Loqtorzi
toripalimab
Sources:FDA multi-discipline review ↗
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.”
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.”
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.”