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.”
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.”
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 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: 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.”
Similar precedents
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