Piasky
crovalimab
Species
Monkey
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
Cynomolgus monkey only
“Crovalimab was evaluated in good laboratory practice-compliant acute and chronic (6-month) toxicology studies in cynomolgus monkeys, which is the only pharmacologically-relevant species.”
Why that species
Binds human and cynomolgus C5 equally (1.72 vs 2.00 ×10-10 M); no rat and weak mouse C5 binding
“Crovalimab binds human C5 (hC5) and cynomolgus monkey C5 (cyC5) to the same extent (1.72 and 2.00 ×10-10 mol/L, respectively) and its binding is pH dependent. No binding to rat C5 (rC5) and a weak binding to mouse C5 (mC5) were detected.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The non-clinical toxicology programme of crovalimab characterised general toxicity and toxicokinetics following IV and SC administrations up to 26 weeks in a single pharmacologically relevant species (cynomolgus monkeys), as recommended in ICH S6(R1) guideline.”
Species: general tox
Cynomolgus monkey only
“Crovalimab was evaluated in good laboratory practice-compliant acute and chronic (6-month) toxicology studies in cynomolgus monkeys, which is the only pharmacologically-relevant species.”
Species: DART
Cynomolgus monkey (ePPND); fertility assessed via reproductive organs in repeat-dose monkey studies
“Since the cynomolgus monkey was the only demonstrated pharmacologically relevant species, an enhanced pre- and postnatal development (ePPND) study was conducted in line with ICH S6(R1) guideline. An assessment of the reproductive organs was also included in the repeat-dose toxicity studies to address any potential effect on fertility.”
Species: carcinogenicity
Not conducted (crovalimab not active in rodents)
“Crovalimab is not active in rodents; therefore, carcinogenicity studies are not feasible.”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkeys
“The non-clinical toxicology programme of crovalimab characterised general toxicity and toxicokinetics following IV and SC administrations up to 26 weeks in a single pharmacologically relevant species (cynomolgus monkeys), as recommended in ICH S6(R1) guideline.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A 6-Month Intermittent Subcutaneous or Intravenous Administration Toxicity Study of SKY59 (Crovalimab) in Mature Cynomolgus Monkeys Followed by a 6-Month Recovery Period (Study 1082669)”
Pivotal GLP studies
26-week GLP monkey study: SC 10, 40, 100 mg/kg weekly after a 100 mg/kg IV dose, plus IV 160 mg/kg group
“Crovalimab was administered SC at dose levels of 10, 40, and 100 mg/kg QW for 26 weeks after a single IV injection of 100 mg/kg on Day 1 of the study and was administered to an additional group IV at a dose level of 160 mg/kg.”
Route in tox
Subcutaneous (weekly) and intravenous (every 2 weeks)
“Then, one pivotal with 2 different administration schemes (IV up to 4 weeks with 17-week recovery and SC up to 5 months with no recovery) was performed as same as the long-term term study in which both administration routes were used (26-week GLP study SC QW and IV Q2W with 26-week recovery).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (biotechnology-derived pharmaceutical)
“No genotoxicity studies were conducted as crovalimab is a biotechnology-derived pharmaceutical.”
Carcinogenicity
Not conducted (not active in rodents); weight-of-evidence low risk, including no preneoplastic lesions in 26-week monkey studies
“Based on the mechanism of action, review of the literature, drug class, and the lack of drug-related preneoplastic lesions in monkeys administered crovalimab for up to 26 weeks, the risk of carcinogenicity of crovalimab is low. Crovalimab is not active in rodents; therefore, carcinogenicity studies are not feasible.”
Reproductive & developmental
Monkey ePPND: NOAEL 100 mg/kg/dose for pre- and postnatal development (5-14-fold human AUC)
“The NOAEL for pre- and postnatal development was 100 mg/kg/dose in this study, corresponding to exposure levels (AUC) 5- to 14-fold higher than in humans at the maximum recommended dose.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; no effects on behaviour, neurobehavioral function, respiration or cardiovascular system
“No dedicated safety pharmacology studies were performed. No effects on general behaviour and neurobehavioral function, respiration and the cardiovascular system were seen after the first dose or following repeated dosing in the repeated-dose pivotal studies.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted as crovalimab is a biotechnology-derived pharmaceutical.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted as crovalimab is a biotechnology-derived pharmaceutical.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted as crovalimab is a biotechnology-derived pharmaceutical.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment (mechanism, literature, class, no preneoplastic lesions in monkeys up to 26 weeks) judged risk low
“Based on the mechanism of action, review of the literature, drug class, and the lack of drug-related preneoplastic lesions in monkeys administered crovalimab for up to 26 weeks, the risk of carcinogenicity of crovalimab is low.”
