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.”
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.”
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 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: 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.”