Imetelstat, a novel, first‐in‐class telomerase inhibitor: Mechanism of action, clinical, and translational science

Abstract

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first‐in‐class, 13‐mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure‐response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower‐risk myelodysplastic syndromes (LR‐MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR‐MDS with transfusion‐dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2‐h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8‐week and ≥24‐week red blood cell‐transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short‐lived and manageable neutropenia and thrombocytopenia. This mini‐review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Clinical and Translational Card for Imetelstat.

• Mechanism of action: Direct and competitive oligonucleotide inhibitor of telomerase.

• Indication(s): Adult patients with low‐ to intermediate‐1‐risk myelodysplastic syndromes with transfusion‐dependent anemia requiring 4 or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents.

• Dosage and administration: 7.1 mg/kg (corresponding to 7.5 mg/kg imetelstat sodium) intravenous infusion over 2 h once every 4 weeks.

• Major metabolic pathway: Nucleases.

• Key PK characteristics: PK increased in a greater than dose‐proportional manner with no appreciable accumulation after repeated dosing; plasma geometric mean maximum concentration (CV%): 89.5 μg/mL (27.3%); AUC_0–28 (CV%): 559 μg*h/mL (43.2%); systemic clearance: 1.00 L/h (43.7%); volume of distribution at steady‐state (CV%): 14.1 L (27.2%); half‐life (CV%): 4.9 h (43.2%).

INTRODUCTION

Telomeres are repetitive DNA sequences located at the end of chromosomes that are reduced during cell division in somatic cells. ¹ After a set number of divisions, telomere length (TL) is shortened to a critical limit, and further cell division is prevented, leading to cell senescence or apoptosis. ¹ Cancer development is frequently accompanied by the preservation of TL. ² This often results from the reactivation of telomerase caused by the upregulation of human telomerase reverse transcriptase (hTERT) expression. ³ Reactivation of telomerase and increased telomerase activity (TA) is believed to be critical for tumor progression as it enables cancer cells to maintain TL, acquire cellular immortality, and avoid apoptosis. ⁴ The ribonucleoprotein enzyme, telomerase, functions by adding the telomeric repeats onto chromosomes at the 3′ ends. ⁵ Telomerase comprises a functional RNA component (hTR), an 11 base pair sequence that acts as a template for telomeric DNA synthesis, and the hTERT catalytic subunit. ⁵ Evaluation of biopsies from a broad range of human cancers showed that approximately 90% have been found to have increased TA, which is correlated with tumor stage. ² , ⁵ Conversely, in most normal adult tissues, telomerase is not detected, with the exception of transient activation in early progenitor stem cells and activated immune cells. ² , ⁴ Thus, the high level of telomerase expression common to most cancers and neoplastic progenitor cells along with the preservation of telomeres compared with their normal tissue counterparts support that telomerase is a rational target for the treatment of cancer.

Imetelstat is a first‐in‐class oligonucleotide competitive inhibitor of human telomerase enzymatic activity that leads to the loss of a cancer cell's ability to maintain TL, resulting in the inhibition of cell proliferation. Imetelstat has demonstrated preferential activity against cancer cells and malignant hematopoietic stem cells/progenitor cells (HSCs/HPCs) and leukemia stem cells (LSCs) while having minimal effect on normal HSCs/HPCs. ⁶ , ⁷ This mini‐review summarizes the mechanism of action, clinical development, and pharmacologic properties of imetelstat that contributed to its approval by the United States (US) Food and Drug Administration in June 2024.

DRUG REGULATORY APPROVAL

Imetelstat was approved for the treatment of adult patients with low‐ to intermediate‐1–risk myelodysplastic syndromes (LR‐MDS) with transfusion‐dependent anemia requiring 4 or more red blood cell (RBC) units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents in the US in June 2024. ⁸ The approved dosing regimen of imetelstat is 7.1 mg/kg as an intravenous (i.v.) infusion over 2 h every 4 weeks (q4w). ⁸ Imetelstat dosage in labeling and throughout this manuscript are expressed in terms of its active moiety, while early imetelstat publications expressed imetelstat dosage as its salt form (corresponding to imetelstat sodium 7.5 mg/kg). The marketing application of imetelstat is under review in the European Union.

MECHANISM OF ACTION

Imetelstat is a 13‐mer oligonucleotide N3′ → P5′ thio‐phosphoramidate with a palmitoyl group attached to the 5′ terminus through an aminoglycerol linker that acts as a potent and specific inhibitor of telomerase. ⁶ , ⁷ Imetelstat binds with high affinity to the template region of the hTR and acts as a direct competitive inhibitor of telomerase enzymatic activity to prevent telomere binding, which leads to reduction of telomere length, reduction of malignant stem and progenitor cell proliferation, and induction of apoptotic cell death (Figure 1). ⁶ , ⁷ The inclusion of the palmitoyl group enhances entry into cells and, consequently, enhances its anti‐TA. ⁷ There may be some structural similarities between imetelstat and other oligonucleotide classes; however, the mechanism of action for imetelstat is not antisense‐based, it acts as a classical active‐site enzyme inhibitor. Nonclinical proof‐of‐concept studies established the correlation between imetelstat dose/exposure, pharmacodynamic (PD) effect (inhibition of TA), and tumor growth inhibition, suggesting that ≥50% inhibition of TA is the mechanism‐of‐action–based PD effect of imetelstat contributing to antitumor efficacy, and that the imetelstat exposure levels required to achieve such PD activity are achievable in patients. ⁹ , ¹⁰ hTERT is the catalytic subunit of the telomerase enzyme; it is the rate‐limiting component of TA. The reduction of TA and hTERT levels by imetelstat treatment has been demonstrated in clinical studies and correlated with clinical benefits. ¹¹ , ¹² Potent in vitro and in vivo activity of imetelstat has been established in myeloproliferative neoplasms, providing evidence that imetelstat at clinically relevant concentrations reduces/eliminates malignant HSCs/HPCs and LSCs, including in models of essential thrombocythemia, ¹³ acute myeloid leukemia (AML), ⁹ and myelofibrosis. ¹⁴ In LR‐MDS, malignant HSCs are associated with increased TA and hTERT, shorter TL, and reduced ability to differentiate, leading to cytopenias, particularly anemia, due to ineffective hematopoiesis when compared with healthy cells. ¹⁵ Elimination of such malignant HPCs by imetelstat facilitates restoration of normal hematopoiesis. Further, imetelstat treatment has been shown to reduce/eliminate malignant cytogenetic abnormal clones and mutational burden and this effect is associated with increases in hemoglobin and longer RBC‐transfusion independence (RBC‐TI) in LR‐MDS, indicating recovery of normal hematopoiesis. ¹² , ¹⁶

FIGURE 1.

Imetelstat mechanism of action. MDS, myelodysplastic syndromes.

