Rytelo
imetelstat
Species
MonkeyMouseRabbit
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and cynomolgus monkey (general tox); mouse and rabbit (EFD)
“The mouse and monkey were used for the single- and repeat-dose toxicity studies, and mouse and rabbit were used for the EFD toxicity studies.”
Why that species
Sequence homology to hTR template region; 100% complementary in monkey, 9/13 mouse, 11/13 rat/rabbit
“These species were selected based on sequence homology to the template region of the RNA component of human telomerase and expected relevant pharmacologic action of imetelstat across species, from human to monkey to rabbit to rodent, as well as species-specific sensitivities to known ODN class effects.”
Surrogate molecule
No surrogate; clinical molecule tested in mouse, monkey and rabbit despite rodent mismatches
“Despite the mismatches, IC50 values are similar in tumour cell lines from all tested species, supporting their relevance for toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Dose and frequency of dosing: 0, 5, 10 or 15 mg/kg for 9 months + 14 weeks recovery; once a week dosing.”
Pivotal GLP studies
GLP IV: 6-month mouse (bolus BIW) and 9-month cynomolgus monkey (2-h infusion weekly); mouse and rabbit EFD
“Additional imetelstat toxicities observed in the chronic pivotal toxicity studies, ie, the 6-month study in mice (003-TOX-2008) and the 9-month study in monkeys, included microscopic findings in the liver and kidney”
Route in tox
Intravenous (bolus in mice, 2-hour infusion in monkeys), matching clinical route
“The drug was dosed for 6 months in rats and 9 months in monkeys via IV administration, which is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
“In genetic toxicity studies, imetelstat was not mutagenic in the in vitro bacterial reverse mutation assay.”
Carcinogenicity
Not conducted pre-approval; mouse and rat carcinogenicity studies required as PMRs
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
Reproductive & developmental
EFD in mice and rabbits: post-implantation loss/resorptions; no fertility or PPND studies
“Increased rates of post-implantation loss and early resorptions that resulted in a decreased number of viable fetuses and litter size per animal, and decreased uterine weight were observed at”
Safety pharmacology
Stand-alone telemetered monkey CV/CNS/respiratory study plus ECG in 9-month monkey study; no effects
“There were no test article-related changes observed in the cardiovascular, central nervous or respiratory systems.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Mouse NOAEL 20 mg/kg; monkey HNSTD 15 mg/kg/week; cytopenias, complement activation, aPTT prolongation, liver/kidney
“No NOAEL could be determined. Instead, a highest non-severely toxic dose (HNSTD) of 15 mg/kg was established, as no mortalities or life-threatening were observed at this dose.”
Risksopen answer page →
Immune & cytokine safety
Alternative complement activation (Bb, C5a); no immunotoxicity; no ADA assessment in animals
“No immunogenicity (e.g., anti-drug antibody) assessment has been conducted.”
Biodistribution & persistence
Highest in liver and kidney, then bone marrow and spleen; urinary excretion
“The highest concentration of imetelstat was seen in the liver and kidney, followed by the bone marrow and spleen.”
Modality-specific risk
Oligonucleotide class effects: thrombocytopenia/cytopenias, complement activation, coagulation (aPTT); mitigated by 2-h infusion
“The general toxicities observed in rodents and/or non-rodents with imetelstat dosing were cytopenias (most notably thrombocytopenia), complement activation, and coagulation abnormalities.”