Decnupaz
pivekimab sunirine
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).”
Species: general tox
Cynomolgus monkey only (single-dose and 13-week GLP studies)
“Studies included single-dose GLP toxicology studies with pivekimab sunirine in cynomolgus monkeys (doses of 0, 0.1, 0.3, or 0.6 mg/kg) with a 28-day recovery period and a 13-week repeat-dose GLP study with pivekimab sunirine in cynomolgus monkeys (0, 0.01, 0.03, or 0.1 mg/kg administered once every three weeks for five doses) with an 8-week recovery period.”
Species: DART
Not conducted (ICH S9 and FDA feedback)
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103).”
Species: carcinogenicity
Not conducted (ICH S9)
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
Surrogate used in
No surrogate used; clinical ADC does not cross-react with CD123 in mouse, rat or cynomolgus monkey
“pivekimab sunirine does not cross-react with CD123 in standard animal species used for toxicology studies (mouse, rat, or cynomolgus monkey).”
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.”
Genotox: Ames
FGN849 payload: positive in Ames (strain TA102)
“Genotoxicity studies conducted with the FGN849 payload demonstrated positive results in the bacterial mutagenicity (Ames) assay (specifically in strain TA102), in vitro micronucleus assay in TK6 cells, and in vivo rat micronucleus assay, consistent with the DNA-alkylating mechanism of action.”
Genotox: in vitro mammalian
FGN849 payload: positive in in vitro micronucleus assay (TK6 cells)
“Genotoxicity studies conducted with the FGN849 payload demonstrated positive results in the bacterial mutagenicity (Ames) assay (specifically in strain TA102), in vitro micronucleus assay in TK6 cells, and in vivo rat micronucleus assay, consistent with the DNA-alkylating mechanism of action.”
Genotox: in vivo
FGN849 payload: positive in in vivo rat micronucleus assay
“Genotoxicity studies conducted with the FGN849 payload demonstrated positive results in the bacterial mutagenicity (Ames) assay (specifically in strain TA102), in vitro micronucleus assay in TK6 cells, and in vivo rat micronucleus assay, consistent with the DNA-alkylating mechanism of action.”
Carcinogenicity model
Not conducted (ICH S9)
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
Carcinogenicity timing
Not required (ICH S9); none conducted
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
hERG / QT
FGN849 payload hERG IC50 >1 µM
“The IC50 for the inhibitory effect of FGN849 on hERG potassium current was estimated to be greater than 1 µM.”
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 Decnupaz 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (FDA multi-discipline review, p. 61)
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).”
Anti-drug antibodies: animals
ADA-positive monkeys had decreased ADC and total antibody exposure on Day 85 vs Day 1
“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.”
Anti-drug antibodies: patients
24% (19/80) BPDCN patients ADA-positive; neutralizing in 78% (14/18) of evaluable ADA-positive patients
“Following administration of pivekimab sunirine-pvzy in CADENZA in BPDCN patients, 19/80 (24%) of patients tested positive for treatment emergent antibodies against pivekimab sunirine-pvzy. Of those who tested positive for anti-drug antibody, neutralizing antibodies were detected in 14/18 (78%) of evaluable patients.”
Label warnings
Boxed warning: Hepatotoxicity, including hepatic veno-occlusive disease (vod) (also known as sinusoidal obstruction syndrome)
- Hepatotoxicity , Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)
- Infusion-Related Reactions
- Edema
- Sulfite Allergic Reactions
- Embryo-Fetal Toxicity
HepatotoxicityHypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 Decnupaz 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (FDA multi-discipline review, p. 61)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study (every 3 weeks, five doses) with 8-week recovery
“a 13-week repeat-dose GLP study with pivekimab sunirine in cynomolgus monkeys (0, 0.01, 0.03, or 0.1 mg/kg administered once every three weeks for five doses) with an 8-week recovery period.”
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).”
DART package
Species: DART
Not conducted (ICH S9 and FDA feedback)
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103).”
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).”
PPND / ePPND: when
Not conducted: no reproductive and developmental studies, per ICH S9 and FDA feedback
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103).”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
Carcinogenicity model
Not conducted (ICH S9)
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
Carcinogenicity timing
Not required (ICH S9); none conducted
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in 13-week monkey study: thymic atrophy at the lowest dose (0.01 mg/kg)
“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Two BPDCN patient-derived xenograft (PDX) models in NSG mice
“In vivo activity was evaluated against two patient-derived xenograft (PDX) models of BPDCN using immunocompromised (NSG) mice and weekly intravenous injections beginning 24 hours after FcR blockade for three weeks.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: agrees with most of the primary pharmacology assessment, but ADCC activity is not negligible
“We agree with most of the Applicant’s assessment of the primary pharmacology studies, with some caveats. The Applicant’s position that immune effector cell activity is negligible, is contrary to the immune effector activity study (RD241447) that contained data showing comparable antibody-dependent cell-mediated cytotoxicity to the positive control, rituximab (detailed below).”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically relevant toxicology species: no CD123 cross-reactivity in mouse, rat or cynomolgus monkey; monkey studies assess off-target and payload toxicity only
“pivekimab sunirine does not cross-react with CD123 in standard animal species used for toxicology studies (mouse, rat, or cynomolgus monkey).”
DARTAccepted
No reproductive and developmental toxicity studies, including embryo-fetal development, for the ADC
Why: In accordance with ICH S9 and prior FDA feedback · Within the guideline
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103). The FDA's Assessment: The FDA concurs.”
Safety marginVerdict not stated
No NOAEL in the 13-week monkey study: thymic atrophy at the lowest dose tested
“Adverse toxicity was observed at all doses since even the lowest tested dose of 0.01 Ab mg/kg produced thymic atrophy in males.”
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