PHARMACOKINETIC (PK) CHARACTERISTICS

A summary of phase I through III imetelstat clinical studies is provided in Table 1. The clinical PK of imetelstat has been evaluated across a wide range of doses (0.4–11.0 mg/kg) and schedules (every week to q4w) (Table 1). Imetelstat plasma concentrations were determined using a hybridization enzyme‐linked immunosorbent assay with a lower limit of quantification ranging from 0.367 to 0.588 μg/mL. ¹⁷ A power model was applied to assess dose proportionality on cycle 1, day 1 maximum plasma concentration (C _max) and the area under the concentration–time curve from 0 days to infinity (AUC_inf) after administration of imetelstat 0.4–11.0 mg/kg over 2‐h i.v. infusion in solid tumor and hematologic malignancy populations (studies CP05‐101, CP14B015, MYF2001, and MDS3001). The estimated slope was 1.29 (90% CI, 1.17–1.41) for C _max and 1.54 (90% CI, 1.33–1.75) for AUC_inf, demonstrating that imetelstat PK increased in a greater than dose‐proportional manner across the evaluated dose range (Figure 2). After repeated dosing administration, there was no appreciable accumulation (Figure 2). ¹⁷ After administration of the recommended dosage of imetelstat 7.1 mg/kg via an i.v. infusion over 2 h in patients with LR‐MDS, plasma geometric mean (coefficient of variation [CV] %) C _max was 89.5 μg/mL (27.3%) and the area under the concentration–time curve from 0 to 28 days (AUC_0–28) was 559 μg*h/mL (43.2%) (Figure 2). ⁸ , ¹⁷

TABLE 1.

Tabulated list of imetelstat clinical studies providing clinical pharmacology data in new drug application.

