Beovu
brolucizumab
Species
Monkey
Longest study
n/a
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
“Cynomolgus monkeys were chosen as they are the only species in which brolucizumab is both pharmacologically active and possessing a similar ocular anatomy to humans.”
Why that species
Only species in which brolucizumab is pharmacologically active and has human-like ocular anatomy
“Cynomolgus monkeys were chosen as they are the only species in which brolucizumab is both pharmacologically active and possessing a similar ocular anatomy to humans.”
Surrogate molecule
No surrogate; the clinical antibody fragment was tested in cynomolgus monkeys and rabbits
“The non-clinical safety of up to 6 mg brolucizumab was established for intravitreal IVT in cynomolgus monkeys and rabbits”
Species: general tox
Cynomolgus monkey (intravitreal, three GLP repeat-dose studies)
“3 GLP repeat-dose studies (Study N-10-104, Study N-12-042 and Study N-14-007) were conducted with the GMP material to determine the potential ocular toxicity, tolerability, and systemic exposure of brolucizumab in Cynomolgus monkeys after repeated IVT injections.”
Species: DART
Cynomolgus monkey (IVT every 4 weeks, organogenesis to birth; pre/postnatal development)
“In an animal reproduction study, intravitreal administration of brolucizumab to pregnant monkeys once every 4 weeks in one eye from organogenesis to birth did not indicate any harmful effects with respect to pre- or postnatal development at 10-fold the maximum recommended human dose (MRHD) on a mg/kg basis”
Species: carcinogenicity
Not conducted
“No studies have been conducted on the carcinogenic or mutagenic potential of BEOVU.”
Surrogate used in
No surrogate used; brolucizumab cross-reacts with mouse and rat VEGF for efficacy models
“These results showing a cross-reactivity towards mouse and rat VEGF allow assessment of ESBA 1008 efficacy in rat and mouse animal models such as the laser-induced CNV (choroidal neovascularization) during in vivo pharmacology studies.”
Study lengthopen answer page →
Longest pivotal study
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.
Pivotal GLP studies
Three GLP repeat-dose intravitreal studies in cynomolgus monkeys (N-10-104, N-12-042, N-14-007)
“3 GLP repeat-dose studies (Study N-10-104, Study N-12-042 and Study N-14-007) were conducted with the GMP material to determine the potential ocular toxicity, tolerability, and systemic exposure of brolucizumab in Cynomolgus monkeys after repeated IVT injections.”
Route in tox
Intravitreal
“The non-clinical safety of up to 6 mg brolucizumab was established for intravitreal IVT in cynomolgus monkeys and rabbits”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“No genotoxicity studies have been conducted. Since brolucizumab is an antibody fragment, the lack of genotoxicity studies is in accordance with the available guideline ICH S6 (R1) and this point is accepted.”
Carcinogenicity
Not conducted (ICH S6(R1))
“Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals.”
Reproductive & developmental
Monkey ePPND (IVT, every 4 weeks): no effects on embryo-fetal development, pregnancy, parturition or offspring at 6 mg/eye; no fertility studies
“There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis).”
Safety pharmacology
Incorporated into repeat-dose toxicity studies; no respiratory, cardiovascular or CNS effects
“No effect on respiratory function or cardiovascular function, and no effects on the central nervous system were detected in toxicological studies.”
Genotox: Ames
Not conducted (ICH S6(R1))
“No genotoxicity studies have been conducted. Since brolucizumab is an antibody fragment, the lack of genotoxicity studies is in accordance with the available guideline ICH S6 (R1) and this point is accepted.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“No genotoxicity studies have been conducted. Since brolucizumab is an antibody fragment, the lack of genotoxicity studies is in accordance with the available guideline ICH S6 (R1) and this point is accepted.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“No genotoxicity studies have been conducted. Since brolucizumab is an antibody fragment, the lack of genotoxicity studies is in accordance with the available guideline ICH S6 (R1) and this point is accepted.”
Carcinogenicity model
Not conducted (ICH S6(R1))
“Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals.”
