Enhancing the Lives of Patients with Heme Malignancies - Corporate Presentation March 2023
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Enhancing the Lives of Patients with Heme Malignancies Corporate Presentation March 2023
Forward-Looking Statements and Safe Harbor
Except for the historical information contained herein, this presentation contains forward-looking statements made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Investors are
cautioned that such statements, include, without limitation, those regarding: (i) that Geron plans to submit regulatory filings in the U.S. in mid-2023 and the EU in the second half of 2023, and is preparing for a potential regulatory
approval and commercial launch in lower risk MDS in the U.S. in the first half of 2024 and in the EU by the end of 2024; (ii) that for IMpactMF, Geron expects to conduct an interim analysis in 2024 and a final analysis in 2025; (iii) that
for the next generation telomerase inhibitor program, the Company expects completion of the current discovery effort in 2023 and potentially advance any lead compounds into the next step of discovery research; (iv) that Geron
expects its projected financial resources to fund operations, including completion of preparatory activities for potential U.S. commercial launch of imetelstat in lower risk MDS, until the third quarter of 2025; (v) that IMerge Phase 3
and IMpactMF have registrational intent; (vi) that there is clinical and molecular evidence supporting the potential for MDS disease modification with imetelstat and that imetelstat also has the potential to demonstrate disease-
modifying activity in patients by reducing the malignant stem and progenitor cells of the underlying disease; (vii) that the Company expects imetelstat to be a highly differentiated product in the lower risk MDS commercial
marketplace; (viii) that the Company projects that the addressable patients in 2030 for imetelstat in LR MDS are approximately 33,000 and for R/R MF are approximately 18,000; (ix) that the Company believes imetelstat has potential
large market opportunities with potential peak 2030 market opportunity from the U.S. and key European markets of approximately ~$3 billion, with ~$1.2 billion from LR MDS sales and ~$1.8 billion from R/R MF sales; (x) that there
are unmet needs in LR MDS and R/R MF potentially addressed with imetelstat treatment; (xi) that the telomerase inhibition of imetelstat gives it the potential for expanding into new indications; (xii) that the Company the planned
first site opening for IMpress is in 2023; (xiii) that the Company expects that the TELOMERE Phase 1 clinical trial will be initiated pending data from the IMpress Phase 2 clinical trial; (xiv) that the Company expects further experiments
from the preclinical program in lymphoid malignancies; and (xv) other statements that are not historical facts, constitute forward-looking statements. These forward-looking 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, risks and uncertainties related to: (a) the impact of general economic, industry or political
climate in the U.S. or internationally, the current or evolving effects of macroeconomic conditions, such as the COVID-19 pandemic, civil or political unrest or military conflicts around the world, such as the military conflict between
Ukraine and Russia, inflation, rising interest rates or prospects of a recession, on Geron’s business and business prospects, its financial condition and the future of imetelstat; (b) whether Geron overcomes all of the potential delays
and other adverse impacts caused by the current or evolving effects of the COVID-19 pandemic and/or geopolitical events, as well as all the enrollment, clinical, safety, efficacy, technical, scientific, intellectual property,
manufacturing and regulatory challenges in order to have the financial resources for, and to meet the expected timelines and planned milestones in (i) to (iii), (ix) and (xii) to (xiv) above; (c) whether regulatory authorities accept for
filing Geron’s planned NDA and MAA submissions and permit the further development of imetelstat on a timely basis, or at all, without any clinical holds; (d) whether imetelstat is demonstrated to be safe and efficacious in IMerge
Phase 3 and IMpactMF to enable regulatory approval; (e) whether any future efficacy or safety results may cause the benefit-risk profile of imetelstat to become unacceptable; (f) whether imetelstat actually demonstrates disease-
modifying activity in patients and the ability to target the malignant stem and progenitor cells of the underlying disease; (g) that Geron may seek to raise substantial additional capital in order to complete the development and
commercialization of imetelstat and to meet all of the expected timelines and planned milestones in (i) to (iii), (ix) and (xii) to (xiv) above; (h) whether regulatory authorities require additional clinical testing of imetelstat prior to or
after granting approval in lower risk MDS even though IMerge Phase 3 met its primary endpoint; (i) whether there are failures in manufacturing or supplying sufficient quantities of imetelstat that would delay, or not permit, the
anticipated launches in (i) above or not enable the other ongoing or planned clinical trials; (j) whether imetelstat is able to obtain and maintain the exclusivity terms and scopes provided by patent and patent term extensions, orphan
drug, data and marketing and pediatric coverages and have freedom to operate; (k) whether the follow-up period of 12 months for the IMerge Phase 3 primary analysis results in not obtaining adequate data to demonstrate safety
and efficacy, including transfusion independence, in the primary analysis; (l) whether Geron can accurately project the timing of complete enrollment in its clinical trials, whether due to the current or evolving effects of the COVID-19
pandemic and/or geopolitical events or otherwise; (m) whether Geron is able to enroll its clinical trials at a pace that would enable the financial resources for, and to meet the expected timelines and planned milestones in (i) to (iii),
(ix) and (xii) to (xiv) above; (n) that Geron may be unable to successfully commercialize imetelstat due to competitive products, or otherwise; (o) if the FDA does not grant priority review to the IMerge data, then the launch date in
lower risk MDS may be later than the first half of 2024; (p) whether Geron may decide to partner and not to commercialize independently in the U.S. and in key European markets; and (q) for IMpactMF, Geron’s projected rates for
enrollment and death events may differ from actual rates, which may cause the interim analysis to occur later than 2024 and the final analysis to occur later than 2025. Additional information on the above risks and uncertainties and
additional risks, uncertainties and factors that could cause actual results to differ materially from those in the forward-looking statements are contained under the heading “Risk Factors” or other similar headings found in
documents Geron files from time to time with the Securities and Exchange Commission (the “SEC”), including the Company’s Report on Form 10-K for the year ended December 31, 2023 and subsequent filings. 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.
