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

Precedia/Monoclonal antibodies/Lartruvo/Tox package

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

olaratumab · PDGFRα

Before first-in-human

First-in-human: where

United States: single-agent dose-escalation study in patients with advanced solid tumours and lymphomas (2 US centres)

“JGDC (IMCL CP15-0601) is a phase 1 multicentre open-label dose escalation study of olaratumab single agent in advanced solid tumours and lymphomas, conducted in 2 US centres between December 2006 and March 2009.”

✓ VerifiedEMA assessment report, p. 51Source ↗

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 Lartruvo 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: NOAEL 75 mg/kg (highest dose) in 39-week monkey study; non-adverse ALT rise and liver infiltrates; potential targets skin, liver, lung, pancreas (EMA assessment report, p. 35)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

39-week cynomolgus monkey (weekly IV infusion) GLP study with 8-week recovery

“Weekly I.V. infusion of olaratumab for 39 weeks induced an increase in the incidence and/or severity of lymphocyte infiltration in numerous tissues, which often persisted or developed during the 8-week recovery period.”

✓ VerifiedFDA multi-discipline review, p. 30Source ↗

Pivotal GLP studies

GLP monkey studies, weekly IV infusion for 5, 13 and 39 weeks with 7- or 8-week recovery

“by i.v. infusion over 5, 13 and 39 weeks, followed by recovery periods of 7 or 8 weeks.”

✓ VerifiedEMA assessment report, p. 21Source ↗

DART package

Species: DART

Mouse EFD with chimeric surrogate IMC-1E10, plus literature review

“the Applicant provided a scientific literature review and assessment of the potential reproductive toxicity of olaratumab in conjunction with an embryo-fetal development study in mice using a chimeric surrogate antibody, IMC-1E10.”

✓ VerifiedFDA multi-discipline review, p. 30Source ↗

Reproductive & developmental

No fertility or PPND studies. Mouse EFD with surrogate IMC-1E10: teratogenic (eyelid, skeletal malformations) below human exposure

“IMC-1E10 was teratogenic at maternal IMC-1E10 exposures below the human exposure to olaratumab at the recommended dose of 15 mg/kg.”

✓ VerifiedFDA multi-discipline review, p. 31Source ↗

PPND / ePPND: when

Not conducted: not required for advanced cancer (mouse surrogate EFD only)

“Prenatal and Postnatal Development Not conducted and not required to support the approval of a pharmaceutical intended for the treatment of patients with advanced cancer.”

✓ VerifiedFDA multi-discipline review, p. 51Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (ICH S6, S1, S9)

“Not conducted per ICH S6, ICH S1, and ICH S9.”

✓ VerifiedFDA multi-discipline review, p. 46Source ↗

Carcinogenicity model

Not conducted: not warranted for advanced cancer (ICH S9); no carcinogenicity signal in 39-week monkey study

“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICHS9). In addition, there were no findings observed in the 39-week repeat-dose study in monkeys that would indicate a carcinogenicity risk”

✓ VerifiedEMA assessment report, p. 35Source ↗

Carcinogenicity timing

Not required (advanced cancer, ICH S9)

“Carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICHS9).”