Tevimbra
tislelizumab
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
“The toxicity of tislelizumab was assessed in several studies in cynomolgus monkeys, the relevant species.”
Why that species
Binds human and cynomolgus PD-1 but not murine PD-1
“From the results shown, tislelizumab seems to specifically bind to PD-1 (and to cynomolgus PD-1, but not to murine PD-1) with KD in the order of 0.1-0.2 nM.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“The toxicity of tislelizumab was assessed in several studies in cynomolgus monkeys, the relevant species.”
Species: general tox
Cynomolgus monkey only
“The toxicity of tislelizumab was assessed in several studies in cynomolgus monkeys, the relevant species.”
Species: DART
Not conducted (ICH S9); fertility/EFD and pre-/postnatal studies omitted
“Reproductive and developmental toxicity studies have not been conducted with tislelizumab. In line with ICH S9, omission of fertility/early embryonic development studies and of pre-/post-natal development studies is accepted.”
Species: carcinogenicity
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Surrogate used in
No surrogate used
“The toxicity of tislelizumab was assessed in several studies in cynomolgus monkeys, the relevant species.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant performed a first repeat-dose toxicology study in monkeys (P14-057-CD), where 0/3/10/30 mg/kg tislelizumab was administered IV once biweekly for 13 weeks to 6 animals/sex/group followed by a 6-week recovery period”
Pivotal GLP studies
Cynomolgus monkey 13-week IV studies, 3-60 mg/kg every 2 weeks (7 doses)
“In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration for 13 weeks at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations)”
Route in tox
IV; two single SC doses in males in the second study
“Doses of 0/30/60 mg/kg tislelizumab was administered IV once every two weeks for 13 weeks to 3 animals/sex/group or as two single doses (14 days apart to 3 males only) via subcutaneous injection (SQ).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Carcinogenicity
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Reproductive & developmental
No dedicated studies; PD-1/PD-L1 role in materno-fetal tolerance implies risk of abortion or stillbirth
“Given the role of the PD-1/PD-L1 pathway in maintaining materno-fetal tolerance, treatment with tislelizumab during pregnancy may lead to abortion or still births.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no respiratory, neural or cardiovascular effects
“Safety pharmacology parameters were incorporated in the toxicology studies and no effects were noted on parameters evaluating respiratory, neural or cardiovascular system.”
Genotox: Ames
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Genotox: in vitro mammalian
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Genotox: in vivo
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Carcinogenicity model
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Carcinogenicity timing
Not required under ICH S9
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
hERG / QT
No hERG assay; no cardiovascular, respiratory or neural effects in monkey repeat-dose studies
“Safety pharmacology parameters were incorporated in the toxicology studies and no effects were noted on parameters evaluating respiratory, neural or cardiovascular system.”
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 Tevimbra 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 30 mg/kg Q2W, 4.3-6.6x human exposure at 200 mg; no treatment-related toxicity or histopathology (EMA assessment report, p. 30)
NOAEL / key findings
NOAEL 30 mg/kg Q2W, 4.3-6.6x human exposure at 200 mg; no treatment-related toxicity or histopathology
“no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.”
Risksopen answer page →
Immune & cytokine safety
In vitro immunotoxicity/cytokine release assays: only neutralising ADA and possible enhanced recall response
“Beside the potential of tislelizumab to induce neutralising ADA and to possibly induce an enhanced recall response to the re-challenge antigen, no other toxicities were detected.”
Biodistribution & persistence
No specific tissue cross-reactivity in cynomolgus monkey or human tissues
“No specific tissue-cross reactivity with tislelizumab was noted in cynomolgus monkey or human tissues.”
Modality-specific risk
Increased infection severity and enhanced inflammatory responses from PD-1/PD-L1 blockade
“In animal models, inhibition of PD-L1/PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses.”
Anti-drug antibodies: animals
ADA in most monkeys, mostly neutralising; reduced Cmax/AUC especially at low dose, but exposure maintained
“ADA were detected in most of the animals and determined to be mostly neutralising. An impact on Cmax and AUC was evident especially in the low dose group and potentially also on AUC for the mid and high-dose group, nevertheless exposure was still present.”
Anti-drug antibodies: patients
Monotherapy pool: treatment-emergent ADA 16.3% (232/1424); neutralizing 0.6% (11)
“Among 1424 evaluable patients treated with tislelizumab 200 mg Q3W as monotherapy, 232 (16.3%) had treatment-emergent ADA, of which 224 (15.7%) had treatment-induced ADA, and 8 (0.6%) had treatment-boosted ADA, and 11 (0.6%) had neutralizing antibodies (Table 5-3).”
