Hympavzi
marstacimab
Species
MonkeyRat
Longest study
26 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
Rat and cynomolgus monkey
“Toxicokinetics were evaluated as part of the RDT GLP studies in rats and Cynomolgus monkeys.”
Why that species
Similar binding affinity to TFPI K1K2 (via K2) across human, cynomolgus monkey, rabbit, mouse and Wistar Han rat
“Marstacimab showed similar binding affinity to the combined K1K2 domains (via the K2 domain) of TFPI from human, cynomolgus monkey, rabbit, mouse, and the Wistar Han rat.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rats and cynomolgus monkeys
“Toxicokinetics were evaluated as part of the RDT GLP studies in rats and Cynomolgus monkeys.”
Species: general tox
Wistar Han rat (up to 6 months) and cynomolgus monkey (up to 3 months)
“Wistar Han rats and Cynomolgus monkeys in GLP-compliant repeat-dose studies of up to 3 months (monkeys) or 6 months (rats) in duration.”
Species: DART
Male-only testing: no female reproduction studies because hemophilia A and B occur almost exclusively in males
“Marstacimab was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Species: carcinogenicity
Not conducted; weight-of-evidence assessment instead of 2-year rat study
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
Surrogate used in
No surrogate used; marstacimab binds TFPI of all test species
“Marstacimab showed similar binding affinity to the combined K1K2 domains (via the K2 domain) of TFPI from human, cynomolgus monkey, rabbit, mouse, and the Wistar Han rat.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“the toxicity and toxicokinetics of marstacimab were examined in male and female Crl:WI(Han) rats (n=15 per sex in vehicle and dosing groups, and n=3 (vehicle) and 4 (test-article) per sex in test-article TK satellite groups) via intravenous injections of 0, 60, 180, or 1000 mg/kg/week for 26 weeks.”
Pivotal GLP studies
GLP repeat-dose studies in cynomolgus monkeys (up to 3 months) and Wistar Han rats (up to 6 months)
“Wistar Han rats and Cynomolgus monkeys in GLP-compliant repeat-dose studies of up to 3 months (monkeys) or 6 months (rats) in duration.”
Route in tox
IV (weekly) and SC
“Intravenous administration of marstacimab at doses ranging from 30 to 500 mg/kg/week and SC administration of 90 mg/kg/week to monkeys had no effect on respiratory, neurological, or cardiovascular parameters.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not scientifically appropriate for a monoclonal antibody
“As a monoclonal antibody, genotoxicity assessment of marstacimab was not scientifically appropriate and therefore was not conducted.”
Carcinogenicity
Not conducted; weight-of-evidence: unlikely carcinogenic concern, 2-year rat study not useful
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
Reproductive & developmental
Male rat FEED: no adverse effects at 1000 mg/kg/week (>200x MRHD exposure)
“The study identified no adverse effects at 1000 mg/kg/week (i.e., the no observed adverse effect level (NOAEL), which represented exposure >200-times the clinical exposure at the MRHD).”
Safety pharmacology
Incorporated into repeat-dose monkey study; no respiratory, neurological or cardiovascular effects at IV 30-500 or SC 90 mg/kg/week
“Intravenous administration of marstacimab at doses ranging from 30 to 500 mg/kg/week and SC administration of 90 mg/kg/week to monkeys had no effect on respiratory, neurological, or cardiovascular parameters.”
Genotox: Ames
Not conducted (monoclonal antibody)
“As a monoclonal antibody, genotoxicity assessment of marstacimab was not scientifically appropriate and therefore was not conducted.”
Genotox: in vitro mammalian
Not conducted (monoclonal antibody)
“As a monoclonal antibody, genotoxicity assessment of marstacimab was not scientifically appropriate and therefore was not conducted.”
Genotox: in vivo
Not conducted (monoclonal antibody)
“As a monoclonal antibody, genotoxicity assessment of marstacimab was not scientifically appropriate and therefore was not conducted.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity assessment (2-year rat study judged not useful)
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
Carcinogenicity timing
Not required; weight-of-evidence accepted, 2-year rat study not warranted
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
hERG / QT
No hERG assay; no cardiovascular, respiratory or neurological effects in monkeys at IV 30-500 or SC 90 mg/kg/week
“Intravenous administration of marstacimab at doses ranging from 30 to 500 mg/kg/week and SC administration of 90 mg/kg/week to monkeys had no effect on respiratory, neurological, or cardiovascular parameters.”
