Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Geron Netherlands B.V., Naritaweg 165, 1043 BW Amsterdam, Netherlands
Pharmacotherapeutic group: Antineoplastic agents, Other antineoplastic agents
ATC code: L01XX80
Imetelstat is an oligonucleotide telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), which prevents telomere binding.
Telomerase activity and human telomerase reverse transcriptase (hTERT) RNA expression are known to be significantly increased in MDS and malignant stem and progenitor cells. Imetelstat treatment leads to reduction of telomere length, inhibition of malignant stem and progenitor cell proliferation and induction of apoptotic cell death leading to reduction of malignant clones.
During treatment with imetelstat at the recommended dose, anti-drug antibodies (ADA) were detected in 17% of participants. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.
The efficacy of imetelstat was evaluated in a Phase 3, randomised, double-blind, placebo-controlled, multicentre IMerge trial (MDS3001) in 178 adult patients enrolled with International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS who were transfusion-dependent (requiring ≥4 red blood cell (RBC) units over an 8-week period during the 16 weeks prior to randomisation). The diagnosis of MDS for inclusion was based on the WHO 2008 classification. Eligible patients were required to have failed to respond or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs); and had an absolute neutrophil count of 1.5 × 109/L or greater and platelets 75 × 109/L or greater. Patients were ineligible if they had a deletion 5q (del5q) cytogenetic abnormality or received prior treatment with lenalidomide or hypomethylating agents.
Participants were randomised in a 2:1 ratio to receive an intravenous infusion of imetelstat (n=118) 7.1 mg/kg or placebo (n=60) administered over 2 hours once every 4 weeks until disease progression, unacceptable toxicity, or withdrawal from the study. Randomisation was stratified by prior RBC transfusion burden and by IPSS risk group. Patients were pretreated with an antihistamine and a corticosteroid prior to dosing to mitigate infusion-related reactions. Dose delays or dose reductions for Grade 3 or Grade 4 toxicities observed at the time of the next planned dose were evaluated according to the specified dose modifications (see section 4.2). All patients received supportive care, which included RBC transfusions.
Of the 178 patients enrolled, 62% were male, and 80% White. The median age was 72 years (range: 39 to 87 years) with 20% (36/178) of patients ˂65, 47% (84/178) ≥65 to <75, and 33% (58/178) ≥75 years of age. A total of 118 patients received imetelstat for a median of 7.8 months (range: 0.03 to 32.5 months) and 59 patients received placebo for a median of 6.5 months (range: 0.03 to 26.7 months). The median follow-up time was 19.5 months (range: 1.4 to 36.2) in the imetelstat group and 17.5 months (range: 0.7 to 34.3) in the placebo group. The key baseline disease characteristics of the efficacy population are shown in Table 6.
Table 6. Baseline disease characteristics of patients with MDS in Phase 3 study MDS3001:
| Disease characteristics | Imetelstat (N=118) | Placebo (N=60) |
|---|---|---|
| Time since original diagnosis | ||
| Median years | 3.5 | 2.8 |
| ECOG score (0, 1, 2), n (%) | ||
| 0: Asymptomatic | 42 (35.6) | 21 (35) |
| 1: Symptomatic fully ambulatory | 70 (59.3) | 39 (65) |
| 2: Symptomatic in bed less than 50% of the day | 6 (5.1) | 0 |
| IPSS risk classification, n (%) | ||
| Low | 80 (67.8) | 39 (65) |
| Intermediate-1 | 38 (32.2) | 21 (35) |
| Prior RBC transfusion burdena, n (%) | ||
| 4 to 6 units | 62 (52.5) | 33 (55) |
| ˃6 units | 56 (47.5) | 27 (45) |
| WHO classification (2008), n (%) | ||
| RS+b | 73 (61.9) | 37 (61.7) |
| RS˗c | 44 (37.3) | 23 (38.3) |
| Missing | 1 (0.8) | 0 |
| Baseline serum erythropoietin (EPO), n (%) | ||
| ≤500 mU/mL | 87 (73.7) | 36 (60) |
| ˃500 mU/mL | 26 (22) | 22 (36.7) |
| Missing | 5 (4.2) | 2 (3.3) |
| Prior ESA use, n (%) | ||
| Yes | 108 (91.5) | 52 (86.7) |
| No | 10 (8.5) | 8 (13.3) |
Abbreviations: ECOG = Eastern cooperative oncology group; ESA = erythropoiesis-stimulating agent; IPSS = International Prognostic Scoring System; MDS = Myelodysplastic syndromes; RS+ = ring sideroblast positive; RS- = ring sideroblast negative; WHO = World Health Organization.
