- New analyses from IMerge Phase 3 reported higher 24-week
transfusion independence (TI) responses for imetelstat-treated
patients vs. placebo across key myelodysplastic syndromes (MDS)
subgroups and across spectrum of MDS mutations
- New data and analyses indicated greater variant allele
frequency (VAF) reductions for imetelstat-treated patients vs.
placebo across multiple genes commonly mutated in MDS; these
reductions also were correlated with clinical endpoints of TI
response, longer TI duration and increase in hemoglobin levels,
providing further evidence of disease-modifying activity of
imetelstat
- First data on patient-reported outcomes (PRO) described a
sustained meaningful improvement in fatigue for imetelstat-treated
patients vs. placebo
- Data support NDA submission, which is on track for June 2023 to
support potential U.S. commercial launch in first half of 2024
Geron Corporation (Nasdaq: GERN), a late-stage clinical
biopharmaceutical company, today announced new data and analyses
from IMerge Phase 3 reporting robust durability of transfusion
independence (TI), evidence for disease-modifying activity and
favorable fatigue patient-reported outcomes (PRO) in lower risk
myelodysplastic syndromes (MDS) patients treated with the Company’s
first-in-class telomerase inhibitor, imetelstat, vs. placebo. The
data and analyses were presented at the European Hematology
Association (EHA) Annual Meeting, which took place from June 8-11,
2023 in Frankfurt, Germany and virtually.
“The new IMerge Phase 3 data and analyses presented at EHA
continue to support the unprecedented and differentiating
attributes of imetelstat, including 24-week transfusion
independence across key MDS subgroups, potential disease-modifying
activity, as well as favorable patient-reported outcomes (PRO) data
on meaningful improvement in fatigue,” said Faye Feller, M.D.,
Executive Vice President, Chief Medical Officer of Geron. “Each of
these qualities address important unmet needs for lower risk MDS
patients due to the limitation of current treatment options.
Submission of our New Drug Application later this month is a
significant step to hopefully bring imetelstat to these transfusion
burdened patients.”
Presentation Title: Continuous Transfusion Independence with
Imetelstat in Heavily Transfused Non-Del(5q) Lower Risk
Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis
Stimulating Agents in IMerge Phase 3
Top-line results from the primary analysis of IMerge Phase 3
presented earlier this month at the 2023 American Society of
Hematology (ASCO) Annual Meeting were also covered in the EHA
presentation, including the primary endpoint of 8-week transfusion
independence (TI) and key secondary endpoint of 24-week TI were met
with high statistical significance (P<0.001) for
imetelstat-treated patients vs. placebo. Further, mean hemoglobin
levels in imetelstat-treated patients increased significantly
(P<0.001) over time compared to placebo patients.
In addition to these results, the EHA presentation also provided
new data and analyses highlighting clinically meaningful and
durable TI for imetelstat-treated patients vs. placebo. As of a
January 2023 data cut-off, 17.8% (21/118) of imetelstat-treated
patients vs. 1.7% (1/60) of placebo-treated patients achieved
1-year TI (P=0.002), representing 63.6% of 24-week TI imetelstat
responders.
Two new analyses presented at EHA on TI responses by subgroups
underscored the breadth of potential effect of imetelstat vs.
placebo. The first analysis reported higher durability of TI for
imetelstat-treated patients vs. placebo across key MDS
subgroups:
Durability of RBC-TI for 8-Week TI
Responders Across Key LR MDS Subgroups
Imetelstat median, weeks (95%
CI)
Placebo median, weeks (95%
CI)
Hazard ratio (95%
CI)
P-value
Overall
51.6 (26.9–83.9)
13.3 (8.0–24.9)
0.23 (0.09–0.57)
<0.001
WHO category
RS+
46.9 (25.9–83.9)
16.9 (8.0–24.9)
0.32 (0.11–0.95)
0.035
RS-
51.6 (11.9–NE)
11.2 (10.1–NE)
0.11 (0.01–1.43)
0.062
Prior RBC transfusion burden per IWG
2006
4–6 units/8 weeks
51.9 (24.9–122.9)
16.9 (10.1–24.9)
0.35 (0.13–0.96)
0.035
6 units/8 weeks
39.9 (15.9–NE)
8.4 (8.0–NE)
0.04 (0.003–0.48)
<0.001
IPSS risk category
Low
43.9 (25.0–NE)
15.1 (8.0–24.9)
0.26 (0.10–0.68)
0.004
Intermediate-1
51.6 (11.9–NE)
10.1 (NE–NE)
0.15 (0.01–2.47)
0.128
Baseline sEPO
≤500 mU/mL
51.6 (26.9–83.9)
13.3 (8.0–24.9)
0.21 (0.075–0.61)
0.002
>500 mU/mL
122.9 (8.14–NE)
14.6 (12.3–NE)
0.34 (0.03–3.85)
0.364
Prior ESA use
Yes
43.9 (26.9–80.0)
13.3 (8.0–24.9)
0.26 (0.10–0.72)
0.006
No
122.9 (8.14–NE)
14.6 (12.3–NE)
0.34 (0.03–3.85)
0.364
____________________ Data cut-off: October
13, 2022.
