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.”
Species: general tox
Rhesus monkey (up to 2 months) and cynomolgus monkey (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.”
Species: DART
Cynomolgus monkey (pre-/postnatal study only); no fertility or embryo-fetal studies
“No reproductive, no early embryonic or embryo-fetal developmental studies were performed. According to ICH 6 guideline, the potential maternal and developmental effects of ibalizumab in pregnant cynomolgus monkeys and their offspring were evaluated.”
Species: carcinogenicity
Not conducted: ibalizumab does not bind rodent CD4
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
Surrogate used in
Murine parent antibody Mu5A8 used in some in vivo monkey pharmacology studies
“In vivo, there was an expected pharmacological effect on CD4+ cell increase in monkeys treated with Mu5A8.”
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.”
Genotox: Ames
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.”
Genotox: in vitro mammalian
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.”
Genotox: in vivo
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 model
Not conducted: 2-year rodent and 6-month transgenic mouse studies not possible (no rodent CD4 binding)
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
Carcinogenicity timing
Not required: 2-year rodent and 6-month transgenic mouse studies not possible (no rodent CD4 binding)
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
hERG / QT
No hERG assay; safety pharmacology endpoints included in monkey repeat-dose studies, outcome not stated
“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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
Cynomolgus: ADA in 83% (25 mg/kg) and 58% (50 mg/kg); severe ADA in 7 low-dose and 1 high-dose animal caused loss of exposure and euthanasia
“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. In total, 7 animals at the low dose and 1 animal at the high dose developed a severe anti-drug-antibody response, resulting in lack of exposure, after which these animals were euthanized and necropsied around 6.5 months.”
Anti-drug antibodies: patients
One sample positive (low titer); no adverse reaction or reduced efficacy attributed
“One sample tested positive with low titer anti-ibalizumab antibodies. No adverse reaction or reduced efficacy was attributed to the positive sample reported in this subject.”
Label warnings
- Hypersensitivity Including Infusion-Related and Anaphylactic Reactions
- Immune Reconstitution Inflammatory Syndrome
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) IV cynomolgus monkey study; recovery not described
“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.”
DART package
Species: DART
Cynomolgus monkey (pre-/postnatal study only); no fertility or embryo-fetal studies
“No reproductive, no early embryonic or embryo-fetal developmental studies were performed. According to ICH 6 guideline, the potential maternal and developmental effects of ibalizumab in pregnant cynomolgus monkeys and their offspring were evaluated.”
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 ).”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the EU marketing application
“An enhanced pre- and post-natal development study was performed with cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted: ibalizumab does not bind rodent CD4
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
Carcinogenicity model
Not conducted: 2-year rodent and 6-month transgenic mouse studies not possible (no rodent CD4 binding)
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
Carcinogenicity timing
Not required: 2-year rodent and 6-month transgenic mouse studies not possible (no rodent CD4 binding)
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
Safety marginopen answer page →
Safety margin at NOAEL
Cynomolgus NOAEL (ADA-negative animals) ~4x exposure at MRHD
“At the NOAEL ibalizumab exposure in cynomolgus monkeys without an anti-ibalizumab response was approximately 4 fold exposure at the MRHD.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
SIV-infected rhesus monkeys: SIV viral load reduced up to day 10 despite neutralizing ADA
“The humanized form of ibalizumab was also tested in SIV-infected rhesus monkeys. Anti-ibalizumab antibodies were produced in the treated monkeys, which neutralized ibalizumab, reduced exposure and inhibited efficacy. Nevertheless, reductions in SIV viral load were seen in the monkeys up to day 10 of treatment.”
Why that model
Ibalizumab is active against SIV in vitro, so SIV-infected rhesus monkeys were an appropriate model
“Since it was shown in vitro that ibalizumab is also active against SIV, this is considered an appropriate animal model.”
Reviewer's view of the efficacy data
EMA: potent antiviral activity against diverse HIV strains regardless of CCR5/CXCR4 tropism
“Overall, it can be concluded that ibalizumab has potent antiviral activity against diverse strains of HIV regardless of tropism for CCR5 or CXCR4 co-receptors.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for a chronic HIV therapy; risk addressed by clinical monitoring and post-marketing surveillance
Why: No binding to rodent CD4; clinical monitoring and post-marketing surveillance judged the most clinically meaningful approach · No relevant species · Human data
“Standard 2-year carcinogenicity studies in rodents or 6-month studies in transgenic mice were not possible, because ibalizumab does not bind rodent CD4.”
“Therefore, the most clinically meaningful approach to address the potential human carcinogenicity risk of ibalizumab, including risks associated with human oncoviruses, was through clinical monitoring and post-marketing surveillance of human patients chronically administered ibalizumab.”
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