Bimzelx
bimekizumab
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
“The only relevant species for nonclinical testing is the nonhuman primate.”
Why that species
No or very low affinity for mouse IL-17A, IL-17F or IL-17AF; binds cynomolgus IL-17A/F
“The non-clinical evaluation has been conducted in the Cynomolgus monkey only since bimekizumab has no or very low affinity for mouse IL-17A, IL-17F or IL-17AF.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys (no anti-rodent IL-17A/F surrogate available)
“Bimekizumab is not pharmacologically active in rodents and no anti-rodent IL-17 A/F surrogate is available.”
Species: general tox
Cynomolgus monkey only
“Cynomolgus monkeys were used in all studies as they were considered to be the only relevant non-clinical species by the applicant.”
Species: DART
Cynomolgus monkey (ePPND; fertility endpoints in 26-week repeat-dose study)
“The effects on male and female fertility were assessed by examination of reproductive organs, menstrual cycle lengths, or sperm analysis in the 26-week repeat-dose toxicity study in monkeys. In a pre- and postnatal developmental study, bimekizumab was administered to pregnant cynomolgus monkeys”
Species: carcinogenicity
Not conducted: not pharmacologically active in rodents and no anti-rodent IL-17A/F surrogate
“Bimekizumab is not pharmacologically active in rodents and no anti-rodent IL-17 A/F surrogate is available. Thus, conventional rodent carcinogenicity studies were not conducted for evaluation of the carcinogenic potential of bimekizumab.”
Surrogate used in
No surrogate used (no anti-rodent IL-17A/F surrogate available)
“Bimekizumab is not pharmacologically active in rodents and no anti-rodent IL-17 A/F surrogate is available.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The Applicant has conducted repeat dose toxicity studies in cynomolgus monkeys with weekly doses administered by subcutaneous injection for up to 26 weeks, followed by a treatment-free recovery period of up to 21 weeks”
Pivotal GLP studies
Cynomolgus monkey weekly SC repeat-dose studies up to 26 weeks with up to 21-week recovery
“The Applicant has conducted repeat dose toxicity studies in cynomolgus monkeys with weekly doses administered by subcutaneous injection for up to 26 weeks, followed by a treatment-free recovery period of up to 21 weeks”
Route in tox
Subcutaneous and intravenous
“Intravenous and subcutaneous routes of administration were explored.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“No genotoxicity studies have been conducted with bimekizumab in line with ICH S6 (R1) guideline.”
Carcinogenicity
Not conducted; literature weight-of-evidence shows no clear carcinogenicity concern from IL-17A/F inhibition
“In conclusion, the literature does not suggest a clear concern that inhibition of IL-17A and IL-17F would lead to carcinogenicity or tumor development.”
Reproductive & developmental
Monkey ePPND: NOAEL 50 mg/kg/week for maternal and developmental toxicity (38x MRHD)
“The no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was identified as 50 mg/kg/week which is 38 times (based on mg/kg comparison) the maximum recommended human dose”
Safety pharmacology
Incorporated into monkey repeat-dose studies; no CNS, respiratory, ECG or blood pressure effects up to 200 mg/kg/week
“Clinical observations from the repeat-dose toxicity studies conducted in cynomolgus monkeys indicate bimekizumab does not induce central nervous system or respiratory effects. No ECG or blood pressure effects were observed in cynomolgus monkeys treated subcutaneously for 26 weeks with up to 200 mg/kg/week bimekizumab.”
Genotox: Ames
Not conducted (ICH S6(R1))
“As per ICH Guidance S6 R1, Preclinical safety evaluation of biotechnology-derived pharmaceuticals (Section 4.7 Genotoxicity Studies), no genetic toxicology testing is warranted for bimekizumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“As per ICH Guidance S6 R1, Preclinical safety evaluation of biotechnology-derived pharmaceuticals (Section 4.7 Genotoxicity Studies), no genetic toxicology testing is warranted for bimekizumab.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“As per ICH Guidance S6 R1, Preclinical safety evaluation of biotechnology-derived pharmaceuticals (Section 4.7 Genotoxicity Studies), no genetic toxicology testing is warranted for bimekizumab.”
