Ilumya
tildrakizumab
Species
Monkey
Longest study
39 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 with tildrakizumab were conducted in cynomolgus monkeys which were shown to be a relevant species, based on the binding of tildrakizumab to cynomolgus IL-23p19.”
Why that species
98% IL-23p19 sequence homology and high-affinity binding in cynomolgus monkey; no binding to mouse IL-23p19
“Comparison of the amino acid sequences of IL-23p19 between human and various preclinical species revealed that cynomolgus monkeys had a 98% homology to humans.”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkey (mouse surrogate SCH 900598 used for pharmacology)
“Due to the lack of cross-reactivity with mouse IL-23p19 and in order to test the potency efficacy in vivo a surrogate antibody, SCH 900598, was generated against the mouse IL-23p19.”
Species: general tox
Cynomolgus monkey only
“Toxicology studies with tildrakizumab were conducted in cynomolgus monkeys which were shown to be a relevant species, based on the binding of tildrakizumab to cynomolgus IL-23p19.”
Species: DART
Cynomolgus monkey (fertility from repeat-dose studies, EFD, PPND)
“Reproductive and developmental toxicity of tildrakizumab was evaluated in cynomolgus monkeys.”
Species: carcinogenicity
Not conducted; weight-of-evidence including mouse tumour models
“Classical carcinogenicity animal studies were not conducted; instead the risk of carcinogenicity was assessed based on a weight of evidence approach. To this end, the applicant has conducted several in vivo studies in mouse tumour models and an extensive analysis of current literature.”
Surrogate used in
Yes, pharmacology only: mouse anti-IL-23p19 surrogate SCH 900598 in colitis and infection models; toxicology used tildrakizumab
“Due to the lack of cross-reactivity with mouse IL-23p19 and in order to test the potency efficacy in vivo a surrogate antibody, SCH 900598, was generated against the mouse IL-23p19.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Toxicity of tildrakizumab was evaluated in repeated dose studies of 3-months and 9 months treatment duration.”
Pivotal GLP studies
Cynomolgus monkey 3-month IV/SC Q2W and 9-month SC Q2W repeat-dose studies
“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”
Route in tox
SC and IV
“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“No genotoxicity studies were performed, in line with ICH S6(R1).”
Carcinogenicity
Not conducted; weight-of-evidence (literature, mouse tumour models, no pre-neoplastic changes) indicates carcinogenic risk unlikely
“Taken together the weight of evidence supports the position that tildrakizumab is unlikely to be associated with increased carcinogenic risk.”
Reproductive & developmental
Monkey EFD: no fetal effects up to 159x MRHD; PPND: increased neonatal deaths at 59x MRHD, significance unknown
“An embryofetal developmental study conducted with tildrakizumab in pregnant monkeys revealed no treatment-related effects to the developing fetus when tildrakizumab was administered subcutaneously during organogenesis to near parturition at doses up to 159 times the maximum recommended human dose (MRHD). When dosing was continued until parturition, an increase in neonatal death was observed at 59 times the MRHD (see Data).”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or CNS effects
“No tildrakizumab-related effects on the cardiovascular, respiratory and central nervous systems were noted.”
Genotox: Ames
Not conducted (ICH S6(R1))
“No genotoxicity studies were performed, in line with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“No genotoxicity studies were performed, in line with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6(R1))
“No genotoxicity studies were performed, in line with ICH S6(R1).”
Carcinogenicity model
No classical studies; tildrakizumab did not alter tumour growth in a xenograft model
“Mechanistic studies performed by the applicant have shown that tildrakizumab did not alter the growth of tumours in a xenograft model.”
Carcinogenicity timing
Not required; weight-of-evidence approach accepted; malignancies monitored clinically and post marketing
“Taken together the weight of evidence supports the position that tildrakizumab is unlikely to be associated with increased carcinogenic risk.”
hERG / QT
No stand-alone safety pharmacology; no cardiovascular, respiratory or CNS effects in monkey repeat-dose studies
“No tildrakizumab-related effects on the cardiovascular, respiratory and central nervous systems were noted.”
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 Ilumya 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 140 mg/kg Q2W IV/SC (3-month) and 100 mg/kg SC Q2W (9-month), highest doses; no adverse effects (EMA assessment report, p. 24)
NOAEL / key findings
NOAEL 140 mg/kg Q2W IV/SC (3-month) and 100 mg/kg SC Q2W (9-month), highest doses; no adverse effects
“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”
Risksopen answer page →
Immune & cytokine safety
No tildrakizumab-related changes in infant lymphocyte counts or TDAR responses (PPND study)
“The results of these analyses did not reveal any tildrakizumab-related changes in lymphocyte numbers or TDAR responses.”
Biodistribution & persistence
Cytoplasmic-only TCR staining in human and monkey tissues, considered not relevant in vivo
“The Applicant has argued that since these staining were all cytoplasmic in nature it is unlikely that such tissue cross reactivity would be able to occur in vivo.”
Modality-specific risk
Serious infections from impaired IL-17/Th17-dependent host defence after IL-23 blockade
“Nevertheless, since IL-23 is required for generation of Th17 cells, an impaired IL-17-dependent immune response against pathogens cannot be excluded.”
Anti-drug antibodies: animals
No ADAs in 9-month monkey study; 1 animal in 3-month study with apparently neutralising ADA and reduced exposure
“Of note, no ADAs were detected in any of the animals in the 9-month toxicity study, whilst only 1 animal in the 3-month study tested positive for ADAs which appeared to be neutralising based on the reduced exposure in this animal.”
