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.”
Species: general tox
Cynomolgus monkey only (up to 39 weeks)
“Olaratumab was evaluated in GLP-compliant repeat-dose toxicology studies in cynomolgus monkeys of up to 39 weeks in duration.”
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.”
Species: carcinogenicity
Not conducted (ICH S6, S1, S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
Surrogate used in
Yes: chimeric anti-mouse PDGFRα surrogate IMC-1E10 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.”
Genotox: Ames
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“Not conducted per ICH S6.”
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”
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).”
hERG / QT
Not conducted: no hERG or dedicated safety pharmacology studies
“No dedicated safety pharmacology studies have been submitted in this application.”
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)
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.”
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.”
Anti-drug antibodies: animals
ADA in at least 22% of monkeys, causing variable exposure across toxicology studies
“though anti-drug antibody (ADA) responses seen in at least 22% of monkeys resulted in variable exposure in all toxicology studies.”
Anti-drug antibodies: patients
3.5% (13/370) treatment-emergent anti-olaratumab antibodies; all were neutralizing
“In clinical trials, 13/370 (3.5%) of evaluable LARTRUVO-treated patients tested positive for treatment-emergent anti-olaratumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in all patients who tested positive for treatment-emergent anti-olaratumab antibodies.”
Tox packageopen answer page →
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.”
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.”
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)
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.”
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.”
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.”
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.”
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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6, S1, S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
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”
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).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 75 mg/kg weekly up to 39 weeks (no mortality) AUC ~6-9.5x human steady-state AUC at recommended dose
“There were no mortalities following intravenous (I.V.) administration of the antibody at dose levels up to 75 mg/kg once weekly for up to 39 weeks. This dose resulted in exposures approximately 9.5- and 6-fold higher based on AUC0-t and AUC0-168, respectively, than the steady-state AUCtau seen on Day 8 at the recommended human dose”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Human sarcoma xenografts (leiomyosarcoma, osteosarcoma) in nude mice treated with olaratumab, alone and with doxorubicin
“In keeping with these findings, olaratumab exhibited in vivo anti-tumor activity in nude mice bearing human sarcoma xenografts.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: in vitro and in vivo results relevant to indication, but mechanism of action not fully elucidated given discrepancies
“The in vitro and in vivo results are deemed relevant for the proposed indication, although the identification of the mechanism of action could not be fully elucidated, in light of the discrepancies noted throughout all studies.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive toxicity studies with olaratumab; literature assessment plus mouse embryo-fetal study with surrogate antibody IMC-1E10
Why: Alternative approach described in ICH S6(R1); FDA agreed the dual literature-plus-surrogate approach was reasonable · Within the guideline · Weight of evidence
“Rather, consistent with the alternative approach to providing information on the potential for reproductive toxicity described in ICH S6(R1), 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.”
“Following the Applicant’s subsequent proposal to also conduct an embryo-fetal development study in mice with IMC-1E10, FDA agreed in June 2015 that this dual approach appeared reasonable.”
Similar precedents
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