Loqtorzi
toripalimab
Species
Monkey
Longest study
26 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
“Toripalimab does not cross-react with mouse or rat PD-1, so that toxicity studies were performed in cynomolgus monkeys, the only relevant species.”
Why that species
Similar binding to human and cynomolgus PD-1 on primary T cells; no binding to mouse or rat PD-1
“Toripalimab did not bind to the ECD of mouse or rat PD-1. On primary T cells, toripalimab had similar binding to human and cynomolgus PD-1 with EC50 values of 3.5 and 4.3 nM, respectively.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“Toripalimab does not cross-react with mouse or rat PD-1, so that toxicity studies were performed in cynomolgus monkeys, the only relevant species.”
Species: general tox
Cynomolgus monkey only (4-week and 26-week studies)
“Toripalimab does not cross-react with mouse or rat PD-1, so that toxicity studies were performed in cynomolgus monkeys, the only relevant species.”
Species: DART
Not conducted; public information that anti-PD-1 antibodies may cause fetal harm
“no reproductive and development toxicity studies have been conducted as there is public information indicating that antibodies targeting PD-1 may cause fetal harm when administered to a pregnant woman, obviating the need for reproductive studies.”
Species: carcinogenicity
Not conducted (ICH S6(R1); ICH S9 advanced cancer)
“No carcinogenicity studies were conducted. In accordance with ICH S6(R1) “Standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals””
Surrogate used in
No surrogate molecule; human PD-1 knock-in mice used for anti-tumor pharmacology with toripalimab
“Toripalimab had antitumor activity in human PD-1 knock-in (KI) mice generated by swapping mouse PD-1 exon 2 with human PD-1 exon 2 encoding the entire extracellular domain”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The FDA agrees that there were no toripalimab-related adverse effects up to doses of 100 mg/kg on male or female cynomolgus monkeys treated once weekly for 26 weeks.”
Pivotal GLP studies
GLP cynomolgus monkey 4-week IV Q2W (10-100 mg/kg, 7-week recovery) and 26-week IV weekly studies
“In the 4-week GLP-compliant (Q2W) repeat- dose study (10, 30, 100 mg/kg) with a 7-week recovery period, toripalimab was well tolerated at doses up to 100 mg/kg.”
Route in tox
IV
“Monkeys received intravenous toripalimab once weekly at doses of 0, 10, 30, and 100 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“No genotoxicity testing was conducted. Toripalimab is a large protein molecule and per ICH S6(R1), the range and type of genotoxicity studies “are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.””
Carcinogenicity
Not conducted (ICH S6(R1), ICH S9 advanced cancer)
“No carcinogenicity studies were conducted. In accordance with ICH S6(R1) “Standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals””
Reproductive & developmental
No dedicated studies; weight-of-evidence literature assessment; no adverse effects on reproductive organs in 4- and 26-week monkey studies
“In the pivotal 4-week and 26-week GLP-compliant toxicity studies, evaluation of sexually mature male and female cynomolgus monkey reproductive tissues (organ weights, macroscopic and microscopic examination) did not reveal any adverse effects of toripalimab on reproductive organs.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or CNS effects up to 100 mg/kg
“The FDA agrees that there were no adverse effects of toripalimab at doses up to 100 mg/kg given once weekly for 4 weeks on cardiovascular, respiration, and central nervous system parameters in male and female cynomolgus monkeys.”
Genotox: Ames
Not conducted (ICH S6(R1))
“No genotoxicity testing was conducted. Toripalimab is a large protein molecule and per ICH S6(R1), the range and type of genotoxicity studies “are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.””
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“No genotoxicity testing was conducted. Toripalimab is a large protein molecule and per ICH S6(R1), the range and type of genotoxicity studies “are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.””
Genotox: in vivo
Not conducted (ICH S6(R1))
“No genotoxicity testing was conducted. Toripalimab is a large protein molecule and per ICH S6(R1), the range and type of genotoxicity studies “are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.””
Carcinogenicity model
Not conducted (ICH S6(R1); ICH S9 advanced cancer)
“No carcinogenicity studies were conducted. In accordance with ICH S6(R1) “Standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals””
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
““Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer”.”
hERG / QT
No hERG assay; no cardiovascular, respiratory or CNS effects up to 100 mg/kg in monkeys
“The FDA agrees that there were no adverse effects of toripalimab at doses up to 100 mg/kg given once weekly for 4 weeks on cardiovascular, respiration, and central nervous system parameters in male and female cynomolgus monkeys.”
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 Loqtorzi 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 100 mg/kg (highest dose) in 26-week study; no toripalimab-related adverse effects (FDA multi-discipline review, p. 91)
NOAEL / key findings
NOAEL 100 mg/kg (highest dose) in 26-week study; no toripalimab-related adverse effects
“Therefore, the NOAEL was considered 100 mg/kg for this study.”
Risksopen answer page →
Immune & cytokine safety
In vitro cytokine release with immobilized or soluble antibody similar to negative control; cytokine release unlikely
“In an in vitro assay using human blood, the cytokine release profile for immobilized and soluble toripalimab was similar to that of the negative control, indicating that toripalimab is unlikely to induce cytokine release.”
Biodistribution & persistence
Human TCR: expected staining of PD-1-expressing mononuclear cells; no unexpected tissue cross-reactivity
“This staining was expected based on PD-1 expression in mononuclear cell types, including T cells, B cells, and other myeloid cells. No unexpected tissue cross-reactivity was observed.”
Modality-specific risk
Increased susceptibility to pathogens such as tuberculosis from loss of PD-1 function
“While loss of PD-1 function enhances clearance of some tumors and viral infections, it increases susceptibility to certain other pathogens such as tuberculosis in some animal models.”
