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.”
Species: general tox
Mouse and monkey
“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.”
Species: DART
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.”
Species: carcinogenicity
Not conducted; 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.”
Surrogate used in
No surrogate used; clinical molecule active across tested species
“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.”
Genotox: Ames
Negative (bacterial reverse mutation)
“In genetic toxicity studies, imetelstat was not mutagenic in the in vitro bacterial reverse mutation assay.”
Genotox: in vitro mammalian
In vitro micronucleus in human lymphocytes: negative
“The drug was also negative for clastogenicity in both the in vitro micronucleus assay in human lymphocyte cultures and the in vivo mouse bone marrow micronucleus assay.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“The drug was also negative for clastogenicity in both the in vitro micronucleus assay in human lymphocyte cultures and the in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted pre-approval; mouse and rat studies to follow 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.”
Carcinogenicity timing
Not conducted before approval; mouse and rat carcinogenicity studies are postmarketing requirements
“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.”
hERG / QT
No hERG inhibition up to 750 µg/mL (~150 µM)
“Imetelstat did not inhibit hERG currents up to a concentration of 750 µg/ml (~150 µM).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rytelo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology oligonucleotides (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Mouse NOAEL 20 mg/kg; monkey HNSTD 15 mg/kg/week; cytopenias, complement activation, aPTT prolongation, liver/kidney (EMA assessment report, p. 32)
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.”
Anti-drug antibodies: animals
No anti-drug antibody assessment conducted in animals
“No immunogenicity (e.g., anti-drug antibody) assessment has been conducted.”
Anti-drug antibodies: patients
Seventeen percent (28/166) of evaluable low/intermediate-1 risk MDS patients ADA positive
“Seventeen percent (28/166) of evaluable patients with low- or intermediate-1 risk MDS tested positive for imetelstat anti-drug antibodies”
Label warnings
- Thrombocytopenia
- Neutropenia
- Infusion-Related Reactions
- Embryo-Fetal Toxicity
ThrombocytopeniaCytopeniasHypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rytelo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology oligonucleotides (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Mouse NOAEL 20 mg/kg; monkey HNSTD 15 mg/kg/week; cytopenias, complement activation, aPTT prolongation, liver/kidney (EMA assessment report, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (IV infusion, weekly) with 14-week recovery
“002-TOX-2008 was a 9-month toxicity study of GRN163L in Cynomolgus Monkeys followed by a 14- week recovery period.”
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”
DART package
Species: DART
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.”
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”
PPND / ePPND: when
No PPND study: considered acceptable for an indication mainly in older people and negligible oral bioavailability
“No PPND study has been submitted. This was considered acceptable based on the proposed indication which is primarily relevant for older people and that imetelstat has little or no oral bioavailability thereby removing the likelihood of postnatal exposure via lactation.”
Carcinogenicity
Species: carcinogenicity
Not conducted; 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.”
Carcinogenicity model
Not conducted pre-approval; mouse and rat studies to follow 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.”
Carcinogenicity timing
Not conducted before approval; mouse and rat carcinogenicity studies are postmarketing requirements
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse NOAEL 2.4x and monkey HNSTD 28.1x human exposure at recommended dose
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Xenograft mice with ovarian cancer and AML cell lines and paediatric AML patient-derived cells
“In vivo, tumour growth inhibition and prolonged survival were demonstrated in xenograft mice models using cancer cell lines (ovarian cancer or AML cell lines) and patient-derived cancer cells (paediatric AML).”
Why that model
No MDS-specific cell lines or xenograft models; models of related myeloid and other tumors used
“Due to the lack of MDS specific cell lines and mouse xenograft models and given the increased expression of telomerase across most cancer types, particularly myeloid malignancies that are closely related to MDS, nonclinical data were generated in models of other tumor types that are relevant to demonstrate imetelstat’s mechanism of action and antitumor activity.”
Reviewer's view of the efficacy data
EMA: no MDS-specific proof-of-concept; reliance on other myeloid malignancy models
“No specific proof-of concept for the proposed indication (MDS) is presented due to lack of MDS-specific cell lines and xenograft models”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a condition
No carcinogenicity studies before approval; ICH S9 waiver claim not accepted by FDA; mouse and rat studies required postmarketing
Why: Life expectancy of lower-risk MDS patients exceeds 5 years, so carcinogenicity assessment is warranted · Within the guideline
“Based on the literature provided by the Applicant and discussion with the clinical team, the life expectancy for patients with lower risk MDS (defined variously, but usually as low or intermediate-1 risk disease by IPSS) and ESA failure or transfusion dependency is > 5 years and carcinogenicity risk assessment is warranted for the intended patient population.”
“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.”
DARTAcceptedBeyond the letter
No fertility or pre/postnatal development studies
Why: Indication mainly in older people; little or no oral bioavailability · Other reason · Pharmacology or kinetics
“No PPND study has been submitted. This was considered acceptable based on the proposed indication which is primarily relevant for older people and that imetelstat has little or no oral bioavailability”
Efficacy modelVerdict not stated
No MDS xenograft or MDS cell-line studies; antitumor activity shown in other myeloid and solid tumor models
Why: No MDS-specific cell lines or mouse xenograft models exist
“No xenograft studies were conducted in MDS cells lines, and this was described by the Applicant as being due to the lack of MDS specific cell lines and mouse xenograft models.”
SpeciesQuestioned
Many potential off-target hybridization transcripts not covered in toxicology species owing to lack of sequence homology
“Importantly though, many of the identified transcripts were not covered in the nonclinical toxicology studies due to lack of sequence homology in the toxicology species.”
Impurity or metaboliteQuestioned
No dedicated metabolism studies; oligonucleotide degradation metabolites not identified or characterized
“The rat data indicates that imetelstat is rapidly degraded (including in the bone marrow) but the resulting degradation metabolites have not been identified (e.g., no identification of N-1, N-2 etc. metabolites has been provided by the applicant).”
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