On December 12, 2022 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported results from an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on longer follow-up data from the IMerge Phase 2 clinical trial of imetelstat, the Company’s first-in-class telomerase inhibitor, in lower risk myelodysplastic syndromes (MDS) (Press release, Geron, DEC 12, 2022, View Source [SID1234625111]). The data in the presentation focused on the patients who achieved greater than one-year sustained continuous transfusion independence and included their baseline characteristics, clinical benefits and observed safety profile.
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"Achievement of one year or more uninterrupted transfusion independence represents significant clinical benefit given the high transfusion burden of the patients in the IMerge Phase 2 trial," said Faye Feller, M.D., Executive Vice President, Chief Medical Officer of Geron. "The durability of transfusion independence, which was correlated to decreases in mutated cells with variant alleles, provide strong evidence of disease modification with imetelstat treatment. If the data from the Phase 2 are confirmed by the top-line results from IMerge Phase 3, which we expect in early January 2023, imetelstat could transform the lower risk MDS treatment landscape."
Longer Follow-Up Data from IMerge Phase 2 Clinical Trial in Lower Risk MDS
IMerge Phase 2 is an open label, single arm study to assess the efficacy and safety of imetelstat in transfusion dependent patients with Low or Intermediate-1 risk myelodysplastic syndromes (lower risk MDS), who are relapsed or refractory to prior treatment with erythropoiesis stimulating agents (ESAs). The primary efficacy endpoint is 8-week transfusion independence (TI) rate, which is defined as the proportion of patients achieving red blood cell TI during any consecutive eight weeks since entry into the trial. Secondary endpoints include 24-week TI rate and duration of TI.
The oral presentation at ASH (Free ASH Whitepaper) described the 29% (11/38) of patients in IMerge Phase 2 who achieved ≥1 year sustained continuous TI with imetelstat. The median time on study for these patients was approximately 4.8 years with a median treatment duration of approximately 2.4 years. For these 11 patients, the median TI duration was approximately 1.8 years, which is the longest reported to date with imetelstat. In addition, these patients experienced increases in hemoglobin ≥3g/dL. Furthermore, these 11 patients represented 69% of the ≥8-week TI responders and 92% of the ≥24-week TI responders. As such, attainment of 24-week TI was indicative of the likelihood to achieve TI ≥1 year.
New efficacy data related to the 16% (6/38) of patients in IMerge Phase 2 who were relapsed/refractory to ESAs and had also been treated previously with luspatercept are as follows:
50% (3/6) of these patients achieved ≥8-week TI
67% (2/3) of those ≥8-week TI responders also achieved ≥24-week TI
100% (2/2) of those ≥24-week TI responders also achieved >1 year TI
Safety findings for the 11 patients were consistent with the overall patients in the target population, including resolution of each of Grade 3/4 thrombocytopenia and neutropenia to Grade 2 or lower within 4 weeks for >97% of patients in the >1 year TI population.
Mutation data were available for nine of the 11 patients, and 89% had a reduction in SF3B1 variant allele frequency (VAF) while 56% achieved greater than or equal to 50% VAF reduction. Reduction in VAF correlated with longer TI duration (median, >20 months) and shorter time to onset of TI (median, <10 weeks). These correlations, along with the clinical benefits of durable continuous TI and meaningful rises in hemoglobin, provide strong evidence of disease modification for imetelstat’s unique mechanism of action as a telomerase inhibitor.
Imetelstat Presentations in Myelofibrosis (MF) and Acute Myeloid Leukemia (AML)
Preclinical Data in AML
An oral presentation described results from non-clinical in vitro and in vivo experiments of imetelstat using AML cell lines and AML patient samples. The experiments found that imetelstat promotes the formation of polyunsaturated fatty acids-containing phospholipids which cause excessive levels of lipid peroxidation and oxidative stress in AML cells, potentially leading to programmed cell death. The mechanistic insights from this preclinical work could be leveraged to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat and may result in significant delay of relapse in AML.
Trials in Progress Posters in MF
MYF3001, or IMpactMF (NCT04576156), is a Phase 3, randomized (2:1), open label multicenter study of imetelstat compared with best available therapy (BAT) in approximately 320 adult patients with Intermediate-2 or High-Risk MF whose disease has relapsed after or is refractory to janus associated kinase inhibitor, or JAKi, treatment. The primary endpoint is overall survival and secondary endpoints include symptom and spleen response rates at Week 24, progression-free survival, clinical response assessments, time to and duration of response, reduction in degree of bone marrow fibrosis, safety, pharmacokinetics and patient-reported outcomes. Biomarkers and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones. Approximately 180 sites are planned in North and South America, Europe, Middle East, Australia and Asia. The study is actively enrolling.
MYF1001, or IMproveMF (NCT05371964), is a single arm, open label, two-part Phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of imetelstat in combination with ruxolitinib as a frontline treatment in patients with Intermediate-1 or -2 or High-risk MF (frontline MF). In both parts, patients will receive ruxolitinib followed by imetelstat. Part 1 will enroll up to 20 frontline MF patients who, at the time of enrollment, have received an optimized dose of ruxolitinib, to which imetelstat treatment will be added at increasing dose levels based on safety and tolerability. The primary purpose of Part 1 is to identify a safe dose for treating frontline MF patients with a combination of imetelstat and ruxolitinib. If a safe dose is identified in Part 1, participants in Part 2 will be JAKi naïve and will receive treatment with ruxolitinib after screening and enrollment at a starting dose based on standard-of-care or local prescribing information. Treatment with single-agent ruxolitinib will continue for at least 12 weeks, including four consecutive weeks at a stable dose prior to the addition of imetelstat. Part 2 is designed to confirm the safety profile of imetelstat in combination with ruxolitinib and to evaluate for preliminary clinical activity of the combination. Part 1 is open for enrollment, with approximately three sites planned in North America.
The presentations or abstracts from the 2022 ASH (Free ASH Whitepaper) Annual Meeting are available at www.geron.com/r-d/publications.
About Imetelstat
Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from Phase 2 clinical trials 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 United States Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis stimulating agent, and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment.