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

Precedia/Monoclonal antibodies/Soliris/Tox package

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

eculizumab · 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 Soliris 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: Surrogate 26-week mouse study: no treatment effects on any toxicity parameter at either dose; no target organs (EMA assessment report, p. 9)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week IV mouse study with surrogate anti-C5 antibody BB5.1, with 4-week recovery

“Serum analysis indicated that the extent of mean % haemolysis decreased from pre-treatment levels of 70-80 % to below 20 % in treated mice at weeks 12 and 25. Although results were similar for both treated mice groups, the mean % haemolysis was slightly less for the 60 mg/kg/week mice in most instances. Following a four-week recovery period, the mean % haemolysis approximated pre-study values for both treatment groups.”

✓ VerifiedEMA assessment report, p. 9Source ↗

Pivotal GLP studies

26-week IV study of surrogate BB5.1 in CD-1 mice, once or twice weekly (30 or 60 mg/kg/week)

“Crl:CD-1®(ICR) BR mice received by IV route BB5.1 mAb at 0 mg/kg twice weekly, 30 mg/kg once weekly, or 30 mg/kg twice weekly (resulting in dose levels of 0, 30 and 60 mg/kg/week respectively).”

✓ VerifiedEMA assessment report, p. 9Source ↗

DART package

Species: DART

Mouse with murine anti-C5 surrogate (fertility, embryo-fetal, pre/postnatal)

“Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human SOLIRIS dose, based on a body weight comparison.”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Mouse surrogate fertility, EFD, PPND: no fertility effects; retinal dysplasia and umbilical hernia at high dose; more male offspring deaths

“When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death.”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

PPND in CD-1 mouse with surrogate anti-C5 antibody BB5.1: completed before the marketing application

“Female Crl:CD-1®(ICR) BR mice received BB5.1 mAb at 30 mg/kg/dose once or twice weekly (groups 2 and 3, low and high dose, respectively) or vehicle.”

✓ VerifiedEMA assessment report, p. 10Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”

✓ VerifiedEMA assessment report, p. 9Source ↗

Carcinogenicity model

Not conducted; 26-week surrogate (BB5.1) mouse study showed no proliferative activity up to 60 mg/kg/week

“The 26-week repeat dose toxicity study with a murine anti-mouse C5 antibody (BB5.1mAb) showed no cytotoxic or proliferative activities suggestive of carcinogenic risk at dose levels up to 60 mg/kg/week, i.e. a dose level showing significant inhibition of C5 activation.”

✓ VerifiedEMA assessment report, p. 9Source ↗

Carcinogenicity timing

Not conducted with eculizumab or any surrogate anti-C5 antibody; no reason or waiver stated

“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”

✓ VerifiedEMA assessment report, p. 9Source ↗

Summary across all 117 monoclonal antibodies →

Soliris: 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