Rystiggo
rozanolixizumab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The repeat dose studies were primarily performed in cynomolgus monkey, as the NHP was found to be the only pharmacological relevant species.”
Why that species
Much weaker (nanomolar) affinity for mouse and rat FcRn and no binding to rabbit FcRn
“Affinity (KDs) for rozanolixizumab for mouse and rat FcRn was much weaker (nanomolar range) and binding to rabbit FcRn was not observed at all.”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkeys (mouse surrogate 4470 used in pharmacology only)
“The ability of a mouse surrogate (4470) of rozanolixizumab to increase clearance of IgG was evaluated in a mouse disease model of immune thrombocytopenia (ITP).”
Species: general tox
Cynomolgus monkey only (4-, 13- and 26-week studies)
“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”
Species: DART
Cynomolgus monkey (ePPND; fertility endpoints in 26-week study)
“Given that only the nonhuman primates (NHP) was found to be a relevant species – an ePPND study was performed in cynomolgus monkeys. No stand-alone fertility and early embryonic development studies have been conducted with rozanolixizumab. Fertility endpoints were included in the pivotal 26 weeks repeat dose study.”
Species: carcinogenicity
Not conducted (weight-of-evidence assessment)
“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”
Surrogate used in
Yes: mouse surrogate (4470) in a mouse ITP disease model (pharmacology only)
“The ability of a mouse surrogate (4470) of rozanolixizumab to increase clearance of IgG was evaluated in a mouse disease model of immune thrombocytopenia (ITP).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”
Pivotal GLP studies
Cynomolgus monkey 4-, 13- and 26-week studies, up to 150 mg/kg SC every 3 days; monkey ePPND
“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”
Route in tox
Subcutaneous and intravenous
“This included GLP-compliant general toxicology studies of up to 26- weeks duration where animals received IV or SC doses of up to 150 mg/kg rozanolixizumab every three days”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genetic toxicology studies were conducted.”
Carcinogenicity
Not conducted; weight-of-evidence assessment judged studies unnecessary
“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”
Reproductive & developmental
Monkey ePPND (0, 50, 150 mg/kg SC every 3 days, GD 20 to parturition): embryonic losses in 3 of 19 females at both doses
“Subcutaneous administration of 0, 50, or 150 mg/kg UCB7665 every 3 days to pregnant female cynomolgus monkeys from gestational day (GD) 20 through parturition caused embryonic losses in 3 of 19 females at both doses.”
Safety pharmacology
Incorporated into 4- and 13-week monkey studies; no cardiovascular, neurobehavioral or respiratory effects
“No stand-alone safety pharmacology studies were conducted. There were no test article-related effects on cardiovascular, neurobehavioral, or respiratory (no plethysmography) safety pharmacology parameters that were incorporated into the 4- and 13-week general toxicity studies.”
Genotox: Ames
Not conducted (ICH S6)
“In accordance with the International Council for Harmonisation (ICH) Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S6 (R1) (EMA/CHMP/ICH/731268/1998), genotoxicity studies were not performed.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“In accordance with the International Council for Harmonisation (ICH) Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S6 (R1) (EMA/CHMP/ICH/731268/1998), genotoxicity studies were not performed.”
Genotox: in vivo
Not conducted (ICH S6)
“In accordance with the International Council for Harmonisation (ICH) Guideline for the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S6 (R1) (EMA/CHMP/ICH/731268/1998), genotoxicity studies were not performed.”
Carcinogenicity model
Not conducted; carcinogenicity assessment (weight of evidence) accepted
“The applicant did not provide carcinogenicity studies which is supported. The provided carcinogenicity assessment supports the lack of any conventional carcinogenicity studies.”
Carcinogenicity timing
Not required (weight-of-evidence assessment)
“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”
hERG / QT
No QT, ECG or heart rate changes in 4- and 13-week monkey studies (no hERG assay)
“No dose-related changes were observed for electrocardiogram (ECG), the QRS complex duration, PR interval, RR interval, QT interval or heart rate in any phase or study.”
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 Rystiggo 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: No adverse effects up to 150 mg/kg SC every 3 days for 4, 13 and 26 weeks; reduced IgG, total protein and albumin (pharmacology) (FDA integrated review, p. 91)
NOAEL / key findings
No adverse effects up to 150 mg/kg SC every 3 days for 4, 13 and 26 weeks; reduced IgG, total protein and albumin (pharmacology)
“No adverse effects were seen in male and female cynomolgus monkeys administered subcutaneous (SC) doses of up to 150 mg/kg UCB7665 every 3 days for 4, 13, and 26 weeks.”
Risksopen answer page →
Immune & cytokine safety
No cytokine release in any of four in vitro assay formats
“All assays, conducted using appropriate positive and negative controls, did not indicate the potential for stimulation of UCB7665-induced cytokine release.”
Biodistribution & persistence
TCR in human and cynomolgus tissues: generally similar staining patterns between species
“The staining patterns were generally similar between species; however, the study report did not specify whether specific binding was membranous or cytoplasmic.”
Modality-specific risk
Infection risk from FcRn blockade reducing circulating IgG
“Infections were of special interest because Fc receptor inhibition results in a reduction of circulating IgG, which potentially increases the risk of infection.”
Anti-drug antibodies: animals
ADA in most monkeys; higher titers reduced exposure and IgG-lowering effect
“In both studies, anti-drug antibody (ADA) development in most animals was observed. The ADA response was generally correlated with reduced pharmacodynamic (PD) effect (i.e., a reduction in IgG levels) and reduced exposure in animals with higher ADA titers.”
