imetelstat (GRN163L)

P2, N=46, Recruiting, GCP-Service International West GmbH | Trial primary completion date: Jan 2024 --> Feb 2025

P1, N=36, Not yet recruiting, Children's Oncology Group

P2/3, N=289, Active, not recruiting, Geron Corporation | Trial primary completion date: Nov 2022 --> Oct 2023

This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs.

Hence, our data demonstrate that imetelstat reduces TL and targets JAK/STAT signaling, particularly in CALR-mutated cells. Although the exact patient subpopulation who will benefit most from imetelstat needs to be defined, our data propose that CALR-mutated clones are highly vulnerable.

Higher RBC-TI rates were observed in patients with various baseline mutational profiles treated with imetelstat compared with placebo in IMerge. While the sample size for specific mutations was small, consistent with the observation that patients with LR-MDS have a low number of specific mutations, TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. Imetelstat showed comparable TI rates across different molecularly defined subgroups, suggesting that clinical benefit of imetelstat in patients with LR-MDS is independent of the underlying molecular pattern.

In the IMerge phase 3 trial, imetelstat produced higher rates of TI for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in pts with non-del(5q) LR-MDS that was RBC-TD, R/R to/ineligible for ESAs, and naïve to lenalidomide or hypomethylating agents (HMAs; Platzbecker et al. Treatment with imetelstat resulted in ≥1-year sustained, continuous TI in 17.8% of pts in the IMerge phase 3 trial. In this ESA-R/R/ineligible population with a high prior transfusion burden, a reduction to 0 RBC transfusions for ≥1 year represents an opportunity to achieve relief from iron overload and other transfusion associated complications, and decreased demand on already limited blood product supply. Furthermore, durable TI and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity.

Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population...Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients...Summary: Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

A subset of these patients with del(5q) may do better with lenalidomide. Recently, in randomized trials, luspatercept has shown better responses compared with ESAs in treatment-naive patients and imetelstat in patients refractory to ESAs. Other evaluated novel compounds (fostamatinib, H3B-880, roxadustat, pyruvate kinase receptor activator) have not yet shown meaningful efficacy...While lower-risk myelodysplastic syndromes/neoplasms tend to have an indolent course, a subset of them has a dismal prognosis. Improving prognostication and serial monitoring will help in identifying high-risk patients for appropriate management.

Patients: Heavily RBC transfusion-dependent (TD) non-del(5q) LR-MDS; relapsed/refractory/ineligible for erythropoiesis-stimulating agents (ESA); naïve to lenalidomide and hypomethylating agents. Imetelstat may improve the ineffective erythropoiesis and thus alter the underlying biology of disease in patients with LR- MDS. Author Contributions: AMZ and RSK contributed equally.

We go on to discuss the development of telomere and telomerase targeted therapeutic candidates within the realm of myeloid malignancies. We overview all mechanisms of targeting telomerase that are currently in development with a particular focus on imetelstat, an oligonucleotide with direct telomerase inhibitory properties that has advanced the furthest in clinical development and has demonstrated promising data in multiple myeloid malignancies.

The recent approval of luspatercept and decitabine/cedazuridine have added on to the current armamentarium of erythropoietic stimulating agents and lenalidomide (for MDS with isolated deletion 5q). Several newer agents are being evaluated in phase 3 clinical trials for this group of patients, such as imetelstat and oral azacitidine. This review provides a summary of the classification systems, the prognostic scores and clinical management of patients with lower risk MDS.

We can retain luspatercept for MDS with excess ring of sideroblasts, lenalidomide, and some molecules currently being tested such as imetelstat or roxedustat. However, the search for new therapeutic options for ESA-resistant low-risk MDS remains necessary. We can use androgenotherapy or TPO agonists in limited access for symptomatic thrombocytopenia.

P=N/A, Available, Geron Corporation

Currently, erythropoiesis stimulating agents (recombinant erythropoietin), erythroid maturation agents (luspatercept), disease modifying agents (lenalidomide) and hypomethylating agents are the agents of choice in the treatment of LR-MDS. This review will discuss the current treatment standards, meaningful clinical outcomes, and emerging therapies in LR-MDS.