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 Tevimbra 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 30 mg/kg Q2W, 4.3-6.6x human exposure at 200 mg; no treatment-related toxicity or histopathology (EMA assessment report, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IV cynomolgus monkey study (P14-057-CD) with 6-week recovery
“The Applicant performed a first repeat-dose toxicology study in monkeys (P14-057-CD), where 0/3/10/30 mg/kg tislelizumab was administered IV once biweekly for 13 weeks to 6 animals/sex/group followed by a 6-week recovery period”
Pivotal GLP studies
Cynomolgus monkey 13-week IV studies, 3-60 mg/kg every 2 weeks (7 doses)
“In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration for 13 weeks at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations)”
DART package
Species: DART
Not conducted (ICH S9); fertility/EFD and pre-/postnatal studies omitted
“Reproductive and developmental toxicity studies have not been conducted with tislelizumab. In line with ICH S9, omission of fertility/early embryonic development studies and of pre-/post-natal development studies is accepted.”
Reproductive & developmental
No dedicated studies; PD-1/PD-L1 role in materno-fetal tolerance implies risk of abortion or stillbirth
“Given the role of the PD-1/PD-L1 pathway in maintaining materno-fetal tolerance, treatment with tislelizumab during pregnancy may lead to abortion or still births.”
PPND / ePPND: when
Not conducted; PPND omission accepted under ICH S9 (oncology)
“Reproductive and developmental toxicity studies have not been conducted with tislelizumab. In line with ICH S9, omission of fertility/early embryonic development studies and of pre-/post-natal development studies is accepted.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Carcinogenicity model
Not conducted (ICH S9)
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Carcinogenicity timing
Not required under ICH S9
“No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity in line with ICH guideline S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey no-toxicity dose 30 mg/kg Q2W: 4.3-6.6x human exposure at 200 mg
“In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration for 13 weeks at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations), no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.”
NOAEL / key findings
NOAEL 30 mg/kg Q2W, 4.3-6.6x human exposure at 200 mg; no treatment-related toxicity or histopathology
“no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft tumour models engrafted with human PBMCs: anti-tumour efficacy against several tumour cell lines
“In vivo studies using murine xenograft tumour models and human PBMCs showed tislelizumab efficacy against several tumour cell lines.”
Why that model
Tislelizumab binds human and cynomolgus PD-1 but not murine PD-1
“From the results shown, tislelizumab seems to specifically bind to PD-1 (and to cynomolgus PD-1, but not to murine PD-1) with KD in the order of 0.1-0.2 nM.”
Reviewer's view of the efficacy data
EMA: in vivo comparison with nivolumab/pembrolizumab of Fc-effector-null design would have strengthened proof of concept
“Therefore, a comparative study with Nivolumab and Pembrolizumab in an animal model to determine the lack of antibody effector function in vivo would have been supportive of the non-clinical proof of concept of tislelizumab.”
Flexibilityopen answer page →
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
Pivotal 13-week monkey toxicology study failed GLP inspection; a new GLP-compliant 13-week study was run during the procedure
Why: New GLP study confirmed the 30 mg/kg NOAEL; target well known; primate studies poorly predict checkpoint-inhibitor toxicity · Weight of evidence · Class precedent
“Importantly, despite the Applicant declared the pivotal toxicology study as GLP-compliant, the outcome of the triggered GLP inspection was negative.”
“Considering the new study results confirming the NOAEL at 30mg/kg, the results of additional tests confirming the specific binding of tislelizumab to PD-1, the well-known target and that “nonclinical toxicity studies in nonhuman primates have been poor in predicting clinical toxicities for antibodies mediating immune checkpoint blockade (Wang et al 2014)” the GLP and the specificity findings have been resolved.”
GLPAcceptedBeyond the letter
Tissue cross-reactivity studies not GLP-compliant; replaced by a Retrogenix cell-microarray binding assay
Why: Retrogenix results cleared doubts about insufficient binding · Other reason
“The GLP TCR studies submitted in the original application were not considered GLP compliant therefore the study results were replaced with Retrogenix assay”
“These results, together with the data provided for answer 45 contribute to clear up the doubts about tislelizumab possible insufficient binding. The major objection is therefore considered solved.”
DARTAccepted
No reproductive and developmental toxicity studies; pregnancy risk assessed by weight of evidence
Why: In line with ICH S9; weight-of-evidence approach per ICH S6(R1) for pregnancy risk · Within the guideline · Weight of evidence
“Reproductive and developmental toxicity studies have not been conducted with tislelizumab. In line with ICH S9, omission of fertility/early embryonic development studies and of pre-/post-natal development studies is accepted.”
“A weight of evidence approach, as outlined in ICH S6(R1) was applied to describe the potential risk of tislelizumab to human pregnancy, which is acceptable.”
Efficacy modelVerdict not stated
No in vivo comparison with nivolumab or pembrolizumab to confirm lack of Fc effector function
“Therefore, a comparative study with Nivolumab and Pembrolizumab in an animal model to determine the lack of antibody effector function in vivo would have been supportive of the non-clinical proof of concept of tislelizumab.”
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