Poteligeo
mogamulizumab
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
“Toxicology studies were only conducted in cynomolgus monkeys due to the limited cross reactivity profile of mogamulizumab.”
Why that species
Binds lymphocytes only from humans and cynomolgus monkeys (identical CCR4 epitope sequence); no binding in dog, rat, mouse
“Biotinylated mogamulizumab specifically bound peripheral lymphocytes from humans and cynomolgus monkeys only; most the specific binding was in the CD4-positive subset. Similar binding in humans and cynomolgus monkeys is expected given the CCR4 amino acid sequence at the mogamulizumab binding region is identical in humans and cynomolgus monkeys.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Toxicology studies were only conducted in cynomolgus monkeys due to the limited cross reactivity profile of mogamulizumab.”
Species: general tox
Cynomolgus monkey only
“Toxicology studies were only conducted in cynomolgus monkeys due to the limited cross reactivity profile of mogamulizumab.”
Species: DART
Cynomolgus monkey (embryo-fetal development, organogenesis to late 3rd trimester)
“In an embryo-fetal development study pregnant cynomolgus monkeys were administered mogamulizumab IV once weekly at 40 mg/kg (approximately 27 times the exposure in patients at the recommended dose, based on AUC) from the start of organogenesis until late 3rd trimester.”
Species: carcinogenicity
Not conducted (not required for the indication)
“No carcinogenicity studies were conducted or are required to support a marketing application for the current indication.”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkeys
“Toxicology studies were only conducted in cynomolgus monkeys due to the limited cross reactivity profile of mogamulizumab.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Dose and frequency of dosing: 0, 2.5, 10, or 40 mg/kg; test article was administered once weekly for 26 weeks”
Pivotal GLP studies
GLP cynomolgus monkey 26-week once-weekly IV study (2.5, 10, 40 mg/kg), plus 4-week study
“In the 26-week study, mogamulizumab was administered IV at doses of 2.5, 10, or 40 mg/kg once weekly. Mogamulizumab was well-tolerated, and no adverse mogamulizumab-related changes were observed.”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Not conducted per ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S6(R1), S1, S9; advanced cancer)
“Not conducted per ICH S6(R1), S1, and S9.”
Reproductive & developmental
Monkey EFD (organogenesis through delivery): no embryo-fetal lethality, teratogenicity or fetal growth retardation
“administration of mogamulizumab to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show a potential for embryo-foetal lethality, teratogenicity, or foetal growth retardation.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory, renal or CNS effects
“Safety pharmacology endpoints were incorporated into the repeat-dose toxicity studies, and there was no evidence of mogamulizumab-related effects on the cardiovascular, respiratory, renal, or central nervous systems.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted or are required to support a marketing application for biotechnology-derived products such as mogamulizumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted or are required to support a marketing application for biotechnology-derived products such as mogamulizumab.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted or are required to support a marketing application for biotechnology-derived products such as mogamulizumab.”
Carcinogenicity model
Not conducted (ICH S6(R1), S1 and S9)
“Not conducted per ICH S6(R1), S1, and S9.”
Carcinogenicity timing
Not required for the indication
“No carcinogenicity studies were conducted or are required to support a marketing application for the current indication.”
hERG / QT
No hERG assay; no cardiovascular effects in repeat-dose monkey studies
“Safety pharmacology endpoints were incorporated into the repeat-dose toxicity studies in male and female cynomolgus monkeys. No evidence of deleterious effects on the cardiovascular, respiratory, renal, or central nervous systems were observed in these studies.”
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 Poteligeo 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Monkey NOAEL ≥40 mg/kg (highest dose); no toxicologically significant changes (EMA assessment report, p. 47)
NOAEL / key findings
Monkey NOAEL ≥40 mg/kg (highest dose); no toxicologically significant changes
“The NOAEL of mogamulizumab was judged to be 40 mg/kg or greater since no toxicologically significant changes were observed in any examination.”
Risksopen answer page →
Immune & cytokine safety
In vitro cytokine release (IL-6, TNF-α, IFN-γ) varied by assay format, greatest in solid-phase PBMC assays
“Results of the cytokine release assays varied by the experimental conditions; mogamulizumab generally caused greater cytokine release (IL-6, TNF-α, and IFN-γ) in solid phase assays with isolated PBMCs.”
Biodistribution & persistence
Placental transfer: fetal plasma exposure ~60% of maternal in monkeys
“At the end of the study plasma exposure of mogamulizumab in the fetuses was ~60% that observed in the dams; this finding is consistent with the expected transfer of mogamulizumab across the placental barrier.”
Modality-specific risk
Dermatologic adverse events in patients not predicted by monkey repeat-dose studies
“Dermatologic adverse events (AE) were observed in humans that were not predicted by the repeat-dose toxicity studies in cynomolgus monkeys.”
Anti-drug antibodies: animals
ADA in only 1 monkey in 26-week study; ADA-positive animals showed faster decline in drug concentration
“In the 26-week repeat-dose study, development of anti-mogamulizumab antibodies was observed in only one animal (1 female in the 2.5 mg/kg group). The plasma mogamulizumab concentrations of the animals in which anti-mogamulizumab antibodies were observed decreased more rapidly than the plasma concentration in animals that did not produce anti-mogamulizumab antibodies.”
