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”
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.”
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 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: 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.”