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).”
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.).”
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 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: 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”
Similar precedents
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