Jemperli
dostarlimab
Species
Monkey
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1, supporting the use of cynomolgus monkey as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Similar PD-1 affinity in human and monkey (KD 1.8 vs 1.5 nM); no binding to mouse PD-1
“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“The Applicant evaluated the safety of dostarlimab in cynomolgus monkeys in GLP‐compliant repeat‐dose toxicity studies of up to 13 weeks duration.”
Species: general tox
Cynomolgus monkey only
“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1, supporting the use of cynomolgus monkey as the single pharmacologically relevant species for toxicity”
Species: DART
Not conducted: PD-1/PD-L1 blockade risk to fetomaternal tolerance; fertility not expected for cancer (ICH S9)
“No reproductive and developmental studies were conducted because of potential adverse effects of the blockade of PD‐1/programmed death‐ligand 1 (PD‐L1) pathway on the immune tolerance at the fetomaternal interface. Consistent with the ICH S9 guidance, fertility assessments are not typically expected for products intended for the treatment of patients with cancer.”
Species: carcinogenicity
Not conducted (biotechnology product for advanced cancer)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Surrogate used in
Yes: anti-mouse PD-1 surrogate (RMP1-14) for in vivo MC38 tumor pharmacology only; toxicology used dostarlimab
“Because dostarlimab did not bind to mouse PD‐1, the Applicant developed a mouse surrogate anti‐PD‐1 antibody (RMP1‐14) to investigate the effects of PD‐1 pathway inhibition on tumor growth.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant evaluated the safety of dostarlimab in cynomolgus monkeys in GLP‐compliant repeat‐dose toxicity studies of up to 13 weeks duration.”
Pivotal GLP studies
Cynomolgus monkey 4-week and 13-week once-weekly IV studies at 10, 30 and 100 mg/kg
“The single dose and repeat dose studies of 4- and 13-week duration were all performed with similar dose levels of dostarlimab (10, 30 and 100 mg/kg).”
Route in tox
IV infusion
“Route of administration: Intravenous (IV) infusion”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not warranted for a biotechnology-derived product
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Carcinogenicity
Not conducted (biotechnology product for advanced cancer)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Reproductive & developmental
No dedicated studies; literature: PD-L1 blockade in murine pregnancy models disrupts fetal tolerance and increases fetal loss
“Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.”
Safety pharmacology
Incorporated into 4-week monkey study; no effects on CV, respiratory or CNS function up to 100 mg/kg
“The administration of dostarlimab by a weekly IV dose for 4 weeks (5 total doses) to cynomolgus monkeys at dose levels of 0, 10, 30, or 100 mg/kg did not result in any dostarlimab‐related effects on function of the CV system, respiratory system, or CNS”
Genotox: Ames
Not conducted (biotechnology-derived product)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Genotox: in vitro mammalian
Not conducted (biotechnology-derived product)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Genotox: in vivo
Not conducted (biotechnology-derived product)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Carcinogenicity model
Not conducted (ICH S6; advanced cancer per ICH S9)
“No studies have been performed to assess the potential of dostarlimab for carcinogenicity or genotoxicity which was considered acceptable based on ICH S6 (R1).”
Carcinogenicity timing
Not required (biotechnology product for advanced cancer)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
hERG / QT
No hERG assay; no dostarlimab effects on monkey cardiovascular, respiratory or CNS function up to 100 mg/kg
“The administration of dostarlimab by a weekly IV dose for 4 weeks (5 total doses) to cynomolgus monkeys at dose levels of 0, 10, 30, or 100 mg/kg did not result in any dostarlimab‐related effects on function of the CV system, respiratory system, or CNS”
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 Jemperli 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 monoclonal antibodies
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal (EMA assessment report, p. 43)
NOAEL / key findings
NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal
“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg).”
Risksopen answer page →
Immune & cytokine safety
No in vitro cytokine release from human PBMCs at up to 400 µg/well
“Furthermore, in an in vitro cytokine release assay, dostarlimab did not induce cytokine release at concentrations up to 400 µg/well.”
Biodistribution & persistence
TCR: specific membrane binding to lymphocytes in many tissues and to peripheral blood monocytes
“Specific binding of dostarlimab was observed on plasma membrane elements of lymphocytes (including intravascular, perivascular, interstitial, and migrating lymphocytes) in a large number of tissues and to monocytes in peripheral blood.”
Modality-specific risk
Immune-mediated adverse reactions from PD-1 checkpoint blockade
“In clinical trials, toxicities associated with dostarlimab were primarily immune‐mediated adverse reactions that are predicted by its mechanism of action.”
Anti-drug antibodies: animals
ADA in 33.3-66.7% (single dose) and 8.33-75% (repeat dose) of monkeys; no significant overall TK impact
“It was found that between 33.3-66.7% of the single dose animals and 8.33-75% of the repeat dose animals developed ADA during the studies. ADA incidences were however correlated with overall TK parameters and compared to animals negative for ADAs and no significant impact on TK were observed.”
