Molecular mass: 4,610.18 g/mol PubChem compound: 72941969
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.
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.
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