Carcinogenicity timing
Not required: weight-of-evidence assessment accepted, no dedicated carcinogenicity testing
“Therefore, submitted carcinogenicity assessment is considered sufficient and no dedicated carcinogenicity testing is warranted.”
hERG / QT
No hERG assay; no cardiovascular effects in repeat-dose monkey studies
“No dedicated safety pharmacology studies were performed. No effects on general behaviour and neurobehavioral function, respiration and the cardiovascular system were seen after the first dose or following repeated dosing in the repeated-dose pivotal studies.”
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 Piasky 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: NOAEL 10 mg/kg/week SC in 6-month study; arteritis/periarteritis in multiple organs at higher doses (FDA integrated review, p. 178)
NOAEL / key findings
NOAEL 10 mg/kg/week SC in 6-month study; arteritis/periarteritis in multiple organs at higher doses
“The no observed adverse effect level (NOAEL) for crovalimab in cynomolgus monkeys after 6 months of SC intermittent dosing is defined at the low dose of 10 mg/kg/week based on the occurrence of arteritis/periarteritis in multiple organs at higher doses tested”
Risksopen answer page →
Immune & cytokine safety
ADA in 21/30 SC and 8/10 IV monkeys in the 26-week study
“ADA were detected in 21 out of 30 animals in the SC groups (D36) and in 8 out of 10 animals in the IV group (D15).”
Biodistribution & persistence
Vss 69.5-71.8 mL/kg (some tissue distribution); placental transfer in pregnant monkeys
“Vss exceeded the plasma volume (69.5-71.8 mL/kg), indicating some distribution into tissues. Crovalimab was transferred via the placenta in pregnant monkeys.”
Modality-specific risk
Increased infection risk from complement inhibition (class effect)
“The complement system is a well-established, innate immune defense modulator against pathogens and, given crovalimab’s mechanism of action and experience with the drug class (see Section 5.1), treatment with crovalimab is anticipated to increase the risk of infections.”
Anti-drug antibodies: animals
ADA in almost all monkeys; increased clearance and lower exposure in some, but PD activity maintained throughout dosing
“Crovalimab was immunogenic and induced ADA production in cynomolgus monkeys in almost all treated monkeys. In some ADA-positive monkeys, an increased systemic CL was observed with a decreased exposure; however, the PD activity is maintained during the whole treatment period and partially recovered in the treatment free period.”
Anti-drug antibodies: patients
30% (42/140) treatment-naive and 34% (23/67) switch patients ADA-positive in COMMODORE 2
“In the active-controlled COMMODORE 2 study, 30% (42/140) of treatment-naïve patients who received PIASKY and 34% (23/67) of patients who switched from treatment with another C5 inhibitor to PIASKY (switch patients) tested positive for anti-crovalimab-akkz-antibodies.”
Label warnings
Boxed warning: Serious meningococcal infections
- Serious Meningococcal Infection
- Piasky rems
- Type III Hypersensitivity Reactions Related to Drug-Target-Drug Complexes
- Other Infections
- Infusion- and Injection-Related Reactions
- Monitoring PNH Manifestations after Discontinuation of PIASKY
InfectionsHypersensitivity & infusion reactions
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 Piasky 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: NOAEL 10 mg/kg/week SC in 6-month study; arteritis/periarteritis in multiple organs at higher doses (FDA integrated review, p. 178)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week GLP cynomolgus monkey study (SC weekly and IV every 2 weeks) with 26-week recovery
“Then, one pivotal with 2 different administration schemes (IV up to 4 weeks with 17-week recovery and SC up to 5 months with no recovery) was performed as same as the long-term term study in which both administration routes were used (26-week GLP study SC QW and IV Q2W with 26-week recovery).”
Pivotal GLP studies
26-week GLP monkey study: SC 10, 40, 100 mg/kg weekly after a 100 mg/kg IV dose, plus IV 160 mg/kg group
“Crovalimab was administered SC at dose levels of 10, 40, and 100 mg/kg QW for 26 weeks after a single IV injection of 100 mg/kg on Day 1 of the study and was administered to an additional group IV at a dose level of 160 mg/kg.”
DART package
Species: DART
Cynomolgus monkey (ePPND); fertility assessed via reproductive organs in repeat-dose monkey studies
“Since the cynomolgus monkey was the only demonstrated pharmacologically relevant species, an enhanced pre- and postnatal development (ePPND) study was conducted in line with ICH S6(R1) guideline. An assessment of the reproductive organs was also included in the repeat-dose toxicity studies to address any potential effect on fertility.”
