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

United Kingdom: first-in-human study UP0018 (Source: FDA integrated review, p. 159.)

Precedia/Monoclonal antibodies/Rystiggo/Tox package

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

rozanolixizumab · FcRn

Before first-in-human

First-in-human: where

United Kingdom: first-in-human study UP0018

“The Applicant stated that a first-in-human study (UP0018) was conducted and completed in the United Kingdom and there was an ongoing study in patients with immune thrombocytopenia (ITP) (TP0001) in the European Union and Australia.”

✓ VerifiedFDA integrated review, p. 159Source ↗

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 Rystiggo 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: No adverse effects up to 150 mg/kg SC every 3 days for 4, 13 and 26 weeks; reduced IgG, total protein and albumin (pharmacology) (FDA integrated review, p. 91)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week GLP cynomolgus monkey SC study (every 3 days) with 8-week recovery

“NCD2553 GLP Cynomolgus monkey Main study 3 M/F (0 mg/kg) 6/8 * M/F (treated group) Recovery 2 M/F 0, 150 mg/kg sc every 3 days 26 weeks Recovery 8 weeks”

✓ VerifiedEMA assessment report, p. 40Source ↗

Pivotal GLP studies

Cynomolgus monkey 4-, 13- and 26-week studies, up to 150 mg/kg SC every 3 days; monkey ePPND

“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”

✓ VerifiedFDA integrated review, p. 161Source ↗

DART package

Species: DART

Cynomolgus monkey (ePPND; fertility endpoints in 26-week study)

“Given that only the nonhuman primates (NHP) was found to be a relevant species – an ePPND study was performed in cynomolgus monkeys. No stand-alone fertility and early embryonic development studies have been conducted with rozanolixizumab. Fertility endpoints were included in the pivotal 26 weeks repeat dose study.”

✓ VerifiedEMA assessment report, p. 48Source ↗

Reproductive & developmental

Monkey ePPND (0, 50, 150 mg/kg SC every 3 days, GD 20 to parturition): embryonic losses in 3 of 19 females at both doses

“Subcutaneous administration of 0, 50, or 150 mg/kg UCB7665 every 3 days to pregnant female cynomolgus monkeys from gestational day (GD) 20 through parturition caused embryonic losses in 3 of 19 females at both doses.”

✓ VerifiedFDA integrated review, p. 162Source ↗

PPND / ePPND: when

ePPND in cynomolgus monkey: completed and submitted with the marketing application

“An enhanced pre- and postnatal development study in cynomolgus monkey was the only nonclinical study of UCB7665 submitted only to the NDA.”

✓ VerifiedFDA integrated review, p. 162Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (weight-of-evidence assessment)

“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”

✓ VerifiedFDA integrated review, p. 162Source ↗

Carcinogenicity model

Not conducted; carcinogenicity assessment (weight of evidence) accepted

“The applicant did not provide carcinogenicity studies which is supported. The provided carcinogenicity assessment supports the lack of any conventional carcinogenicity studies.”

✓ VerifiedEMA assessment report, p. 48Source ↗

Carcinogenicity timing

Not required (weight-of-evidence assessment)

“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”

✓ VerifiedFDA integrated review, p. 162Source ↗

Summary across all 117 monoclonal antibodies →

Rystiggo: 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