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Precedia/Monoclonal antibodies/Exdensur/Flexibility

Exdensur: what flexibility did regulators accept, and why?

depemokimab · IL-5
Check my plan vs. these
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity study for a chronic non-oncology indication; weight-of-evidence assessment using mepolizumab and literature data
Why: Carcinogenicity information available from the mepolizumab program; updated weight of evidence agreed · Class precedent · Weight of evidence
“After reviewing the nonclinical data, it was decided that conducting a carcinogenicity study in monkeys for depemokimab would not be necessary. Carcinogenicity information can be taken from the mepolizumab program.”
✓ VerifiedFDA multi-discipline review, p. 75Source ↗
“The applicant’s updated weight of evidence is agreed.”
✓ VerifiedEMA assessment report, p. 56Source ↗
DARTAccepted with a conditionBeyond the letter
No DART studies, including no monkey enhanced pre- and postnatal development study; mepolizumab reproductive data used instead
Why: Monkey ePPND study provides hazard identification only; postmarketing pregnancy safety study (DPSS) required · Class precedent · Weight of evidence
“After reviewing the nonclinical data, it was decided that conducting an enhanced pre- and postnatal development (PPND) study in monkeys would not be necessary as the study only provides hazard identification.”
✓ VerifiedFDA multi-discipline review, p. 74Source ↗
“Additionally, based on the prolonged half-life with potential for increased fetal exposure in utero, the lack of pregnancy related nonclinical data for depemokimab, and the potential risk of adverse fetal outcomes with anti-IL-5 monoclonal antibodies, a PMR to conduct a worldwide DPSS will also be issued.”
✓ VerifiedFDA multi-discipline review, p. 31Source ↗
DARTCriticised but acceptedBeyond the letter
In silico placental-transfer model, calibrated on a mepolizumab ePPND study, used to replace an in vivo study for the YTE-modified antibody
Why: Margins of safety adequate even if fetal concentrations exceed maternal maximal levels up to twofold · Class precedent · Pharmacology or kinetics
“The presented in silico model is intended to replace an in vivo study, it is therefore essential that all underlying assumptions are transparently described, thoroughly justified, and any potential concerns adequately addressed.”
✓ VerifiedEMA assessment report, p. 57Source ↗
“Even if foetal concentrations were to exceed maternal maximal levels by up to twofold, the margins of safety are considered adequate.”
✓ VerifiedEMA assessment report, p. 58Source ↗

Same question, other monoclonal antibodies

Actemra

tocilizumab · IL-6R
Safety pharmacology studies, including monkey cardiovascular studies, not conducted under formal GLP

Adakveo

crizanlizumab · P-selectin
No carcinogenicity studies for a chronic non-oncology indication; comprehensive carcinogenic risk assessment instead

Adbry

tralokinumab · IL-13
No 2-year carcinogenicity study for a chronic dermatology indication; literature weight-of-evidence assessment instead

Aduhelm

aducanumab · Aggregated amyloid-β
No fully relevant standard species; chronic toxicity assessed in Tg2576 transgenic disease-model mouse instead

Aimovig

erenumab · CGRP receptor
No carcinogenicity studies for a chronic migraine therapy; waiver granted

Ajovy

fremanezumab · CGRP
No carcinogenicity studies for a chronic migraine therapy; weight-of-evidence assessment (CGRP knockout data, CGRP biology, tox findings) instead

Alhemo

concizumab · TFPI
No dedicated reproductive and developmental toxicity studies (no embryo-fetal or pre/postnatal studies)

Andembry

garadacimab · Factor XIIa
No carcinogenicity study for a chronic prophylaxis indication; rodent study judged not technically feasible, weight-of-evidence assessment instead

Anthim

obiltoxaximab · B. anthracis PA
Rabbit embryo-fetal NOEL (highest dose) gave AUC 0.62 times human exposure at the maximum recommended dose

Arzerra

ofatumumab · CD20
No fertility or pre-/postnatal development studies; embryo-fetal study in monkey only

Avastin

bevacizumab · VEGF-A
No pre- and postnatal development study; rabbit embryo-fetal study only

Bavencio

avelumab · PD-L1
No reproductive or developmental toxicity studies; non-product-specific literature assessment of PD-1/PD-L1 role in pregnancy instead

Benlysta

belimumab · BLyS (BAFF)
No carcinogenicity study for a chronic autoimmune indication; malignancy risk deferred to a clinical post-marketing safety study

Beovu

brolucizumab · VEGF-A
No reproductive and developmental toxicity studies

Beyfortus

nirsevimab · RSV F protein
No juvenile animal toxicity study despite an infant indication

Bimzelx

bimekizumab · IL-17A/IL-17F
No carcinogenicity studies for a chronic psoriasis therapy; rodent studies waived and a literature weight-of-evidence assessment submitted instead

Briumvi

ublituximab · CD20
26-week monkey study tested a single dose level with no recovery period

Cablivi

caplacizumab · von Willebrand factor (A1 domain)
No pre- and postnatal development study; only guinea pig embryo-fetal development and placental transfer studies

