- Longer follow-up data for 1-year transfusion independence (TI) in IMerge Phase 3, which demonstrated statistically significant and clinically meaningful continuous, durable efficacy
- Strong correlation of reduction in MDS-associated mutations with clinical benefits, including TI duration, provides compelling evidence for the potential of disease modification
- Based on PRO data, imetelstat-treated patients were more likely to have sustained meaningful improvement in fatigue, as well as experience such improvement more quickly
- Data support NDA submission which is on track for June 2023 to support potential U.S. commercial launch in first half of 2024
- Virtual Geron-hosted investor event featuring KOL and Company participants planned for June 14 from 8:00-9:30am Eastern Time
Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, today announced that five abstracts related to imetelstat, a first-in-class telomerase inhibitor, have been accepted at the European Hematology Association (EHA) Annual Meeting taking place from June 8-11, 2023 in Frankfurt, Germany and virtually. The three EHA abstracts on IMerge Phase 3 data expand upon and further confirm the differentiating qualities of imetelstat that can address current unmet needs for lower risk MDS patients compared to available treatments. In addition, abstracts submitted by Geron collaborators covering a translational analysis from a subset of IMerge Phase 2 patients and imetelstat MF pre-clinical data were accepted for oral and poster presentation, respectively.
“The longer follow-up data for one-year TI and additional analyses from IMerge Phase 3 in lower risk MDS we are presenting at EHA further confirm the unprecedented durability of imetelstat, as well as provide deeper insight into the clinically meaningful benefit/risk profile of imetelstat in these patients,” said Faye Feller, M.D., Executive Vice President, Chief Medical Officer of Geron. “The strong correlation of reduction in MDS-associated mutations with clinical benefits observed in these patients provides strong evidence for the potential of disease modification with imetelstat. Further, patient reported outcomes presenting sustained meaningful improvement in fatigue is particularly important as fatigue is a specific concern for lower risk MDS patients, and because improvement in fatigue has not been seen with currently available treatments. Overall, as these analyses are completed and as the data continue to mature, a highly compelling and differentiated profile supporting strong clinical benefit is being reinforced for imetelstat in lower risk MDS.”
IMerge Phase 3 Clinical Data – Lower Risk Myelodysplastic Syndromes (MDS)
Abstract #S165: “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”
Oral Presentation on June 9 in session s417 “MPN and MDS: Targeting red cells and platelets” (14:45-16:00 CEST)
Presenter: Uwe Platzbecker, MD, University Hospital of Leipzig
The abstract reports top-line results from IMerge Phase 3 with a data cut-off of October 2022 for the primary analysis and January 2023 for ≥1-yr transfusion independence (TI). As reported in January 2023, imetelstat demonstrated statistically significant and clinically meaningful efficacy with robust 8-week TI, 24-week TI, and 1-year TI rates.
With 3 months additional follow-up, 17.8% (21/178) of imetelstat-treated patients versus 1.7% (1/60) of placebo-treated patients achieved 1-year TI (P = 0.002), representing 63.6% of 24-week TI imetelstat responders. The continuous TI for more than one year represents substantial relief from transfusion-associated complications for this lower risk MDS patient population.
As reported in January, 39.8% (47/118) of imetelstat-treated patients versus 15.0% (9/60) of placebo-treated patients achieved the study primary endpoint of 8-week TI (P < 0.001). In addition, the rate of 8-week TI was also significantly higher for imetelstat-treated patients versus placebo-treated patients across MDS subtypes, including in RS negative and RS positive patients. Median TI duration using Kaplan Meier estimates (95% CI) was 51.6 (26.9–83.9) weeks for imetelstat-treated patients versus 13.3 (8.0–24.9) weeks for placebo-treated patients (P < 0.001). Key secondary endpoint of 24-week TI was achieved in 28.0% (33/118) of imetelstat-treated patients versus 3.3% (2/60) of placebo-treated patients (P < 0.001).
New data on variant allele frequency (VAF) reductions were also reported in the abstract. For four genes frequently mutated in MDS, the VAF reductions were greater in patients treated with imetelstat than placebo: SF3B1 (P < 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). Furthermore, SF3B1 VAF reduction correlated with longer TI duration in imetelstat-treated patients (P < 0.001). These reductions and correlations, together with the durable and continuous TI observed in the trial, support imetelstat’s disease-modifying potential.
The most common Grade 3/4 adverse events with imetelstat were thrombocytopenia and neutropenia with similar rates of Grade ≥3 bleeding and infections observed on imetelstat and placebo. These cytopenias were of short duration, and >80% resolved to Grade ≤2 within 4 weeks. The abstract also noted no new safety signals were identified in the trial.
Abstract #S164: “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”
Oral Presentation on June 11th in session “s448 MDS biology and translational updates” (11:30 - 12:45 CEST)
Presenter: Valeria Santini, MD, University of Florence School of Medicine
As noted in the abstract, a main therapeutic goal in lower risk MDS is to alter disease biology by eradicating malignant clones. MDS-initiating cells carrying cytogenetic abnormalities, mutant alleles, or both and arise from malignant stem and progenitor cells. SF3B1, involved in RNA splicing, and TET2, involved in DNA methylation, are recurrently mutated genes in lower risk MDS., Measuring change in VAF of these genes is used to denote disease burden.
Of the 178 patients enrolled in IMerge Phase 3, 22.0% of imetelstat-treated patients and 21.7% of placebo-treated patients had baseline cytogenetic abnormalities. Cytogenetic response was observed in 34.6% (9/26) of imetelstat treated patients (95% CI=17.2–55.7) versus 15.4% (2/13) of placebo-treated patients (95% CI=1.9–45.5). In addition, imetelstat-treated patients demonstrated a higher rate of ≥50% VAF decreases in SF3B1, TET2, DNMT3A, and ASXL1 mutations as compared with placebo.
