Siliq
brodalumab
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
“Repeat-dose toxicity studies were performed in cynomolgus monkeys, because comparable potency was shown for brodalumab for the inhibition of monkey IL-17RA compared to human IL-17RA”
Why that species
Comparable potency against monkey and human IL-17RA; no cross-reactivity with rodent IL-17RA; dog binding inconclusive; rabbit unsuitable (ADA)
“because comparable potency was shown for brodalumab for the inhibition of monkey IL-17RA compared to human IL-17RA, whereas brodalumab does not cross-react with rodent IL-17RA and assessment of binding to dog IL-17RA was inconclusive.”
Surrogate molecule
No surrogate in toxicology; rat anti-mouse IL-17RA surrogates used only for in vivo pharmacology; clinical antibody tested in monkeys
“In order to demonstrate the proof of concept, in vivo activity was investigated using surrogate antibodies against mouse IL-17RA.”
Species: general tox
Cynomolgus monkey only (comparable potency vs monkey IL-17RA; no rodent cross-reactivity)
“Repeat-dose toxicity studies were performed in cynomolgus monkeys, because comparable potency was shown for brodalumab for the inhibition of monkey IL-17RA compared to human IL-17RA, whereas brodalumab does not cross-react with rodent IL-17RA and assessment of binding to dog IL-17RA was inconclusive.”
Species: DART
Cynomolgus monkey (ePPND); rabbit dose range-finding study limited by immunogenicity
“Reproductive and developmental toxicity studies included a dose range-finding study in rabbits and an enhanced pre- and postnatal developmental toxicity study in cynomolgus monkeys. The rabbit study was limited by immunogenicity and the rabbit was not further used for evaluation of reproductive and developmental toxicity.”
Species: carcinogenicity
Not conducted
“No genetic toxicity or carcinogenicity studies have been conducted with brodalumab.”
Surrogate used in
Yes: rat anti-mouse IL-17RA surrogates M750 and M751 for in vivo pharmacology; toxicology used brodalumab in monkeys
“Surrogate antibodies that were used were M750, a rat anti-mouse IL-17RA monoclonal antibody IgG2b, and M751, a chimeric rat anti-mouse IL-17RA monoclonal antibody with a mouse IgG1.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Cynomolgus monkeys dosed with 0, 10, 25 or 90 mg/kg/dose SC brodalumab weekly for six months were observed with mild skin changes and histopathology (MD and HD), increased neutrophil counts (HD) and decreased albumin/globulin ratios (MD and HD).”
Pivotal GLP studies
Pivotal 6-month weekly SC cynomolgus study (0, 10, 25, 90 mg/kg/dose); shorter monkey studies supportive
“In the pivotal repeat dose cynomolgus monkey toxicity study, animals dosed with 0, 10, 25 or 90 mg/kg/dose SC brodalumab weekly for six months were observed with mild skin changes and histopathology (MD and HD)”
Route in tox
Subcutaneous and intravenous
“The NOAEL for this study was determined to be 350 mg/kg/dose for both SC and IV routes of administration.”
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 brodalumab.”
Carcinogenicity
Not conducted; literature-based assessment inconclusive, carcinogenicity risk unknown
“Therefore, it is impossible to know the carcinogenicity risk of brodalumab.”
Reproductive & developmental
Monkey ePPND (combined EFD/PPND): NOAEL 90 mg/kg/week for embryofetal and pre/postnatal development
“Under the experimental conditions, a NOAEL for embryofetal development and for prenatal and postnatal development was identified as 90 mg/kg/week.”
Safety pharmacology
Incorporated into monkey repeat-dose studies; no effects on heart rate, ECG, blood pressure or respiration
“Safety pharmacology evaluations were incorporated in the repeat dose toxicology studies in cynomolgus monkeys. No effects were observed on heart rate, ECG, blood pressure and respiration.”