Carcinogenicity timing
Not required: standard bioassays generally not performed for biotechnology-derived pharmaceuticals (ICH S6(R1))
“Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals.”
hERG / QT
No hERG assay; no test-article ECG changes in pivotal monkey studies
“No test-article changes in body weight, haematology parameters, clinical chemistry parameters, ERGs and ECGs were observed during pivotal studies.”
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 Beovu 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 6 mg/eye (highest dose tested); well tolerated, no systemic toxicity (EMA assessment report, p. 29)
NOAEL / key findings
NOAEL 6 mg/eye (highest dose tested); well tolerated, no systemic toxicity
“Overall, results of the different studies revealed that brolucizumab was well tolerated with a NOAEL value of 6 mg/eye corresponding to the highest tested dose and no systemic toxicity was observed.”
Risksopen answer page →
Immune & cytokine safety
Weakly immunogenic; ADA in all groups (including pre-existing) without effect on exposure
“ADA response was assessed in the in vivo studies. Although antibodies were detected in all the studied groups, no effects were detected in brolucizumab exposure.”
Biodistribution & persistence
Serum exposure after IVT >7000-fold (monkey) and >20000-fold (rabbit) lower than vitreous
“Following IVT administration, systemic (serum) exposure of free brolucizumab in rabbits and cynomolgus monkeys was found to be >20000-fold and >7000-fold lower than in vitreous humor.”
Modality-specific risk
Systemic VEGF inhibition: potential impairment of fertility and embryo-fetal development
“Based on its mechanism of action (VEGF inhibitor), brolucizumab has the potential to impair fertility and embryo-foetal development in relation to the degree of systemic VEGF-inhibition.”
Anti-drug antibodies: animals
Monkey: ADA up to 47% (17/36) after final IVT dose; no correlation with dose or systemic exposure
“Regarding levels of ADA during pivotal repeated dose toxicity studies, increase was observed after the final injection (6 IVT) in Alcon Study N-12-042, wherein ADA levels were up to 47% (17/36 animals). However, no dose-response relationship and no correlation between ADA titers and systemic exposure were observed.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 53% to 76% of patients; pre-existing in 36% to 64%
“Anti-brolucizumab antibodies were detected in the pre-treatment sample of 36% to 64% of treated naive patients. After initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 76% of patients treated with BEOVU.”
Label warnings
- Endophthalmitis and Retinal Detachment
- Retinal Vasculitis and/or Retinal Vascular Occlusion
- Increase in Intraocular Pressure
- Thromboembolic Events
Ocular toxicityThrombosis & embolism
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 Beovu 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 6 mg/eye (highest dose tested); well tolerated, no systemic toxicity (EMA assessment report, p. 29)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Duration not stated: longest GLP study is cynomolgus monkey intravitreal study N-12-042 with 6 injections; no recovery described
“Regarding levels of ADA during pivotal repeated dose toxicity studies, increase was observed after the final injection (6 IVT) in Alcon Study N-12-042, wherein ADA levels were up to 47% (17/36 animals).”
Pivotal GLP studies
Three GLP repeat-dose intravitreal studies in cynomolgus monkeys (N-10-104, N-12-042, N-14-007)
“3 GLP repeat-dose studies (Study N-10-104, Study N-12-042 and Study N-14-007) were conducted with the GMP material to determine the potential ocular toxicity, tolerability, and systemic exposure of brolucizumab in Cynomolgus monkeys after repeated IVT injections.”
DART package
Species: DART
Cynomolgus monkey (IVT every 4 weeks, organogenesis to birth; pre/postnatal development)
“In an animal reproduction study, intravitreal administration of brolucizumab to pregnant monkeys once every 4 weeks in one eye from organogenesis to birth did not indicate any harmful effects with respect to pre- or postnatal development at 10-fold the maximum recommended human dose (MRHD) on a mg/kg basis”
Reproductive & developmental
Monkey ePPND (IVT, every 4 weeks): no effects on embryo-fetal development, pregnancy, parturition or offspring at 6 mg/eye; no fertility studies
“There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis).”