Study number/phase	Study design/population	Imetelstat starting dose/(number of patients treated with imetelstat)	Key PK, PD, and immunogenicity assessments a and outcomes	Key efficacy outcomes	Key safety outcomes
CP04‐151 Phase I	Open‐label, sequential dose cohort, dose‐escalation, monotherapy study Chronic lymphoproliferative disease	6‐h i.v. infusion weekly: 18.8 (n = 3), 37.7 (n = 3), 75.3 (n = 3), 150.7 (n = 6), and 226 (n = 1) mg/m2 2‐h i.v. infusion at the following frequencies and dose levels: Weekly in each 4‐week cycle: 150.7 (n = 3) and 188.3 (n = 8) mg/m2 Days 1 and 8 in 3‐week cycle: 188.3 (n = 1) mg/m2	Assessments: PK (serial sampling; popPK) Outcomes: Range of mean terminal t 1/2: 1.79–4.67 h Mean systemic CL: 2 h infusion, 0.9–1.7 L/h; 6‐h infusion, 2.7–4.5 L/h Range of mean C max: 2 h infusion, 29.2–56.2 μg/mL; 6 h infusion, 1.5–26.8 μg/mL Range of mean AUCinf: 2 h infusion, 188.6–409.8 h*μg/mL; 6 h infusion, 11.2–191.3 h*μg/mL C max slope estimate (95% CI), 1.027 (0.8159–1.239) AUCinf slope estimate (95% CI), 1.256 (0.9347–1.577)	82.1% (23/28) evaluable for clinical response BOR: PR, n = 1 (median duration of response: 0.2 y); SD, n = 6; progressive disease, n = 15	Most common imetelstat‐related AEs: fatigue, thrombocytopenia, nausea, pyrexia Most significant safety issue: cytopenias, especially thrombocytopenia ≥1 AE: 100% (28/28); 281 total AEs ≥1 gr ≥3 AE: 53.6% (n = 15) ≥1 imetelstat‐related AE: 92.9% (n = 26) ≥1 gr ≥3 imetelstat‐related AE: 35.7% (n = 10) ≥1 SAE: 25.0% (n = 7); 8 total SAEs reported ≥1 imetelstat‐related SAE: 10.7% (n = 3) Deaths: none MTD: not determined
CP05‐101 Phase I	Open‐label, sequential dose cohort, dose‐escalation, monotherapy study Relapsed or refractory solid tumor malignancies	2‐h i.v. infusion at the following frequencies and dose levels: Weekly in each 4‐week cycle: 0.4 (n = 2), 0.8 (n = 2), 1.5 (n = 2), 3.0 (n = 8), and 4.5 (n = 14) mg/kg Days 1 and 8 in each 3‐week cycle: 4.5 (n = 6), 5.6 (n = 4), 7.1 (n = 3), 8.9 (n = 12), and 11.0 (n = 6) mg/kg Day 1 in each 4‐week cycle: 8.9 (n = 3) and 11.0 (n = 13) mg/kg	Assessments: PK (serial sampling; popPK); PD: TA Outcomes: Mean terminal t 1/2: 3.13–5.29 h Imetelstat CL: 0.4 mg/kg, 2.4 L/h; 3.0 mg/kg, 3.3 L/h; 4.5 mg/kg–11.0 mg/kg, 0.6–1.3 L/h Range of mean C max: 3.2–202 μg/mL Range of mean AUCinf: 14–1471 h*μg/mL C max slope estimate (95% CI), 1.230 (1.094–1.366) AUCinf slope estimate (95% CI) for 0.4–11.0 mg/kg, 1.381 (1.043–1.719) Median TA inhibition: 5.6–11.0 mg/kg (n = 23), 40.5%; 8.9 mg/kg, 34.0%; 11.0 mg/kg, 48.0%	89.3% (67/75) evaluable for response 100% were nonresponders BOR: SD, 17.4% (4/23) in the weekly cohort, 33.3% (10/30) in the days 1 and 8 cohort, and 7.1% (1/14) in the day 1 cohort BOR: progressive disease, 78.3% (18/23) in the weekly cohort, 53.3% (16/30) in the days 1 and 8 cohort; 64.3% (9/14) in the day 1 cohort	≥1 AE: 100% (75/75); 929 total AEs Most common hematologic toxicity: thrombocytopenia, 60% (45/75); considered to be imetelstat‐related in 42.7% (n = 32) ≥1 gr ≥3 AE: 81.3% (n = 61) AE; most frequent: partial thromboplastin time prolongation, 54.7% (n = 41); thrombocytopenia, 10.7% (n = 8); neutropenia, 9.3% (n = 7); anemia, 8.0% (n = 6); disease progression, 8.0% (n = 6) ≥1 imetelstat‐related AE: 93.3% (n = 70) ≥1 SAE: 33.3% (n = 25); 47 total SAEs ≥1 imetelstat‐related SAE: 12.0% (n = 9) Deaths: 9; 1 attributed to imetelstat because the immediate and underlying causality of the death was unknown
CP14A004 Phase I	Open‐label, sequential dose cohort, dose‐escalation, monotherapy study Refractory or relapsed multiple myeloma	2‐h i.v. infusion at the following frequencies and dose levels: Weekly in each 3‐week cycle: 3 (n = 3), 4.5 (n = 4), 5.6 (n = 7), 6.8 (n = 5) mg/kg Days 1 and 8 in each 3‐week cycle: 5.6 (n = 1) mg/kg	Assessments: PK (sparse sampling; popPK); PD: TA Outcomes: PK included in popPK analysis 17 Patients with evaluable malignant plasma cells (CD138+ cells) isolated from BM: n = 4; combined analysis indicated trend toward inhibition (p = 0.125, signed‐rank test; p = 0.057, t‐test) TA inhibition in CD138‐negative cells: 75% (3/4 samples) with no overall trend	100% (12/12) were nonresponders BOR: SD, 41.7% (n = 5); progressive disease, 50.0% (n = 6); response for 1 patient was unknown	≥1 AE: 100% (20/20); 176 total AEs ≥1 gr ≥3 AE: 70.0% (n = 14) ≥1 imetelstat‐related AE: 95.0% (n = 19) ≥1 gr ≥3 imetelstat‐related AE: 65.0% (n = 13) ≥1 SAE: 15.0% (n = 3); 5 total SAEs; 1 imetelstat‐related SAE Deaths: none
CP14A011 Phase I	Open‐label, dose‐escalation of imetelstat in combination with bortezomib with or without dexamethasone Relapsed or refractory multiple myeloma	2‐h i.v. infusion on days 1 and 8 of each 3‐week cycle: 150.7 (n = 3), 188.3 (n = 6) mg/m2	Assessments: PK (sparse sampling) Geometric mean (CV%) EOI concentration on Cycle 1, Day 1 was 79.5 μg/mL (32.3%); on Cycle 1, Day 8 was 106 μg/mL (20.0%); on Cycle 2, Day 1 was 101 μg/mL (22.7%); and on Cycle 2, Day 8 was 98.1 μg/mL (13.5%) for 150.7 mg/m2 imetelstat dose Geometric mean (CV%) EOI concentration on Cycle 1, Day 1 was 61.3 μg/mL (29.2%); on Cycle 1, Day 8 was 61.2 μg/mL (47.5%); and on Cycle 2, Day 1 was 62.6 μg/mL (24.1%) for 188.3 mg/m2 imetelstat dose Geometric mean (CV%) 1‐ and 2‐h concentrations on Cycle 2, Day 1 was 69.6 μg/mL (28.4%) and 55.8 μg/mL (28.5%), respectively, for 150.7 mg/m2 imetelstat dose Geometric mean (CV%) 1‐ and 2‐h concentrations on Cycle 2, Day 1 was 45.6 μg/mL (25.2%) and 36.5 μg/mL (23.3%), respectively, for 188.3 mg/m2 imetelstat dose	88.9% (8/9) were evaluable for efficacy BOR: CR, n = 1; very good PR, n = 1; PR, n = 1; SD, n = 2; progressive disease, n = 3	≥1 AE: 100% 9/9; 152 total AEs reported ≥1 gr ≥3 AE: 88.9% (n = 8) ≥1 imetelstat‐related AE: 77.8% (n = 7) ≥1 imetelstat‐related gr ≥3 AE: 33.3% (n = 3) ≥1 SAE: 11.1% (n = 1); unrelated to imetelstat Deaths: none
CP14B012 Phase II	Open‐label, multicenter, randomized study of imetelstat with or without bevacizumab after initial induction of chemotherapy Advanced NSCLC	2‐h i.v. infusion on days 1 and 8 of each 3‐week cycle: 8.9 mg/kg (n = 50 for imetelstat alone, n = 27 for imetelstat + bevacizumab)	Assessments: PK (sparse sampling) Geometric mean (CV%) EOI concentration on Cycle 2, Day 8 was 135 μg/mL (19.3%); on Cycle 3, Day 8 was 114 μg/mL (20.4%); and on Cycle 4, Day 8 was 125 μg/mL (36.0%) for 7.1 mg/m2 imetelstat dose Geometric mean (CV%) EOI concentration on Cycle 2, Day 8 was 111 μg/mL (39.7%); on Cycle 3, Day 8 was 112 μg/mL (39.8%); and on Cycle 4, Day 8 was 140 μg/mL (28.4%) for 8.9 mg/m2 imetelstat dose	Median PFS: imetelstat, 2.76 mo; control, 2.57 mo; HR (95% CI): stratified RECIST, 0.708 (0.46–1.09), p = 0.1126; unstratified RECIST: 0.784 (0.51–1.20), p = 0.2597; stratified clinical or radiologic progression, 0.786 (0.51–1.21), p = 0.2689 Median (95% CI) OS: imetelstat, 14.31 mo (9.90–18.36); control, 12.04 mo (7.57–16.09); median follow‐up: 11.23 and 11.28 mo, respectively; HR (95% CI), 0.796 (0.49–1.30), p = 0.3568 6‐month survival rate: imetelstat, 81.3% (95% CI, 70.5–88.5); control, 75.0% (95% CI, 57.5–86.1) Objective response rates: imetelstat, 3.0% (n = 2, both were PRs); control, 0% (p = 0.3209)	≥1 AE: 93.9% (107/114); most common (≥50% in any arm): thrombocytopenia, nausea ≥1 gr ≥3 AE: imetelstat only, 59.6%; imetelstat + bevacizumab, 70.8%; bevacizumab only, 33.3%; observation arm, 23.1% ≥1 gr ≥3 AE: imetelstat‐related AEs in imetelstat arms, 48.7%; bevacizumab‐related AEs in the bevacizumab arms, 16.7% ≥1 SAE: imetelstat only, 19.2%; imetelstat + bevacizumab, 29.2%; bevacizumab only, 16.7%; observation arm, 15.4% Deaths: AE (n = 5; imetelstat only, n = 2 (intracranial hemorrhage and sepsis), imetelstat + bevacizumab, n = 1 (NSCLC); bevacizumab only (after crossover to imetelstat treatment), n = 1 (respiratory failure); observation arm, n = 1 (pneumonia)