Carcinogenicity model
Not conducted; literature-based carcinogenic risk assessment instead
“No genetic toxicology or carcinogenicity studies were conducted with bimekizumab. The Applicant provided a carcinogenic risk assessment, using information from the published literature.”
Carcinogenicity timing
Waived: CDER ECAC agreed rodent carcinogenicity studies are not feasible
“The Executive Carcinogenicity Assessment Committee of CDER agreed that rodent carcinogenicity studies are not feasible and the Applicant was granted a waiver for their conduct (March 28, 2018).”
hERG / QT
No hERG assay; no ECG or blood pressure effects in monkeys up to 200 mg/kg/week for 26 weeks
“No ECG or blood pressure effects were observed in cynomolgus monkeys treated subcutaneously for 26 weeks with up to 200 mg/kg/week bimekizumab.”
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 Bimzelx 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: NOAEL was highest dose in 8-week studies (200 and 20 mg/kg/week); none in 26-week study (skin findings, GI infection deaths) (EMA assessment report, p. 25)
NOAEL / key findings
NOAEL was highest dose in 8-week studies (200 and 20 mg/kg/week); none in 26-week study (skin findings, GI infection deaths)
“The no-observed adverse effect level (NOAEL) was the highest dose tested in the 8-week studies (200mg/kg/week and 20mg/kg/week, respectively, for Study NCD2260 and Study NCD2384). Due to the severity of skin findings in some high-dose animals and mortalities in the low dose group consecutive to GI infection, no NOAEL could be determined in the 26-week study.”
Risksopen answer page →
Immune & cytokine safety
Increased infection risk from reduced muco-epidermal immunity in single and repeat-dose monkey studies
“The main finding in single and repeat dose studies was the increased risk of infection due to reduced muco-epidermal immunity.”
Biodistribution & persistence
No cross-reactive binding in any human or cynomolgus monkey tissue
“No cross-reactive binding of bimekizumab conjugated to fluorescein isothiocyanate was observed in any human or monkey tissue at any concentration tested”
Modality-specific risk
Infections from exaggerated IL-17A/F pharmacology reducing muco-epidermal immunity
“Bimekizumab specifically inhibits IL-17A and IL-17F and as such muco-epidermal infections are considered to be related to exaggerated pharmacology, leading to decreased muco-epidermal immunity.”
Anti-drug antibodies: animals
Not systematically evaluated; some ADA-positive monkeys in the 8-week adalimumab co-treatment study, with reduced exposure only in co-treated animals
“In the 8-week study with adalimumab, only co-treated animals displayed reduced bimekizumab exposure after repeated doses and select animals in 2 mg/kg/week and 20 mg/kg/week groups were positive for anti-bimekizumab antibodies.”
Anti-drug antibodies: patients
45% (116/257) of psoriasis patients developed ADA; ~16% of ADA-positive had neutralizing antibodies
“116/257 (45%) of BIMZELX-treated subjects (at the recommended dosage) developed anti-bimekizumab-bkzx antibodies (also referred to as ADA). Of the BIMZELX-treated subjects who developed ADA in these trials, approximately 16% had neutralizing antibodies.”
Label warnings
- Suicidal Ideation and Behavior
- Infections
- Tuberculosis
- Liver Biochemical Abnormalities
- Inflammatory Bowel Disease
- Immunizations
PsychiatricInfectionsHepatotoxicityGastrointestinal
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Outside the US (country not named): first-in-human placebo-controlled study UP0008, not under the US IND
“Trial UP0008 was conducted outside the United States and not under the IND. This was a phase 1, first-in-human, randomized, subject-blind, investigator-blind, placebo-controlled”
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 Bimzelx 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: NOAEL was highest dose in 8-week studies (200 and 20 mg/kg/week); none in 26-week study (skin findings, GI infection deaths) (EMA assessment report, p. 25)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week GLP cynomolgus monkey (SC) with 21-week recovery
“repeat dose toxicity studies including two 8-week studies (one with adalimumab, 12-week recovery in both), a 26- week study (21-week recovery) and an ePPND study.”
