Trogarzo
ibalizumab
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
Rhesus and cynomolgus monkey
“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”
Why that species
Ibalizumab does not recognize CD4 in other animal species; only monkeys are relevant
“Pharmacokinetic and toxicokinetic studies with ibalizumab were only performed in monkeys (Rhesus and Cynomolgus), because CD4 in other animal models is not recognized by Hu5A8.”
Surrogate molecule
No surrogate in toxicology studies; the clinical antibody was tested in rhesus and cynomolgus monkeys
“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”
Pivotal GLP studies
IV repeat-dose studies in rhesus monkeys (up to 2 months) and cynomolgus monkeys (up to 9 months)
“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”
Route in tox
Intravenous
“Repeated intravenous exposure to ibalizumab was studied up to 2 months in rhesus monkeys and up to 9 months in cynomolgus monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“As ibalizumab is a biotechnology-derived protein product made of natural amino acids, and as per ICH S6(R1), genotoxicity studies are not applicable and therefore have not been conducted.”
Carcinogenicity
Not conducted (no rodent CD4 binding); weight-of-evidence assessment concluded ibalizumab is not expected to be carcinogenic
“The conclusion of this report made by the applicant was that given the weight of evidence, ibalizumab is not expected to be carcinogenic. Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
Reproductive & developmental
No fertility/EFD studies; monkey ePPND: reversible infant CD4+ T- and B-cell decreases and CD8+ increases in first 4 weeks
“In a reproductive study in monkeys, reversible decreases in CD4+ T cells and B cells and increases in CD8+ T cells were observed within the first 4 weeks after birth in infants born to pregnant monkeys receiving ibalizumab-uiyk intravenously ( see Data ).”
Safety pharmacology
Incorporated into repeat-dose rhesus and cynomolgus monkey studies
“Safety pharmacology endpoints were assessed as part of the repeated dose toxicity studies in rhesus and cynomolgus monkeys.”
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 Trogarzo 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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Cynomolgus monkey: glomerulopathy and reduced albumin only in animals with strong anti-drug antibody responses (EMA assessment report, p. 29)
NOAEL / key findings
Cynomolgus monkey: glomerulopathy and reduced albumin only in animals with strong anti-drug antibody responses
“Multifocal glomerulopathy was observed together with reduced albumin levels, which can be an indication for protein loss through the kidney. As these effects were observed only in animals with a strong antibody response against ibalizumab, its relevance for humans is limited.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies in 83% (25 mg/kg) and 58% (50 mg/kg) of cynomolgus monkeys
“However, throughout the study, antibodies against ibalizumab were observed in 83% (10/12) and 58% (7/12) of the animals at the low and high dose (25 and 50 mg/kg), respectively.”
Biodistribution & persistence
Monkey volume of distribution 47-52 ml/kg, approximately plasma volume; largely restricted to the vasculature
“distribution (47-52 ml/kg), approximately the plasma volume of the monkeys, suggesting that the drug was largely restricted to the vasculature.”
Modality-specific risk
CD4 binding: reversible CD4+ T- and B-cell lymphocytopenia and immunosuppression in infants exposed in utero
“Based on animal data, ibalizumab-uiyk use during pregnancy may cause reversible immunosuppression (CD4+ T cell and B cell lymphocytopenia) in infants exposed to ibalizumab-uiyk in utero.”
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