Imetelstat-treated patients achieving 8-week TI, 24-week TI, and 1-year TI had higher VAF reductions in SF3B1 and TET2 mutations compared with placebo-treated patients.
Additionally, both 8-week TI and 24-week TI responders on imetelstat had significantly greater VAF reductions in SF3B1 mutation versus non-responders (P<0.001, for both) on imetelstat. Importantly, greater VAF reductions in SF3B1 mutation for imetelstat-treated patients correlated significantly with hemoglobin increase; r=−0.626 (P<0.001), and longer TI duration; r=−0.549 (P<0.001). The abstract concludes that these data, taken together with robust rates of TI that are continuous and durable in the trial, may indicate improvement of the ineffective erythropoiesis characteristic of lower risk MDS with imetelstat and suggest imetelstat may alter the underlying biology of disease in these patients.
Abstract #P732: “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)”
Poster on June 9 at 18:00 - 19:00 CEST
Presenter: Mikkael Sekeres, MD, University of Miami Health System and Sylvester Comprehensive Cancer Center
The abstract noted that patients with lower risk MDS and anemia experience severe fatigue that negatively impacts overall functioning and daily life. The goals for lower risk MDS treatments are to minimize transfusions and improve patient-reported outcomes (PRO). However, fatigue can also be commonly reported with currently available treatments.
In the trial, an exploratory analysis of patient-reported fatigue was conducted using Functional Assessment of Chronic Illness Therapy, or FACIT, a validated 13-item patient questionnaire, to measure the rate of deterioration or improvement of fatigue during treatment with imetelstat or placebo. Proportion of sustained meaningful deterioration/improvement was defined as percentage of patients with ≥3-point decrease/increase on the FACIT Fatigue Scale (0–52) for ≥2 consecutive treatment cycles. Time-to-deterioration/improvement was estimated by Kaplan-Meier analysis.
118 patients on imetelstat and 57 patients on placebo were assessed for PRO. Overall, 50.0% of imetelstat-treated patients reported sustained meaningful improvement in fatigue versus 40.4% of placebo-treated patients. In addition, imetelstat-treated patients reported a shorter median time to first sustained meaningful improvement in fatigue versus placebo-treated patients; 28.3 vs 65.0 weeks, respectively, hazard ratio=1.34 (95% CI, 0.82–2.20).
After 12 weeks, more imetelstat-treated patients reported improvement in the FACIT Fatigue Scale than placebo-treated patients. In addition, in imetelstat-treated patients, a significantly higher proportion of TI responders had sustained meaningful improvement in fatigue scores versus non-responders. This was consistent across 8-week TI and 24-week TI and hematologic improvement-erythroid (HI-E) response per 2006 International Working Group criteria, for imetelstat-treated patients, which was not an association observed in placebo-treated patients.
With both imetelstat- and placebo-treated patients reporting similar rates of deterioration in fatigue, these data suggest that imetelstat did not worsen the rate of deterioration, which has been reported with other available treatments. Importantly, imetelstat-treated patients were more likely to have sustained meaningful improvement in fatigue, as well as experience such improvement more quickly. The abstract concludes that a significant association between TI and HI-E responses and sustained meaningful improvement in fatigue support the clinical benefit of imetelstat treatment.
Translational Analysis from IMerge Phase 2 – Lower Risk MDS
Abstract #S169: “Modulation of the immune landscape in lower-risk myelodysplastic syndromes with imetelstat-induced transfusion independency”
Oral Presentation on June 9 in session “s417 MPN and MDS: Targeting red cells and platelets” (14:45-16:00 CEST)
Presenter: Nicolas Chapuis, Assistance Publique-Hopitaux de Paris, Centre-Universite Paris Cite
As noted in an abstract by Geron collaborators, this analysis aimed to identify biological pathways associated with the clinical response, by analyzing bone marrow mononuclear cell transcriptome and peripheral blood immune cell landscape of a subset of patients with lower risk MDS enrolled in the IMerge Phase 2 clinical trial. The abstract concludes that low inflammatory features at baseline and induction of an adaptive immune profile by imetelstat are associated with the TI response, suggesting that immune cell remodeling could contribute to hematopoietic activity of imetelstat treatment.
Imetelstat Pre-Clinical Data in Myelofibrosis (MF)
Abstract # P1008: “The telomerase inhibitor imetelstat differentially targets JAK2V617F- versus CALR-mutant Myeloproliferative Neoplasm cells and inhibits JAK-STAT signaling”
Poster on Friday, June 9 at 18:00-19:00 CEST
Presenter: Nicolas Chatain, PhD, University Hospital Aachen
An abstract by Geron collaborators reports on a single patient study which analyzed clonal evolution of the myeloproliferative neoplasms mutation profile during a two-year course of imetelstat treatment. In the study, using the human TF-1MPL and murine 32DMPL cell lines, the authors demonstrated a stronger effect of imetelstat on CALRdel52-positive vs. JAK2V617F-positive cell viability (p=0.0361 and p=0.0311 for 5 μM imetelstat, respectively), and this was associated with an immediate downregulation of JAK2 protein phosphorylation and downstream signaling as well as a reduction of telomerase reverse transcriptase (hTERT) and STAT3 mRNA expression. The authors report these data confirm that imetelstat reduces hTERT expression and telomere length (TL) and JAK2 and CALR clones by targeting the JAK/STAT signaling, particularly in CALR-mutated cells. According to the abstract conclusion, the data propose that CALR-mutated clones are highly vulnerable to imetelstat treatment.
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 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 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.
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.
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) that imetelstat has the potential to demonstrate disease-modifying activity in patients; and (iii) 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 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 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.