a Prior RBC transfusion burden is defined as the maximum number of RBC units transfused over an 8-week period during the 16 weeks prior to randomisation.
b RS+ includes: refractory anaemia with ring sideroblasts (RARS)/refractory cytopenia with multilineage dysplasia and ≥15% ringed sideroblasts (RCMD-RS).
c RS˗ includes: others.
Efficacy was determined based on the proportion of patients who achieved 8-week and 24-week red blood cell transfusion independence (RBC-TI). RBC-TI is presented as the absence of RBC transfusion(s) during any consecutive 8-week (56-day) period, and during any consecutive 24-week (168-day) period respectively, regardless of treatment discontinuations or use of subsequent anti-cancer therapy (treatment-policy strategy). The efficacy results are summarised in Table 7.
Table 7. Efficacy results in Phase 3 study MDS3001:
| Imetelstat (N=118) | Placebo (N=60) | |
|---|---|---|
| Rate of ≥8-week RBC TI in the First 24 weeksa | ||
| ≥8-week RBC TI, n (%) | 36 (30.5) | 6 (10.0) |
| 95% CI for response rate (%)b | (22.4, 39.7) | (3.8, 20.5) |
| % Difference (95% CI)c | 20.5 (6.8, 31.5) | |
| p-valued | 0.002 | |
| Rate of ≥24-week RBC TI in the First 48 weeksa | ||
| ≥24-week RBC TI, n (%) | 30 (25.4) | 2 (3.3) |
| 95% CI for response rate (%)b | (17.9, 34.3) | (0.4, 11.5) |
| % Difference (95% CI)c | 22.1 (10.3, 31.5) | |
| p-valued | <0.001 | |
CI = confidence interval; RBC = red blood cell; TI = transfusion independence.
a TI regardless of treatment discontinuations or use of subsequent anti-cancer therapy (treatment-policy strategy).
b The 95% CI for response rate based on Exact Clopper-Pearson confidence interval.
c The 95% CI for difference based on Wilson Score method.
d P-value is based on Cochran Mantel-Haenszel test stratified by prior RBC transfusion burden (≤6 vs. ˃6 units RBC) and IPSS risk group (low vs. intermediate-1).
The median duration of ≥8-week RBC TI was 51.6 weeks and the median haemoglobin (Hb) increase during the longest RBC TI period was 3.55 g/dL in imetelstat responders.
The treatment effect of imetelstat on RBC-TI ≥8 weeks was consistent across all clinically relevant disease characteristic subgroups, including in patients without ring sideroblasts.
The European Medicines Agency has deferred the obligation to submit the results of studies with Rytelo in the treatment of myelodysplastic syndromes, including juvenile myelomonocytic leukaemia, in one or more subsets of the paediatric population (see section 4.2 for information on paediatric use).
Imetelstat is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
In subjects with MDS receiving an intravenous infusion of 7.1 mg/kg imetelstat over 2 hours, the geometric mean (coefficient of variation [CV] ) maximum concentration (Cmax) in plasma was 89.5 mcg/mL (27.3) with peak concentrations observed at the end of the infusion. Based on Cmax, imetelstat does not accumulate between treatment cycles following every four-week dosing in patients with MDS.