Reproductive & developmental
Monkey ePPND: NOAEL 100 mg/kg/dose for pre- and postnatal development (5-14-fold human AUC)
“The NOAEL for pre- and postnatal development was 100 mg/kg/dose in this study, corresponding to exposure levels (AUC) 5- to 14-fold higher than in humans at the maximum recommended dose.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application
“An enhanced pre- and postnatal development (ePPND) study was conducted in cynomolgus monkeys administered an IV loading dose of 100 mg/kg on GD20, followed by once weekly SC injections of either 10 or 100 mg/kg up to parturition.”
Carcinogenicity
Species: carcinogenicity
Not conducted (crovalimab not active in rodents)
“Crovalimab is not active in rodents; therefore, carcinogenicity studies are not feasible.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment (mechanism, literature, class, no preneoplastic lesions in monkeys up to 26 weeks) judged risk low
“Based on the mechanism of action, review of the literature, drug class, and the lack of drug-related preneoplastic lesions in monkeys administered crovalimab for up to 26 weeks, the risk of carcinogenicity of crovalimab is low.”
Carcinogenicity timing
Not required: weight-of-evidence assessment accepted, no dedicated carcinogenicity testing
“Therefore, submitted carcinogenicity assessment is considered sufficient and no dedicated carcinogenicity testing is warranted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 3.3- and 2.6-times patient exposure at maximum recommended human dose (males, females)
“The NOAEL for crovalimab in cynomolgus monkeys is associated with a maximum plasma concentration (Cmax) of 996 μg/mL and area under the concentration-time curve (AUC) from 0 to 7 days of 5750 μg·d/mL that corresponds to 3.3- and 2.6-times the exposure observed in patients with PNH at the maximum recommended human dose for male and female animals, respectively.”
NOAEL / key findings
NOAEL 10 mg/kg/week SC in 6-month study; arteritis/periarteritis in multiple organs at higher doses
“The no observed adverse effect level (NOAEL) for crovalimab in cynomolgus monkeys after 6 months of SC intermittent dosing is defined at the low dose of 10 mg/kg/week based on the occurrence of arteritis/periarteritis in multiple organs at higher doses tested”
Efficacy evidenceopen answer page →
Efficacy evidence
No PNH animal model; complement inhibition (CH50, free C5) in monkey PK/PD and repeat-dose studies plus in vitro RBC lysis
“A pharmacology study in an animal model of PNH was not conducted; however, the Applicant assessed complement inhibition in a pharmacokinetics/pharmacodynamics study and in repeat-dose toxicology studies in monkeys as well as in patients with PNH.”
Why that model
Rat, mouse and rabbit not pharmacologically relevant; monkey the only relevant species
“These in vitro results confirmed that rat, mice and rabbit were not pharmacologically relevant species and therefore were excluded to be selected as species in the toxicity studies.”
Reviewer's view of the efficacy data
In vitro and monkey CH50 data show C5 binding and inhibition of RBC lysis; expected to reduce complement activation in PNH
“The totality of the in vitro pharmacology, in vitro RBC lysis, and in vivo CH50 activity in nonhuman primates demonstrate that crovalimab binds C5 protein, inhibits C5-dependent RBC lysis, and is expected to reduce uncontrolled C5-dependent complement activation in patients with PNH.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for chronic PNH use; weight-of-evidence assessment as crovalimab is not active in rodents
Why: Mechanism, literature, drug class and no preneoplastic lesions in 26-week monkey studies; not active in rodents · Weight of evidence · No relevant species · Class precedent
“Based on the mechanism of action, review of the literature, drug class, and the lack of drug-related preneoplastic lesions in monkeys administered crovalimab for up to 26 weeks, the risk of carcinogenicity of crovalimab is low. Crovalimab is not active in rodents; therefore, carcinogenicity studies are not feasible.”
“Therefore, submitted carcinogenicity assessment is considered sufficient and no dedicated carcinogenicity testing is warranted.”
Efficacy modelVerdict not stated
No pharmacology study in an animal model of PNH; complement inhibition assessed in monkey PK/PD and toxicology studies and patients
Why: Complement inhibition assessed in monkey studies and in patients with PNH · Human data
“A pharmacology study in an animal model of PNH was not conducted; however, the Applicant assessed complement inhibition in a pharmacokinetics/pharmacodynamics study and in repeat-dose toxicology studies in monkeys as well as in patients with PNH.”
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