Anti-drug antibodies: patients
ADA 2.1% (8/384) in GARNET at recommended dosage; neutralizing 1% (4/384)
“Anti‑drug antibodies against dostarlimab-gxly were detected in 2.1% (8/384) of patients who received JEMPERLI at the recommended dosage. Neutralizing antibodies were detected in 1% (4/384) of patients.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT
- Embryo-Fetal Toxicity
Immune-mediated reactionsHypersensitivity & 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 Jemperli 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 monoclonal antibodies
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal (EMA assessment report, p. 43)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey (IV, once weekly) GLP study with 8-week recovery
“The study consisted in 13-Week Once Weekly Intravenous Toxicity Study in Cynomolgus Monkeys with an 8-Week Recovery Period (GLP).”
Pivotal GLP studies
Cynomolgus monkey 4-week and 13-week once-weekly IV studies at 10, 30 and 100 mg/kg
“The single dose and repeat dose studies of 4- and 13-week duration were all performed with similar dose levels of dostarlimab (10, 30 and 100 mg/kg).”
DART package
Species: DART
Not conducted: PD-1/PD-L1 blockade risk to fetomaternal tolerance; fertility not expected for cancer (ICH S9)
“No reproductive and developmental studies were conducted because of potential adverse effects of the blockade of PD‐1/programmed death‐ligand 1 (PD‐L1) pathway on the immune tolerance at the fetomaternal interface. Consistent with the ICH S9 guidance, fertility assessments are not typically expected for products intended for the treatment of patients with cancer.”
Reproductive & developmental
No dedicated studies; literature: PD-L1 blockade in murine pregnancy models disrupts fetal tolerance and increases fetal loss
“Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.”
PPND / ePPND: when
Not conducted: PD-1/PD-L1 blockade risks fetomaternal tolerance; no reproductive and developmental studies
“No reproductive and developmental studies were conducted because of potential adverse effects of the blockade of PD‐1/programmed death‐ligand 1 (PD‐L1) pathway on the immune tolerance at the fetomaternal interface.”
Carcinogenicity
Species: carcinogenicity
Not conducted (biotechnology product for advanced cancer)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Carcinogenicity model
Not conducted (ICH S6; advanced cancer per ICH S9)
“No studies have been performed to assess the potential of dostarlimab for carcinogenicity or genotoxicity which was considered acceptable based on ICH S6 (R1).”
Carcinogenicity timing
Not required (biotechnology product for advanced cancer)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in 13-week monkey study; lowest dose 10 mg/kg AUC ~6x and 5x human exposure at 500 mg Q3W/Q6W
“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg). At this dose level, the AUC0-168h was 74,500 μg•h/mL, corresponding to approximately 6 and 5 times the clinical exposure at 500 mg Q3W andQ6W.”
NOAEL / key findings
NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal
“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg).”
Efficacy evidenceopen answer page →
Efficacy evidence
MC38 syngeneic mouse colon tumor model with anti-mouse PD-1 surrogate RMP1-14; dostarlimab tested in vitro only
“Due to lack of cross‐reactivity between dostarlimab and mouse PD‐1, a surrogate anti‐mouse PD‐1 antibody (RMP1‐14) was used to assess the potential for PD‐1 inhibition to suppress tumor growth in an MC38 syngeneic mouse colon tumor model.”
Why that model
Dostarlimab does not bind mouse PD-1, so a surrogate was needed for mouse tumor models
“Because dostarlimab did not bind to mouse PD‐1, the Applicant developed a mouse surrogate anti‐PD‐1 antibody (RMP1‐14) to investigate the effects of PD‐1 pathway inhibition on tumor growth.”
Reviewer's view of the efficacy data
EMA: in vitro and surrogate in vivo proof of concept considered established
“From a non-clinical point of view, exposure-response relationship and the posology in patients appear to be justified. In vitro and in vivo proof of concept is considered established.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies; literature-based assessment of PD-1/PD-L1 blockade risk instead
Why: PD-1/PD-L1 blockade expected to disrupt fetomaternal immune tolerance; literature-based assessment judged acceptable · Weight of evidence · Pharmacology or kinetics
“No reproductive and developmental studies were conducted because of potential adverse effects of the blockade of PD‐1/programmed death‐ligand 1 (PD‐L1) pathway on the immune tolerance at the fetomaternal interface.”
“The FDA agrees that dedicated reproductive and developmental toxicity studies are not needed to support this BLA submission, and the Applicant’s literature‐based assessment of the potential reproductive toxicity of dostarlimab is acceptable.”
DARTQuestioned
No fertility studies; monkey reproductive organ data from sexually immature animals, so fertility risk unknown
“While fertility studies were not submitted, no notable effects on the male and female reproductive organs were observed in monkeys in the 1 month and 3 month repeat dose toxicology studies; however, these results may not be representative at all of the potential clinical risk because of the immaturity of the reproductive system of animals used in the studies.”
“Therefore, fertility toxicity remains unknown (see SmPC section 5.3).”
Safety marginAcceptedBeyond the letter
No NOAEL established in the 13-week monkey study (finding in one low-dose 10 mg/kg animal)
Why: Dostarlimab well tolerated; no special hazard identified in monkey studies up to 3 months · Weight of evidence
“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg).”
“Overall, dostarlimab appears to be well tolerated and no special hazard were identified for humans based on repeat-dose toxicity studies of duration up to 3 months in the cynomolgus monkey (see SmPC section 5.3).”
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