Campath

alemtuzumab · CD52
No long-term repeat-dose toxicity study in cynomolgus monkey

Cimzia

certolizumab pegol · TNF-α
Toxicology in cynomolgus monkey, a species in which certolizumab pegol is far less potent against TNFα than in human

Cinqair

reslizumab · IL-5
Mouse and rabbit embryo-fetal studies without toxicokinetic data or demonstrated pharmacological effect

Cosentyx

secukinumab · IL-17A
No carcinogenicity study for chronic psoriasis use; literature-based weight-of-evidence assessment plus clinical malignancy monitoring

Crysvita

burosumab · FGF23
Monkey NOAELs at 0.3-0.9x human AUC; no exposure margin at the NOAEL

Cyramza

ramucirumab · VEGFR2
No embryo-fetal, fertility or pre/postnatal studies; reproductive risk assessed from non-product-specific literature on VEGFR2 inhibition

Danyelza

naxitamab · GD2
Repeat-dose toxicity only in immunodeficient nude rats, judged an inadequate toxicology model; juvenile study in a relevant species required postmarketing

Darzalex

daratumumab · CD38
Chimpanzee the only relevant species; exploratory studies in cynomolgus monkey used surrogate antibody HuMab-CD38

Dupixent

dupilumab · IL-4Ra
All toxicology conducted with homologous surrogate antibodies (REGN646 in cynomolgus monkey, REGN1103 in mouse), not with dupilumab

Ebanga

ansuvimab · Zaire ebolavirus glycoprotein
No dedicated reproductive toxicology studies; tissue cross-reactivity study in human fetal/neonatal tissues requested postmarketing

Ebglyss

lebrikizumab · IL-13
No carcinogenicity studies for a chronic atopic dermatitis indication; weight-of-evidence risk assessment instead

Emgality

galcanezumab · CGRP
No carcinogenicity studies for a chronic migraine indication; weight-of-evidence assessment instead

Empliciti

elotuzumab · SLAMF7
No pharmacologically relevant species or valid transgenic mouse; no repeat-dose toxicity studies; safety program mainly in vitro with human cells and tissues

Enflonsia

clesrovimab · RSV F protein (site IV)
No relevant toxicology species; short-term toxicity study in rat rather than NHP

Enjaymo

sutimlimab · Complement C1s
No carcinogenicity studies for chronic therapy; weight-of-evidence assessment instead

Enspryng

satralizumab · IL-6R
No carcinogenicity studies for a chronic NMOSD indication; no rodent IL-6R binding and mouse homolog not feasible

Entyvio

vedolizumab · α4β7-integrin
No rodent carcinogenicity bioassay for a chronic IBD therapy; in vitro tumour-cell study with murine homologue Act-1 instead

Erbitux

cetuximab · EGFR
No reproductive and developmental toxicity studies; menstrual cyclicity evaluated within the 39-week monkey study

Evenity

romosozumab · Sclerostin
Bioanalytical method validations for pivotal toxicity studies not formally GLP

Evkeeza

evinacumab · ANGPTL3
No in vivo carcinogenicity studies; weight-of-evidence assessment from literature and toxicology studies

Fasenra

benralizumab · IL-5Rα
No carcinogenicity studies or mouse surrogate for chronic asthma therapy; carcinogenicity risk assessment instead

Gamifant

emapalumab · IFN-γ
Embryo-fetal development tested in mice with the rodent surrogate antibody XMG1.2 instead of emapalumab

Gazyva

obinutuzumab · CD20
Hypersensitivity reactions in the 26-week monkey study at all doses, at 0.7-6 times clinical exposure

Herceptin

trastuzumab · HER2
No animal model of trastuzumab-anthracycline cardiotoxicity; only a rat surrogate antibody study in a doxorubicin model

Humira

adalimumab · TNF-α
No carcinogenicity studies for chronic immune-mediated indications; no conventional or alternative model available

Hympavzi

marstacimab · TFPI
No 6-month repeat-dose toxicity study in the non-rodent (cynomolgus monkey)

Ilaris

canakinumab · IL-1β
Marmoset is the only cross-reactive species (no binding to mouse, rat, rabbit or cynomolgus IL-1β), so canakinumab toxicology was run in marmoset

Ilumya

tildrakizumab · IL-23 p19
No carcinogenicity studies for chronic psoriasis use; weight-of-evidence assessment instead

Imaavy

nipocalimab · FcRn
No binding-affinity screen in non-rodent species other than monkey to select the toxicology species

Imfinzi

durvalumab · PD-L1
No fertility and early embryonic development study; fertility assessed by reproductive organ weights and histopathology in the 13-week monkey study

Imjudo

tremelimumab · CTLA-4
No NOAEL in the chronic monkey study; lowest dose gave an exposure margin of only 1-2

Jemperli

dostarlimab · PD-1
No reproductive and developmental toxicity studies; literature-based assessment of PD-1/PD-L1 blockade risk instead