Human plasma protein binding of imetelstat was 94%.
Imetelstat is likely metabolised by nucleases in tissue into smaller fragments.
The geometric mean (CV%) apparent half-life for imetelstat in plasma is approximately 4.9 hours (43.2%) in patients with MDS following a 7.1 mg/kg dose. Linearity/non-linearity Imetelstat plasma AUC0-24h increases in a more than dose proportional manner over the 0.4 to 11.0 mg/kg dose range.
No relevant data are available for evaluation of the pharmacokinetics of imetelstat in special populations.
Among the subjects with MDS, who received imetelstat during Study MDS3001, based on liver function test (NCI-ODWG), 31 subjects had mildly abnormal liver function tests (total bilirubin ≤ ULN and AST ˃ ULN, or total bilirubin ˃ 1× to 1.5× ULN (Grade 1) and any AST), 17 subjects had moderately abnormal liver function tests (total bilirubin ˃ 1.5× to 3× ULN (Grade 2) and any AST) nd 2 subjects had severely abnormal liver function tests (total bilirubin ˃ 3× ULN (Grade 3) and any AST).
Based on creatinine clearance (CrCL), 42 subjects had mild renal impairment (CrCL 60 to ˂90 mL/min), 39 subjects had moderate renal impairment (CrCL 30 to ˂60 mL/min), and 1 subject had severe renal impairment (CrCL 15 to ˂30 mL/min).
In 6-month mouse and 9-month monkey studies, dose-related increases in liver and kidney weights were observed. Microscopic analysis showed mild to moderate liver changes (inflammatory cell foci, increases in Kupffer cells, pigment deposition, telangiectasis) and kidney changes (mesangial thickening, glomerulonephritis/sclerosis, interstitial deposition, renal tubular haemorrhage, protein casts). These changes were fully recovered or reduced in severity after the 8- to 14-week treatment-free period. There were no significant alterations in hepatic or kidney function parameters. In these studies, the no observed adverse effect level (NOAEL) in mice and highest non-severely toxic dose (HNSTD) in monkeys were identified as the highest doses administered, which produced exposures that were up to 2.4- and 28.1-times, respectively, the human exposure at the recommended clinical dose.
Carcinogenicity studies have not been conducted with imetelstat.
Imetelstat did not exhibit genotoxic potential in in vitro and in vivo studies.
Assessment of effects on reproductive organs in chronic repeat-dose toxicity studies indicate the potential for impaired female fertility. Uterine endometrial atrophy was observed in monkeys administered 14.1 mg/kg once weekly for 9 months, at a mean exposure (based on AUC) that is approximately 20.0-times the human exposure at the recommended clinical dose. This effect was reversible following a 14-week recovery period.
No gross or histological changes for the male reproductive tissues were observed at any dose tested in chronic repeat-dose toxicity studies (up to 18.8 mg/kg in mice and 14.1 mg/kg in monkeys), with mean exposures (based on AUC) that are 2.4-times (mice) and 28.1-times (monkeys) the human exposure at the recommended clinical dose.
In embryo-foetal developmental toxicity studies, imetelstat doses of 4.7, 14.1 or 28.2 mg/kg were administered to pregnant mice and rabbits during the period of organogenesis. Imetelstat was not teratogenic, and there was no evidence of any foetal malformations in mice. Increases in fused sternebrae were noted at 28.2 mg/kg in rabbits, a dose considered to be maternally toxic based on decreases in mean gestational body weight. Embryo-lethal effects were observed at 28.2 mg/kg in both species, noted as increased post-implantation loss due to an increase in early resorptions, resulting in a decrease in viable foetuses and litter size per animal. No significant increase in post-implantation loss was observed at exposures (based on AUC) up to 1.5-times (mice) or 13.0-times (rabbits) the human exposure at the recommended clinical dose. The significance of these effects in humans is unknown.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.