Penpulimab
penpulimab
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
“In in vitro studies, penpulimab bound to human and cynomolgus monkey PD-1 but did not bind rodent PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Binds human and cynomolgus PD-1 (EC50 0.053 and 0.215 nM) but not mouse or rat PD-1
“with EC50 values of 0.053 and 0.215 nM, respectively, but did not bind to mouse or rat PD-1, supporting the use of cynomolgus monkeys as a pharmacologically relevant species for toxicity assessment.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys (human PD-1 knock-in mice used only for efficacy)
“Given that pempulimab does not bind mouse PD-1, the Applicant investigated the in vivo antitumor activity of pempulimab in a human PD-1 knock-in genetically engineered mouse model (HuGEMM)”
Species: general tox
Cynomolgus monkey only
“The Applicant evaluated the safety of penpulimab in cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Species: DART
Not conducted; literature-based assessment of reproductive toxicity instead
“No reproductive or embryo-fetal developmental toxicology studies were conducted with penpulimab. Rather, the Applicant provided a literature-based assessment of the potential reproductive toxicity of penpulimab”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of penpulimab in the currently proposed indication per ICH S9.”
Surrogate used in
No surrogate used; efficacy used human PD-1 knock-in mice with the clinical antibody
“Given that pempulimab does not bind mouse PD-1, the Applicant investigated the in vivo antitumor activity of pempulimab in a human PD-1 knock-in genetically engineered mouse model (HuGEMM)”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant evaluated the safety of penpulimab in cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”
Pivotal GLP studies
GLP monkey IV infusion studies (6-week and 13-week), 4, 15 or 60 mg/kg once every two weeks
“In 6-week repeat-dose toxicity study, no apparent toxicity was observed in cynomolgus monkeys following intravenous infusion of penpulimab at 4, 15, or 60 mg/kg once every two weeks for 6 weeks.”
Route in tox
Intravenous infusion
“In the 6- and 13-week studies, monkeys received IV infusion of pempulimab at doses up to 60 mg/kg once every 2 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“FDA agrees that genetic toxicology studies are not needed to support the use of penpulimab per ICH S6.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9); penpulimab not active in rodents
“Carcinogenicity studies were not conducted with penpulimab, which is consistent with its use in patients with advanced malignancies (see the ICH Guidance S9).”
Reproductive & developmental
No dedicated studies; literature-based assessment of reproductive toxicity used instead
“No reproductive or embryo-fetal developmental toxicology studies were conducted with penpulimab. Rather, the Applicant provided a literature-based assessment of the potential reproductive toxicity of penpulimab”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no effects on body temperature, respiration, oxygen saturation, ECG or blood pressure
“There were no treatment-related effects on body temperature, respiratory rate, blood oxygen saturation, electrocardiograms, or blood pressure found in the repeat dose toxicology study.”
Genotox: Ames
Not conducted (ICH S6)
“FDA agrees that genetic toxicology studies are not needed to support the use of penpulimab per ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“FDA agrees that genetic toxicology studies are not needed to support the use of penpulimab per ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“FDA agrees that genetic toxicology studies are not needed to support the use of penpulimab per ICH S6.”
Carcinogenicity model
Not conducted; rodent bioassays inappropriate as penpulimab is not active in rodents
“however rodent bioassays are inappropriate, as penpulimab does not appear to be active in rodents.”
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of penpulimab in the currently proposed indication per ICH S9.”
hERG / QT
No hERG assay; no ECG or blood pressure effects in repeat-dose monkey studies
“There were no treatment-related effects on body temperature, respiratory rate, blood oxygen saturation, electrocardiograms, or blood pressure found in the repeat dose toxicology study.”
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 Penpulimab 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: 13-week monkey NOAEL 60 mg/kg; lymph node increased cellularity and erythrophagocytosis (FDA multi-discipline review, p. 53)
NOAEL / key findings
13-week monkey NOAEL 60 mg/kg; lymph node increased cellularity and erythrophagocytosis
“Histological findings included increased cellularity and erythrophagocytosis in the inguinal, mandibular, and mesenteric lymph nodes. • The NOAEL was 60 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
ADA incidence 63.33% (6-week study) and 93.33% (13-week study) in monkeys
“The incidence of anti-drug antibody formation was 63.33% in the 6-week study and 93.33% in the 13-week study, which may explain the limited findings noted in the 13-week study.”
Biodistribution & persistence
TCR: binding to human spleen and lymph nodes and monkey lymphoid and GI tissues; no unexpected binding
“PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, and as the results of penpulimab tissue cross-reactivity (TCR) studies showed no unexpected binding of penpulimab to human or cynomolgus monkey tissues was found.”
Modality-specific risk
Immune-mediated adverse reactions predicted by the mechanism of action
“In clinical trials done to support the approval of penpulimab in the proposed patient population, toxicities associated with penpulimab were primarily immune-mediated adverse reactions that are predicted by its mechanism of action.”