2
Geron Today
Positive Phase 3 Top-Line Catalyst-Rich Multi-Billion Dollar
Results in Lower Risk MDS Next Two Years Expected Market Potential
Statistically significant and 2023 U.S. NDA and EU MAA Expected imetelstat profile to meet
clinically meaningful submissions for LR MDS unmet needs in LR MDS and R/R MF
improvements with imetelstat vs.
placebo: Commercial preparations ongoing
• Primary 8-week transfusion 2024 U.S. commercial launch • Hiring experienced senior leadership
independence (TI) endpoint and key of imetelstat in LR MDS*
secondary 24-week TI endpoint met • Executing “go-to-market” plan
• Substantial increases in hemoglobin Interim analysis overall • Engaging stakeholders for marketplace
levels and reductions in transfusions survival Phase 3 readout in readiness
• Efficacy across key MDS subtypes, R/R MF
including RS+ and RS- patients Potential market opportunity
2023-25 Significant life cycle • >$3B combined potential peak market
Safety results consistent with prior opportunity for LR MDS and R/R MF
management program
imetelstat clinical experience readouts
Clinical and molecular evidence
supporting the potential for
disease modification
* If the NDA is accepted for filing and imetelstat is approved for commercialization by the FDA
References on slide 52 3
LR MDS = lower risk myelodysplastic syndromes; NDA = new drug application; MAA = marketing authorization application; R/R MF = relapsed/refractory myelofibrosis; RS+ = ring sideroblast positive; RS- = ring sideroblast negative
Anticipated Momentum Going Forward
2024
IMpactMF Ph3
1H 2024 interim analysis for
Jan 4, 2023 Mid-2023 LR MDS
median overall
survival (OS) in
Positive IMerge LR MDS U.S. approval & relapsed/
U.S. NDA commercial launch* refractory MF
Ph3 LR MDS TLR
submission
reported
2H 2023 2H 2H
2024
2024
LR MDS
LR MDS EU MAA LR MDS
EU approval &
EU approval &
submission commercial
commercial launch*
launch
commercial launch*
If the NDA / MAA are accepted for filing and imetelstat is approved for commercialization by the FDA / EMA, as applicable
LR MDS = lower risk myelodysplastic syndromes; TLR = top-line results; NDA = new drug application; MAA = marketing authorization application; MF = myelofibrosis 4
Novel Target, Novel Drug
Telomerase inhibition and imetelstat to potentially
alter the course of hematologic malignancies
5
Telomerase, a Unique
Oncology Target
Malignant HSCs are the malignant Heme
source of disease in heme
hematopoietic malignancies
stem cells
malignancies
• Malignant hematopoietic Myelodysplastic
stem cells (HSCs) give rise Syndromes (MDS)
to uncontrolled proliferation
of malignant blood cells
• Malignant HSCs rely on
continual upregulation of Telomerase Myelofibrosis (MF)
telomerase to support continually
uncontrolled proliferation upregulated
Telomerase is a novel Acute Myeloid
Leukemia (AML)
target in malignantly uncontrolled proliferation
transformed HSCs of malignant cells
(malignant hematopoiesis)
References on slide 52 6
Imetelstat, First-in-Class
Telomerase Inhibitor
Imetelstat enables
recovery of bone marrow
Imetelstat binds to
telomerase and and blood cell production
inhibits its activity
Evidence for potential disease
modification:
• Clinical efficacy results: durable TI (LR
MDS); improved OS (R/R MF)
• Molecular data: reductions in variant allele
apoptosis of frequency (VAF)
malignant cells
• Depletion of mutated abnormal malignant
cells that have been associated with the
malignant disease, such as SF3B1, ASXL1,
JAK2V617F and CALR
TI = transfusion independence; LR MDS = lower risk myelodysplastic syndromes; OS = overall survival
References on slide 52
7
Imetelstat in Lower Risk MDS
Positive top-line results from IMerge Phase 3
8
Phase 3 IMerge trial design
Phase 3
Double blind, randomized Imetelstat
118 clinical sites in 17 countries 7.5mg/kg every 4 weeks Primary Endpoint:
(n=118) 8-week RBC Transfusion
Independence (TI)**
Patient Population ( ITT n=178): R Stratification:
• Transfusion burden (4 - 6 vs. >6 units) Key Secondary
• IPSS Low- or Intermediate 1- Risk MDS A
• Relapsed/Refractory* to ESA or EPO
N • IPSS risk category (Low vs. Intermediate-1) Endpoints:
D Supportive care, including RBC and platelet • 24-week RBC TI**
>500 mU/ml transfusions, myeloid growth factors (e.g., G-CSF), and
O
2:1 • Duration of TI
• Transfusion dependent: ≥4 units RBCs M
iron chelation therapy administered as needed on study
every 8 weeks over 16-week pre-study I
per investigator discretion
• Hematologic
Improvement-
• Non-deletion 5q Z
Erythroid (HI-E)
• No prior treatment with lenalidomide E
Placebo
or HMAs (n=60)
* Received at least 8 weeks of ESA treatment (epoetin alfa ≥40,000 U, Safety population (treated) n=177 ** Proportion of patients without any RBC
epoetin beta ≥30,000 U or darbepoetin alfa 150 mcg or equivalent per transfusion for at least eight consecutive weeks
week) without Hgb rise ≥1.5 g/dL or decreased RBC transfusion Imetelstat n=118 since entry to the trial (8-week TI); proportion of
requirement ≥ 4 units/8 weeks or transfusion dependence or reduction patients without any RBC transfusion for at least
in Hgb by ≥1.5 g/dL after hematologic improvement from ≥ 8 weeks of Placebo n=59
24 consecutive weeks since entry to the trial (24-
ESA treatment.