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 Hympavzi 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: NOAELs at top weekly IV doses: 1000 mg/kg rat, 500 mg/kg monkey (~200x MRHD AUC) (FDA integrated review, p. 122)
NOAEL / key findings
NOAELs at top weekly IV doses: 1000 mg/kg rat, 500 mg/kg monkey (~200x MRHD AUC)
“Thus, the top weekly intravenous dose of 1000 mg/kg/dose in rats and 500 mg/kg/dose in monkeys were regarded as the no observed adverse effect level (NOAEL) doses, with AUC exposures approximately 200-times greater than clinical exposure at the maximum recommended human dose”
Risksopen answer page →
Immune & cytokine safety
Non-neutralizing ADA in ~28% of rats in 3-month study; no ADA in 3-month monkey or 6-month rat studies
“Analysis of plasma samples for antidrug antibody (ADA) detected ADA in a minority of rats (~28%) in the 3-month study found no evidence of marstacimab neutralization (Table 52). There was no evidence of ADA in the 3-month monkey or 6-month rat studies.”
Biodistribution & persistence
TCR (human, monkey, rat): binding in TFPI-expressing endothelium, placental trophoblasts, islet cells, endocrine epithelium, mesothelium
“Therefore, as expected marstacimab binding was noted in endothelial cells one would expect release of TFPI (endothelial cell, placental spongiotrophoblasts, placental trophoblast, islet cells, endocrine epithelium, mesothelium).”
Modality-specific risk
Thrombosis/emboli from TFPI inhibition; minimal lung emboli in healthy animals, risk in hemophilia patients cannot be excluded
“Despite the unclear relationship between lung emboli in healthy animals and marstacimab, the anticipated risk of thrombi/emboli in hemophilia patients cannot be dismissed.”
Anti-drug antibodies: animals
Non-neutralizing ADA in ~28% of rats (3-month study); none in 3-month monkey or 6-month rat studies
“Analysis of plasma samples for antidrug antibody (ADA) detected ADA in a minority of rats (~28%) in the 3-month study found no evidence of marstacimab neutralization (Table 52). There was no evidence of ADA in the 3-month monkey or 6-month rat studies.”
Anti-drug antibodies: patients
ADA in 19.8% (33/167) of patients in BASIS; 24.2% of these neutralizing; reduced steady-state concentrations
“Following weekly subcutaneous marstacimab‑hncq dosing in patients with hemophilia 12 years of age and older with and without inhibitors for approximately a year in the BASIS study, 33 of the 167 (19.8%) ADA‑evaluable patients treated with marstacimab‑hncq developed ADAs. Among the 33 patients who developed ADAs, 8 patients (24.2%) developed neutralizing anti-drug antibodies (NAbs).”
Label warnings
- Thromboembolic Events
- Hypersensitivity
- Embryofetal Toxicity
- Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1.2
Thrombosis & embolismHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 Hympavzi 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: NOAELs at top weekly IV doses: 1000 mg/kg rat, 500 mg/kg monkey (~200x MRHD AUC) (FDA integrated review, p. 122)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week rat (IV) with 6-week recovery (toxicokinetics only, 60 mg/kg/week cohort)
“via intravenous injections of 0, 60, 180, or 1000 mg/kg/week for 26 weeks. Also in this study, the toxicokinetics of the test-article was assessed in a follow-up test-article free 6-week recovery phase (only in the 60 mg/kg/week toxicokinetic cohort).”
Pivotal GLP studies
GLP repeat-dose studies in cynomolgus monkeys (up to 3 months) and Wistar Han rats (up to 6 months)
“Wistar Han rats and Cynomolgus monkeys in GLP-compliant repeat-dose studies of up to 3 months (monkeys) or 6 months (rats) in duration.”
DART package
Species: DART
Male-only testing: no female reproduction studies because hemophilia A and B occur almost exclusively in males
“Marstacimab was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Reproductive & developmental
Male rat FEED: no adverse effects at 1000 mg/kg/week (>200x MRHD exposure)
“The study identified no adverse effects at 1000 mg/kg/week (i.e., the no observed adverse effect level (NOAEL), which represented exposure >200-times the clinical exposure at the MRHD).”