P2, N=46, Recruiting, GCP-Service International West GmbH | Not yet recruiting --> Recruiting

Although anemic patients with lower-risk MDS are currently treated with an erythropoiesis-stimulating agent, luspatercept, and transfusions, the telomerase inhibitor imetelstat and the hypoxia-inducible factor α inhibitor roxadustat have shown encouraging early results and are now in phase III clinical trials. For higher-risk MDS patients, hypomethylating agent monotherapy continues to be the standard of care. However, with various novel hypomethylating agent-based combination therapies in advanced clinical testing and an increased emphasis on individualized biomarker-driven treatment decisions, the standard therapy paradigms might change in the future.

P2, N=46, Not yet recruiting, GCP-Service International West GmbH | Initiation date: Dec 2022 --> May 2023

Patients with heavily red blood cell (RBC) transfusion-dependent (TD) erythropoiesis stimulating agent (ESA) relapsed/refractory (R/R) or ineligible non-del(5q) LR-MDS naive to lenalidomide and hypomethylating agents (len/HMA) received 2-hr infusions of imetelstat 7.5 mg/kg or placebo every 4 weeks. In the phase 3 IMerge study, heavily RBC TD ESA R/R/ineligible non-del(5q) LR-MDS patients naive to len/HMA treated with imetelstat experienced more cytogenetic response and reduction in SF3B1 , TET2 , DNMT3A, and ASXL1 mutational burden compared with placebo. Furthermore, SF3B1 VAF reduction correlated with clinically meaningful endpoints of increased hemoglobin and TI duration. These data, taken together with robust rates of TI that are continuous and durable, may indicate improvement of the ineffectiveerythropoiesis characteristic of LR-MDS and suggest imetelstat may alter the underlying biology of disease in these patients.

In the IMerge Phase 3 (Ph3) study (NCT02598661), imetelstat, a first-in-class telomerase inhibitor, demonstrated statistically significant and meaningfully improved 8- and 24-wk transfusion independence (TI) rates, durable TI, and increased hemoglobin levels compared with placebo in heavily red blood cell (RBC) transfusion-dependent (TD) non-del(5q) LR-MDS pts who were ineligible/relapsed/refractory to ESA and naive to lenalidomide/hypomethylating agents. In this heavily TD population, both imetelstat- and placebo-treated pts reported similar rates of deterioration in fatigue, suggesting imetelstat did not worsen the rate of deterioration, which has been reported with other available treatments. After 12 wks, greater improvement in fatigue was reported with imetelstat compared to placebo; pts on imetelstat were more likely to have sustained meaningful improvement infatigue and quicker to experience it. A significant association between TI and HI-E responses and sustained meaningful improvement in fatigue support the clinical benefit of imetelstat treatment.

In IMerge Phase 2 (NCT02598661), treatment with imetelstat, a telomerase inhibitor, resulted in prolonged, durable transfusion independence (TI) across a broad range of heavily RBC TD ESA relapsed/refractory non-del(5q) LR-MDS patients (pts) naive to lenalidomide and hypomethylating agents (len/HMA). Imetelstat demonstrated statistically significant and clinically meaningful efficacy with robust 8-wk, 24-wk, and 1-yr TI rates and durable continuous TI. For this LR-MDS patient population, almost one fifth of imetelstat-treated pts achieved continuous TI for ≥1 yr, representing substantial relief from transfusion- associated complications. VAF reduction and its correlation to clinical endpoints, including durable TI, supportimetelstat's disease-modifying potential.

Treatment with imetelstat achieved >1 year sustained, continuous TI in 29% of RBC TD, ESA-R/R LR-MDS patients who were non-del(5q) and lenalidomide/HMA-naïve and was safe and well tolerated. Of the overall population, attainment of 24-week TI was indicative of a likelihood to achieve TI >1 year. In this ESA-R/R population with a high transfusion burden prior to treatment, a decrease to zero RBC transfusions for a period >1 year represents relief from iron overload and other transfusion-associated complications, and decreased demand on health care resources.

