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

Precedia/Monoclonal antibodies/Enjaymo/Tox package

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

sutimlimab · Complement C1s

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 Enjaymo 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 180 mg/kg/week (highest dose) in repeat-dose monkey study; no adverse findings despite near-complete classical complement inhibition (FDA pharmacology/toxicology review, p. 40)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week cynomolgus monkey (IV) GLP study with 8-week recovery

“In a GLP-compliant chronic toxicology study, sutimlimab was administered to cynomolgus monkeys by 30-minute intravenous infusion at 2 doses (60 and 180 mg/kg/week) for 26 consecutive weeks with an 8-week treatment-free recovery period.”

✓ VerifiedFDA pharmacology/toxicology review, p. 22Source ↗

Pivotal GLP studies

Cynomolgus monkey 5-week (up to 100 mg/kg/week) and 26-week (up to 180 mg/kg/week) IV studies with 8-week recovery

“Sutimlimab has been evaluated in repeat-dose studies in cynomolgus monkey for 5 (up to 100 mg/kg/week) and 26 weeks (up to 180 mg/kg/week) with 8 weeks of recovery.”

✓ VerifiedEMA assessment report, p. 25Source ↗

DART package

Species: DART

Cynomolgus monkey (ePPND, 60 and 180 mg/kg/week); no dedicated fertility study

“An enhanced pre- and post-natal developmental (ePPND) toxicity study was conducted in pregnant monkeys with intravenous administration of 60 and 180 mg/kg/week sutimlimab (during organogenesis to parturition) to evaluate the potential for embryo-fetal and pre/post-natal developmental toxicity.”

✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Reproductive & developmental

Monkey ePPND up to 180 mg/kg/week (~4x clinical exposure): no adverse reproductive or developmental effects; no dedicated fertility study

“There were no adverse effects on reproductive or developmental outcomes at 180 mg/kg/week, which represents 4 times the human exposure at the 7.5 g clinical dose.”

✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

PPND / ePPND: when

ePPND in cynomolgus monkey completed before the marketing application

✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (weight-of-evidence assessment instead)

“The applicant’s non-clinical package did not include a traditional in vivo carcinogenicity assessment. Instead, the applicant provided a weight-of-evidence (WOE)-based assessment of carcinogenic potential (per ICH S6).”

✓ VerifiedFDA pharmacology/toxicology review, p. 40Source ↗

Carcinogenicity model

Not conducted; weight-of-evidence assessment (ICH S6)

✓ VerifiedFDA pharmacology/toxicology review, p. 40Source ↗

Carcinogenicity timing

Not required; ECAC concurred no additional carcinogenicity studies warranted

“CDER’s Executive Carcinogenicity Assessment Committee concurred with this assessment, and no additional studies of the carcinogenic potential of sutimlimab are warranted at this time.”

✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Summary across all 117 monoclonal antibodies →

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

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other monoclonal antibodies