CP14B015 Phase II	Open‐label, monotherapy study Essential thrombocythemia (ET) or polycythemia vera (PV)	2‐h i.v. infusion weekly in each 4‐week cycle: 7.1 (n = 7), 8.9 (n = 13) mg/kg	Assessments: PK (serial sampling; popPK); PD: TA Outcomes: Median T max for 7.1 and 8.9 mg/kg dose: occurred at EOI Mean terminal t 1/2: 7.1 mg/kg, 3.99 h; 8.9 mg/kg, 6.20 h Mean EOI concentration values: 0%–20% higher in cycles 3 through 12 vs. cycle 1 AUC0–4: mean increases of 12% after repeat dosing through cycle 12 vs. cycle 1 Cmax slope estimate (95% CI), 1.22 (0.813–1.628); increase was somewhat greater than dose‐proportional across the 7.1–11.0 mg/kg dose range AUC0–4 slope estimate (95% CI), 1.21 (0.772–1.654); increased dose proportionally from 7.1 to 11.0 mg/kg; goodness of fit (r 2): 0.32–0.33 TA inhibition (n = 6): 36% (p < 0.001 by pairwise permutation test)	BOR in patients with ET (n = 18): CR, 88.9% (7.1 mg/kg, 100.0% [7/7]; 8.9 mg/kg, 81.8% [9/11]; PR, 11.1% (8.9 mg/kg, n = 2); median (range) time to response: 1.2 mo (1.0–4.4); median (range) duration of response: 29.5 mo (2.4–29.5) Median (range) time to treatment failure for patients with ET: 18.4 mo (6.9–36.6) BOR in patients with PV (n = 2): hematologic response, 100% (8.9 mg/kg) Allele burden reduction ≥50%: 87.5% (7/8 patients with ET with JAK2 V617F mutations at baseline) BM response in patients with ET (77.8% [14/18] had abnormal BM results at baseline): 14.3% (n = 2; 7.1 mg/kg, 20% [1/5]; 8.9 mg/kg, 11.1% [1/9]) BM response in patients with PV (50.0% [1/2] had abnormal BM results at baseline): 0% Clinicohematologic response in patients with ET: 100% (18/18); best clinicohematologic response within the first year: CR, 94.4% (n = 17); PR, 5.6% (n = 1) Clinicohematologic response in patients with PV: 100% (2/2); best clinicohematologic response within the first year: PR (n = 2)	≥1 AE: 100% (20/20); most common (≥ 50% of patients overall): fatigue, diarrhea, nausea, dizziness, headache, epistaxis, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased ≥1 gr ≥3 AE: 85.0% (n = 17) ≥1 imetelstat‐related AE: 100% (n = 20) ≥1 imetelstat‐related gr ≥3 AE: 65.0% (n = 13); most common: neutropenia, 30.0% (n = 6); neutrophil count decreased, 20.0% (n = 4) ≥1 SAE: 55.0% (n = 11) ≥1 IRR: 40.0% (n = 8); all events except 1 gr 3 syncope were gr ≤2 Discontinuation due to AEs: 25.0% (n = 5, all with ET); imetelstat‐related AEs leading to discontinuation: 15.0% (n = 3) Deaths: AEs, n = 1 (bleeding esophageal varices 85 days after the last dose) Cytopenias: most were gr 1–2 except for neutropenia (gr 3–4: 11/16 patients; gr 4, n = 3; no fatal cytopenias; no patients discontinued imetelstat due to cytopenias
CP14B013 Phase II	Open‐label study of imetelstat alone or in combination with lenalidomide maintenance therapy Multiple myeloma	2‐h i.v. infusion on days 1 and 8 in each 4‐week cycle: 7.15 (n = 6) and 8.9 (n = 7) mg/kg	Assessments: PK (sparse sampling; popPK) Outcomes: Imetelstat BM cellular concentrations: 0.917 μg/mL at 41 h after infusion (n = 1); 2.52 μg/mL at 45 h after infusion (n = 1); below the limit of quantification, n = 10	Objective responses: 69.2% (9/13) (7.1 mg/kg, 66.7% [4/6]; 8.9 mg/kg, 71.4% [5/7]) BOR: CR, n = 1 (8.9 mg/kg); very good PR, n = 6 (7.1 mg/kg, n = 3; 8.9 mg/kg, n = 3); PR, n = 2 (7.1 mg/kg, n = 1; 8.9 mg/kg, n = 1); SD, n = 1 (8.9 mg/kg) PFS events: 53.8% (7/13); median duration of follow‐up: 5.1 mo; median PFS: 5.3 mo	≥1 AE: 100% (13/13) ≥1 imetelstat‐related AE: 100% (n = 13) ≥1 gr ≥3 AE: 84.6% (n = 11) ≥1 imetelstat‐related gr ≥3 AE: 84.6% (n = 11) ≥1 SAE: 23.1% (n = 3); 4 total SAEs; gr 4 or 5 SAEs: 0%; imetelstat‐related gr ≥3 SAE: febrile neutropenia (n = 1) ≥1 IRR: n = 1 (8.9 mg/kg; gr 1) Discontinuation due to imetelstat‐related AEs: n = 1 (8.9 mg/kg) Deaths: none
MYF2001 Phase II	Randomized, single‐blind, dose‐finding, monotherapy study Intermediate‐2 or high‐risk MF relapsed/refractory to JAK inhibitor	2‐h i.v. infusion once every 3‐week cycle: 4.4 (n = 11) and 8.9 (n = 17) mg/kg	Assessments: PK (serial sampling; popPK); PD: TA and hTERT; ADA Outcomes: Mean terminal t 1/2: 4.4 mg/kg, 4.6 h; 8.9 mg/kg, 5.5 h Mean systemic CL: 4.4 mg/kg, 2.34 L/h; 8.9 mg/kg, 1.7 L/h Mean EOI concentrations: cycle 1, 82 μg/mL; cycles 13–16, 100–125 μg/mL; CV% range across cycles: 30%–90% Mean dose‐normalized C max and AUCinf: similar range for 4.4 mg/kg and 8.9 mg/kg; CV% for C max and AUCinf: 49%–127% Patients with relapsed/refractory MF treated with imetelstat had a median spleen volume >13 times the upper limit of normal and >6 times the definition of massive splenomegaly, which was found to underly variability in imetelstat PK in the final popPK model Range of imetelstat concentrations in BM: 15–28,000 ng/g (n = 17) ≥50% TA reduction from baseline: 8.9 mg/kg, 51.1% (n = 23/45); 4.4 mg/kg, 29.4% (n = 10/34) ≥50% hTERT RNA level reduction from baseline: 8.9 mg/kg, 61.4% (n = 35/57); 4.4 mg/kg, 41.7% (n = 20/48) ADA: 20.6% (22/107); all exhibited a treatment‐induced ADA response; median time to onset of ADA: ≈25 weeks after the start of treatment, or after 8 treatment cycles; peak titer range: 10–2560 (median: 60)	Spleen response (SVR ≥35% [95% CI]) at week 24: 8.9 mg/kg, 10.2 (3.8%–20.8%; n = 6); 4.4 mg/kg, 0 Median (range) time to spleen response: 24.4 weeks (11.0–35.3); median (95% CI) duration of response for 8.9 mg/kg: 25 weeks (11.0–NE) Symptom response (total symptom score reduction ≥50%) at week 24: 8.9 mg/kg, 32.2% (n = 19); 4.4 mg/kg, 6.3% (n = 3); median (range) time to symptom response: 8.9 mg/kg, 9.9 weeks (1.9–56.0); 4.4 mg/kg, 3.9 weeks (0.7–33.9); median (95% CI) duration of response: 8.9 mg/kg, 4.0 weeks (3.0–13.0); 4.4 mg/kg, 10.3 weeks (3.0–20.0) BOR per modified 2013 IWG‐MRT criteria: PR: 8.9 mg/kg, 1.7% (n = 1); 4.4 mg/kg, 0%; clinical improvement, 8.9 mg/kg, 25.4%; 4.4 mg/kg, 16.7% Median (95% CI) OS: 8.9 mg/kg, NE (21.5–NE); 4.4 mg/kg, 19.9 mo (17.1–NE)	≥1 AE: 8.9 mg/kg: 100% (59/59); 4.4 mg/kg, 97.9% (47/48); most common (>30%): diarrhea, nausea, anemia, thrombocytopenia, neutropenia ≥1 gr ≥3 AE: 8.9 mg/kg, 88.1% (n = 52); 4.4 mg/kg, 81.3% (n = 39) ≥1 SAE: 8.9 mg/kg, 39% (n = 23); 4.4 mg/kg, 43.8% (n = 21); most common (>4%): splenic infarction, abdominal pain, pneumonia ≥1 IRR: 8.9 mg/kg, 25.4% (n = 15); 4.4 mg/kg, 10.4% (n = 5); most common: chills, pyrexia; gr 3 IRR: 8.9 mg/kg, n = 3; 4.4 mg/kg, n = 1; all resolved with the exception of 1 patient in the 8.9‐mg/kg group with an AE of cough; 12 patients received concomitant or additional treatment, 6 had cycle delays, 1 had dose of study drug reduced Deaths: 8.9 mg/kg, 35.6% (n = 21); 4.4 mg/kg, 54.2% (n = 26)
MDS3001 Phase II/III	Two‐part monotherapy study; phase II: open‐label, single‐arm design; phase III: double‐blind, randomized, placebo‐controlled design Transfusion‐dependent, low‐ or intermediate‐1–risk MDS that is relapsed/refractory to ESA treatment	2‐h i.v. infusion once every 4‐week cycle: 7.1 mg/kg (n = 57 in phase II, and 118 in phase III)	Assessments: PK (serial sampling; popPK); PD: TA and hTERT; ADA; ECG b Outcomes: Median (range) T max: 2 h (1.92–2.13) Geometric mean (geometric CV%) maximum concentration (n = 11): 78.6 μg/mL (34.8%) Mean EOI concentration (n = 129 with sparse sampling in cycle 1): 101 μg/mL (43.9%) Geometric mean (CV%) AUCinf: 386 h*μg/mL (47.6%) Geometric mean (CV%) t 1/2: 4.76 h (15.8%) Geometric mean (CV%) systemic CL and Vss: 1.52 L/h (44.5%) and 8.95 L (35.0%), respectively ADA: 16.9% (28/166); median time to onset of ADA: ≈38 weeks after the start of treatment, or after 8 treatment cycles; peak titer range: 10–160 (median: 30) ≥50% TA reduction from baseline: 42.9% (n = 9/21) in phase II and 60% (n = 21/35) in phase III, respectively ≥50% hTERT RNA level reduction from baseline: 58.8% (n = 30/51) in phase II and 43.2% (n = 41/95) in phase III, respectively	Primary and secondary efficacy outcomes from phase III (excludes phase II): ≥8‐week RBC‐TI: imetelstat, 39.8% (47/118); placebo, 15% (9/60; p < 0.001) ≥24‐week RBC‐TI: imetelstat, 28.0% (n = 33); placebo, 3.3% (n = 2; p < 0.001) ≥1‐year RBC‐TI: imetelstat, 13.6% (n = 16); placebo, 1.7% (n = 1; p = 0.012) Significant and clinically meaningful improvement in rates of ≥8‐week RBC‐TI were observed for imetelstat vs. placebo across all key subgroups, regardless of RS status, baseline transfusion burden, or IPSS risk category Median (95% CI) RBC‐TI duration in ≥8‐week RBC‐TI responders: imetelstat, 51.6 (26.86–83.86; n = 47); placebo, 13.3 (8.00–24.86; n = 9; p < 0.001) Robust and sustained increase in mean Hb was achieved with imetelstat treatment in patients with or without RBC‐TI vs. placebo (p < 0.001) Improvement in Hb levels was accompanied by a robust reduction in transfusion burden for imetelstat vs. placebo (p = 0.042) HI‐E rate based on IWG 2006 criteria: imetelstat, 63.6%; placebo, 51.7% HI‐E + Hb increase ≥1.5 g/dL above pretreatment and lasting ≥8 weeks: imetelstat, 33.9%; placebo, 10.0% (p < 0.001)	Phase III summary (excludes phase II): ≥1 AE: imetelstat, 99.2% (117/118), placebo, 100% (59/59); most common (≥20% in imetelstat group): thrombocytopenia, 75.4%; neutropenia, 73.7%; anemia, 20.3% ≥1 treatment‐related AE: imetelstat, 82.2% (n = 97); placebo, 33.9% (n = 20); most common imetelstat‐related AEs: thrombocytopenia, 67.8%; neutropenia, 64.4% ≥1 gr ≥3 AE: imetelstat, 90.7% (n = 107); placebo, 47.5% (n = 28); most common in the imetelstat group: neutropenia, 67.8%; thrombocytopenia, 61.9%; anemia, 19.5% ≥1 treatment‐related gr ≥3 AE: imetelstat, 72.0%; placebo, 10.2%; most common imetelstat‐related AE: neutropenia, 58.5%; thrombocytopenia, 54.2%; anemia, 6.8% ≥1 SAE: imetelstat, 32.2%; placebo, 22.0%; imetelstat‐related SAE: 5.1% ≥1 AE leading to study treatment discontinuation: imetelstat, 14.4%; placebo, 0%; median (range) time to AE that led to study treatment discontinuation: 21.1 weeks (2.3–44.0) Death: imetelstat, 16.1% (n = 9) after a median follow‐up of 19.48 mo; placebo, 13.6% (n = 8) after a median follow‐up of 17.51 mo; gr 5 AEs during treatment period: imetelstat, n = 1 (sepsis; unrelated to treatment); placebo, n = 1 (aortic stenosis; unrelated to treatment)