Hazard ratio (95% CI) from the Cox proportional hazard model,
stratified by prior RBC transfusion burden (≥4 to ≤6 vs >6 RBC
units/8 weeks during a 16-week period prior to randomization) and
baseline IPSS risk category (low vs intermediate-1), with treatment
as the only covariate. P-value (2-sided) for superiority of
imetelstat vs placebo in hazard ratio based on stratified log-rank
test.
ESA, erythropoiesis-stimulating agent;
IPSS, International Prognostic Scoring System; IWG, International
Working Group; LR-MDS, lower-risk myelodysplastic syndromes; NE,
not estimable; RBC, red blood cell; RS, ring sideroblast; sEPO,
serum erythropoietin; TI, transfusion independence.
The second analysis reported higher 24-week TI for
imetelstat-treated patients vs. placebo across key MDS
subgroups:
Comparable 24-Week RBC-TI Rate Across Key
LR MDS Subgroups
Imetelstat n/N (%)
Placebo, n/N (%)
% Difference
(95% CI)
P-value
Overall
33/118 (28.0)
2/60 (3.3)
24.6 (12.64–34.18)
<0.001
WHO category
RS+
24/73 (32.9)
2/37 (5.4)
20.5 (−0.03–35.75)
0.003
RS-
9/44 (20.5)
0/23 (0.0)
0.11 (0.01–1.43)
0.019
Prior RBC transfusion burden per IWG
2006
4–6 units/8 weeks
19/62 (30.6)
2/33 (6.1)
24.6 (5.68–38.66)
0.006
6 units/8 weeks
39.9 (15.9–NE)
8.4 (8.0–NE)
0.04 (0.003–0.48)
<0.001
IPSS risk category
Low
23/80 (28.8)
2/39 (5.1)
23.6 (7.23–35.75)
0.003
Intermediate-1
10/38 (26.3)
0/21 (0)
26.3 (3.46–43.39)
0.009
Baseline sEPO
≤500 mU/mL
29/87 (33.3)
2/36 (5.6)
27.8 (10.46–39.71)
0.002
>500 mU/mL
4/26 (15.4)
0/22 (0)
15.4 (−5.81–35.73)
0.050
Prior ESA use
Yes
31/108 (28.7)
2/52 (3.8)
24.9 (11.61–35.00)
<0.001
No
2/10 (20)
0/8
20.0 (-23.47–55.78)
0.225
_____________ Data cut-off: October 13,
2022.
95% CI based on Wilson Score method.
P-value determined by the Cochran-Mantel-Haenszel test, with
stratification for prior RBC transfusion burden (≥4 to ≤6 vs >6
RBC units/8 weeks during a 16-week period prior to randomization)
and baseline IPSS risk category (low vs intermediate-1) applied to
randomization.
ESA, erythropoiesis-stimulating agent;
IPSS, International Prognostic Scoring System; IWG, International
Working Group; LR-MDS, lower-risk myelodysplastic syndromes; RBC,
red blood cell; RS, ring sideroblast; sEPO, serum erythropoietin;
TI, transfusion independence.
Additionally, the rate of 24-week TI was higher with imetelstat
vs. placebo regardless of baseline mutation status, telomerase
activity (TA), telomerase length (TL), and human telomerase reverse
transcriptase (hTERT).
