Decnupaz
pivekimab sunirine
Sources:FDA multi-discipline review ↗
Species
MonkeyRat
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (no CD123 cross-reactivity; off-target/payload toxicity) plus rat for FGN849 payload
“pivekimab sunirine does not cross-react with CD123 in standard animal species used for toxicology studies (mouse, rat, or cynomolgus monkey).”
Why that species
No CD123 cross-reactivity in standard species; monkey used for off-target/payload effects; weaker monkey TCR staining
“PVEK produced less intense and less frequently observed staining in monkey mononuclear cells.”
Surrogate molecule
No surrogate; clinical ADC tested in monkey; FGN849 payload tested alone in rats
“Additional studies were conducted with the FGN849 payload alone in rats, including single-dose studies (doses of 0, 15, or 25 μg/kg) and 5-day repeat-dose studies (doses of 0, 1, or 3 μg/kg daily for five days).”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Groups of monkeys received 0, 0.01, 0.03, 0.1 mg/kg intravenous doses once every 21 days for 13 weeks.”
Pivotal GLP studies
GLP IV cyno single-dose (0.1-0.6 mg/kg, 28-day recovery) and 13-week Q3W (0.01-0.1 mg/kg, 8-week recovery); FGN849 rat studies
“The toxicity of PVEK has been characterized in single- and repeat-dose studies (up to 13 weeks in duration).”
Route in tox
IV (10-minute infusion single-dose; bolus in 13-week study)
“Dosing Route IV Infusion (10 minutes)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC (ICH S9); FGN849 positive in Ames TA102, in vitro and in vivo micronucleus
“In accordance with ICH S9, genotoxicity studies have not been conducted with PVEK.”
Carcinogenicity
Not conducted (ICH S9)
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
Reproductive & developmental
Not conducted (ICH S9 and FDA feedback); embryo-fetal harm expected from alkylating payload
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103).”
Safety pharmacology
Incorporated into GLP monkey studies (ECG, respiration); FGN849 hERG IC50 >1 µM; tremors at 0.1 mg/kg
“Stand-alone in vivo safety pharmacology studies were not conducted with PVEK or FGN849.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
FDA: no NOAEL in 13-week (thymic atrophy ≥0.01 mg/kg); single-dose max nonlethal 0.4 mg/kg; marrow, GI, skin, thymus
“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”
Risksopen answer page →
Immune & cytokine safety
ADA in monkeys reduced exposure; thymic lymphoid depletion and lymphopenia; ADCC present in vitro
“In animals that were ADA positive, there was a noticeable decrease in systemic exposure to both PVEK and TAb on Day 85 vs Day 1.”
Biodistribution & persistence
[3H]PVEK in rat: highest in marrow, liver, kidney, lung, heart, spleen; tissue:plasma <1; mainly fecal/biliary excretion
“The highest concentrations of radioactivity were observed in tissues with high blood volume: bone marrow, liver, kidneys, lungs, heart and spleen.”
Modality-specific risk
DNA-alkylating IGN payload: myelosuppression, GI, skin, liver/VOD; genotoxic payload
“Most notably from the nonclinical studies, bone marrow depletion, gastrointestinal toxicity, and elevated liver enzymes corresponded directly to the most significant clinical adverse events requiring management through dose modifications and supportive care, including veno-occlusive disease (VOD).”