Anti-drug antibodies: patients
ADA 37% (49/133) after one 6-week cycle; neutralizing 21% (28/133)
“The anti-drug antibody (ADA) incidence from Study 1 (MG0003) was 37% (49/133) at the end of the observation period after one treatment cycle of 6-week dosing. The incidence of neutralizing antibodies was 21% (28/133).”
Label warnings
- Infections
- Aseptic Meningitis
- Hypersensitivity Reactions
InfectionsHypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
United Kingdom: first-in-human study UP0018
“The Applicant stated that a first-in-human study (UP0018) was conducted and completed in the United Kingdom and there was an ongoing study in patients with immune thrombocytopenia (ITP) (TP0001) in the European Union and Australia.”
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 Rystiggo 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: No adverse effects up to 150 mg/kg SC every 3 days for 4, 13 and 26 weeks; reduced IgG, total protein and albumin (pharmacology) (FDA integrated review, p. 91)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week GLP cynomolgus monkey SC study (every 3 days) with 8-week recovery
“NCD2553 GLP Cynomolgus monkey Main study 3 M/F (0 mg/kg) 6/8 * M/F (treated group) Recovery 2 M/F 0, 150 mg/kg sc every 3 days 26 weeks Recovery 8 weeks”
Pivotal GLP studies
Cynomolgus monkey 4-, 13- and 26-week studies, up to 150 mg/kg SC every 3 days; monkey ePPND
“General toxicity studies of 4-, 13- and 26-weeks’ duration were conducted in cynomolgus monkey administered up to 150 mg/kg UCB7665 by SC injection every 3 days.”
DART package
Species: DART
Cynomolgus monkey (ePPND; fertility endpoints in 26-week study)
“Given that only the nonhuman primates (NHP) was found to be a relevant species – an ePPND study was performed in cynomolgus monkeys. No stand-alone fertility and early embryonic development studies have been conducted with rozanolixizumab. Fertility endpoints were included in the pivotal 26 weeks repeat dose study.”
Reproductive & developmental
Monkey ePPND (0, 50, 150 mg/kg SC every 3 days, GD 20 to parturition): embryonic losses in 3 of 19 females at both doses
“Subcutaneous administration of 0, 50, or 150 mg/kg UCB7665 every 3 days to pregnant female cynomolgus monkeys from gestational day (GD) 20 through parturition caused embryonic losses in 3 of 19 females at both doses.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed and submitted with the marketing application
“An enhanced pre- and postnatal development study in cynomolgus monkey was the only nonclinical study of UCB7665 submitted only to the NDA.”
Carcinogenicity
Species: carcinogenicity
Not conducted (weight-of-evidence assessment)
“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”
Carcinogenicity model
Not conducted; carcinogenicity assessment (weight of evidence) accepted
“The applicant did not provide carcinogenicity studies which is supported. The provided carcinogenicity assessment supports the lack of any conventional carcinogenicity studies.”
Carcinogenicity timing
Not required (weight-of-evidence assessment)
“Based on a weight of evidence assessment, conduct of carcinogenicity studies were deemed not necessary for UCB7665.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey toxicity-study exposure 36-228x model-predicted human exposure
“Finally, model derived human exposure was used to calculate margins of safety, when compared with non-compartmentally derived exposure of free rozanolixizumab in monkeys in the toxicology studies. Margin of safety is in the range of 36-228 and therefore fully acceptable.”
NOAEL / key findings
No adverse effects up to 150 mg/kg SC every 3 days for 4, 13 and 26 weeks; reduced IgG, total protein and albumin (pharmacology)
“No adverse effects were seen in male and female cynomolgus monkeys administered subcutaneous (SC) doses of up to 150 mg/kg UCB7665 every 3 days for 4, 13, and 26 weeks.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse surrogate anti-FcRn mAb in an immune thrombocytopenia (ITP) disease model
“The ability of a mouse surrogate (4470) of rozanolixizumab to increase clearance of IgG was evaluated in a mouse disease model of immune thrombocytopenia (ITP).”
Why that model
Much weaker affinity for mouse and rat FcRn and no binding to rabbit FcRn
“Affinity (KDs) for rozanolixizumab for mouse and rat FcRn was much weaker (nanomolar range) and binding to rabbit FcRn was not observed at all.”
Reviewer's view of the efficacy data
EMA: adequate evidence of MoA, supported by disease models though none of gMG
“Overall, the primary PD studies provided adequate evidence of MoA, which is considered well-established for rozanolixizumab both in vitro and in vivo and supported by meaningful effects as observed in in vivo disease models, however not in a model of gMG.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies for a chronic non-oncology indication; weight-of-evidence carcinogenicity risk assessment instead
Why: Carcinogenicity risk assessment in line with ICH S6(R1) supports omitting conventional studies · Weight of evidence · Within the guideline
“In line with ICH S6(R1) a carcinogenicity risk assessment has been provided, discussing the relevance and need for in vivo carcinogenicity studies.”
“The applicant did not provide carcinogenicity studies which is supported. The provided carcinogenicity assessment supports the lack of any conventional carcinogenicity studies.”
OtherCriticised but acceptedBeyond the letter
Pivotal 26-week monkey study with a single treated dose group, so no dose-response for fertility endpoints
Why: Menstrual cycle changes linked to clinical or group-dynamic causes; no direct effect on female fertility expected · Other reason
“It should however also be noted that only 1 treated group was included in the 26-week study, hence the number of animals exposed was limited, and any dose relationship would not be possible to ascertain.”
“However, it is agreed that, as the observed changes in menstrual cycling appear to be linked with clinical or group dynamic reasons, any direct effect of rozanolixizumab on female fertility is not expected.”
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