Pivotal GLP studies
Cynomolgus monkey weekly SC repeat-dose studies up to 26 weeks with up to 21-week recovery
“The Applicant has conducted repeat dose toxicity studies in cynomolgus monkeys with weekly doses administered by subcutaneous injection for up to 26 weeks, followed by a treatment-free recovery period of up to 21 weeks”
DART package
Species: DART
Cynomolgus monkey (ePPND; fertility endpoints in 26-week repeat-dose study)
“The effects on male and female fertility were assessed by examination of reproductive organs, menstrual cycle lengths, or sperm analysis in the 26-week repeat-dose toxicity study in monkeys. In a pre- and postnatal developmental study, bimekizumab was administered to pregnant cynomolgus monkeys”
Reproductive & developmental
Monkey ePPND: NOAEL 50 mg/kg/week for maternal and developmental toxicity (38x MRHD)
“The no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was identified as 50 mg/kg/week which is 38 times (based on mg/kg comparison) the maximum recommended human dose”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed and submitted with the marketing application
“The applicant submitted a toxicology package consisting of a single dose toxicity study, an 8-week repeat dose study, an 8-week repeat dose study with adalimumab, a 26-week repeat dose study and an ePPND toxicity study.”
Carcinogenicity
Species: carcinogenicity
Not conducted: not pharmacologically active in rodents and no anti-rodent IL-17A/F surrogate
“Bimekizumab is not pharmacologically active in rodents and no anti-rodent IL-17 A/F surrogate is available. Thus, conventional rodent carcinogenicity studies were not conducted for evaluation of the carcinogenic potential of bimekizumab.”
Carcinogenicity model
Not conducted; literature-based carcinogenic risk assessment instead
“No genetic toxicology or carcinogenicity studies were conducted with bimekizumab. The Applicant provided a carcinogenic risk assessment, using information from the published literature.”
Carcinogenicity timing
Waived: CDER ECAC agreed rodent carcinogenicity studies are not feasible
“The Executive Carcinogenicity Assessment Committee of CDER agreed that rodent carcinogenicity studies are not feasible and the Applicant was granted a waiver for their conduct (March 28, 2018).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey ePPND NOAEL exposure 27-fold clinical exposure (AUC); no NOAEL in 26-week study
“The safety margin to the anticipated clinical exposure was 27-fold (based on AUC).”
NOAEL / key findings
NOAEL was highest dose in 8-week studies (200 and 20 mg/kg/week); none in 26-week study (skin findings, GI infection deaths)
“The no-observed adverse effect level (NOAEL) was the highest dose tested in the 8-week studies (200mg/kg/week and 20mg/kg/week, respectively, for Study NCD2260 and Study NCD2384). Due to the severity of skin findings in some high-dose animals and mortalities in the low dose group consecutive to GI infection, no NOAEL could be determined in the 26-week study.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro only: primary human dermal fibroblasts and keratinocytes; no in vivo pharmacodynamics
“Primary and secondary pharmacodynamics studies with bimekizumab were conducted in vitro. Pharmacodynamic activity of bimekizumab was investigated in primary cultures of normal human dermal fibroblasts (NHEK) and epithelial keratinocytes (NHDF).”
Why that model
No relevant psoriasis animal model, low IL-17A/F expression in normal tissue, no direct PD markers
“No in vivo pharmacodynamics assessment has been conducted given the low expression of IL- 17A and IL-17F in normal tissues, as no direct pharmacodynamics markers are available, and as no appropriate and relevant animal model of PSO is available.”
Reviewer's view of the efficacy data
FDA: in vitro data support dual IL-17A/F blockade possibly giving increased clinical efficacy
“These results support the hypothesis that bimekizumab, which targets both IL-17A and IL-17F, may show increased clinical efficacy.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic psoriasis therapy; rodent studies waived and a literature weight-of-evidence assessment submitted instead
Why: Not pharmacologically active in rodents and no surrogate available; literature review of IL-17A/F inhibition substituted · No relevant species · Weight of evidence
“Bimekizumab is not pharmacologically active in rodents and no anti-rodent IL-17 A/F surrogate is available. Thus, conventional rodent carcinogenicity studies were not conducted for evaluation of the carcinogenic potential of bimekizumab.”
“A carcinogenetic assessment has been submitted in lieu of formal carcinogenicity studies reviewing the potential pro-and anti-tumorigenic effects of IL-17A and IL-17F inhibition; this is considered acceptable by the CHMP.”
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