week TI)
EPO = erythropoietin; ESA = erythropoietin stimulating agents; G-CSF = granulocyte colony stimulating factor; Hgb = hemoglobin; IPSS = International Prognostic Scoring System; ITT = intent to treat;
RBC = red blood cell; HI-E = hematologic improvement-erythroid; HMAs = hypomethylating agents; MDS = myelodysplastic syndromes 9
References on slide 52
Key trial metrics
Balanced time on study and treatment time between two arms
Imetelstat Placebo
(n=118) (n=60)
Median time on study, months (range) 19.5 (1.4-36.2) 17.5 (0.7-34.3)
Median time on treatment, months (range) 7.8 (0.03-32.5) 6.5 (0.03-26.7)
Median time on treatment for 8-week TI responders, months (range) 17.2 (1.8-32.5) 15.0 (4.1-25.8)
Median treatment, cycles (range) 8 (1-34) 8 (1-30)
Median treatment cycles for 8-week TI responders, months (range) 18 (3-34) 17 (3-29)
References on slide 52
8-week TI = proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial
TI = transfusion independence 10Baseline patient demographics and disease characteristics
Comparable between both arms
Imetelstat Placebo
(n=118) (n=60)
Age, years, median (range) 71.5 (44-87) 73.0 (39-85)
WHO 2001 category, n (%)
RS+ 73 (61.9) 37 (61.7)
RS- 44 (37.3) 23 (38.3)
RBC transfusion burden, units/8 weeks, median (range) 6 (4-33) 6 (4-13)
4 - 6 units / 8 weeks, n (%) 62 (52.5) 33 (55.0)
>6 units / 8 weeks, n (%) 56 (47.5) 27 (45.0)
IPSS risk category, n (%)
Low 80 (67.8) 39 (65.0)
Intermediate-1 38 (32.2) 21 (35.0)
Prior luspatercept use, n (%)* 7 (5.9) 4 (6.7)
Pre-treatment hemoglobin**, median (range), g/dL 7.9 (5.3-10.1) 7.8 (6.1-9.2)
* Insufficient number of patients previously treated with luspatercept to draw conclusions about the effect of imetelstat treatment in such patients. None of the imetelstat-treated patients
and one of the placebo patients achieved 8-week TI.
** Pretreatment hemoglobin is defined as the average of all hemoglobin values in the eight weeks prior to the first dose date, excluding values that were within 14 days after transfusion
(thus considered to be influenced by transfusion).
References on slide 52
11
RS+ = ring sideroblast positive; RS- = ring sideroblast negative; WHO = World Health OrganizationPatient disposition after 18 months median follow up
Imetelstat Placebo
(n=118) (n=59)
Treatment ongoing, n (%) 27 (22.9) 14 (23.7)
Treatment discontinued, n (%) 91 (77.1) 45 (76.3)
Lack of efficacy 28 (23.7) 25 (42.4)
Adverse event 19 (16.1) 0
Cytopenias 11 (9.3) 0
Unrelated 8 (6.8) 0
Disease relapse after initial response on study 17 (14.4) 1 (1.7)
Patient decision 16 (13.6) 10 (16.9)
Progressive disease 7 (5.9) 5 (8.5)
AML progression 2 (1.7) 1 (1.7)
Investigator decision 2 (1.7) 2 (3.4)
Death* 1 (0.8) 2 (3.4)
Lost to follow up 1 (0.8) 0
* On imetelstat treatment arm, patient death: neutropenic sepsis not related to drug after ~ two-year treatment duration
On placebo treatment arm, patient deaths: (1) COVID-19 and (1) heart valve issue
References on slide 52
12
AML = acute myeloid leukemiaTop-Line Efficacy Results
Primary and key secondary endpoint met with high statistical
significance and clinically meaningful improvements
13Met primary endpoint (8-week TI)
Highly statistically significant and clinically meaningful improvement in 8-week TI
Imetelstat Placebo
P-value*
(n=118) (n=60)
8-week TI, n (%) 47 (39.8) 9 (15.0) 6 units of RBCs/8 weeks) and baseline IPSS risk score (Low or Intermediate-1)
References on slide 52
8-week TI = proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial 14Continuous sustained TI with imetelstat treatment
83% of imetelstat 8-week TI responders had a single continuous TI period
* *
* Pre-treatment hemoglobin was 6.2 g/dL with transfusion burden of 5 units/8 weeks before study start; on-study hemoglobin wasMedian duration of 8-week TI*
Highly statistically significant and clinically meaningful durability of TI
1
100%
Imetelstat Placebo HR P-value*
Percentage of patients with 8-week TI
0.9
90%
0.8
80% Median TI duration (weeks)* 51.6 13.3 0.23Met key secondary endpoint (24-week TI)
Highly statistically significant and clinically meaningful improvement in 24-week TI
Median TI duration+ for imetelstat patients who achieved 24-week TI was 80.0 weeks (51.6, NE)
Approximately 70% of patients treated with imetelstat who achieved 8-week TI,
Imetelstat Placebo
went on to achieve 24-week TI P-value*
(n=118) (n=60)
24-week TI, n (%) 33 (28.0) 2 (3.3) 6 units of RBCs/8 weeks) and baseline IPSS risk score (Low or Intermediate-1)
+ Kaplan-Meier estimates of duration of RBC TI
References on slide 52 17
24-week TI = proportion of patients without any RBC transfusion for at least 24 consecutive weeks since entry to the trial ; NE = not estimableTransfusion independence over longer periods
Increasing magnitude of benefit for imetelstat vs. placebo with longer time intervals
PMean change in hemoglobin levels for all imetelstat patients
Highly statistically significant increase in hemoglobin levels over time for imetelstat patients
5
8-week TI Imetelstat Placebo
PMean change in RBC transfusion units over time
Statistically significant decrease in number of RBC units transfused
1
P=0.042
Mean Change in RBC Transfusion 0
-1
(units; +/- SE)
-2
-3
-4
-5
1 9 17 25 33 41 49 57 65 73 81 89 97
Weeks
Imetelstat Placebo
Number of patients
Imetelstat 115 104 95 76 60 55 45 43 33 26 22 14 10
Placebo 58 53 48 32 27 22 15 14 8 5 5 5 4
P-value is based on a mixed model for repeated measures with change in RBC transfusion as the dependent variable, week, stratification factors, prior transfusion burden, and treatment arm as the
independent variables with autoregressive moving average (ARMA(1,1)) covariance structure.
