Alhemo
concizumab
Species
MonkeyRabbit
Longest study
52 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 (rabbit used for efficacy and PK/PD)
“The rabbit was selected as efficacy species, the Cynomolgus monkey was selected as the nonrodent safety species and both species were used in pharmacokinetic/pharmacodynamic (PK/PD) assessment.”
Why that species
Sub-nanomolar TFPI binding with similar constants in rabbit, monkey and human (KD 0.22, 0.06, 0.04 nM)
“Characterisation of concizumab binding to TFPI showed high affinity, sub-nanomolar binding to rabbit, NHP and human TFPI with similar binding constants (KD of 0.22 nM, 0.06 nM and 0.04 nM for rabbit, Cynomolgus monkey and human, respectively).”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Toxicity studies of up to 52-week duration have been conducted in Cynomolgus monkeys with a normal coagulation system (non-haemophilic).”
Species: general tox
Cynomolgus monkey only
“The cynomolgus monkey was selected as the non-rodent nonclinical safety species for repeat-dose toxicology and both species were used in pharmacokinetic/pharmacodynamic (PD) assessments.”
Species: DART
Not conducted; product for predominantly male hemophilia population, clinical program in males only (fertility assessed within 26-week monkey study)
“Dedicated reproductive and developmental toxicology studies were not conducted as concizumab is primarily indicated for use in male patients with hemophilia and the clinical development program was conducted exclusively in males.”
Species: carcinogenicity
Not conducted; concizumab not functional in rodents
“Concizumab is not functional in rodents and standard carcinogenicity studies have not been conducted.”
Surrogate used in
No surrogate used; clinical antibody tested in rabbits (efficacy) and cynomolgus monkeys (safety)
“Based on the pharmacology data and the lack of cross reactivity to rodent species, the rabbit was selected as the nonclinical efficacy species (hemophilia animal models).”
Study lengthopen answer page →
Longest pivotal study
52 weeks
“In a 52-week repeat dose toxicity study in sexually mature Cynomolgus monkeys, animals received 0.5, 1 or 9 mg concizumab/kg/day for 52 weeks.”
Pivotal GLP studies
Monkey studies up to 52 weeks; 26-week study: SC 3 or 9 mg/kg/day or IV 30 mg/kg/week, 13-week recovery
“In a 26-week repeat dose toxicology study in sexually mature Cynomolgus monkeys, animals were given 0, 3 or 9 mg concizumab/kg/day s.c. or 30 mg/kg/week i.v. with a 13-week recovery period.”
Route in tox
Subcutaneous (once daily) and intravenous (once weekly)
“toxicity studies, concizumab was dosed i.v. once weekly or s.c. once daily.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“According to ICH S6(R1), genotoxicity studies were not performed.”
Carcinogenicity
Not conducted; weight-of-evidence evaluation with up to 52-week monkey data suggests no carcinogenic potential
“A thorough weight of evidence evaluation, in combination with data from the repeat dose toxicity studies, which included exposure to concizumab up to 52 weeks, does not suggest that concizumab has carcinogenic potential.”
Reproductive & developmental
Fertility unaffected in 26-week monkey study up to 9 mg/kg/day SC (3400-fold human exposure)
“In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC 0 to 24h ), concizumab-mtci did not affect fertility”
Safety pharmacology
Incorporated into monkey DRF, 13-week and 52-week studies; no effects up to 200 mg/kg/week IV and 50 mg/kg/day SC
“No effects of concizumab on safety pharmacology endpoints were observed in any of these studies at repeat doses up to 200 mg/kg/once weekly (i.v.) and 50 mg/kg/day (s.c.).”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies were not conducted, as concizumab consists of naturally occurring amino acids (endogenous) and is not anticipated to be genotoxic and there were no mechanistic data that suggested a mutagenic potential for concizumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies were not conducted, as concizumab consists of naturally occurring amino acids (endogenous) and is not anticipated to be genotoxic and there were no mechanistic data that suggested a mutagenic potential for concizumab.”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies were not conducted, as concizumab consists of naturally occurring amino acids (endogenous) and is not anticipated to be genotoxic and there were no mechanistic data that suggested a mutagenic potential for concizumab.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity risk assessment (mode of action, literature, nonclinical and clinical data)
“Instead, the Applicant conducted a carcinogenicity risk assessment of concizumab using a weight-of-evidence (WOE) approach that considered the mode of action (MOA), a review of relevant literature and an evaluation of the nonclinical and clinical data.”