Abbreviations: ADA, anti‐drug antibody; AE, adverse event; AUC_inf, area under the concentration–time curve from 0 days to infinity; BM, bone marrow; BOR, best overall response; CI, confidence interval; CL, clearance; C _max, maximum concentration; CR, complete response; CV, coefficient of variation; ECG, electrocardiogram; EOI, end of infusion; ESA, erythropoiesis‐stimulating agent; gr, grade; Hb, hemoglobin; HI‐E, hematologic improvement‐erythroid; HR, hazard ratio; hTERT, human telomerase reverse transcriptase; IPSS, International Prognostic Scoring System; IRR, infusion‐related reaction; i.v., intravenous; IWG, International Working Group; JAK, Janus kinase; MDS, myelodysplastic syndromes; MF, myelofibrosis; MRT, myeloproliferative neoplasms research and treatment; MTD, maximum tolerated dose; NE, not estimable; NSCLC, non–small cell lung cancer; OS, overall survival; PD, pharmacodynamics; PFS, progression‐free survival; PK, pharmacokinetics; popPK, population pharmacokinetics; PR, partial response; RBC‐TI, red blood cell‐transfusion independence; RECIST, Response Evaluation Criteria in Solid Tumors; RS, ring sideroblast; SAE, serious adverse event; SD, stable disease; SVR, spleen volume reduction; t _1/2, half‐life; TA, telomerase activity; T _max, time to maximum concentration; V _ss, volume of distribution at steady‐state.

