Saphnelo
anifrolumab
Species
Monkey
Longest study
39 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
“All in vivo toxicity studies were conducted in cynomolgus monkeys which can be considered as a relevant species for evaluation of safety of anifrolumab.”
Why that species
Binding and neutralisation activity of anifrolumab in monkey cells
“Cynomolgus monkey was selected as the pharmacologically relevant toxicology model for nonclinical safety assessment based on binding and neutralisation activity of anifrolumab in monkey cells.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“All in vivo toxicity studies were conducted in cynomolgus monkeys which can be considered as a relevant species for evaluation of safety of anifrolumab.”
Species: general tox
Cynomolgus monkey only (single-dose and repeat-dose up to 39 weeks)
“The nonclinical safety profile of anifrolumab was characterised in single IV dose toxicity studies in cynomolgus monkeys, in repeat dose toxicity studies in cynomolgus monkeys for up to 39-weeks of duration”
Species: DART
Cynomolgus monkey (ePPND only); no fertility or EFD studies, fertility assessed in repeat-dose study
“A pre- and post-natal developmental toxicity study was conducted with anifrolumab in cynomolgus monkeys. Fertility or embryo-foetal developmental toxicity studies were not conducted.”
Species: carcinogenicity
Not conducted (anifrolumab does not bind murine IFNAR1)
“Carcinogenicity studies with anifrolumab were not conducted. Anifrolumab does not bind to murine IFNAR1 and does not inhibit the biological activity of murine IFN-α.”
Surrogate used in
Yes: anti-murine IFNAR1 mAb 5A3 in scleroderma and NZB/W F1 lupus mouse models (pharmacology only)
“Anti-murine IFNAR1 MAb 5A3 (anifrolumab surrogate) was effective in a murine model of scleroderma (Study# RIA546-0007) and an accelerated NZB/W F1 murine model of lupus”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Repeat-dose toxicity of anifrolumab was evaluated in cynomolgus monkeys in 4-weeks and 39-weeks GLP toxicity studies with an additional recovery period of 7 or 12 weeks, respectively.”
Pivotal GLP studies
Cynomolgus monkey 4-week IV and 39-week IV/SC weekly GLP studies
“Repeat-dose toxicity of anifrolumab was evaluated in cynomolgus monkeys in 4-weeks and 39-weeks GLP toxicity studies with an additional recovery period of 7 or 12 weeks, respectively.”
Route in tox
IV (30-minute infusion) and SC, once weekly
“In this study, cynomolgus monkeys were given 40 IV infusion (30 minutes) doses of anifrolumab at 5 and 50 mg/kg/week once a week (QW) or 40 subcutaneous (SC) injection doses of anifrolumab at 15 and 60 mg/kg/week QW.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genetic toxicity studies have not been conducted with anifrolumab. Genetic toxicity studies are generally not applicable for biotechnology-derived pharmaceuticals such as anifrolumab, as discussed in the ICH S6(R1) guidance document.”
Carcinogenicity
Not conducted: anifrolumab does not bind murine IFNAR1 or inhibit murine IFN-α
“Carcinogenicity studies with anifrolumab were not conducted. Anifrolumab does not bind to murine IFNAR1 and does not inhibit the biological activity of murine IFN-α.”
Reproductive & developmental
Monkey ePPND: no maternal toxicity, embryo-fetal toxicity or postnatal developmental effects
“There was no evidence of anifrolumab-fnia related maternal toxicity, embryo-fetal toxicity, or post-natal developmental effects.”
Safety pharmacology
No stand-alone studies; ECG and blood pressure in 4- and 39-week monkey studies, no adverse CV findings; CNS/respiratory via clinical signs
“No stand-alone safety pharmacology studies were conducted with anifrolumab. The effect of anifrolumab on the CV system was evaluated in a GLP-compliant 39-week general IV toxicity study in monkeys (Study# 7140-129).”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicity studies have not been conducted with anifrolumab. Genetic toxicity studies are generally not applicable for biotechnology-derived pharmaceuticals such as anifrolumab, as discussed in the ICH S6(R1) guidance document.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicity studies have not been conducted with anifrolumab. Genetic toxicity studies are generally not applicable for biotechnology-derived pharmaceuticals such as anifrolumab, as discussed in the ICH S6(R1) guidance document.”
Genotox: in vivo
Not conducted (ICH S6)
“Genetic toxicity studies have not been conducted with anifrolumab. Genetic toxicity studies are generally not applicable for biotechnology-derived pharmaceuticals such as anifrolumab, as discussed in the ICH S6(R1) guidance document.”