Carcinogenicity timing
Not required; FDA (with ECAC concurrence) determined no additional carcinogenicity studies warranted
“The Division determined that no additional nonclinical studies assessing the carcinogenic potential of concizumab were warranted for the indications of hemophilia A and hemophilia B and the CDER Executive Carcinogenicity Assessment Committee (ECAC) concurred with the Division’s recommendation.”
hERG / QT
No hERG assay; no QT prolongation in monkeys up to 9 mg/kg/day SC for 52 weeks (4300x MRHD AUC)
“In addition, QT prolongation was not observed during ECG assessments in cynomolgus monkeys administered repeat doses of concizumab up to 9 mg/kg/day (SC), 4300x MRHD (AUC) and 4400X MRHD (Cmax), for up to 52 weeks.”
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 Alhemo 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: 52-week NOAEL 0.5 mg/kg/day SC (~70x clinical exposure), based on thrombus formation (EMA assessment report, p. 37)
NOAEL / key findings
52-week NOAEL 0.5 mg/kg/day SC (~70x clinical exposure), based on thrombus formation
“The NOAEL for this study was 0.5 mg/kg/day based on thrombus formation. The exposure at the NOAEL was approximately 70-times that of the intended clinical exposure.”
Risksopen answer page →
Immune & cytokine safety
ADA induced in all monkey repeat-dose studies, causing loss of exposure without affecting study interpretation
“Concizumab induced ADA in all repeat dose toxicity studies. ADA led to loss in exposure although this did not affect the overall interpretation of the studies.”
Biodistribution & persistence
TCR: binding to TFPI-expressing tissues; cytoplasmic off-target binding unlikely to be relevant in vivo
“In a tissue cross reactivity study, concizumab showed anticipated binding to tissue in which TFPI is expressed. Off target binding was observed for cytoplasm but it is very unlikely that concizumab will be able to reach the cytoplasm in vivo.”
Modality-specific risk
Thrombosis from exaggerated procoagulant pharmacology: thrombi at ≥10 (13-week), ≥3 (26-week) and ≥1 mg/kg/day (52-week) SC
“Pharmacology mediated formation of thrombi manifested in cynomolgus monkeys dosed subcutaneously during toxicology studies of 13-weeks (≥ 10 mg/kg/day), 26-weeks (≥ 3 mg/kg/day) and 52-weeks (≥ 1 mg/kg/day) in duration”
Anti-drug antibodies: animals
ADAs in cynomolgus monkeys correlated with reduced exposure and pharmacodynamic activity; considered inhibitory (particularly at low dose)
“When ADAs were detected, their presence correlated with a decline in pharmacodynamic activity (e.g., fibrinogen, TAT, and D-dimers) and a reduction in systemic exposure, indicating that the ADAs produced in cynomolgus monkeys (particularly at the LD) were inhibitory in nature.”
Anti-drug antibodies: patients
22.2% (71/320) developed ADA; 25.4% of ADA-positive had neutralizing antibodies
“71 out of the 320 treated patients (22.2%) developed anticoncizumab-mtci antibodies. Among the 71 patients who tested positive for ADA, 18 patients (25.4%) developed neutralizing antibodies (NAbs) against concizumab-mtci.”
Label warnings
- Thromboembolic Events
- Hypersensitivity Reactions
- Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1.2
Thrombosis & embolismHypersensitivity & infusion reactions
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 Alhemo 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: 52-week NOAEL 0.5 mg/kg/day SC (~70x clinical exposure), based on thrombus formation (EMA assessment report, p. 37)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey SC study (GLP) with no recovery assessment
“52-Week Toxicity Study by the Subcutaneous Route of Administration in Cynomolgus Monkeys with No Assessment of Recovery (Study 213542, GLP)”
Pivotal GLP studies
Monkey studies up to 52 weeks; 26-week study: SC 3 or 9 mg/kg/day or IV 30 mg/kg/week, 13-week recovery
“In a 26-week repeat dose toxicology study in sexually mature Cynomolgus monkeys, animals were given 0, 3 or 9 mg concizumab/kg/day s.c. or 30 mg/kg/week i.v. with a 13-week recovery period.”
DART package
Species: DART
Not conducted; product for predominantly male hemophilia population, clinical program in males only (fertility assessed within 26-week monkey study)
“Dedicated reproductive and developmental toxicology studies were not conducted as concizumab is primarily indicated for use in male patients with hemophilia and the clinical development program was conducted exclusively in males.”
Reproductive & developmental
Fertility unaffected in 26-week monkey study up to 9 mg/kg/day SC (3400-fold human exposure)
“In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC 0 to 24h ), concizumab-mtci did not affect fertility”
PPND / ePPND: when
Not conducted: no dedicated DART studies; indication primarily male hemophilia, clinical program in males only
“Dedicated reproductive and developmental toxicology studies were not conducted as concizumab is primarily indicated for use in male patients with hemophilia and the clinical development program was conducted exclusively in males.”