Anti-drug antibodies: animals
ADA in 63.33% (6-week) and 93.33% (13-week) of monkeys; may explain limited 13-week findings
“The incidence of anti-drug antibody formation was 63.33% in the 6-week study and 93.33% in the 13-week study, which may explain the limited findings noted in the 13-week study.”
Anti-drug antibodies: patients
30% (105/349) ADA with single agent; 17% (18/105) of ADA-positive had neutralizing antibodies
“30% (105/349) of patients tested positive for anti-drug antibodies (ADA) at one or more post-baseline timepoints. Of those who tested positive for ADA, 17% (18/105) had neutralizing antibodies against penpulimab-kcqx.”
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
Australia: first-in-human study in patients
“two different assays were used to characterize the ADAs and NAbs in the Phase 1 study conducted in Australia and the three Phase 2 studies conducted in China, respectively.”
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 Penpulimab 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: 13-week monkey NOAEL 60 mg/kg; lymph node increased cellularity and erythrophagocytosis (FDA multi-discipline review, p. 53)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey IV infusion study with 6-week recovery
“A 13-Week Intravenous Infusion Toxicity Study of AK105 Injection With a 6-Week Recovery Period in Cynomolgus Monkeys”
Pivotal GLP studies
GLP monkey IV infusion studies (6-week and 13-week), 4, 15 or 60 mg/kg once every two weeks
“In 6-week repeat-dose toxicity study, no apparent toxicity was observed in cynomolgus monkeys following intravenous infusion of penpulimab at 4, 15, or 60 mg/kg once every two weeks for 6 weeks.”
DART package
Species: DART
Not conducted; literature-based assessment of reproductive toxicity instead
“No reproductive or embryo-fetal developmental toxicology studies were conducted with penpulimab. Rather, the Applicant provided a literature-based assessment of the potential reproductive toxicity of penpulimab”
Reproductive & developmental
No dedicated studies; literature-based assessment of reproductive toxicity used instead
“No reproductive or embryo-fetal developmental toxicology studies were conducted with penpulimab. Rather, the Applicant provided a literature-based assessment of the potential reproductive toxicity of penpulimab”
PPND / ePPND: when
Not conducted: not warranted for advanced cancer (ICH S9)
“Pre- and postnatal toxicity studies were not conducted with penpulimab. As described in ICH Guidance S9, pre- and postnatal toxicity study is not warranted for marketing of pharmaceuticals for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of penpulimab in the currently proposed indication per ICH S9.”
Carcinogenicity model
Not conducted; rodent bioassays inappropriate as penpulimab is not active in rodents
“however rodent bioassays are inappropriate, as penpulimab does not appear to be active in rodents.”
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of penpulimab in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey highest dose 60 mg/kg ≥4.7x human AUC at the 200 mg clinical dose
“there were no notable effects on male and female reproductive organs up to the highest dose tested of 60 mg/kg (approximately ≥4.7 times the human exposure based on AUC at the 200 mg clinical dose)”
NOAEL / key findings
13-week monkey NOAEL 60 mg/kg; lymph node increased cellularity and erythrophagocytosis
“Histological findings included increased cellularity and erythrophagocytosis in the inguinal, mandibular, and mesenteric lymph nodes. • The NOAEL was 60 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human PD-1 knock-in mice (HuGEMM) bearing MC38 colon adenocarcinoma, dosed with penpulimab
“Given that pempulimab does not bind mouse PD-1, the Applicant investigated the in vivo antitumor activity of pempulimab in a human PD-1 knock-in genetically engineered mouse model (HuGEMM) implanted subcutaneously with MC38 mouse colon adenocarcinoma cells.”
Why that model
Penpulimab does not bind mouse PD-1, so a human PD-1 knock-in mouse model was used
“Given that pempulimab does not bind mouse PD-1, the Applicant investigated the in vivo antitumor activity of pempulimab in a human PD-1 knock-in genetically engineered mouse model (HuGEMM)”
Reviewer's view of the efficacy data
FDA: no outstanding pharmacology/toxicology issues preventing approval
“There are no outstanding issues from a pharmacology/toxicology perspective that would prevent the approval of penpulimab (either in combination with gemcitabine and cisplatin or carboplatin, or as a single agent) for the treatment of adult patients with non-keratinizing NPC.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development study; weight-of-evidence literature assessment of reproductive toxicity instead
Why: Dedicated reproductive and developmental toxicity studies not needed for this BLA; weight-of-evidence approach reasonable · Weight of evidence
“To address the potential effects of penpulimab on embryo-fetal development, the Applicant submitted an assessment of the potential reproductive toxicity of penpulimab using a weight-of-evidence approach. FDA agreed in January 2021 that this approach appeared reasonable.”
“The FDA’s Assessment: FDA agrees that dedicated reproductive and developmental toxicity studies are not needed to support this BLA submission.”
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