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.”
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.”
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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
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.”