKi)
Refractory MFInt2/High-risk (n=320)
Final Analysis for OSEvent-driven
Est timing: 1H 2024
OS
2:1
Interim Analysis for OS
Event-drivenEst timing: 1H 2023
Principal Investigators: John Mascarenhas, M.D., Icahn School of Medicine, Mt. SinaiSrdan Verstovsek, M.D., MD Anderson Cancer Center
Closing Remarks
John Scarlett, M.D.
Chairman and Chief Executive Officer
Geron
Confidential & Proprietary
Thank YouIf you have any questions, please contact us: [email protected]