^a PopPK indicates that PK samples were included in the population PK analysis.

^b Study MDS3001 includes an ongoing QT substudy with collection of time‐matched PK and ECG samples.

FIGURE 2.

Imetelstat dose‐normalized C _max (a) and AUC_inf (b) across the 0.4–11.0 mg/kg dose range; PK profile after administration of 7.1 mg/kg in patients with LR‐MDS (c) and distribution of EOI values after repeated 7.1 mg/kg q4w administration in patients with LR‐MDS (d). Panels a and b are boxplots of observed dose‐normalized C _max and AUC_inf estimated with noncompartmental analysis using data after administration of a single dose of imetelstat 0.4–11.0 mg/kg over 2‐h i.v. infusion in patients with STs (study CP05‐101), ET/PV (study CP14B015), MF (study MYF2001), or LR‐MDS (study MDS3001). Panel c shows the imetelstat concentration–time profile in a typical patient with LR‐MDS receiving imetelstat 7.1 mg/kg in cycle 1 derived from the final imetelstat population PK model. ¹⁷ Panel d is a boxplot of observed imetelstat EOI concentrations in patients with LR‐MDS receiving imetelstat 7.1 mg/kg q4w in study MDS3001. AUC_inf, area under the csoncentration–time curve from 0 days to infinity; C _max, maximum plasma concentration; EOI, end of infusion; ET/PV, essential thrombocythemia/polycythemia vera; i.v., intravenous; LLOQ, lower limit of quantification (0.588 μg/mL); LR‐MDS, lower‐risk myelodysplastic syndromes; MF, myelofibrosis; PK, pharmacokinetic; q4w, every 4 weeks; ST, solid tumor.

Imetelstat has been exclusively administered via i.v. infusion throughout its clinical development program, and C _max approximates the end of infusion. Extravascular administration was investigated in preclinical species via intraduodenal administration in rodents and subcutaneous injection in nonhuman primates. Consistent with known absorption properties for chemically modified oligonucleotides, ¹⁸ , ¹⁹ no bioavailability was achieved for imetelstat through the gastrointestinal route, while bioavailability following subcutaneous administration was essentially complete [Geron, data on file]. Distribution properties for imetelstat were evaluated preclinically and are characterized by high protein binding (>94%) independent of concentration and broad tissue distribution, with the highest concentrations achieved in the liver, kidney, spleen, and bone marrow (the site of action for myeloid diseases). ²⁰ Exploratory bone marrow samples collected from patients with myelofibrosis revealed a strong correlation between plasma and bone marrow imetelstat concentrations (r ² = 0.957; excluding one outlier) [Geron, data on file], confirming imetelstat distribution to bone marrow and supporting its evaluation in myeloid malignancies. Like other oligonucleotides, ¹⁸ imetelstat is likely metabolized into smaller fragments by nucleases that are ubiquitous in tissues, with the component fragments excreted in urine. Cross‐study evaluations of preclinical PK and radioactivity data revealed that imetelstat was the major circulating moiety, accounting for nearly 90% of radioactivity, while metabolite profiling did not detect imetelstat‐related metabolites in processed plasma. ²⁰ Given metabolic pathways are anticipated to be similar between preclinical species and humans, ¹⁹ data support imetelstat as the major moiety in circulation and its disposition is via nuclease digestion. Preclinical excretion studies evaluating routes and rates of elimination revealed that near‐complete recovery of imetelstat‐related radioactivity was achieved within 168 h after dosing, with the majority of radioactivity excreted in the urine (62%–82%) and less in feces (18%–21%). ²⁰ Unchanged imetelstat was not detected in urine in the preclinical excretion studies. These analyses support that unchanged imetelstat is not substantially altered in special populations with underlying organ (liver or kidney) impairment, consistent with knowledge on large chemically modified oligonucleotide disposition. ¹⁸

Imetelstat population PK was well described by a two‐compartment, nonlinear disposition model with saturable binding/distribution and dose‐ and time‐dependent elimination from the central compartment based on pooled PK data across seven imetelstat clinical studies. ¹⁷ The geometric mean (CV%) estimates for imetelstat systemic clearance, volume of distribution at steady‐state, and apparent half‐life were 1.00 L/h (43.7%), 14.1 L (27.2%), and 4.9 h (43.2%), respectively. ⁸ , ¹⁷ Imetelstat, like other oligonucleotides, ¹⁸ exhibits biphasic elimination from plasma in nonclinical studies and is expected to be associated with an initial rapid distribution from plasma followed by a longer terminal elimination phase (Figure 2), thus its apparent half‐life likely represents its rapid distribution into tissue. In population PK analyses, evaluation of intrinsic factors revealed no clinically significant differences in imetelstat PK based on age (21–87 years), race (White, Asian, Black, other/unknown), or mild to moderate renal or hepatic impairment. ⁸ , ¹⁷ Sex was included in the final population PK model and showed a modest, non‐clinically significant effect with 30% lower clearance in females. ⁸ , ¹⁷ Bodyweight was included as a covariate using allometric exponents, supporting a bodyweight‐based dosing approach. ⁸ , ¹⁷ Disease‐based differences in exposure were identified between LR‐MDS and myelofibrosis populations (Figure 2), ¹⁷ supporting dose differences between these indications (see Clinical Efficacy and Safety). Additional discussion of the covariate effects, including the effect of time on clearance, are provided in González‐Sales 2024. ¹⁷ Overall, imetelstat PK is associated with moderate between‐patient variability. ¹⁷ The completed population PK analyses informed the posology of imetelstat in the approved US prescribing information and established that no dose adjustments are required in specific populations (age, race, sex, and mild to moderate hepatic or renal impairment). ⁸

