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.”
Species: general tox
Cynomolgus monkey only (other species not pharmacologically sensitive)
“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.”
Species: DART
Cynomolgus monkey (fertility, EFD, pre- and postnatal development)
“Fertility, embryofetal development and peri- and postnatal development studies have been conducted with ixekizumab in cynomlgus monkeys treated by subcutaneous injection with up to 50 mg/kg/week.”
Species: carcinogenicity
Not conducted
“No genetic toxicity or carcinogenicity studies have been conducted with ixekizumab.”
Surrogate used in
Surrogate anti-mouse IL-17 antibodies used in pharmacology models (CIA, EAE); toxicity studies used ixekizumab
“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.”
Genotox: Ames
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.”
Genotox: in vitro mammalian
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.”
Genotox: in vivo
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 model
Not conducted; literature review of IL-17A inhibition used instead
“No genetic toxicity or carcinogenicity studies have been conducted with ixekizumab. The sponsor has conducted a literature review to assess the carcinogenic potential of inhibiting IL-17A which correlates to potential effects after treatment with ixekizumab.”
Carcinogenicity timing
Not required; no nonclinical carcinogenicity studies recommended
“No nonclinical studies to address the carcinogenic potential of ixekizumab are recommended.”
hERG / QT
No hERG assay; no effects on heart rate, QT or QTc in 39-week monkey ECGs
“No effects on heart rate or on QT or corrected-QT intervals. All ECGs were qualitatively and quantitatively within normal limits and no arrhythmias were found.”
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
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: 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.”
Anti-drug antibodies: animals
Neutralizing ADA in 1 high-dose female monkey at end of recovery (39-week study)
“At the end of the recovery period, one high dose female was positive for anti-drug neutralizing antibody.”
Anti-drug antibodies: patients
~22% over 60 weeks at recommended regimen; higher titers associated with lower drug concentration and clinical response
“Approximately 22% of subjects treated with TALTZ at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.”
Label warnings
- Infections
- Pre-treatment Evaluation for Tuberculosis
- Hypersensitivity
- Eczematous Eruptions
- Inflammatory Bowel Disease
- Immunizations
InfectionsHypersensitivity & infusion reactionsSkin reactionsGastrointestinal
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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) SC cynomolgus monkey study with 4-month recovery
“A repeat-dose toxicity, toxicokinetic, and immunotoxicology study in cynomolgus monkeys given LY2439821 by subcutaneous injection once weekly for 9 months with a 4-month recovery”
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.”
DART package
Species: DART
Cynomolgus monkey (fertility, EFD, pre- and postnatal development)
“Fertility, embryofetal development and peri- and postnatal development studies have been conducted with ixekizumab in cynomlgus monkeys treated by subcutaneous injection with up to 50 mg/kg/week.”
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.”
PPND / ePPND: when
PPND in cynomolgus monkey (with fertility and EFD studies): completed before the marketing application
“Fertility, embryofetal development and peri- and postnatal development studies have been conducted with ixekizumab in cynomlgus monkeys treated by subcutaneous injection with up to 50 mg/kg/week.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No genetic toxicity or carcinogenicity studies have been conducted with ixekizumab.”
Carcinogenicity model
Not conducted; literature review of IL-17A inhibition used instead
“No genetic toxicity or carcinogenicity studies have been conducted with ixekizumab. The sponsor has conducted a literature review to assess the carcinogenic potential of inhibiting IL-17A which correlates to potential effects after treatment with ixekizumab.”
Carcinogenicity timing
Not required; no nonclinical carcinogenicity studies recommended
“No nonclinical studies to address the carcinogenic potential of ixekizumab are recommended.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 39-week NOAEL 5 mg/kg: AUC 6.5x human steady-state (61x at 50 mg/kg LOAEL)
“39-Week repeat-dose toxicity study 50 mg/kg LOAEL 5 mg/kg NOAEL 144c 15.3d 61x 6.5x”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Surrogate anti-mouse IL-17 antibodies in mouse collagen-induced arthritis and EAE 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.”
Why that model
Ixekizumab binds human and monkey IL-17A but not mouse or rat IL-17A
“Ixekizumab is a humanized IgG4 monoclonal antibody that binds to human and monkey IL-17A. Ixekizumab does not bind to mouse or rat IL-17A.”
Reviewer's view of the efficacy data
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.
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for chronic psoriasis use; weight-of-evidence review of nonclinical data and IL-17A literature instead
Why: Carcinogenic potential considered low; malignancy kept as an important potential risk in the RMP · Weight of evidence
“Animal studies to assess the carcinogenic potential of ixekizumab were not submitted. Instead, a critical evaluation of the nonclinical ixekizumab data and published literature on IL-17A function was conducted.”
“Overall, the carcinogenic potential of ixekizumab was considered to be low. 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.”
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