Lartruvo
olaratumab
Species
Monkey
Longest study
39 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“In in vitro studies, olaratumab bound to human and cynomolgus monkey PDGFR-α with similar affinity, but did not bind appreciably to mouse or rabbit PDGFR-α, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Binds human and monkey PDGFRα with similar affinity; no appreciable binding to mouse or rabbit PDGFRα
“In in vitro studies, olaratumab bound to human and cynomolgus monkey PDGFR-α with similar affinity, but did not bind appreciably to mouse or rabbit PDGFR-α, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Surrogate molecule
Yes: chimeric anti-mouse PDGFRα antibody IMC-1E10, used for mouse embryo-fetal development study
“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.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Olaratumab was evaluated in GLP-compliant repeat-dose toxicology studies in cynomolgus monkeys of up to 39 weeks in duration.”
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.”
Route in tox
IV infusion
“by i.v. infusion over 5, 13 and 39 weeks, followed by recovery periods of 7 or 8 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9); no 39-week monkey findings indicating carcinogenicity risk
“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”
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.”
Safety pharmacology
Cardiovascular, respiratory and CNS endpoints incorporated into repeat-dose monkey studies; no dedicated studies
“Safety pharmacology endpoints (cardiovascular, respiratory, and central nervous system) were evaluated in these repeat-dose studies.”
First doseopen answer page →
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”
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)
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
“In this study, monkey serum Cmin was 1164 μg/mL at the no observed adverse effect level (NOAEL) of 75 mg/kg”
Risksopen answer page →
Immune & cytokine safety
ADA in at least 22% of monkeys causing variable exposure; peripheral blood immunophenotyping unremarkable
“though anti-drug antibody (ADA) responses seen in at least 22% of monkeys resulted in variable exposure in all toxicology studies.”
Biodistribution & persistence
TCR with rabbit anti-PDGFRα: similar human and monkey staining of mesenchymal, glial, endothelial cells; surrogate crossed mouse placenta
“Anti-PDGFR-α staining was generally similar between human and cynomolgus monkey tissues.”
Modality-specific risk
Embryo-fetal toxicity from PDGFRα inhibition (critical for organogenesis); potential delayed tissue inflammation/fibrosis
“Data from PDGFR-α knockout mice demonstrated that PDGFR-α is critical for normal embryonic survival, development, and organogenesis, and suggested that inhibition of the PDGFR-α signaling pathway with olaratumab may be embryonic lethal and teratogenic.”