Imetelstat, like other oligonucleotides, is likely metabolized by nucleases and is not a substrate of classical hepatic enzymes (e.g., cytochrome P450), thus victim‐based drug–drug interactions (DDIs) are unlikely. ¹⁸ Similarly, modulation of transporters is unlikely to significantly affect oligonucleotides like imetelstat. ²¹ Preclinical perpetrator‐based DDI assessments revealed no imetelstat inhibition or induction of cytochrome P450 enzymes and limited in vitro inhibition of transporters, namely OAT1 and OATP1B1/1B3. ²² Considering its short plasma half‐life and infrequent dosing schedule, the time at which imetelstat levels are above critical concentrations expected to result in transporter inhibition based on in vitro assessments is short based on observed and model‐predicted plasma concentrations in patients, and thus clinically meaningful DDIs are unlikely. ⁸ , ¹⁷

PROARRYTHMIC POTENTIAL

Because of their pharmacologic and physicochemical properties, the proarrhythmic potential of oligonucleotides is low. ²³ Imetelstat did not inhibit the hERG channel at concentrations >140 times imetelstat unbound C _max in patients with LR‐MDS. ²⁰ An in vivo safety pharmacology study in telemetered cynomolgus monkeys demonstrated that single i.v. doses of imetelstat up to 14.1 mg/kg were well tolerated with no treatment‐related clinical signs or changes in mean arterial pressure, heart rate, body temperature, electrocardiogram activity, neurological condition, blood gas parameters or chemistry/hematology parameters at plasma concentrations >2.6 times imetelstat C _max in patients with LR‐MDS. ²⁰ A clinical ventricular repolarization substudy of the phase III study IMerge/MDS3001 (NCT02598661, see Clinical Studies) recently demonstrated no positive concentration‐QTc relationship at concentrations exceeding the imetelstat geometric mean C _max in patients with LR‐MDS [manuscript in preparation]. Collectively, imetelstat showed low proarrhythmic potential, consistent with known properties of oligonucleotides. ²³

CLINICAL STUDIES

Over the course of its extensive development, the imetelstat clinical program included numerous clinical studies with >750 patients exposed to imetelstat alone or in combination with systemic anticancer agents in patients with various solid tumors and hematologic malignancies. ²² Key clinical studies evaluating single‐agent imetelstat efficacy and safety included IMbark/MYF2001 (NCT02426086), a phase II study in myelofibrosis, and IMerge/MDS3001 (NCT02598661), a phase II/III study in LR‐MDS (Table 1).

SUMMARY OF CLINICAL EFFICACY AND SAFETY

IMbark/MYF2001, a phase II dose‐finding study, investigated imetelstat 8.9 and 4.4 mg/kg every 3 weeks (q3w) in patients with myelofibrosis who were relapsed/refractory to Janus kinase inhibitor therapy. ¹¹ In the primary analysis, symptom response rates at week 24 were achieved by 32.2% (95% confidence interval [CI], 20.6–45.6) and 6.3% (95% CI, 1.3–17.2) of patients in the 8.9‐mg/kg arm and the 4.4‐mg/kg arm, respectively. Spleen response rates at week 24 were achieved by six patients (10.2%; 95% CI, 3.8–20.8) in the 8.9‐mg/kg arm and none in the 4.4‐mg/kg arm. The median overall survival (OS) was 29.9 months in the 8.9‐mg/kg arm (95% CI, 22.8–not estimable [NE]) and 19.9 months in the 4.4‐mg/kg arm (95% CI, 17.1–NE) following a median follow‐up of 27.4 months. The most common grade 3/4 adverse events (AEs) were hematologic. Grade 3/4 neutropenia and grade 3/4 thrombocytopenia were reported in 32% and 41%, respectively, of patients who received 8.9 mg/kg, and in 10% and 23%, respectively, of those who received 4.4 mg/kg. Overall, clinical results, alongside exposure–response (E‐R) analyses (below), demonstrated clinical benefit and acceptable safety with imetelstat 8.9 mg/kg q3w for patients with myelofibrosis.

IMerge/MDS3001, a phase II/III study, investigated imetelstat 7.1 mg/kg q4w in patients with LR‐MDS. ¹² , ¹⁶ MDS is a serious, life‐threatening disease that constitutes a heterogeneous group of hemopoietic clonal disorders characterized by ineffective hematopoiesis, in which hematopoietic progenitor cells have a reduced ability to differentiate and an increased likelihood of apoptosis. ²⁴ LR‐MDS is characterized by the presence of bone marrow dysplasia, low bone marrow blast percentage, and a variety of karyotypic and molecular abnormalities. ²⁴ Chronic anemia is the predominating presentation of LR‐MDS, leading to RBC transfusion dependency in about one quarter of patients. ²⁴ In phase II, initial efficacy and safety were established in the patient subset with International Prognostic Scoring System low‐risk or intermediate‐1–risk, non‐del(5q) MDS who were transfusion‐dependent and relapsed after or refractory to erythropoiesis‐stimulating agents. ¹² In the randomized phase III portion of the study in a similar patient population with the additional requirement that patients had to be lenalidomide‐ and hypomethylating agent‐naive, imetelstat demonstrated statistically significant and clinically meaningful superiority over placebo for the primary endpoint of ≥8‐week RBC‐TI (40% [95% CI, 30.9–49.3] vs. 15% [7.1–26.6]). ¹⁶ Further, imetelstat demonstrated a statistically significant improvement over placebo for the key secondary endpoint of ≥24‐week RBC‐TI (28% [95% CI, 20.1–37.0] vs. 3% [0.4–11.5]). ¹⁶ Imetelstat 7.1 mg/kg q4w was associated with an acceptable safety profile. Grade 3/4 neutropenia and thrombocytopenia were reported in 68% and 62% of patients in the imetelstat arm, respectively. While neutropenia and thrombocytopenia were frequent with imetelstat treatment, these cytopenias were largely based on changes in laboratory values, were managed by dose modifications, and were transient, with the majority of patients recovering to grade ≤2 within the 4‐week dosing schedule. Of clinical importance, potential consequences of cytopenias, namely severe infections or bleeding, occurred at low rates that were similar to those in the placebo arm. ¹⁶

IMMUNOGENICITY

Immunogenicity was evaluated in the IMbark/MYF2001 and IMerge/MDS3001 trials using a validated bioanalytical method via a three‐tiered approach for screening, confirmation, and semi‐quantitation of imetelstat anti‐drug antibody (ADA) titers. ²² In IMbark/MYF2001, 22 of 107 (20.6%) evaluable patients developed ADAs to imetelstat. ²⁰ In the pivotal IMerge/MDS3001 trial, 28 of 166 (16.9%) evaluable patients developed ADAs to imetelstat, with a median time to onset of ADAs of approximately 38 weeks after starting treatment. ⁸ There was no clinically significant effect of ADAs on the PK, safety, or efficacy of imetelstat when comparing patients with LR‐MDS who did and did not develop ADAs. ⁸ , ¹⁷ Overall, imetelstat ADAs occurred at a generally low incidence and did not impact the benefit/risk profile of imetelstat.