References on slide 52 20
NOTE: graph starts at Week 1-8 with the number of the patients with transfusion follow-up data available at least eight weeks on study for imetelstat and placebo armsSecondary endpoint: hematologic improvement-erythroid (HI-E)
Highly statistically significant HI-E using updated IWG 2018 criteria
Most recent HI-E criteria (IWG 2018) puts greater emphasis on durability by measuring response at >16 weeks
Imetelstat Placebo
P-value *
(n=118) (n=60)
HI-E per IWG 2018 , n (%) 50 (42.4) 8 (13.3)Key lower risk MDS subtypes analyses
Statistically significant 8-week TI rates (p6 units of RBCs/8 weeks) and baseline IPSS risk score (Low or Intermediate-1)
^ One patient on imetelstat arm missing RS category 22
References on slide 52Primary (8-week TI) and secondary endpoint (24-week TI)
by RS status
RS+ and RS- demonstrate statistically significant improvement in both 8-week and 24-week TI
RS+ RS-
60
P=0.016
Percentage of patients (%)
50 45.2%
P=0.003 P=0.038
40
32.9% 31.8%
P=0.019
30
18.9% 20.5%
20
8.7%
10 5.4% Imetelstat
0%
Placebo
0
8-week
8-week TI n(%)
TI rate, 24-week
24-week TI n (%)
TI rate, 8-week
8-week TI rate,TIn(%) 24-week
24-week TI n (%)
TI rate,
RS+ RS-
Imetelstat Placebo Imetelstat Placebo
P-value* P-value*
(n=73) (n=37) (n=44) (n=23)
8-week TI responders, n 33 7 14 2
Median duration of TI *, weeks (95% CI) 46.9 (25.9, 83.9) 16.9 (8.0, 24.9) 0.035 51.6 (11.9, NE) 11.2 (10.1, NE) 0.062
24-week TI responders, n 24 2 9 0
Median duration of TI *, weeks (95% CI) 80.0 (41.6, NE) NE (24.9, NE) 0.808 122.9 (25.0, NE) NE (NE, NE) NE
* Kaplan-Meier estimates of duration of RBC TI; 8-week/24-week TI Responder Analysis Set; P-value for TI rate is based on Cochran Mantel Haenszel test stratified for prior RBC
transfusion burden (≤6 units or >6 units of RBCs/8 weeks) and baseline IPSS risk score (Low or intermediate-1); P-value for duration of TI is based on stratified log-rank test. 23
References on slide 52Molecular data in imetelstat treated patients
>50% VAF decrease in SF3B1, TET2, DNMT3A, ASXL1 mutations
Imetelstat
Placebo
45.0
Percentage of patients with ≥50% VAF reduction
40.0% * P=NS
40.0
34.3% * P=NS
35.0
29.5% * P=0.001
30.0
25.0
20.0
16.7%
15.0
11.1% * P=NS
10.0 8.3%
2.6%
5.0 0.0%
0.0
23/78 1/38 12/35 1/12 2/18 0/8 4/10 1/6
SF3B1 TET2 DNMT3A ASXL1
Note: Ratios underneath the bars represent the number of patients with ≥50% variant allele frequency (VAF) reduction as numerator and the total number of patients with
detectable assessment (≥5% VAF) in specified mutation at baseline and any post baseline mutation assessment as denominator.
* P-value is based on Cochran Mantel Haenszel test stratified for prior RBC transfusion burden (≤6 units or >6 units of RBCs/8 weeks) and baseline IPSS risk score (Low or Intermediate-1)
References on slide 52 24
VAF = variant allele frequency; NS = not significantEfficacy results summary • Trial demonstrated highly statistically significant (p
Top-Line Safety Results
Safety results consistent with prior imetelstat clinical
experience with no new safety signals
26Non-hematologic adverse events occurring in ≥10% of patients+
generally low grade and consistent with prior imetelstat clinical trials
Imetelstat Placebo
AE, n (%)
(n=118) (n=59)
All Grades Grade 3/4 All Grades Grade 3/4
Asthenia 22 (18.6) 0 8 (13.6) 0
COVID-19* 21 (17.8) 2 (1.7) 9 (15.2) 3 (5.1)
Peripheral edema 13 (11.0) 0 8 (13.6) 0
Headache 15 (12.7) 1 (0.8) 3 (5.1) 0
Diarrhea 14 (11.9) 1 (0.8) 7 (11.9) 1 (1.7)
Alanine aminotransferase increased 14 (11.9) 3 (2.5) 4 (6.8) 2 (3.4)
Hyperbilirubinemia 11 (9.3) 1 (0.8) 6 (10.2) 1 (1.7)
Constipation 9 (7.6) 0 7 (11.9) 0
Pyrexia 9 (7.6) 2 (1.7) 7 (11.9) 0
+ On either imetelstat or placebo arms
* Includes COVID-19, asymptomatic COVID-19, COVID-19 pneumonia
References on slide 52 27
AE= adverse eventTreatment emergent liver function test (LFT) lab abnormalities
No cases of Hy’s Law or Drug-Induced Liver Injury observed
• Grade 3 elevations on imetelstat were short in duration (median < 2 weeks)Placebo
Imetelstat and more than
80% LFT
resolved to Grade
Lab Abnormality, n (%) 2 or lower within 4 weeks
(n=118) (n=59)
All Grades Grade 3 All Grades Grade 3
Alanine Aminotransferase (ALT*) 46 (39.3) 4 (3.4) 22 (37.3) 3 (5.1)
Alkaline Phosphatase (ALP) 53 (44.9) 0 7 (11.9) 0
Aspartate Aminotransferase (AST) 57 (48.3) 1 (0.8) 13 (22.0) 1 (1.7)
Bilirubin 46 (39.0) 1 (0.8) 23 (39.0) 1 (1.7)
* n=117 for ALT imetelstat patients
References on slide 52
28Consistent with prior imetelstat clinical trials,
the most frequent AEs are hematologic
Imetelstat Placebo
AE, n (%)
(n=118) (n=59)
All Grades Grade 3/4 All Grades Grade 3/4
Thrombocytopenia 89 (75.4) 73 (61.9) 6 (10.2) 5 (8.5)
Neutropenia 87 (73.7) 80 (67.8) 4 (6.8) 2 (3.4)
Anemia 24 (20.3) 23 (19.5) 6 (10.2) 4 (6.8)
Leukopenia 12 (10.2) 9 (7.6) 1 (1.7) 0
Clinical consequences from cytopenias are similar
in imetelstat and placebo treated patients
Imetelstat Placebo
Event, n (%)
(n=118) (n=59)
Grade ≥3 Bleeding Events * 3 (2.5) 1 (1.7)
Grade ≥3 Infections+ 13 (11.0) 8 (13.6)
Grade 3 Febrile Neutropenia ** 1 (0.8) 0
* No ≥Grade 3 bleeding events in the setting of Grade 3/4 thrombocytopenia; on imetelstat: two patients with Grade 4 gastrointestinal bleeding, unrelated and resolved and one Grade 3 hematuria,
unrelated and resolved.