Anti-drug antibodies: patients
14.1% (44/313) ADA-positive; no neutralizing antibodies; no clinically significant effect
“Among 313 patients treated with POTELIGEO and whose antibodies were tested, 44 (14.1%) tested positive for anti-mogamulizumab-kpkc antibodies. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, safety, or effectiveness of POTELIGEO. There were no positive neutralizing antibody responses.”
Label warnings
- Dermatologic Toxicity
- Infusion Reactions
- Infections
- Autoimmune Complications
- Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) after POTELIGEO
Skin reactionsHypersensitivity & infusion reactionsInfectionsImmune-mediated reactions
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 Poteligeo 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Monkey NOAEL ≥40 mg/kg (highest dose); no toxicologically significant changes (EMA assessment report, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey IV study, once weekly; recovery not stated
“In the 26-week study, mogamulizumab was administered IV at doses of 2.5, 10, or 40 mg/kg once weekly.”
Pivotal GLP studies
GLP cynomolgus monkey 26-week once-weekly IV study (2.5, 10, 40 mg/kg), plus 4-week study
“In the 26-week study, mogamulizumab was administered IV at doses of 2.5, 10, or 40 mg/kg once weekly. Mogamulizumab was well-tolerated, and no adverse mogamulizumab-related changes were observed.”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal development, organogenesis to late 3rd trimester)
“In an embryo-fetal development study pregnant cynomolgus monkeys were administered mogamulizumab IV once weekly at 40 mg/kg (approximately 27 times the exposure in patients at the recommended dose, based on AUC) from the start of organogenesis until late 3rd trimester.”
Reproductive & developmental
Monkey EFD (organogenesis through delivery): no embryo-fetal lethality, teratogenicity or fetal growth retardation
“administration of mogamulizumab to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show a potential for embryo-foetal lethality, teratogenicity, or foetal growth retardation.”
PPND / ePPND: when
Not conducted: PPND not required for products treating advanced cancer
“Fertility/early embryonic development and pre/postnatal development studies were not conducted as these studies are not required to support a marketing application for products intended to treat patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not required for the indication)
“No carcinogenicity studies were conducted or are required to support a marketing application for the current indication.”
Carcinogenicity model
Not conducted (ICH S6(R1), S1 and S9)
“Not conducted per ICH S6(R1), S1, and S9.”
Carcinogenicity timing
Not required for the indication
“No carcinogenicity studies were conducted or are required to support a marketing application for the current indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey EFD study at 40 mg/kg (no adverse findings) approximately 27 times patient exposure at recommended dose (AUC)
“In an embryo-fetal development study pregnant cynomolgus monkeys were administered mogamulizumab IV once weekly at 40 mg/kg (approximately 27 times the exposure in patients at the recommended dose, based on AUC) from the start of organogenesis until late 3rd trimester.”
NOAEL / key findings
Monkey NOAEL ≥40 mg/kg (highest dose); no toxicologically significant changes
“The NOAEL of mogamulizumab was judged to be 40 mg/kg or greater since no toxicologically significant changes were observed in any examination.”
Efficacy evidenceopen answer page →
Efficacy evidence
SCID mouse xenografts of human CTCL (HH) and ATL (TL-Om1) cell lines
“The antitumor activity of mogamulizumab was evaluated in mouse xenograft models of CTCL and ATL. Male SCID mice (Fox CHASE C.B-17/Icr-scidJcl) were subcutaneously injected with the human CTCL cell line HH or the ATL cell line TL-Om1.”
Why that model
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.
Reviewer's view of the efficacy data
Tumour growth suppressed in xenografts; FDA noted studies in NK-cell-deficient mice were not conducted
“Once-weekly treatment with mogamulizumab (20 mg/kg) suppressed tumor growth without affecting body weight. Studies evaluating the antitumor activity of mogamulizumab in mice lacking natural killer (NK) cells were not conducted.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No fertility/early embryonic or pre/postnatal development studies; monkey embryo-fetal study only
Why: Not required for products treating patients with advanced cancer · Within the guideline · Serious disease
“Fertility/early embryonic development and pre/postnatal development studies were not conducted as these studies are not required to support a marketing application for products intended to treat patients with advanced cancer.”
Efficacy modelVerdict not stated
No antitumour studies in NK-cell-deficient mice to confirm the ADCC mechanism in vivo
“Studies evaluating the antitumor activity of mogamulizumab in mice lacking natural killer (NK) cells were not conducted.”
Similar precedents
BavencioAntibodies · avelumab · PD-L1Monkey only · 13 wkCyramzaAntibodies · ramucirumab · VEGFR2Monkey only · 39 wkDarzalexAntibodies · daratumumab · CD38Monkey only · 6 wkHerceptinAntibodies · trastuzumab · HER2Monkey only · 26 wkImfinziAntibodies · durvalumab · PD-L1Monkey only · 13 wkImjudoAntibodies · tremelimumab · CTLA-4Monkey only · 26 wk