Genotox: Ames
Not conducted (ICH S6)
“In accordance with ICHS6(R1), no genotoxicity studies were conducted.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“In accordance with ICHS6(R1), no genotoxicity studies were conducted.”
Genotox: in vivo
Not conducted (ICH S6)
“In accordance with ICHS6(R1), no genotoxicity studies were conducted.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment (ICH S6)
“In line with ICH S6 (R1), a weight-of-evidence approach was applied to evaluate the carcinogenic potential of brodalumab.”
Carcinogenicity timing
Not required: no nonclinical carcinogenicity studies recommended
“No nonclinical studies to assess the carcinogenic potential of brodalumab were/are recommended.”
hERG / QT
No effects on heart rate, ECG, blood pressure or respiration in monkey repeat-dose studies (no hERG assay)
“Safety pharmacology evaluations were incorporated in the repeat dose toxicology studies in cynomolgus monkeys. No effects were observed on heart rate, ECG, blood pressure and respiration.”
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 Siliq 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: 6-month monkey NOAEL 90 mg/kg/dose; findings at least partially reversible during six-month recovery (FDA pharmacology/toxicology review, p. 21)
NOAEL / key findings
6-month monkey NOAEL 90 mg/kg/dose; findings at least partially reversible during six-month recovery
“These changes were at least partially reversible during the six month recovery period. The NOAEL for this study was determined to be 90 mg/kg/dose.”
Risksopen answer page →
Immune & cytokine safety
No significant effects on standard immune endpoints, immunophenotyping or KLH TDAR in adult and juvenile monkeys
“Immunotoxicity was investigated in cynomolgus monkeys by means of standard endpoints in repeated dose toxicity studies as well as immunophenotyping and T-cell dependent antibody response assays (KLH test) in adult and in juvenile monkeys. No significant effects were observed.”
Biodistribution & persistence
TCR binding largely comparable in human, monkey and rabbit tissues, matching reported IL-17RA expression
“Brodalumab binding was largely comparable in human, monkey and rabbit tissues. The binding pattern largely corresponds to reported expression of IL-17RA”
Modality-specific risk
Increased infection risk from receptor blockade, confirmed by some observations in the 6-month monkey study
“Data from the literature suggest an increased risk of infections, which was confirmed by some observations in the 6-month monkey study.”
Anti-drug antibodies: animals
ePPND: ADA in 24/35 (69%) dosed adult females; seven of these (29%) had neutralizing antibodies
“24 out of 35 (69%) adult female LD and HD animals were positive for ADAs on at least one time point. Seven out of 24 (29%) immunoassay positive brodalumab-dosed animals also tested positive in the bioassay for the presence of anti-brodalumab neutralizing antibodies.”
Anti-drug antibodies: patients
About 3% developed anti-brodalumab antibodies through 52 weeks; none neutralizing
“Approximately 3% of subjects treated with SILIQ developed antibodies to brodalumab through the 52-week treatment period. Of the subjects who developed antibodies to brodalumab, none had antibodies that were classified as neutralizing.”
Label warnings
Boxed warning: Suicidal ideation and behavior
- Suicidal Ideation and Behavior
- SILIQ REMS Program
- Hypersensitivity Reactions
- Infections
- Risk for Latent Tuberculosis Reactivation
- Eczematous Eruptions
- Crohn’s Disease
- Immunizations
PsychiatricHypersensitivity & infusion reactionsInfectionsSkin reactions
US prescribing information, Boxed Warning and 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 Siliq 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: 6-month monkey NOAEL 90 mg/kg/dose; findings at least partially reversible during six-month recovery (FDA pharmacology/toxicology review, p. 21)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week (6-month) SC cynomolgus monkey study with 6-month treatment-free recovery
“Study title: 6 Month Subcutaneous Injection Toxicity Study of AMG 827 in Cynomolgus Monkeys with a 6-Month Treatment-Free Phase”
Pivotal GLP studies
Pivotal 6-month weekly SC cynomolgus study (0, 10, 25, 90 mg/kg/dose); shorter monkey studies supportive
“In the pivotal repeat dose cynomolgus monkey toxicity study, animals dosed with 0, 10, 25 or 90 mg/kg/dose SC brodalumab weekly for six months were observed with mild skin changes and histopathology (MD and HD)”
DART package
Species: DART
Cynomolgus monkey (ePPND); rabbit dose range-finding study limited by immunogenicity
“Reproductive and developmental toxicity studies included a dose range-finding study in rabbits and an enhanced pre- and postnatal developmental toxicity study in cynomolgus monkeys. The rabbit study was limited by immunogenicity and the rabbit was not further used for evaluation of reproductive and developmental toxicity.”