“For the first time at EHA, we see comparable 24-week TI across
key MDS subgroups, which is especially meaningful for patients
without ring sideroblasts (RS-) and very heavily transfusion
burdened patients, who particularly have limited options today,”
said Uwe Platzbecker, M.D., Department of Hematology, Cellular
Therapy and Hemostaseology, Leipzig University Hospital, Leipzig,
Germany, who presented the data at EHA and is an IMerge
investigator. “In addition to the durability of TI,
imetelstat-treated patients also achieved significant increases in
hemoglobin and reductions of transfusion units that could be life
changing for lower risk MDS patients, who often present with
symptomatic anemia and transfusion dependence.”
As previously reported, the safety profile observed with
imetelstat in IMerge Phase 3 was consistent with prior clinical
experience with no new safety signals. The EHA presentation
provided new data on the consequences of the grade 3-4
thrombocytopenia and neutropenia which were most often reported
during Cycles 1-3 and led to dose modifications. While
approximately 50% of patients treated with imetelstat had dose
reductions due to treatment emergent adverse events (TEAE), less
than 15% of patients discontinued treatment due to TEAE.
Discontinuation of imetelstat treatment in these patients due to a
TEAE generally occurred late in treatment, with a median time to
treatment discontinuation of 21.1 weeks (range 2.3 to 44.0
weeks).
Presentation Title: Disease-Modifying Activity of Imetelstat
in Patients with Heavily Transfused Non-Del(5q) Lower Risk
Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis
Stimulating Agents in IMerge Phase 3
“In IMerge Phase 3, not only did we observe efficacy with
imetelstat across the spectrum of genetic mutations associated with
lower risk MDS, but we also saw a reduction in mutation burden, as
measured by variant allele frequency (VAF). Furthermore, greater
reduction of VAF in multiple genes correlated with the clinical
endpoints of TI response, longer TI duration and increase in
hemoglobin levels, suggesting the potential of imetelstat to modify
the disease. This is the first therapy we know of that may alter
the underlying biology of lower risk MDS by potentially reducing or
eliminating malignant clones and improving ineffective
erythropoiesis,” said Valeria Santini, M.D., MDS Unit, Azienda
Ospedaliero Universitaria Careggi, University of Florence,
Florence, Italy, who presented the data at EHA and is an IMerge
investigator.
In the EHA presentation, new data on cytogenetic responses and
reductions in bone marrow RS supported the telomerase inhibition
mechanism of action (MOA) of imetelstat. Among patients with
cytogenetic abnormalities at baseline, the cytogenetic response
rate was 35% (9/26) in imetelstat-treated patients and 15% (2/13)
in the placebo group. Among cytogenetic responders, 89% (8/9) of
patients in the imetelstat group and 50% (1/2) in the placebo group
also achieved 8-week TI. A higher percentage of patients treated
with imetelstat (40.8%) vs. placebo (9.7%) had a ≥50% reduction in
central bone marrow RS. TI responses were enriched in patients
achieving a ≥50% reduction in central bone marrow RS.
Furthermore, the EHA presentation provided updated data on VAF
reductions and new analyses on the correlation of such reductions
with clinical responses which further support the potential
disease-modifying activity of imetelstat. Reductions in variant
allele frequency (VAF) of genes frequently mutated in MDS were
greater for imetelstat-treated patients than placebo: SF3B1 (P<
0.001), TET2 (P= 0.032), DNMT3A (P= 0.019) and ASXL1 (P= 0.146).
More patients treated with imetelstat vs. placebo had ≥50% VAF
reduction in these mutations.
For patients with the SF3B1 mutation, 29.5% (23/78) of those
treated with imetelstat vs. 2.6% (1/38) on placebo (P=0.001) had a
≥50% VAF reduction. Imetelstat treatment resulted in sustained
reduction of SF3B1 VAF over time. In the imetelstat group, 83%
(19/23) of patients had 8-week TI among patients who achieved ≥50%
maximum reduction from baseline in SF3B1 VAF vs. 38% (21/55) of
those who did not.
Similarly, TI responders were also enriched in
imetelstat-treated patients achieving ≥50% reduction in TET2 VAF.