PPND / ePPND: when
Not conducted: no female reproduction studies because hemophilia A and B occur almost exclusively in males
“Marstacimab was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Carcinogenicity
Species: carcinogenicity
Not conducted; weight-of-evidence assessment instead of 2-year rat study
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity assessment (2-year rat study judged not useful)
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
Carcinogenicity timing
Not required; weight-of-evidence accepted, 2-year rat study not warranted
“Based on the WoE provided by the Applicant, the Division agreed that marstacimab is unlikely to pose a significant carcinogenicity safety concern for humans and therefore considered a 2-year study in rats unlikely to provide additional useful information.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAELs (rat 1000, monkey 500 mg/kg/week IV) ~200x human AUC at the MRHD
“Thus, the top weekly intravenous dose of 1000 mg/kg/dose in rats and 500 mg/kg/dose in monkeys were regarded as the no observed adverse effect level (NOAEL) doses, with AUC exposures approximately 200-times greater than clinical exposure at the maximum recommended human dose (Table 55).”
NOAEL / key findings
NOAELs at top weekly IV doses: 1000 mg/kg rat, 500 mg/kg monkey (~200x MRHD AUC)
“Thus, the top weekly intravenous dose of 1000 mg/kg/dose in rats and 500 mg/kg/dose in monkeys were regarded as the no observed adverse effect level (NOAEL) doses, with AUC exposures approximately 200-times greater than clinical exposure at the maximum recommended human dose”
Efficacy evidenceopen answer page →
Efficacy evidence
Hemophilia A (FVIII-deficient) and B (FIX-deficient) mouse models; blood loss reduced 76% and 65%
“The pharmacological activity of marstacimab was evaluated in vivo in mouse models of HA (FVIII-deficient) and HB (FIX-deficient). Marstacimab dose-dependently reduced blood loss in both HA (76%) and HB (65%) mouse models relative to controls.”
Why that model
Marstacimab binds TFPI from mouse, rat, rabbit and monkey with affinity similar to human
“Marstacimab showed similar binding affinity to the combined K1K2 domains (via the K2 domain) of TFPI from human, cynomolgus monkey, rabbit, mouse, and the Wistar Han rat.”
Reviewer's view of the efficacy data
CHMP: efficacy shown in hemophilia A and B mouse disease models; PD shown in monkeys by dPT shortening
“Overall, the pharmacodynamic effect of iv or sc marstacimab in Cynomolgus monkeys was demonstrated by shortening of dPT with a stable decrease in dPT clotting time from 24 to 240 hours. Additionally, efficacy of intravenously administered marstacimab was shown in a model of disease, using acute tail clip injury and/or laser induced injury in haemophilia A and B mice.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAccepted
No 6-month repeat-dose toxicity study in the non-rodent (cynomolgus monkey)
Why: ICH S6(R1) allows deviation when scientifically justified; justification agreed in EMA scientific advice · Within the guideline
“Even though ICH M3(S2) specifies that in the EU/EEA 6-months studies in rodents and non-rodents are required, ICH S6(R1) specifies that there might also be derivations from this principle when scientifically justified. Justification on this aspect was provided in the scientific advice procedure EMA/H/SA/3363/1/2016/I, 21 July 2016.”
DARTAcceptedBeyond the letter
No female reproduction studies; male fertility and early embryonic development study only
Why: Hemophilia A and B occur almost exclusively in males · Other reason
“Marstacimab was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
“The absences of other than male FEED studies in this submission is acceptable, no concerns were identified on the scope of the submitted developmental and reproductive toxicity studies.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for chronic prophylaxis; weight-of-evidence assessment with 26-week repeat-dose data
Why: Weight of evidence indicates low carcinogenic risk · Weight of evidence
“However, a thorough weight of evidence evaluation, in combination with data from the repeat dose toxicity studies, which included exposure to marstacimab up to 26 weeks, does not suggest any carcinogenic potential.”
“In summary, the weight of evidence indicates the carcinogenic risk of marstacimab is low and additional studies are not warranted.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal study; adolescent-age monkeys in the 3-month study cited instead
Why: Some monkeys in the 3-month study were of age aligned with adolescent patients · Weight of evidence
“However, the Applicant argued that in the 3-month repeat-dose toxicity Study 20062114 in Cynomolgus monkeys, the age of some of the animals aligned with the age of adolescent patients (monkeys were 3.7 to 7.2 years at dosing initiation).”
“Considering non-clinical aspects, a sufficient justification was provided why no juvenile toxicity studies were conducted.”
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