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.”
Species: general tox
Cynomolgus monkey only
“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.”
Species: DART
Not conducted (hemophilia A is X-linked recessive)
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
Species: carcinogenicity
Not conducted (no pharmacologically relevant rodent species)
“Carcinogenicity studies were not conducted due to lack of a pharmacologically relevant rodent species.”
Surrogate used in
No surrogate used; clinical molecule tested in cynomolgus monkey
“Emicizumab was shown to bind similarly to the corresponding cynomolgus monkey coagulation factors, as such the cynomolgus monkey is a pharmacologically relevant species.”
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.”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies were not conducted as these types of studies are not applicable to biotechnology-derived pharmaceuticals (per ICH S6).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies were not conducted as these types of studies are not applicable to biotechnology-derived pharmaceuticals (per ICH S6).”
Genotox: in vivo
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 model
Not conducted (not active in mice or rats; restoring hemostasis not expected to increase tumorigenesis)
“Carcinogenicity studies have not been conducted with emicizumab because the product is not active in mice or rats; restoring hemostasis is not expected to increase the potential for tumorigenesis.”
Carcinogenicity timing
Not required; carcinogenicity assessment accepted and ECAC agreed no studies needed
“The ECAC agreed with the Division that there was no need for additional nonclinical carcinogenicity studies for emicizumab on August 7, 2015.”
hERG / QT
No dedicated safety pharmacology; no CNS, respiratory or cardiovascular effects in monkey repeat-dose studies
“The safety pharmacology endpoints were evaluated during the repeated-dose toxicity studies described in Section 2.3.4 of this report. No effects on the CNS, respiratory or CNS were identified.”
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 Hemlibra 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 multispecifics
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 30 mg/kg/wk SC (26-week), ~11x clinical AUC; findings limited to injection-site reactions and aPTT shortening (EMA assessment report, p. 35)
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.”
Anti-drug antibodies: animals
ADA in 9/40 monkeys in 26-week study; 4 of the 9 neutralizing
“Anti-drug antibodies (ADA) were identified in 9 out of 40 monkeys in the 26-week study, and 4 of those 9 developed neutralizing antibodies (NAb).”
Anti-drug antibodies: patients
5.1% (34/668) ADA-positive; 2.7% (18/668) neutralizing
“5.1% of patients (34/668) tested positive for anti-emicizumab-kxwh antibodies and 2.7% of patients (18/668) developed anti-emicizumab-kxwh antibodies that were neutralizing in vitro.”
Label warnings
Boxed warning: Thrombotic microangiopathy and thromboembolism
- Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC
- Thromboembolism Associated with HEMLIBRA and aPCC
- Immunogenicity
- Laboratory Coagulation Test Interference
Thrombosis & embolismImmunogenicity
US prescribing information, Boxed Warning and 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 Hemlibra 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 multispecifics
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 30 mg/kg/wk SC (26-week), ~11x clinical AUC; findings limited to injection-site reactions and aPTT shortening (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week SC cynomolgus monkey study (weekly) with 13-week recovery
“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).”
DART package
Species: DART
Not conducted (hemophilia A is X-linked recessive)
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
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.”
PPND / ePPND: when
No PPND or other DART studies: hemophilia A is X-linked recessive (patients mostly male)
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no pharmacologically relevant rodent species)
“Carcinogenicity studies were not conducted due to lack of a pharmacologically relevant rodent species.”
Carcinogenicity model
Not conducted (not active in mice or rats; restoring hemostasis not expected to increase tumorigenesis)
“Carcinogenicity studies have not been conducted with emicizumab because the product is not active in mice or rats; restoring hemostasis is not expected to increase the potential for tumorigenesis.”
Carcinogenicity timing
Not required; carcinogenicity assessment accepted and ECAC agreed no studies needed
“The ECAC agreed with the Division that there was no need for additional nonclinical carcinogenicity studies for emicizumab on August 7, 2015.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL (30 mg/kg, 26-week) ~11x human AUC at 3 mg/kg QW
“The NOAEL dose of 30 mg/kg in the 26-week study (1060134) resulted in a steady state AUC0−168h (AUC0−168h ss) exposure of 8680 µg.d/mL. 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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cynomolgus monkey models of acute and chronic hemophilia A
“The in vivo pharmacological effects of emicizumab were assessed in cynomolgus monkey models of acute and chronic hemophilia A as described below.”
Why that model
Emicizumab cross-reacts only with monkey (not rat or mouse) FIXa/FX, so hemophilia was induced in monkeys
“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.”
Reviewer's view of the efficacy data
EMA: monkey hemophilia models supportive though initially poorly characterised; parameter choice later justified
“While the results are supportive of the proposed use, at the time of initial application, the models were poorly characterised. However, adequate justification of the choice of parameters measured was subsequently provided.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies for a chronic prophylactic antibody; written carcinogenicity assessment used instead
Why: No pharmacologically relevant rodent species; sponsor's carcinogenicity assessment judged sufficient, with ECAC concurrence · No relevant species · Within the guideline · Weight of evidence
“Carcinogenicity studies were not conducted due to lack of a pharmacologically relevant rodent species.”
“The Sponsor subsequently submitted the requested carcinogenicity assessment to the IND on July 9, 2015, and upon our review the Division agreed that the carcinogenicity assessment was sufficient to waive the requirement for additional nonclinical carcinogenicity studies.”
DARTVerdict not stated
No reproductive or developmental toxicity studies (fertility, embryo-fetal, pre/postnatal)
Why: Hemophilia A is X-linked recessive; 99% of patients are male, so use in females exceedingly rare · Other reason
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner. Males represent 99% of the patients with hemophilia A, thus it would be exceedingly rare for females to be prescribed this drug.”
Efficacy modelCriticised but acceptedBeyond the letter
Monkey acquired hemophilia A efficacy models poorly characterised at initial application
Why: Adequate justification of the parameters measured was subsequently provided · Other reason
“While the results are supportive of the proposed use, at the time of initial application, the models were poorly characterised. However, adequate justification of the choice of parameters measured was subsequently provided.”
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