Carcinogenicity model
Not conducted; weight of evidence (literature on IFNAR-deficient mice and chronic monkey studies)
“Instead, a weight of evidence approach consisting of data from chronic toxicity studies with anifrolumab and literature data was presented to address the risk of carcinogenicity.”
Carcinogenicity timing
Not required; risk addressed in the RMP, no further animal studies necessary
“Based on the weight of evidence, treatment with anifrolumab is likely associated with an increased carcinogenicity risk that has been followed throughout the clinical development programme and addressed in the RMP (see Section 2.7), and thus, no further animal studies are necessary (SmPC section 5.3).”
hERG / QT
No adverse ECG or blood pressure findings in 39-week monkey study (no hERG assay)
“Electrocardiography (ECG) parameters and blood pressure (BP) parameters were measured once during the predose phase, on Days 3 and 276 of the dosing phase, and on Day 83 of the recovery phase for these animals after they were anesthetized with ketamine. No drug-related adverse CV findings were noted.”
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 Saphnelo 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: 39-week males: NOAEL below 5 mg/kg IV and 15 mg/kg SC due to arteritis; at least 50 IV/60 SC if arteritis excluded (EMA assessment report, p. 33)
NOAEL / key findings
39-week males: NOAEL below 5 mg/kg IV and 15 mg/kg SC due to arteritis; at least 50 IV/60 SC if arteritis excluded
“Based on the arterial inflammation observed, the NOAEL for males is less than 5 mg/kg IV and 15 mg/kg SC. If the observed arteritis is not factored into the NOAEL determination, the NOAEL of anifrolumab for males is at least 50 mg/kg IV and 60 mg/kg SC, the highest doses tested.”
Risksopen answer page →
Immune & cytokine safety
Arteritis in high-dose males attributed to ADA-mediated immune complex deposition (anifrolumab, IgM, C3b)
“The arteritis could be due to the deposit of ADA-mediated immunocomplexes based on positive staining of anifrolumab, monkey IgM, and complement component 3b (C3b) but not monkey IgG from kidney samples of 2 HD-IV monkeys with arteritis.”
Biodistribution & persistence
Infant monkey serum on day 30 after birth 4.2-9.7% of maternal concentrations
“In the infants, mean serum concentrations of anifrolumab‑fnia on Day 30 after birth increased with dose and were approximately 4.2% to 9.7% of the respective maternal concentrations.”
Modality-specific risk
Type I IFN blockade: plausible increased cancer risk given IFN anti-tumour role
“Type I interferons have a role in the anti-tumour response. Thus, it is plausible that blockade of IFNAR1 responses would potentially increase the risk of”
Anti-drug antibodies: animals
39-week study: ADA in 11/48 (22.9%) treated monkeys, higher incidence at lower doses
“Anti-drug antibodies were detected in 11/48 (22.9%) animals treated with anifrolumab with higher incidence observed in animals receiving lower doses.”
Anti-drug antibodies: patients
ADA 2.6% (9/350) with recommended IV dosing for up to 4 years
“In Trials 2, 3, and the long-term extension trial, treatment emergent anti-anifrolumab-fnia antibodies were detected in 9 of 350 patients (ADA incidence 2.6%) who received SAPHNELO at the recommended intravenous dosing regimen for up to 4 years.”
Label warnings
- Serious Infections
- Hypersensitivity Reactions Including Anaphylaxis
- Malignancy
- Immunizations
- Not Recommended for Concomitant Use with Other Biologic Therapies
InfectionsHypersensitivity & infusion reactionsSecondary malignancy
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 Saphnelo 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: 39-week males: NOAEL below 5 mg/kg IV and 15 mg/kg SC due to arteritis; at least 50 IV/60 SC if arteritis excluded (EMA assessment report, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week GLP cynomolgus monkey study with 12-week recovery
“Repeat-dose toxicity of anifrolumab was evaluated in cynomolgus monkeys in 4-weeks and 39-weeks GLP toxicity studies with an additional recovery period of 7 or 12 weeks, respectively.”
Pivotal GLP studies
Cynomolgus monkey 4-week IV and 39-week IV/SC weekly GLP studies
“Repeat-dose toxicity of anifrolumab was evaluated in cynomolgus monkeys in 4-weeks and 39-weeks GLP toxicity studies with an additional recovery period of 7 or 12 weeks, respectively.”
DART package
Species: DART
Cynomolgus monkey (ePPND only); no fertility or EFD studies, fertility assessed in repeat-dose study
“A pre- and post-natal developmental toxicity study was conducted with anifrolumab in cynomolgus monkeys. Fertility or embryo-foetal developmental toxicity studies were not conducted.”