Anti-drug antibodies: animals
ADA reduced toripalimab exposure and receptor occupancy in monkeys; no ADA-mediated toxicity
“Decreased in toripalimab exposure and receptor occupancy correlated with the formation of ADA. There were no ADA-mediated toxicity findings.”
Anti-drug antibodies: patients
3.4% treatment-emergent ADA (240 mg Q3W with chemotherapy, JUPITER-02)
“Of the 146 evaluable patients in JUPITER-02 with nasopharyngeal cancer who received LOQTORZI 240 mg every 3 weeks for a median duration of 15.1 months, in combination with gemcitabine and cisplatin, 3.4% tested positive for treatment-emergent ADA.”
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
China: initial clinical studies in patients with a variety of tumor types
“The pharmacokinetic profile of toripalimab was assessed preliminarily in three Phase 1 studies, conducted in China, in patients with a variety of tumor types.”
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 Loqtorzi 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 100 mg/kg (highest dose) in 26-week study; no toripalimab-related adverse effects (FDA multi-discipline review, p. 91)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV, weekly) study with 66-day recovery
“26-week toxicity with 66-day recovery period IV, cynomolgus monkey (1348RD2)”
Pivotal GLP studies
GLP cynomolgus monkey 4-week IV Q2W (10-100 mg/kg, 7-week recovery) and 26-week IV weekly studies
“In the 4-week GLP-compliant (Q2W) repeat- dose study (10, 30, 100 mg/kg) with a 7-week recovery period, toripalimab was well tolerated at doses up to 100 mg/kg.”
DART package
Species: DART
Not conducted; public information that anti-PD-1 antibodies may cause fetal harm
“no reproductive and development toxicity studies have been conducted as there is public information indicating that antibodies targeting PD-1 may cause fetal harm when administered to a pregnant woman, obviating the need for reproductive studies.”
Reproductive & developmental
No dedicated studies; weight-of-evidence literature assessment; no adverse effects on reproductive organs in 4- and 26-week monkey studies
“In the pivotal 4-week and 26-week GLP-compliant toxicity studies, evaluation of sexually mature male and female cynomolgus monkey reproductive tissues (organ weights, macroscopic and microscopic examination) did not reveal any adverse effects of toripalimab on reproductive organs.”
PPND / ePPND: when
Not conducted: public information that anti-PD-1 antibodies may cause fetal harm
“no reproductive and development toxicity studies have been conducted as there is public information indicating that antibodies targeting PD-1 may cause fetal harm when administered to a pregnant woman, obviating the need for reproductive studies.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6(R1); ICH S9 advanced cancer)
“No carcinogenicity studies were conducted. In accordance with ICH S6(R1) “Standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals””
Carcinogenicity model
Not conducted (ICH S6(R1); ICH S9 advanced cancer)
“No carcinogenicity studies were conducted. In accordance with ICH S6(R1) “Standard carcinogenicity bioassays are generally inappropriate for biotechnology-derived pharmaceuticals””
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
““Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer”.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 100 mg/kg weekly (NOAEL, 26-week): 13 to 23-fold human AUC at 240 mg Q3W or 3 mg/kg Q2W
“Exposure achieved in the monkeys at the 100 mg/kg dose level on Day 92 was 13 to 23-fold higher than the AUC in patients receiving either 240 mg flat dose once every 3 weeks (34,212 ug*hr/mL after Dose 6) or 3 mg/kg once every 2 weeks (19,674 ug*hr/mL after Dose 7) on Day 85.”
NOAEL / key findings
NOAEL 100 mg/kg (highest dose) in 26-week study; no toripalimab-related adverse effects
“Therefore, the NOAEL was considered 100 mg/kg for this study.”
Efficacy evidenceopen answer page →
Efficacy evidence
MC38 colon tumors in human PD-1 knock-in mice; melanoma xenograft in NSG mice with CTL transfer
“In vivo toripalimab was found to inhibit the growth of a human melanoma cell lines (624Mel) in a Xenograft Tumour NSG mouse model with adoptive CTL transfer and to inhibit the growth of murine colon MC38 cell line in a human PD-1 Knock-in Mouse.”
Why that model
Toripalimab does not bind mouse or rat PD-1
“Toripalimab did not bind to the ECD of mouse or rat PD-1.”
Reviewer's view of the efficacy data
EMA: tumor models adequate to show efficacy of the therapeutic approach
“Those tumour models are considered adequate to show efficacy of the therapeutic approach.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive or embryo-fetal toxicity studies; weight-of-evidence assessment from published PD-1 pathway data instead
Why: Reproductive and embryofetal risks adequately characterized in accordance with applicable guidance · Weight of evidence · Within the guideline
“After discussion between the FDA and Top Alliance, a weight-of-evidence (WOE) based assessment of the potential for toripalimab to cause reproductive and embryofetal toxicity was provided.”
“The potential risks of reproductive toxicity and embryofetal toxicity have been adequately characterized in accordance with applicable guidance.”
DARTVerdict not stated
No fertility studies; reproductive organs assessed only in repeat-dose monkey studies with animals unlikely sexually mature
“Fertility studies have not been conducted with toripalimab. In 4-week and 26-week repeat-dose toxicology studies in cynomolgus monkeys, there were no adverse or notable effects in the male and female reproductive organs. However, those animals were unlikely sexually mature.”
Similar precedents
JemperliAntibodies · dostarlimab · PD-1Monkey only · 13 wkKeytrudaAntibodies · pembrolizumab · PD-1Monkey only · 26 wkLibtayoAntibodies · cemiplimab · PD-1Monkey only · 26 wkOpdivoAntibodies · nivolumab · PD-1Monkey only · 13 wkPenpulimabAntibodies · penpulimab · PD-1Monkey only · 13 wkTevimbraAntibodies · tislelizumab · PD-1Monkey only · 13 wk