+ On imetelstat: three patients with Grade 3/4 infections in setting of Grade 3/4 neutropenia; all three were sepsis and resolved with only one considered related 29
** Occurred at day 33, lasted 8 days; assessed by investigator as possibly related to imetelstat; patient subsequently achieved TI >40 weeks and remains on treatment at data cut-off
References on slide 52Imetelstat related cytopenias are manageable and reversible with majority being resolved within
Plans for Regulatory Submissions
Lower Risk MDS
31Top-line results supportive of regulatory submissions
On track for 2023 regulatory submissions
• Plans on target for regulatory submissions
◦ Mid-2023 for U.S. New Drug Application (NDA)
◦ 2H 2023 for EU Marketing Authorization Application (MAA)
• Fast Track designation in lower risk MDS enables rolling submission of U.S. NDA and
eligibility for priority review
◦ Rolling submission of NDA initiated
• Pre-NDA meeting conducted
◦ No change to submission plans
Top-line results supportive of regulatory submissions 32Unmet Needs and Market
Opportunities for Imetelstat
Lower Risk MDS
33Expected broad imetelstat opportunity
in lower risk MDS
• ~70% of MDS
patients are classified
MDS: ~37,000* patients diagnosed in the as lower risk
US and Major European Markets in 2021
• Majority of the patients
HR MDS Lower Risk MDS (~70%) with symptomatic
anemia are treated with
ESAs and most will fail
Complex
presentations Symptomatic Anemia (~90%) treatment in ~2 years
1st Line ESA Eligible (~90%) ESA Ineligible
(~10%) • Lower risk MDS
represents a significant
opportunity for
imetelstat
2nd Line or later ESA Failed + ESA Ineligible
Frontline ESA
ineligible
RS+ (~25%) RS- (~75%) ESA-failed, RS+
Imetelstat opportunity ESA-failed, RS-
* Includes ~10% of patients who may present with del(5q)
References on slide 52
HR MDS = higher risk myelodysplastic syndromes; ESA Ineligible = serum EPO >500 mU/mL
34Imetelstat expected profile at planned launch received favorably by
practicing hematologists in both U.S. and key European markets
Key aspects of imetelstat that resonated most strongly with
hematologists in both the community and academic settings
Durability of Potential
transfusion for disease
independence modification
Broad clinical efficacy results Novel MOA,
across patient subtypes non-overlapping with
(RS+ and RS-) current treatments
MOA = mechanism of action
References on slide 52
35Imetelstat potential peak market opportunity in lower risk MDS
~$1.2 billion in 2030
1L ESA Ineligible Patients 3,700
Key addressable
patient segments in
lower risk MDS for
ESA Relapsed/Refractory
RS- Patients 22,000
imetelstat*
ESA Relapsed/Refractory
RS+ Patients 7,000
Imetelstat has the potential to become part of the standard of care in lower risk MDS
* Estimated for 2030 based on DRG MDS Landscape and Forecast syndicated data report 2021 and 2022
References on slide 52
1L = first line 36Commercial Preparedness & Go-to-Market Strategy
Key Focus Areas
Set up and optimize
Hire senior commercial Develop integrated
long-lead time supply
leadership and team clinical and economic
chain and product
imetelstat value
distribution activities
proposition
Engage across broad Evolve organization to
stakeholder base commercial entity
37Imetelstat in Relapsed/Refractory MF
Evaluating potential improved survival
38Median OS in IMbark
Phase 2 Compares Favorably
to Historical Controls ClincialTrials.gov
(NCT02426086)
Improvement in overall Imetelstat 9.4 mg/kg
survival (OS) observed for
JAKi relapsed/refractory MF
patients in IMbark Phase 2
• 14 – 16 mos median OS for 29.9 mos
historical controls for JAKi
relapsed/refractory MF
patients
• 29.9 mos median OS in
imetelstat 9.4 mg/kg arm
References on slide 52 39Median OS More than Double Compared
to BAT Treatment in RWD Study
Evaluating imetelstat vs. BAT in
Evaluating imetelstat
IMbark Phase 2 data vs.world
compared to real BATdata (RWD) from a closely-matched JAKi relapsed/refractory MF
in JAKi
cohort relapsed/refractory
of patients MFwho had discontinued ruxolitinib
at the Moffitt Cancer Center
and were subsequently treated with best available therapy (BAT)
• Improvement in overall survival and
• Improvement in overall survival and lower risk of lower risk of death for imetelstat vs.
death forRWD BAT vs.vs.
imetelstat Imetelstat 9.4 mg/kg BAT in RWD study
BAT in RWD study
◦ Imetelstat: 33.8 mos median OS
- Imetelstat: 33.8 mos median OS
- BAT RWD: 12.0 mos median OS
BAT
Moffitt Imetelstat 9.4 mg/kg ◦ BAT RWD: 12.0 mos median OS
- ◦ 65% lower risk of death with imetelstat
Survival Probability
65% lower risk of death with 33.8
imetelstat
mos compared to
BAT from RWD compared to BAT from RWD
• OS improvement
12.0 mos and lower risk of death for • OS improvement and lower risk of
imetelstat vs. BAT support IMpactMF Phase 3 trial death for imetelstat vs. BAT support
design IMpactMF Phase 3 trial design
• Acknowledging
Same dose and schedule being used in IMpactMF
trialPhase
the limitations of such comparative analyses between RWD and clinical
3 trialthe favorable overall survival (OS) of imetelstat treatment suggested
data, we believe
• Same dose and schedule being used in
by these comparative analyses in this very poor prognosis patient population warrants IMpactMF Phase 3 trial
further evaluation.
