Hemlibra
emicizumab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Emicizumab was shown to bind similarly to the corresponding cynomolgus monkey coagulation factors, as such the cynomolgus monkey is a pharmacologically relevant species.”
Why that species
Binds/activates cynomolgus FIX/FX comparably to human; no FX activation with mouse or rat factors
“In an enzyme assay using purified Cynomolgus monkey, rat and mouse FIXa and FX, emicizumab was found to cross-react only with the corresponding clotting factors of Cynomolgus monkeys.”
Surrogate molecule
No surrogate; clinical molecule tested in monkey (FVIII-neutralizing antibodies used only to create hemophilia models)
“Emicizumab was generally well tolerated in a 26-week toxicology study conducted in cynomolgus monkeys administered weekly SC doses of emicizumab at 1, 6, and 30 mg/kg.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A 26-week intermittent dose (once weekly, 27 doses) subcutaneous administration toxicity study of CH5534262 in mature cynomolgus monkeysfollowed by a 13-week recovery period / Study report no. 1060134”
Pivotal GLP studies
Cynomolgus: 4-week IV (up to 100 mg/kg/wk), 4- and 13-week SC, 26-week SC weekly (1, 6, 30 mg/kg)
“Repeat-dose toxicity was also evaluated in cynomolgus monkeys dosed once weekly in a 4-week IV dose toxicity study (1060140) and 4- and 13-week SC dose toxicity studies (1060133 and 1060134).”
Route in tox
Subcutaneous (clinical route) and intravenous
“In the vast majority of the nonclinical studies, emicizumab was administered via the SC route administration as this mimics the proposed clinical route.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genotoxicity studies were not conducted as these types of studies are not applicable to biotechnology-derived pharmaceuticals (per ICH S6).”
Carcinogenicity
Not conducted (no pharmacologically relevant rodent; waived with ECAC concurrence)
“Carcinogenicity studies were not conducted due to lack of a pharmacologically relevant rodent species.”
Reproductive & developmental
Not conducted (99% of patients male); no reproductive organ effects in 26-week monkey study
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (ICH S6(R1)); no CNS, respiratory or CV effects
“Safety assessment of vital organs was incorporated in the toxicology studies in monkeys.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL 30 mg/kg/wk SC (26-week), ~11x clinical AUC; findings limited to injection-site reactions and aPTT shortening
“This is approximately 11-fold above the clinical exposure in a 3 mg/kg QW dosing regimen which is the regimen that is anticipated to yield the highest exposure in patients.”
Risksopen answer page →
Immune & cytokine safety
Low cytokine release risk in vitro; ADA in 9/40 monkeys (4 NAb); one Arthus-type injection-site reaction
“The results of the assay indicated emicizumab has a low risk for eliciting cytokine release.”
Biodistribution & persistence
No distribution/metabolism studies (ICH S6); monkey t1/2 3-4 weeks, SC bioavailability ~100%
“No studies to evaluate the distribution, metabolism, excretion or potential to cause pharmacokinetic interactions were conducted which is in line with the ICH S6 guideline (R1)”
Modality-specific risk
Thrombogenicity (TMA/thromboembolism) with bypassing agents such as aPCC; coagulation assay interference
“This nonclinical data supports the association of thrombotic microangiopathy (TMA) and thromboembolism (TE) findings in patients receiving aPCC and HEMLIBRA.”