Piasky (crovalimab): what was done before first-in-human, and what came after?

Precedia/Monoclonal antibodies/Piasky/Tox package

Piasky: what was done before first-in-human, and what came after?

crovalimab · Complement C5

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.”

✓ VerifiedEMA 2017: Guideline on strategies to identify and mitigate risks for…, p. 11Source ↗

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)

Full method, every step sourced →

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).”

✓ VerifiedEMA assessment report, p. 25Source ↗

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.”

✓ VerifiedEMA assessment report, p. 28Source ↗

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.”

✓ VerifiedEMA assessment report, p. 25Source ↗

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.”

✓ VerifiedEMA assessment report, p. 29Source ↗

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.”

✓ VerifiedEMA assessment report, p. 29Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (crovalimab not active in rodents)

“Crovalimab is not active in rodents; therefore, carcinogenicity studies are not feasible.”

✓ VerifiedFDA integrated review, p. 188Source ↗

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.”

✓ VerifiedFDA integrated review, p. 188Source ↗

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.”

✓ VerifiedEMA assessment report, p. 32Source ↗

Summary across all 117 monoclonal antibodies →

Piasky: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Email me this as a cited memo

Same question, other monoclonal antibodies