References on slide 52 40Manageable Imetelstat Safety
Results in IMbark Phase 2
Limited clinical consequences of
9.4 mg/kg (n=59)
reversible, on target cytopenias
n (%)
All Grades Grade ≥ 3
ClincialTrials.gov
(NCT02426086) • Thrombocytopenia and neutropenia
Hematologic (≥10% in either arm)§
characterization:
Thrombocytopenia 29 (49) 24 (41)
◦ Short time to onset: Median 9 weeks
Anemia 26 (44) 23 (39) (~3 cycles)
Neutropenia 21 (36) 19 (32) ◦ Short duration: Median 70% within 4 weeks*
Nausea 20 (34) 2 (3)
◦ Manageable with dose hold and
modifications
Diarrhea 18 (31) 0
Fatigue 16 (27) 4 (7)
• Limited clinical consequences:
Dyspnea 14 (24) 3 (5)
◦ 2% Grade 3 febrile neutropenia
Abdominal Pain 14 (24) 3 (5)
◦ 5% Grade 3/4 hemorrhagic events
Asthenia 14 (24) 6 (10)
◦ 10% Grade 3/4 infections
§Treatment emergent, per
reported AEs (not laboratory
Pyrexia 13 (22) 3 (5) values). Frequency of reported
Grade 3/4 hematologic
adverse events were
Edema peripheral 11 (19) 0 consistent with cytopenias
reported through lab values.
*Reversible to Grade 2 or lower.
References on slide 52 41Phase 3 IMpactMF Trial in Relapsed/Refractory MF ClincialTrials.gov
(NCT0457615)
Actively enrolling patients now
Imetelstat Primary Endpoint:
Intermediate-2 9.4mg/kg every 3 weeks • Overall survival (OS)
or High-Risk MF (n ~214)
Relapsed/Refractory to 2:1 Key Secondary Endpoints:
JAK inhibitors (JAKi) • Symptom response
Best Available • Spleen response
(n=320) Therapy (BAT) • Patient Reported Outcomes
(PROs)
(n ~106)
References on slide 52 42First and Only Phase 3 Trial in the U.S. in MF with OS as Primary Endpoint
Actively enrolling global trial
• Sites planned across North America, South America,
Europe, Australia and Asia ClincialTrials.gov
(NCT0457615)
Planned analyses
Primary Endpoint:
• Interim Analysis expected in 2024 when ~35% of the
planned enrolled patients have died; alpha spend ~0.01 • Overall survival (OS)
• Final Analysis expected in 2025 when >50% of the planned
enrolled patients have died
Key Secondary Endpoints:
Statistically well-powered trial • Symptom response
• Designed with >85% power to detect a 40% reduction in the
risk of death in the imetelstat arm compared to BAT (hazard
• Spleen response
ratio=0.60; one-sided alpha=0.025) • Patient Reported Outcomes (PROs)
• Conservative powering assumptions
- Median OS: 14 mos for BAT vs. 23 mos for imetelstat
References on slide 52 43Unmet Needs and Market
Opportunities for Imetelstat
Relapsed/Refractory MF
44Expected MF Market Evolution and Imetelstat Opportunity*
We expect the future MF market to expand significantly with potential approvals of JAKi-based
combination regimens and treatments that address anemia in MF patients. Agents in development
today have primary endpoints focused on addressing spleen, symptoms and anemia
Int-2/High Risk MF Patients
Treated with JAK Inhibitors ~75% discontinuation rate after 5 years
Unresponsive to JAK Inhibitors
Almost all JAKi- median OS ~14 – 16 months per literature reviews
treated patients
expected to become NO APPROVED THERAPY
unresponsive to
JAKis and eligible for Expected Imetelstat Addressable Patient Population
imetelstat ~18,000 patients (US/EU5)
USD ~$1.8 Billion in Potential Peak Market Opportunity Across US & Key European Markets**
*Projections in 2030 in Int-2/HR MF
**Company projections: based on treated prevalence estimates for imetelstat eligible patient populations in Int-2/HR MF (2030); DRG syndicated data, US/G5 payor research and
Geron analysis using assumptions for a) expected target product profile at launch, b) obtaining regulatory approvals and favorable reimbursement in US and key European markets,
c) duration of treatment and d) potential market penetration; Company estimate does not include Int-1 & plateletsFinancial Overview
46Financial Resources to Support Potential
Commercial Launch of Imetelstat
~$173M ~$213M ~$60M Financial resources
As of Net proceeds Proceeds from expected to support
December 31, from Jan 2023 warrant exercises
2022 financing in Jan/Feb 2023 projected level of
operations through
third quarter 2025^
^ Based on current operating plan and expectations regarding the timing of regulatory submissions, and potential
acceptance and approval of planned NDA by the FDA in the U.S. for the use of imetelstat in adult patients with lower
risk MDS and the potential subsequent commercialization in 1H 2024.