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

 Here we established a sensitive ddPCR assay to quantify mean TL in AML patients, which could be used in future clinical research requiring a high sample throughput. Our data suggest telomere lengthening at time of diagnosis to be a common phenomenon associated with a higher burden of immature CD34+/CD38- cells and a more aggressive disease phenotype, reflected by a higher relapse rate after HSCT. Shorter mean TL in remission could be due to either therapeutic toxicity or depletion of AML blasts with prolonged telomeres.

Mice receiving standard chemotherapy consisting of cytarabine and daunorubicin or azacitidine showed prolonged survival compared to the untreated mice. These results were corroborated in vivo in two distinct PDX models which showed reduced LSC population and increased median survival in mice with imetelstat treatment. Combining imetelstat with chemotherapy or azacitidine further enhanced activity against LSCs, suggesting imetelstat could represent an effective therapeutic strategy for pediatric AML.

Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect.

Several promising drugs are in the horizon, including the hypoxia-inducible factor stabilizer roxadustat, telomerase inhibitor imetelstat, oral hypomethylating agents (CC-486), TP53 modulators (APR-246 and ALRN-6924), and the anti-CD47 antibody magrolimab. Targeted therapies approved for acute myeloid leukemia treatment, such as isocitrate dehdyrogenase inhibitors and venetoclax, are also being studied for use in MDS. In this review, we provide a brief overview of pathogenesis and current treatment strategies in MDS followed by a discussion of newer agents that are under clinical investigation.

Several JAK2 inhibitors such as ruxolitinib and gandotinib (LY2784544) currently in clinical trials and, provide improvements in MPNs including myelofibrosis. JAK2 inhibitors thus cause enrichment of LSCs and are unlikely to cure MPN as a monotherapy. Simultaneously targeting JAK2V617F and KLF4 or telomerase may be a novel strategy for MPN therapy, which should be of significance both biologically and clinically.

Specifically, stromal co-culture assays revealed that combined treatment with dasatinib at 1 nM, and imetelstat at 1 µM or 5 µM significantly inhibited survival and replating of blast crisis (BC) CML progenitors compared with aged bone marrow progenitors (p < 0.001, ANOVA). Finally, RNA-seq analysis performed on human CD34+ cells from imetelstat treated LSC mouse models revealed a significant reduction in LSC harboring malignant ADAR1-mediated A-to-I editing at doses that spared normal hematopoietic stem cells. CONCLUSIONS Combined WGS and RNA-Seq analyses, lentiviral ADAR1 overexpression, stromal co-culture assays and humanized pre-LSC and LSC mouse model studies reveal that pre-LSC evolution into LSC coincides with both ADAR1 and hTERT activation, which can be prevented with imetelstat.

P2; N=81; Completed; Sponsor: Janssen Research & Development, LLC; Active, not recruiting --> Completed; Trial completion date: Jan 2019 --> May 2018; Trial primary completion date: Jan 2019 --> May 2018

P3; N=225; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Feb 2022 --> Oct 2021; Trial primary completion date: Feb 2021 --> Oct 2020

P3; N=225; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial completion date: Oct 2021 --> Feb 2022; Trial primary completion date: Oct 2020 --> Feb 2021

"Prior MDS treatments included ESAs (88%), lenalidomide (38%), and decitabine or azacitidine (HMAs) (25%); 41% were both lenalidomide and HMA nave and non-del(5q). Safety and efficacy reported here support continued investigation of imetelstat using the current dosing regimen of 7.5 mg/kg every 4 weeks in IPSS Low/Int-1 RBC TD MDS patients relapsed/refractory to ESA. AEs (mostly cytopenias) were predictable, manageable, and reversible. TI was observed in 38% and erythroid HI in 63% of patients with imetelstat therapy, with a 16% durable 24-week TI rate."

P3; N=225; Recruiting; Sponsor: Janssen Research & Development, LLC; Trial primary completion date: Feb 2021 --> Oct 2020