PPND / ePPND: when
No DART studies; accepted given low systemic exposure after intravitreal dosing and the elderly patient population
“Nevertheless, the absence of reproductive and developmental toxicity studies is considered as acceptable in view of the low systemic exposure levels after IVT dosing, and the age of the patient population undergoing treatment for neovascular (wet) age-related macular degeneration.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No studies have been conducted on the carcinogenic or mutagenic potential of BEOVU.”
Carcinogenicity model
Not conducted (ICH S6(R1))
“Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals.”
Carcinogenicity timing
Not required: standard bioassays generally not performed for biotechnology-derived pharmaceuticals (ICH S6(R1))
“Similarly, no carcinogenicity studies have been conducted with brolucizumab, as noted in ICH S6 (R1), standard carcinogenicity bioassays are generally not performed for biotechnology-derived pharmaceuticals.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 6 mg/eye: 6-fold human AUC, 12-fold Cmax (systemic); 2-fold ocular
“Nonclinical safety data provides a 2-fold ocular margin of safety for the recommended human dose and a 12- and 6-fold systemic margin of safety, based on Cmax and AUC respectively (NOAEL corresponds to the highest tested dose in Alcon study N-12-042 i.e. 6 mg/eye).”
NOAEL / key findings
NOAEL 6 mg/eye (highest dose tested); well tolerated, no systemic toxicity
“Overall, results of the different studies revealed that brolucizumab was well tolerated with a NOAEL value of 6 mg/eye corresponding to the highest tested dose and no systemic toxicity was observed.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent ocular models: VEGF-induced retinal permeability (rat), oxygen-induced retinopathy (neonatal rat), laser-induced CNV (mouse)
“In vivo studies showed a preventive action of brolucizumab on retinal vascular permeability, choroidal neovascularisation (both by IVT administration) and preretinal neovascularisation (IVT and IP administration).”
Why that model
Brolucizumab binds rodent VEGF-A, allowing rodent efficacy models
“In addition to binding to human VEGF-A, brolucizumab also binds to rodent VEGF-A allowing for evaluation in rodent efficacy models.”
Reviewer's view of the efficacy data
EMA: all rodent ocular VEGF permeability/neovascularisation models deemed appropriate
“All the in vivo models are aimed to reproduce the features of VEGF-induced vascular permeability and neovascularisation in the different tissues of the eye. All models were deemed appropriate.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Low systemic exposure after intravitreal dosing and the age of the wet AMD population · Pharmacology or kinetics · Other reason
“Nevertheless, the absence of reproductive and developmental toxicity studies is considered as acceptable in view of the low systemic exposure levels after IVT dosing, and the age of the patient population undergoing treatment for neovascular (wet) age-related macular degeneration.”
Safety pharmacologyVerdict not stated
No dedicated safety pharmacology studies; endpoints incorporated into repeat-dose toxicity studies
Why: Endpoints in repeat-dose studies; human systemic exposure below levels with meaningful VEGF-related effect
“Lack of dedicated safety pharmacology studies was justified by the incorporation of safety pharmacology endpoints in repeat-dose toxicity studies, and the human systemic exposure being below levels where any meaningful effect of a VEGF-related activity is expected.”
OtherVerdict not stated
No secondary pharmacodynamic or tissue cross-reactivity studies
Why: Humanized antibody fragment with specific target engagement; low systemic concentrations after intravitreal dosing
“No dedicated studies, including tissue cross-reactivity, have been conducted with brolucizumab. The justification for the absence of the aforementioned studies relies on the nature of the product (a humanized antibody fragment) and the route of administration (IVT), resulting in specific target engagement and lower systemic concentrations after treatment, respectively.”
OtherAcceptedBeyond the letter
No dedicated local tolerance studies; endpoint covered in intravitreal repeat-dose studies
Why: Local tolerance investigated in intravitreal repeat-dose toxicity studies · Weight of evidence
“The lack of dedicated local tolerance studies is accepted since this endpoint has been investigated during repeated-dose toxicity studies after IVT administration.”
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