47Investment Thesis
48Exploring the broad potential of imetelstat
and telomerase inhibition
Indications Discovery Preclinical Phase 1 Phase 2 Phase 3
LR MDS IMerge
Single Agent
R/R MF
Single Agent
IMpactMF
Frontline MF
Combination Therapy
IMproveMF
R/R AML & HR MDS IMpress
Single Agent
R/R AML
Combination Therapy
TELOMERE*
Lymphoid Malignancies
Ongoing; Company Sponsored
Next Generation
TI Program Planned; Investigator Led
* To follow single agent data from IMpress
LR MDS = lower risk myelodysplastic syndromes; R/R MF = relapsed/refractory myelofibrosis; MF = myelofibrosis; R/R AML = relapsed/refractory acute myeloid
leukemia; HR MDS = higher risk myelodysplastic syndromes; TI = telomerase inhibitor 49Imetelstat - a highly differentiated drug
• Unique Mechanism of Action
• Broad and durable TI in LR MDS demonstrated
in IMerge Phase 3
• Potential OS readout in R/R MF
• Evidence for potential disease modification
Multiple upcoming catalysts expected
Key Takeaways • NDA submission in LR MDS – mid-2023
• MAA submission in LR MDS – 2H 2023
• Interim analysis in R/R MF - 2024
Potential commercial future
• Multi-billion dollar market potential
• U.S. LR MDS launch planned for first half 2024*
• EU planning underway
* If the NDA is accepted for filing and imetelstat is approved for commercialization
by the FDA
References on slide 52 50Thank you! Contact: Investor Relations info@geron.com
References
Slide # Reference Slide # Reference Slide # Reference Slide # Reference
3, 4, IMerge Phase 3 TLR reported Jan 4, 2023 35 KOL Interviews, Advisory Boards, Geron Physician 45 MF patient numbers: Geron Physician Market Research 60 Hu et al, ASH 2019
9-30 Market Research (US/EU5); stimuli included IMerge December 2021, US Hematologist Market survey
Phase 2 LR MDS data and expected target product (n=100); company projections in 2030
profile at launch Market potential: Company projections in 2030 based
on treated prevalence estimates for imetelstat eligible
patient populations in Int-2/HR MF; DRG syndicated
data; Payor research (US/EU5) and Geron analysis using
assumptions for a) expected target product profile at
launch, b) obtaining regulatory approvals and favorable
reimbursement in US and key European markets, c)
duration of treatment and d) potential market
penetration; for MF, does not include Int-1 & plateletsAppendix 1
Strong Phase 2 evidence for
potential disease modification
53Strong Evidence of Imetelstat Disease Modification
in Phase 2 Studies
Killing of Recovery of Bone
Reduced
Telomerase Activity
Malignant Stem and Marrow and Blood Clinical Benefits
Progenitor Cells Cell Production
Correlated with Depletion of mutated and Significant hemoglobin Depth and
clinical benefits, cytogenetically abnormal rise in 75% of responders durability of
MDS confirms MOA malignant cells correlated transfusion
with clinical benefits independence
Correlated with Depletion of cells with Improvements
clinical benefits, key driver mutations and in bone marrow Improved
MF confirms MOA abnormal cytogenetics fibrosis correlated overall survival
correlated with improved OS to improved OS and symptoms
References on slide 52
54
MOA = mechanism of action; OS = overall survivalStrong Evidence of Disease Modification Potential
ClinicalTrials.gov
(NCT02598661)
Imetelstat results in reduction of malignant clones in IMerge Phase 2
Change in VAF of Percent SF3B1 VAF Reduction Imetelstat Reduces Abnormal
A SF3B1 Mutations B vs. Longest TI Duration C Cytogenetic Clones
100%
95% 95%
100%
Cytogenetic Clones
75%
80%
% of Abnormal
Reduction (%)
SF3B1 VAF
VAF (%)
60%
45%
40%
25%
20%
5% 5% 5%
0%
Baseline ~24 wks ~48 wks ~72 wks
Longest Transfusion- 47,XX,+8 47,XY,+8 46,XX,Dup/Tri/Qtp(9)(P13P24)
Free Interval (Weeks)
Greater SF3B1 variant allele frequency Patients with abnormal cytogenetics at
Reduction of SF3B1 mutation burden in LR reduction (VAF) correlates baseline have reduction of their clones and
MDS patients treated with imetelstat with longer duration of TI long (>1year) TI; 2 of 3 patients achieved
partial cytogenetic response
References on slide 52
VAF = variant allele frequency; TI = transfusion independence 55Strong Evidence of Disease Modification Potential
ClincialTrials.gov
(NCT02426086)
Improved bone marrow fibrosis correlated to improved survival in IMbark Phase 2
Significant Dose-Dependent Fibrosis Longer Median OS and Higher Survival Rate
Improvement with Imetelstat Treatment in Patients with Improved Fibrosis
1.0
% Achieved BM Fibrosis
0.9 CENSORED
Yes
Improvement
0.8 No
Survival Probability
0.7
0.6
0.5
41% 0.4
BM Fibrosis Median OS HR
Improvement (months) (95% CI) (95% CI)
0.3
31.6
YES
20% 0.2 (23.6, NE) 0.54
24.6 (0.23, 1.29)
NO
0.1 (18.4, NE)
0.0
4.7 mg/kg 9.4 mg/kg 0 6 12 18 24 30 36
Time on Study (months)
References on slide 52
OS = overall survival; BM = bone marrow; HR = hazard ratio; CI = confidence interval; NE = not evaluable 56Strong Evidence of Disease Modification Potential
ClincialTrials.gov
(NCT02426086)
Reduction in key MF driver mutations correlated to improved survival in IMbark Phase 2
Significant Dose-Dependent ≥20% VAF Longer Median OS and Higher Survival Rate in Patients
Reduction with Imetelstat Treatment Who Achieved ≥ 20% VAF Reduction
p=0.0321
≥20% VAF Median OS HR
Reduction (months) (95% CI) (95% CI)
31.6
YES
(21.5, –) 0.512
% Achieved >=20%
Reduction of VAF
22.8 (0.238, 1.100)
NO
(17.1, 31.6)
Survival Probability
46%
17%
4.7 mg/kg 9.4 mg/kg
Time on Study (months)
References on slide 52
VAF = variant allele frequency; OS = overall survival; HR = hazard ratio; CI = confidence interval 57Strong Evidence of Disease Modification Potential
ClincialTrials.gov
(NCT02426086)
Malignant clones reduced in imetelstat-treated patients in IMbark Phase 2
Dose-Dependent Complete Elimination of Mutation Burden from Multiple Driver- and Non-Driver Genes
9.4
9.4 mg/kg