Reproductive & developmental
Monkey ePPND (combined EFD/PPND): NOAEL 90 mg/kg/week for embryofetal and pre/postnatal development
“Under the experimental conditions, a NOAEL for embryofetal development and for prenatal and postnatal development was identified as 90 mg/kg/week.”
PPND / ePPND: when
ePPND (maternal, embryo-fetal and neonatal) in cynomolgus monkey with 6-month postnatal evaluation: completed (report 2011) before the marketing application
“Maternal, Embryo-Fetal, and Neonatal Toxicity Study of AMG 827 Administered by Subcutaneous Injection to Pregnant Cynomolgus Monkeys with 6-Month Postnatal Evaluation. Study Number 107716. May 23, 2011.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No genetic toxicity or carcinogenicity studies have been conducted with brodalumab.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment (ICH S6)
“In line with ICH S6 (R1), a weight-of-evidence approach was applied to evaluate the carcinogenic potential of brodalumab.”
Carcinogenicity timing
Not required: no nonclinical carcinogenicity studies recommended
“No nonclinical studies to assess the carcinogenic potential of brodalumab were/are recommended.”
Safety marginopen answer page →
Safety margin at NOAEL
6-month monkey 90 mg/kg (NOAEL) AUC 47x human at 210 mg Q2W
“However, there were no proliferative changes in cynomolgus monkeys administered weekly subcutaneous doses of brodalumab at 90 mg/kg for 6 months (AUC exposure 47-fold higher than in human patients receiving Kyntheum 210 mg every 2 weeks).”
NOAEL / key findings
6-month monkey NOAEL 90 mg/kg/dose; findings at least partially reversible during six-month recovery
“These changes were at least partially reversible during the six month recovery period. The NOAEL for this study was determined to be 90 mg/kg/dose.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse anti-IL-17RA surrogate antibodies in a mouse skin-inflammation model
“The proof of concept for brodalumab was demonstrated in a mouse model of skin inflammation by the use of surrogate antibodies against mouse IL-17RA.”
Why that model
No cross-reactivity with rat or mouse IL-17RA
“No cross-reactivity was found with rat or mouse IL-17RA.”
Reviewer's view of the efficacy data
EMA: surrogate skin-inflammation model showed inhibitory effects relevant for the indication
“The proof of concept for brodalumab was demonstrated in a mouse model of skin inflammation by the use of surrogate antibodies against mouse IL-17RA. The inhibition of IL-17RA in this disease model resulted in inhibitory effects which are relevant for the indication.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityCriticised but acceptedBeyond the letter
No carcinogenicity studies for a chronic non-oncology indication; literature-based weight-of-evidence assessment of IL-17RA inhibition, judged inconclusive
Why: Literature not definitive but majority suggests no increased carcinogenic potential; postmarketing malignancy surveillance suggested · Weight of evidence
“Therefore, it is impossible to know the carcinogenicity risk of brodalumab. Postmarketing surveillance of malignancy report frequency compared to background rates may provide the most accurate determination of cancer risk for brodalumab.”
“The majority of the references suggest there is no increased carcinogenic potential from IL-17RA or IL-17 inhibition. No nonclinical studies to assess the carcinogenic potential of brodalumab were/are recommended.”
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