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.”
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.”
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 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: 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.”