mg/kg 4.7
4.7 mg/kg
mg/kg Completely eliminated
JAK2 >=20% reduction
CALR >=10% reduction
MPL
No change
ASXL1
Acquired new clone
EZH2
>=20% increase
IDH2
SRSF2 >=10% increase
SF3B1
U2AF1 • Mutation status and variant
DNMT3A allele frequency (VAF) were
TET2 evaluated by next-
CBL generation sequencing
KRAS (NGS) using Illumina
TruSight Myeloid
NRAS
Sequencing Panel of
TP53 54-genes
GATA2
BCORL1 • Lower limit detection is 5%
ETV6 and 2% for well documented
KIT hotspots
PHF6 • 49 pts had matched pre- and
RUNX1 at least a post-imetelstat
STAG2 treatment NGS data
References on slide 52 58Appendix 2
Pipeline expansion programs
59Phase 1 IMproveMF Study Evaluating
Combination Therapy in Frontline MF
Exploring the potential for disease modification with Imetelstat earlier in MF disease setting
Study Started Preclinical data for ruxolitinib followed by imetelstat:
• Additive inhibitory effect on MF stem cells in vivo
May 2022 • Synergistically depletes stem cells from MF patients (PDX model)
Rationale
Part 1: Dose Finding Part 2: Dose Confirmation & Expansion
(n = up to 20) (n = ~ 20)
Ruxolitinib Imetelstat Ruxolitinib
Frontline MF + Phase 2 Dose +
DIPSS int1/int2/HR Imetelstat Imetelstat
Selected
single arm open label single arm open label
• Objective: Identify recommended • Objective: Confirm safety of doses
Phase 2 doses and evaluate efficacy
• Primary Wk 24 Endpoint: Safety • Primary Wk 24 Endpoints: Safety, TSS
• Other Wk 24 Endpoints: TSS, SVR35, Fibrosis • Other Wk 24 Endpoints: TSS, SVR35, Fibrosis
References on slide 52
RP2D = Recommended Phase 2 Dose; DIPSS = dynamic international prognostic scoring system; int1 = intermediate-1; int2 = intermediate-2; HR = high risk; TSS =
total symptom score; SVR35 = spleen volume reduction > 35%; TI = transfusion independence; IWG-MRT = international working group-myeloproliferative
neoplasms research and treatment 60IMpress – Planned Phase 2 Investigator-Led Study of Single
Agent Imetelstat in Post-HMA Relapsed/Refractory AML
Lead PrincipaI Investigator: Dr. Uwe Platzbecker, University Hospital, Leipzig, Germany
In preclinical models, imetelstat: Planned First Site
• Prevented expansion of human AML leukemic stem cells (PDX model) Opening:
• Prolonged survival of AML PDX mice 2023
Rationale
Open-label, Single-arm Multicenter
(n = ~ 45)
Objective: Evaluate efficacy
R/R/Intolerant
Imetelstat
HR MDS and AML Endpoint: Overall Response Rate per
7.5mg/kg I.V. IWG 2018 criteria (MDS) and the criteria
Post HMA
of the European LeukemiaNet (AML)
References on slide 52
PDX = patient-derived xenografts; R/R = relapsed or refractory; HR MDS = intermediate-2 or high risk MDS per International Prognostic Scoring System; AML = acute
myeloid leukemia; HMA = hypomethylating agent; IWG 2018 = international working group 2018 criteria for hematologic response 61The Tisch
TELOMERE – Pending Phase 1/2 Investigator-Led Study of Imetelstat in Cancer
Institute
Combination with Venetoclax or Azacitidine in Relapsed/Refractory AML
Lead Principal Investigator: Dr. John Mascarenhas, Mt. Sinai Hospital, New York, New York
In preclinical models, imetelstat + venetoclax (Ven):
• Synergistically induced apoptosis in primary AML blasts ex vivo Study Start Expected:
• Enhanced survival with potential cure in AML xenograft model Pending
In preclinical models, imetelstat + azacitidine (Aza): IMpress Data
Rationale • Synergistically induced apoptosis in AML cell lines
Phase 1 Dose Finding (n = up to 20) Phase 2 SIMON 2 Stage Design (n = ~ 50)
STAGE 1 STAGE 2
STABLE DISEASE
Imetelstat + Aza PD Imetelstat + Aza Imetelstat + Aza
Sufficient number of
R/R AML responders needed in
each arm otherwise,
Post Aza and/or Ven the arm is discontinued
Imetelstat + Ven PD Imetelstat + Ven Imetelstat + Ven
STABLE DISEASE
• Objective: Identify recommended Phase 2 dose for each combination • Objective: Evaluate efficacy for each combination
• Endpoint: Safety for each combination • Endpoints: Overall Response Rate for each combination
References on slide 52
R/R = relapsed or refractory; AML = acute myeloid leukemia; PD = progressive disease 62Ongoing and Planned Preclinical Experiments to
Define the Role of Imetelstat in Lymphoid Malignancies
Lead Principal Investigator: Dr. Swaminathan Iyer, MD Anderson Cancer Center, Houston, Texas
T-Cell lymphoma cell lines in vitro have shown:
• Short telomere length (Sezary syndrome; transformed
mycosis fungoides)
• High telomerase activity (cut. anaplastic large-cell
Further experiments of
lymphoma; mycosis fungoides) imetelstat in lymphoid
malignancies expected
In Cutaneous T-Cell lymphoma cell lines in vitro:
Rationale
• Telomerase overexpression increased T-Cell proliferation
• RNAi inhibition of telomerase decreased T-Cell proliferation
In vitro assays in cell lines and patient-derived materials In vivo mouse studies
Studies Being (blood, etc.) from T and B-cell lymphomas in T and B-cell
Conducted at MD • Apoptosis (cell death) assays lymphoma models
• Colony forming cell (CFCs) assays
Anderson Cancer • Cytokine assays
Center • TA, TL, hTERT assays
References on slide 52
TA = telomerase activity; TL = telomere length; hTERT = human telomerase reverse transcriptase
63Next Generation Telomerase
Inhibitor Program Update
Status
• Expect completion of
Program goal current discovery effort
in 2023, at which time
Discover and develop novel small molecules based on chemistry Geron plans to
potentially advance
platforms proprietary to Geron that bind to the active site of the any lead compounds
into the next step of
telomerase molecule and directly inhibit telomerase activity discovery research.
• If successful, these
efforts would permit
initiation
Aspirational profile of IND-enabling
nonclinical studies.
of a lead compound
candidate Oral High potency High potential for
delivery & selectivity combinability
64You can also read