EXPOSURE‐RESPONSE RELATIONSHIPS

E‐R analyses were evaluated for patients with myelofibrosis in the IMbark/MYF2001 trial and those with LR‐MDS in the IMerge/MDS3001 trial.

In IMbark/MYF2001, E‐R relationships were evaluated at the imetelstat dosages of 4.4 mg/kg and 8.9 mg/kg q3w. E‐R analyses evaluated the relationship between efficacy endpoints (symptom response defined as a total symptom score reduction of ≥50% at week 24 and OS) and key safety endpoints (grade 3/4 neutropenia and thrombocytopenia) with imetelstat exposure (average concentration [C _avg] calculated as the total cumulative area under the concentration curve after all imetelstat administrations divided by time). ²⁵ Results demonstrated a positive E‐R relationship for efficacy between quartiles of imetelstat exposure and increasing total symptom score response. Further, a longer OS duration was observed when comparing the highest three imetelstat exposure quartiles (Q2–Q4) to the lowest quartile (Q1; hazard ratio, 0.570; log‐rank p = 0.0302). ²⁵ No clear E‐R relationships were seen for imetelstat safety endpoints, ²⁵ although caution should be considered given the potential confounding influence of dose modifications, particularly as a result of safety events, and patient discontinuations on the C _avg exposure metric. Overall, results from the E‐R analyses confirmed the clinical outcomes of IMbark/MYF2001 showing better clinical benefit of imetelstat 8.9 mg/kg over 4.4 mg/kg q3w and a manageable safety profile, supporting its investigation in the ongoing phase III study, IMpactMF/MYF3001 (NCT04576156; see Future Directions). Further E‐R analyses are planned using data emerging from the phase III IMpactMF/MYF3001 trial.

In IMerge/MDS3001, E‐R relationships were evaluated at the therapeutic imetelstat dosage of 7.1 mg/kg q4w. E‐R analyses evaluated the relationship between efficacy endpoints (≥8‐week and ≥24‐week RBC‐TI) and key safety endpoints (grade 3/4 neutropenia and thrombocytopenia; any grade and grade 3/4 infections and bleeding events) with imetelstat exposure (cycle 1 AUC, cycle 1 C _max, and C _avg up to the time of the event). ²² The completed analyses consisted of multivariate logistic regression adjusting for various baseline factors that could influence the E‐R relationship. Results from the analyses revealed a statistically significant positive E‐R relationship between ≥8‐week and ≥24‐week RBC‐TI and imetelstat exposure (C _avg) (Figure 3). ²² As noted above, there is a potential risk of confounding with this exposure metric. No significant E‐R relationship was seen between efficacy and imetelstat cycle 1 AUC or C _max. E‐R for safety revealed no significant relationship for grade 3/4 neutropenia; however, a positive E‐R relationship was observed for grade 3/4 thrombocytopenia and imetelstat cycle 1 exposure (statistically significant for C _max and approaching significance for AUC; Figure 3). ²⁰ Importantly, no significant E‐R was seen for safety events considered clinical consequences of these cytopenias, in terms of any grade or grade 3/4 infections or bleeding events (Figure 3). Additionally, there was no significant E‐R relationship between patients recovering from grade 3/4 neutropenia or thrombocytopenia and imetelstat exposure ¹⁸ (data not shown) with more patients recovering within 4 weeks compared with 2 weeks, supporting the 4‐week dosing schedule. Taken together, the results from E‐R supported the favorable benefit/risk profile of imetelstat 7.1 mg/kg q4w in LR‐MDS; however, additional opportunities exist to evaluate alternative dosing regimens (see ‘Future Directions’).

FIGURE 3.

Exposure‐response relationships for imetelstat efficacy and safety after administration of imetelstat 7.1 mg/kg q4w in patients with LR‐MDS. Figure illustrates results from univariate logistic regression models evaluating the probability of each efficacy or safety event and imetelstat exposure in the study IMerge/MDS3001. Efficacy or safety events are reported in the header, y axis depicts the proportion of patients with (reported at 1) or without (reported at 0) the event, and x axis reports the imetelstat exposure metric. The results of the linear logistic regression model along with the 95% confidence interval are illustrated in the black line and gray shading. Line and whisker plots illustrate the observed proportion of patients reporting the event within each quartile of imetelstat exposure and 90% confidence intervals. Statistical significance was evaluated by chi‐square statistic and confirmed against the null model using the likelihood ratio test. C _avg, average concentration; C _max, maximum concentration; LR‐MDS, lower‐risk myelodysplastic syndromes; q4w, every 4 weeks.

FUTURE DIRECTIONS

The clinical pharmacology and clinical efficacy and safety profile for imetelstat have been extensively characterized across its development program. Future directions include continued evaluation of imetelstat across multiple disease settings. In the myelofibrosis setting, the ongoing randomized phase III study IMpactMF/MYF3001 (NCT04576156) aims to confirm the benefit/risk profile of imetelstat 8.9 mg/kg q3w, while the ongoing phase Ib study IMproveMF is investigating the combination of imetelstat with ruxolitinib (NCT05371964). The IMpress study is ongoing to evaluate imetelstat in patients with high‐risk MDS or AML failing hypomethylating agent‐based therapy (NCT05583552). In the LR‐MDS population, a post‐approval dose‐optimization/confirmation study will evaluate an alternative imetelstat dosing regimen. ²⁶ Finally, a study is ongoing to evaluate imetelstat in the pediatric population with relapsed/refractory AML, MDS, or myelomonocytic leukemia (NCT06247787).

AUTHOR CONTRIBUTIONS

A.L.L., F.H., M.K.B., M.G.‐S., N.H., Y.W., L.S., F.F., and P.N.M. designed the research. A.L.L., M.G‐S., N.H., T.B., F.F., and P.N.M. performed the research. All authors contributed to the writing of the manuscript and analysis of the data.

FUNDING INFORMATION

The study was funded by Geron Corporation.

CONFLICT OF INTEREST STATEMENT

A.L.L., F.H., M.K.B., Y.W., L.S., T.B., and F.F. are employees of Geron Corporation, the sponsor of the work, and may hold stock or stock options. M.G.‐S., N.B., and P.N.M. are independent consultants and have been paid for the strategic and technical input into the analysis. P.N.M. may hold past or current employment and/or stock or stock options in other organizations.

Lennox AL, Huang F, Behrs MK, et al. Imetelstat, a novel, first‐in‐class telomerase inhibitor: Mechanism of action, clinical, and translational science. Clin Transl Sci. 2024;17:e70076. doi: 10.1111/cts.70076