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

Precedia/Monoclonal antibodies/Vyloy/Tox package

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

zolbetuximab · Claudin 18.2

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 Vyloy 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 oncology monoclonal antibodies (ICH S9)

HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.

“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”

✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗

This product's starting point

NOAEL / key findings: No adverse findings in mice; isolated vomiting in one male each at 10 and 30 mg/kg on Day 8 in the 4-week monkey study (FDA multi-discipline review, p. 52)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week mouse (IV) with 4-week treatment-free recovery

“To investigate reversibility after a 4-week treatment-free period, an additional 5 males and 5 females were assigned to the control and 300 mg/kg groups”

✓ VerifiedFDA multi-discipline review, p. 62Source ↗

Pivotal GLP studies

GLP 13-week mouse and 4-week cynomolgus monkey studies, once weekly IV

“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”

✓ VerifiedFDA multi-discipline review, p. 52Source ↗

DART package

Species: DART

Mouse (EFD only); fertility and pre/postnatal studies omitted per ICH S9

“Reproductive and developmental toxicity studies were performed in mice. In line with ICH S9, only embryofoetal development was assessed; omission of studies on fertility and early embryonic development and on pre-/post-natal development is acceptable.”

✓ VerifiedEMA assessment report, p. 33Source ↗

Reproductive & developmental

Mouse EFD (IV during organogenesis): no embryo-fetal toxicity up to 300 mg/kg (about 1.9 times clinical AUC)

“In an embryo-fetal development toxicity study, zolbetuximab was intravenously administered to pregnant mice during the period of organogenesis and did not result in embryo-fetal toxicity at doses up to 300 mg/kg (approximately 1.9 times the recommended clinical dose based on AUC).”

✓ VerifiedFDA multi-discipline review, p. 53Source ↗

PPND / ePPND: when

PPND not conducted: omission acceptable under ICH S9; only embryo-fetal development assessed (mouse)

“In line with ICH S9, only embryofoetal development was assessed; omission of studies on fertility and early embryonic development and on pre-/post-natal development is acceptable.”

✓ VerifiedEMA assessment report, p. 33Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (advanced cancer, ICH S9)

“No carcinogenicity studies have been conducted. Zolbetuximab. is intended for the treatment of patients with advanced cancer in the scope of the ICH S9.”

✓ VerifiedFDA multi-discipline review, p. 66Source ↗

Carcinogenicity model

Not conducted (monoclonal antibody, advanced cancer population)

“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”

✓ VerifiedEMA assessment report, p. 33Source ↗

Carcinogenicity timing

Not required (ICH S9, advanced cancer)

“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”

✓ VerifiedEMA assessment report, p. 33Source ↗

Summary across all 117 monoclonal antibodies →

Vyloy: 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