In the imetelstat group, 83% (10/12) of patients had 8-week RBC-TI
among patients who achieved ≥50% maximum reduction from baseline in
TET2 VAF vs 43% (10/23) of those who did not.
In imetelstat-treated patients, 24-week and 1-year TI responders
were enriched in patients achieving ≥50% reduction in SF3B1 and
TET2 VAF. VAF reduction in SF3B1, TET2 and DNMT3A correlated with
longer TI duration and increases in hemoglobin levels in
imetelstat-treated patients. Further, 8-week and 24-week TI
correlated with reduction in RS+ cells, cytogenetic responses and
VAF reduction. These correlations suggest the disease-modifying
activity of imetelstat.
Presentation Title: Analysis of Patient-Reported Fatigue in
IMerge Phase 3 Trial of Imetelstat vs. Placebo in Heavily
Transfused Non-Del(5q) Lower Risk Myelodysplastic Syndromes
Relapsed/Refractory to Erythropoiesis Stimulating Agents
(ESA)
“The patient-reported outcome data from IMerge Phase 3 is
particularly important as fatigue is a concern for lower risk MDS
patients, most of whom are elderly. Furthermore, many of the
current treatments for these patients cause fatigue. It is
therefore very welcome news that imetelstat-treated patients showed
sustained meaningful improvement in patient-reported fatigue vs.
placebo. This is the first Phase 3 trial we know of to show an
improvement in fatigue in lower risk MDS patients,” stated Dr.
Platzbecker.
The EHA presentation described results from an exploratory
analysis from IMerge Phase 3 of patient-reported fatigue conducted
using Functional Assessment of Chronic Illness Therapy, or FACIT, a
validated 13-item patient questionnaire. The analysis reported
imetelstat-treated patients were more likely to have sustained
meaningful improvement in fatigue, as well as experience such
improvement more quickly.
Patients treated with imetelstat reported a lower rate of
sustained meaningful deterioration in fatigue than placebo (43.2%
vs 45.6%), while also receiving fewer transfusion units over time.
For patients treated with imetelstat, there was a numerically
higher percentage of patients reporting any episode of sustained
meaningful improvement in fatigue. Further, patients receiving
imetelstat experienced a shorter median time to first sustained
clinically meaningful improvement in fatigue vs placebo (28.3 vs
65.0 weeks).
For patients treated with imetelstat, there were significant
associations between sustained meaningful improvement in fatigue
and 8- and 24-week TI and HI-E response rates, an association not
seen in the placebo group.
Additional analysis showed that patients experiencing grade 3 or
4 neutropenia or thrombocytopenia had the same rates of sustained
meaningful improvement in fatigue (52.5% and 53.4%, respectively)
as the total imetelstat population (50%).
Additional Presentations at EHA
In addition to these IMerge Phase 3 presentations, Geron
collaborators presented a translational analysis from a subset of
IMerge Phase 2 patients, as well as imetelstat myelofibrosis (MF)
pre-clinical results.
The presentation slides and posters are available on the
Publications section of Geron’s website:
https://www.geron.com/research-and-development/publications/.
About IMerge Phase 3
The Phase 3 portion of the IMerge Phase 2/3 study is a
double-blind, 2:1 randomized, placebo-controlled clinical trial to
evaluate imetelstat in patients with IPSS Low or Intermediate-1
risk (lower risk) transfusion dependent MDS who were relapsed
after, refractory to, or ineligible for, erythropoiesis stimulating
agent (ESA) treatment, had not received prior treatment with either
a HMA or lenalidomide and were non-del(5q). To be eligible for
IMerge Phase 3, patients were required to be transfusion dependent,
defined as requiring at least four units of packed red blood cells
(RBCs), over an eight-week period during the 16 weeks prior to
entry into the trial. The primary efficacy endpoint of IMerge Phase
3 is the rate of red blood cell transfusion independence (RBC-TI)
lasting at least eight weeks, defined as the proportion of patients
without any RBC transfusion for at least eight consecutive weeks
since entry to the trial (8-week TI). Key secondary endpoints
include the rate of RBC-TI lasting at least 24 weeks (24-week TI),
the duration of TI and the rate of hematologic improvement
erythroid (HI-E), which is defined under 2006 IWG criteria as a
rise in hemoglobin of at least 1.5 g/dL above the pretreatment
level for at least eight weeks or a reduction of at least four
units of RBC transfusions over eight weeks compared with the prior
RBC transfusion burden. A total of 178 patients were enrolled in
IMerge Phase 3 across North America, Europe, Middle East and
Asia.