Anti-drug antibodies: patients
ADA 6.5% (26/400) to week 64; 38.4% of these neutralizing
“In pooled Phase 2b and Phase 3 analyses, 6.5% (26/400) of subjects treated with tildrakizumab 100 mg up to week 64 developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, 38.4% (10/26 subjects) had neutralizing antibodies.”
Label warnings
- Hypersensitivity
- Infections
- Pretreatment Evaluation for Tuberculosis
- Immunizations
Hypersensitivity & infusion reactionsInfections
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 Ilumya 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 140 mg/kg Q2W IV/SC (3-month) and 100 mg/kg SC Q2W (9-month), highest doses; no adverse effects (EMA assessment report, p. 24)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) study with recovery phase; recovery length not stated
“Histopathology data from recovery animals from the 9 months study were generally unremarkable.”
Pivotal GLP studies
Cynomolgus monkey 3-month IV/SC Q2W and 9-month SC Q2W repeat-dose studies
“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”
DART package
Species: DART
Cynomolgus monkey (fertility from repeat-dose studies, EFD, PPND)
“Reproductive and developmental toxicity of tildrakizumab was evaluated in cynomolgus monkeys.”
Reproductive & developmental
Monkey EFD: no fetal effects up to 159x MRHD; PPND: increased neonatal deaths at 59x MRHD, significance unknown
“An embryofetal developmental study conducted with tildrakizumab in pregnant monkeys revealed no treatment-related effects to the developing fetus when tildrakizumab was administered subcutaneously during organogenesis to near parturition at doses up to 159 times the maximum recommended human dose (MRHD). When dosing was continued until parturition, an increase in neonatal death was observed at 59 times the MRHD (see Data).”
PPND / ePPND: when
PPND in cynomolgus monkey (SC, GD 50 to parturition): completed before the marketing application
“A pre-postnatal development (PPND) study was performed in cynomolgus monkeys administered tildrakizumab by SC injection with 0, 10 or 100 mg/kg every 14 days from GD 50 to parturition with an associated TK study.”
Carcinogenicity
Species: carcinogenicity
Not conducted; weight-of-evidence including mouse tumour models
“Classical carcinogenicity animal studies were not conducted; instead the risk of carcinogenicity was assessed based on a weight of evidence approach. To this end, the applicant has conducted several in vivo studies in mouse tumour models and an extensive analysis of current literature.”
Carcinogenicity model
No classical studies; tildrakizumab did not alter tumour growth in a xenograft model
“Mechanistic studies performed by the applicant have shown that tildrakizumab did not alter the growth of tumours in a xenograft model.”
Carcinogenicity timing
Not required; weight-of-evidence approach accepted; malignancies monitored clinically and post marketing
“Taken together the weight of evidence supports the position that tildrakizumab is unlikely to be associated with increased carcinogenic risk.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 140 mg/kg Q2W (3 months): 133x (SC) or 155x (IV) MRHD by AUC
“No effects on fertility parameters were observed in male or female cynomolgus monkeys that were administered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once every two weeks for 3 months (133 or 155 times the MRHD, respectively, based on AUC comparison).”
NOAEL / key findings
NOAEL 140 mg/kg Q2W IV/SC (3-month) and 100 mg/kg SC Q2W (9-month), highest doses; no adverse effects
“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse surrogate SCH-900598 in T-cell-dependent and anti-CD40 colitis models; unrelated anti-IL-23p19 mAb in psoriasis skin xenograft mice
“Two different models of colitis, a T-cell dependent and an anti-CD40 model, were used and where efficacy of SCH-900598 was assessed.”
Why that model
No cross-reactivity with mouse IL-23p19, so a mouse surrogate antibody was generated
“Due to the lack of cross-reactivity with mouse IL-23p19 and in order to test the potency efficacy in vivo a surrogate antibody, SCH 900598, was generated against the mouse IL-23p19.”
Reviewer's view of the efficacy data
EMA: non-clinical pharmacology package sufficient to support the psoriasis application
“Overall, the provided non-clinical pharmacology package is considered sufficient to support the marketing authorisation application in psoriasis patients.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for chronic psoriasis use; weight-of-evidence assessment instead
Why: Weight of evidence indicates increased carcinogenic risk unlikely; malignancies monitored clinically and post marketing · Weight of evidence
“Classical carcinogenicity animal studies were not conducted; instead the risk of carcinogenicity was assessed based on a weight of evidence approach.”
“Taken together the weight of evidence supports the position that tildrakizumab is unlikely to be associated with increased carcinogenic risk. Nevertheless, malignancies will be monitored in the clinic during clinical studies and post marketing.”
DARTAcceptedBeyond the letter
Male fertility assessed by histopathology in repeat-dose monkey studies with few sexually mature males
Why: No findings in repeat-dose studies; normal fertility in IL-23 or IL-23R deficient mice · Weight of evidence · Pharmacology or kinetics
“While almost all females were sexually mature, the number of sexually mature males was limited.”
“Nevertheless, considering the lack of findings in the repeated dose toxicity studies together with data of normal fertility of mice deficient in IL-23 or IL-23 R the data available from the repeated dose toxicity studies are considered sufficient.”
Efficacy modelAcceptedBeyond the letter
In vivo efficacy shown with mouse surrogate antibody SCH-900598 in colitis models, not tildrakizumab
“Two different models of colitis, a T-cell dependent and an anti-CD40 model, were used and where efficacy of SCH-900598 was assessed.”
“Overall, the provided non-clinical pharmacology package is considered sufficient to support the marketing authorisation application in psoriasis patients.”
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