Carcinogenicity
Species: carcinogenicity
Not conducted; concizumab not functional in rodents
“Concizumab is not functional in rodents and standard carcinogenicity studies have not been conducted.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity risk assessment (mode of action, literature, nonclinical and clinical data)
“Instead, the Applicant conducted a carcinogenicity risk assessment of concizumab using a weight-of-evidence (WOE) approach that considered the mode of action (MOA), a review of relevant literature and an evaluation of the nonclinical and clinical data.”
Carcinogenicity timing
Not required; FDA (with ECAC concurrence) determined no additional carcinogenicity studies warranted
“The Division determined that no additional nonclinical studies assessing the carcinogenic potential of concizumab were warranted for the indications of hemophilia A and hemophilia B and the CDER Executive Carcinogenicity Assessment Committee (ECAC) concurred with the Division’s recommendation.”
Safety marginopen answer page →
Safety margin at NOAEL
52-week monkey NOAEL 0.5 mg/kg/day SC: 74x human AUC at 0.20 mg/kg
“the NOAEL (0.5 mg/kg/day, 1660 µg.hr/mL AUC0-24, Week 52) represents a 74x exposure margin to the anticipated clinical dose (0.20 mg/kg, 22.4 µg.hr/mL AUC0-24).”
NOAEL / key findings
52-week NOAEL 0.5 mg/kg/day SC (~70x clinical exposure), based on thrombus formation
“The NOAEL for this study was 0.5 mg/kg/day based on thrombus formation. The exposure at the NOAEL was approximately 70-times that of the intended clinical exposure.”
Efficacy evidenceopen answer page →
Efficacy evidence
Antibody-induced (anti-FVIII) hemophilia A rabbit cuticle bleeding model: dose-dependent reduction in blood loss
“In vivo proof-of-concept studies were conducted in a cuticle bleeding model in New Zealand White (NZW) rabbits where hemophilia A-like conditions were simulated by administration of a neutralizing FVIII antibody.”
Why that model
No cross-reactivity with rodents; rabbit TFPI binding similar to human, so rabbit chosen for hemophilia models
“Based on the pharmacology data and the lack of cross reactivity to rodent species, the rabbit was selected as the nonclinical efficacy species (hemophilia animal models).”
Reviewer's view of the efficacy data
EMA: rabbit hemophilia A models provide proof of concept for treating hemophilia A and B
“Studies with rabbit models of haemophilia A provide a proof of concept for the clinical treatment of haemophilia A and B.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
No dedicated reproductive and developmental toxicity studies (no embryo-fetal or pre/postnatal studies)
Why: Indicated primarily for male hemophilia patients; clinical program conducted exclusively in males · Other reason
“Dedicated reproductive and developmental toxicology studies were not conducted as concizumab is primarily indicated for use in male patients with hemophilia and the clinical development program was conducted exclusively in males.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic non-oncology indication; weight-of-evidence assessment instead
Why: Not functional in rodents; weight-of-evidence of mode of action, literature, nonclinical and clinical data · Weight of evidence · No relevant species · Human data
“Instead, the Applicant conducted a carcinogenicity risk assessment of concizumab using a weight-of-evidence (WOE) approach that considered the mode of action (MOA), a review of relevant literature and an evaluation of the nonclinical and clinical data.”
“The Division determined that no additional nonclinical studies assessing the carcinogenic potential of concizumab were warranted for the indications of hemophilia A and hemophilia B and the CDER Executive Carcinogenicity Assessment Committee (ECAC) concurred with the Division’s recommendation.”
Juvenile toxAccepted
No dedicated juvenile animal studies
Why: Neonatal and infant monkey studies technically challenging and unlikely to identify new reactions · Within the guideline · Other reason
“Dedicated juvenile animal studies have not been conducted with concizumab as studies in neonatal and infant monkeys are technically challenging and are unlikely to identify potential reactions that were not identified from studies in fully developed (adult) animals.”
“Dedicated juvenile animal studies were not conducted with concizumab, consistent with the guidance provided in ICH M3 (R2)”
RecoveryVerdict not stated
Reversibility of vascular findings not assessed in the 52-week monkey study
“The reversibility of the findings in cynomolgus monkeys was not assessed and the NOAEL (0.5 mg/kg/day, 1660 µg.hr/mL AUC0-24, Week 52) represents a 74x exposure margin to the anticipated clinical dose (0.20 mg/kg, 22.4 µg.hr/mL AUC0-24).”
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