About Imetelstat
Imetelstat is a novel, first-in-class telomerase inhibitor
exclusively owned by Geron and being developed in hematologic
malignancies. Data from non-clinical studies and clinical trials of
imetelstat provide strong evidence that imetelstat targets
telomerase to inhibit the uncontrolled proliferation of malignant
stem and progenitor cells in myeloid hematologic malignancies
resulting in malignant cell apoptosis and potential
disease-modifying activity. Imetelstat has been granted Fast Track
designation by the U.S. Food and Drug Administration for both the
treatment of adult patients with transfusion dependent anemia due
to Low or Intermediate-1 risk MDS that is not associated with
del(5q) who are refractory or resistant to an erythropoiesis
stimulating agent, and for adult patients with Intermediate-2 or
High-risk MF whose disease has relapsed after or is refractory to
janus associated kinase (JAK) inhibitor treatment. Geron plans to
submit a New Drug Application (NDA) in the U.S. in June 2023 and a
Marketing Authorization Application (MAA) in the EU in the second
half of 2023 in the lower risk MDS indication.
About Geron
Geron is a late-stage biopharmaceutical company pursuing
therapies with the potential to extend and enrich the lives of
patients living with hematologic malignancies. Our first-in-class
telomerase inhibitor, imetelstat, harnesses Nobel Prize-winning
science in a treatment that may alter the underlying drivers of
disease. Geron currently has two Phase 3 pivotal clinical trials
underway evaluating imetelstat in lower risk myelodysplastic
syndromes (LR MDS), and in relapsed/refractory myelofibrosis (MF).
To learn more, visit www.geron.com or follow us on LinkedIn.
Use of Forward-Looking Statements
Except for the historical information contained herein, this
press release 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 for IMerge
Phase 3, Geron plans to submit a New Drug Application in the U.S.
in June 2023 and a Marketing Authorization Application in the EU in
the second half of 2023; (ii) a potential U.S. commercial launch of
imetelstat for lower risk MDS in the first half of 2024; (iii) that
imetelstat may alter the underlying biology of lower risk MDS and
has the potential to demonstrate disease-modifying activity in
patients; and (iv) 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) whether the
current or evolving effects of the COVID-19 pandemic and/or
geopolitical events and resulting global economic and financial
disruptions will materially and adversely impact 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, planned milestones and expenses; (c) whether regulatory
authorities permit the further development of imetelstat on a
timely basis, or at all, without any clinical holds; (d) whether
imetelstat has demonstrated sufficient safety, efficacy and
clinical benefit in IMerge Phase 3 to enable regulatory approval;
(e) whether any future safety or efficacy results cause the
benefit-risk profile of imetelstat to become unacceptable; (f)
whether imetelstat actually demonstrates that it alters the
underlying biology of lower risk MDS and has disease-modifying
activity in patients;; (g) that Geron may seek to raise substantial
additional capital in order to complete the development and
commercialization of imetelstat to meet the expected timelines,
planned milestones and expenses; (h) whether there are failures or
delays in manufacturing or supplying sufficient quantities of
imetelstat or other clinical trial materials that impact a
commercial launch in lower risk MDS; (i) whether the follow-up
period of 12 months for the IMerge Phase 3 primary analysis was
sufficient to demonstrate safety and efficacy, including
transfusion independence and clinical benefit, and obtain
regulatory approval; and (j) for IMerge Phase 3, the FDA may
require Geron to submit additional information or require advisory
committee procedures that could cause a regulatory approval, if
any, to be delayed. 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 in Geron’s filings and
periodic reports filed with the Securities and Exchange Commission
under the heading “Risk Factors” and elsewhere in such filings and
reports, including Geron’s quarterly report on Form 10-Q for the
quarter ended March 31, 2023 and future filings and reports by
Geron. 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20230612406549/en/
Aron Feingold Investor and Media Relations investor@geron.com
media@geron.com
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