Taltz
ixekizumab
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
“Toxicity of ixekizumab was evaluated in vitro and in vivo in Cynomolgyus monkeys; studies were justified in Cynomolgus monkeys on the basis that other species did not show pharmacological sensitivity to ixekizumab whereas this was similar between humans and Cynomolgus monkeys.”
Why that species
Binds human and cynomolgus IL-17A with similar affinity; lower rabbit binding; no binding to mouse or rat IL-17A
“The results demonstrate that ixekizumab binds human and cynomolgus monkey IL-17 with similar affinities in a concentration dependent manner. Ixekizumab also binds to rabbit IL-17, but the affinity is lower and heterogenous. However, ixekizumab shows no binding to both mouse and rat IL-17.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey (rat anti-mouse IL-17 antibodies used only in pharmacology models)
“Two surrogate antibodies that cross react with murine IL-17 were used in nonclinical collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) models.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Once weekly subcutaneous injections of ixekizumab for 9 months in cynomolgus monkeys caused no adverse compound-related clinical signs at ≤5 mg/kg/week.”
Pivotal GLP studies
GLP cynomolgus monkey studies: up to 8-week weekly IV and 39-week weekly SC, with recovery groups
“General toxicity studies used intravenous dosing for up to 8 weeks and subcutaneous dosing up to 39 weeks with recovery groups for high dose and controls.”
Route in tox
IV and SC
“General toxicity studies used intravenous dosing for up to 8 weeks and subcutaneous dosing up to 39 weeks with recovery groups for high dose and controls.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Based on ICH S6 (Guideline for the Safety Evaluation of Biotechnology-Derived Pharmaceuticals) guidelines, no genetic toxicology studies were conducted with ixekizumab.”
Carcinogenicity
Not conducted; weight of evidence including literature judged carcinogenic potential low
“Thirdly, the literature does not suggest an increased risk for tumorigenicity in relation to neutralisation of IL-17. Overall, the carcinogenic potential of ixekizumab was considered to be low.”
Reproductive & developmental
Monkey fertility, EFD and PPND up to 50 mg/kg/week: no treatment-related effects; neonatal deaths at 5 and 50 mg/kg/week
“No treatment-related effects were observed during these studies. Neonatal deaths occurred in the infants of two monkeys administered ixekizumab at 5 mg/kg/week and two monkeys administered ixekizumab at 50 mg/kg/week.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no cardiovascular, respiratory or CNS effects
“indicated that ixekizumab did not affect cardiovascular, respiratory or central nervous system functions.”
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 Taltz 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: 9-month SC NOAEL 5 mg/kg/week, limited by injection site reactions requiring dose suspension at the high dose (FDA pharmacology/toxicology review, p. 6)
NOAEL / key findings
9-month SC NOAEL 5 mg/kg/week, limited by injection site reactions requiring dose suspension at the high dose
“Based on the injection site reactions requiring dose suspension, the NOAEL for this 9-month study was 5 mg/kg/week.”
Risksopen answer page →
Immune & cytokine safety
No effects on lymphocyte subsets or KLH TDAR; neutralizing ADA in one high-dose monkey after recovery
“There were no treatment-related changes in the anti-KLH IgG or IgM responses either during the dosing or recovery phases. At the end of the recovery period, one high dose female was positive for anti-drug neutralizing antibody.”
Biodistribution & persistence
No specific TCR staining in any human or cynomolgus monkey tissue
“No specific ixekizumab staining was observed in any human or Cynomolgus monkey tissues examined at either concentration.”
Modality-specific risk
Malignancy risk from immunosuppressive properties with long-term use
“Nevertheless, as the risk for malignancies cannot be completely excluded due to the immunosuppressive properties of ixekizumab especially with long term use, this risk has been included in the Risk Management Plan as an important potential risk.”