Reproductive & developmental
Monkey ePPND: no maternal toxicity, embryo-fetal toxicity or postnatal developmental effects
“There was no evidence of anifrolumab-fnia related maternal toxicity, embryo-fetal toxicity, or post-natal developmental effects.”
PPND / ePPND: when
GLP ePPND in cynomolgus monkey: completed before the marketing application
“In the GLP-compliant enhanced prenatal and postnatal development (ePPND) study in pregnant cynomolgus monkeys, no drug-related adverse effects in maternal animals or infants (body growth, behavior, functional, morphological, and skeletal development”
Carcinogenicity
Species: carcinogenicity
Not conducted (anifrolumab does not bind murine IFNAR1)
“Carcinogenicity studies with anifrolumab were not conducted. Anifrolumab does not bind to murine IFNAR1 and does not inhibit the biological activity of murine IFN-α.”
Carcinogenicity model
Not conducted; weight of evidence (literature on IFNAR-deficient mice and chronic monkey studies)
“Instead, a weight of evidence approach consisting of data from chronic toxicity studies with anifrolumab and literature data was presented to address the risk of carcinogenicity.”
Carcinogenicity timing
Not required; risk addressed in the RMP, no further animal studies necessary
“Based on the weight of evidence, treatment with anifrolumab is likely associated with an increased carcinogenicity risk that has been followed throughout the clinical development programme and addressed in the RMP (see Section 2.7), and thus, no further animal studies are necessary (SmPC section 5.3).”
Safety marginopen answer page →
Safety margin at NOAEL
General toxicity NOAEL >59x human AUC at MRHD (ePPND NOAEL 28x)
“The plasma exposures of anifrolumab at the no-observed-adverse-effect levels (NOAELs) for general toxicity and reproductive and developmental toxicity are >59- and 28-fold higher than the human exposure (AUC) at the MRHD.”
NOAEL / key findings
39-week males: NOAEL below 5 mg/kg IV and 15 mg/kg SC due to arteritis; at least 50 IV/60 SC if arteritis excluded
“Based on the arterial inflammation observed, the NOAEL for males is less than 5 mg/kg IV and 15 mg/kg SC. If the observed arteritis is not factored into the NOAEL determination, the NOAEL of anifrolumab for males is at least 50 mg/kg IV and 60 mg/kg SC, the highest doses tested.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse surrogate anti-IFNAR1 mAb in spontaneous SLE mouse model (prevented proteinuria)
“The in vivo proof-of-concept was investigated in a mouse disease model of lupus, using a mouse surrogate anti-IFNAR1 mAb.”
Why that model
Anifrolumab does not bind murine IFNAR1 or inhibit murine IFN-α
“Anifrolumab does not bind to murine IFNAR1 and does not inhibit the biological activity of murine IFN-α.”
Reviewer's view of the efficacy data
EMA: surrogate lupus-model data supported the therapeutic rationale for type I IFN blockade in SLE
“The data generated with a mouse surrogate anti-IFNAR1 mAb in the in vivo proof-of-concept lupus disease models, supported the therapeutic rationale for blockade of type I interferon signalling in the treatment of SLE.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies for chronic SLE therapy; literature weight of evidence suggests increased malignancy risk from IFNAR blockade
Why: No binding to murine IFNAR1; likely increased carcinogenicity risk followed clinically and addressed in the RMP · No relevant species · Weight of evidence · Human data
“Carcinogenicity studies with anifrolumab were not conducted. Anifrolumab does not bind to murine IFNAR1 and does not inhibit the biological activity of murine IFN-α.”
“Based on the weight of evidence, treatment with anifrolumab is likely associated with an increased carcinogenicity risk that has been followed throughout the clinical development programme and addressed in the RMP (see Section 2.7), and thus, no further animal studies are necessary (SmPC section 5.3).”
DARTCriticised but acceptedBeyond the letter
No dedicated embryo-foetal development study, and no justification provided for omitting it
Why: Limitations of the NHP model, no other pharmacologically responsive species and confounding SLE disease background · No relevant species
“A justification for not performing embryo-foetal developmental toxicity evaluation with anifrolumab was not provided.”
“Due to limitations of the NHP model, lack of other pharmacologically responsive species, possible species-differences, and the underlying confounding disease background in SLE patients, the CHMP concluded that further animal studies are unlikely to provide clinically meaningful data to inform about the risk to reproduction in this patient population.”
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