Kevzara

sarilumab · IL-6R
No carcinogenicity studies for chronic rheumatoid arthritis use; carcinogenicity risk assessment accepted by ECAC, with risk managed in labeling

Keytruda

pembrolizumab · PD-1
No embryo-fetal study in monkey; literature assessment of pregnancy outcomes in PD-1 knockout mice instead

Kisunla

donanemab · Amyloid-β (N3pG)
No pharmacologically active species; off-target toxicity in monkeys (6-week only) and on-target effects with a murine surrogate in transgenic PDAPP mice

Lartruvo

olaratumab · PDGFRα
No reproductive toxicity studies with olaratumab; literature assessment plus mouse embryo-fetal study with surrogate antibody IMC-1E10

Leqembi

lecanemab · Amyloid-β protofibrils
No rodent carcinogenicity studies for long-term use; weight-of-evidence carcinogenicity risk assessment instead

Libtayo

cemiplimab · PD-1
No embryo-fetal development studies; literature review of PD-1/PD-L1 pathway reproductive risk instead

Loqtorzi

toripalimab · PD-1
No reproductive or embryo-fetal toxicity studies; weight-of-evidence assessment from published PD-1 pathway data instead

Lucentis

ranibizumab · VEGF-A
No reproductive toxicology studies

Margenza

margetuximab · HER2
No dedicated fertility studies; embryo-fetal and postnatal effects assessed in a monkey ePPND study only

Monjuvi

tafasitamab · CD19
No reproductive and developmental toxicity studies, including none in the pharmacologically relevant monkey; weight-of-evidence assessment instead

Nemluvio

nemolizumab · IL-31RA
No carcinogenicity studies for chronic prurigo nodularis and atopic dermatitis use; literature weight-of-evidence instead

Niktimvo

axatilimab · CSF-1R
No reproductive or developmental toxicity studies; weight-of-evidence literature risk assessment (CSF-1/CSF-1R deficiency models) instead

Nucala

mepolizumab · IL-5
Carcinogenicity study waived for a chronic asthma indication

Ocrevus

ocrelizumab · CD20
Pivotal chronic toxicity and embryo-fetal studies used early drug substance not shown comparable to the marketed product

Omvoh

mirikizumab · IL-23 p19
No rodent carcinogenicity study; weight-of-evidence assessment instead

Opdivo

nivolumab · PD-1
No fertility and early embryonic development study

Pasatru

garetosmab · Activin A
No NOAEL in the repeat-dose rat study; adverse male reproductive tract toxicity at exposures below clinical exposure

Penpulimab

penpulimab · PD-1
No embryo-fetal development study; weight-of-evidence literature assessment of reproductive toxicity instead

Perjeta

pertuzumab · HER2
No NOAEL in the 26-week monkey study: severe diarrhoea and increased urea nitrogen at all doses

Piasky

crovalimab · Complement C5
No carcinogenicity studies for chronic PNH use; weight-of-evidence assessment as crovalimab is not active in rodents

Portrazza

necitumumab · EGFR
No reproductive toxicity studies; EGFR knockout literature and cetuximab embryo-fetal data used instead

Poteligeo

mogamulizumab · CCR4
No fertility/early embryonic or pre/postnatal development studies; monkey embryo-fetal study only

Praluent

alirocumab · PCSK9
No carcinogenicity study for a chronic lipid-lowering antibody; waiver granted on weight of evidence

Praxbind

idarucizumab · Dabigatran
No reproductive and developmental toxicity studies

Prolia

denosumab · RANKL
No carcinogenicity studies; ovariectomized monkeys treated up to 16 months without preneoplastic lesions

Raxibacumab

raxibacumab · B. anthracis protective antigen
Efficacy established in rabbit and monkey inhalational anthrax models under the Animal Rule instead of human efficacy trials

Remicade

infliximab · TNF-α
Chimpanzee the only relevant species; only a small, limited single/short repeat-dose chimpanzee study, rat studies not relevant

Repatha

evolocumab · PCSK9
Combination toxicity study used a rosuvastatin dose without pharmacological activity in monkeys

Rituxan

rituximab · CD20
No long-term animal studies; observation limited to 90 days although B-cell recovery was incomplete

Rystiggo

rozanolixizumab · FcRn
No carcinogenicity studies for a chronic non-oncology indication; weight-of-evidence carcinogenicity risk assessment instead

Saphnelo

anifrolumab · IFNAR1
No carcinogenicity studies for chronic SLE therapy; literature weight of evidence suggests increased malignancy risk from IFNAR blockade

Sarclisa

isatuximab · CD38
No pharmacologically relevant toxicology species (only chimpanzee binds); monkey toxicity study in a non-relevant species

Siliq

brodalumab · IL-17RA
No carcinogenicity studies for a chronic non-oncology indication; literature-based weight-of-evidence assessment of IL-17RA inhibition, judged inconclusive

Simponi

golimumab · TNF-α
Nominal monkey margins of 50 and above uncertain: golimumab has 34-fold lower affinity and 72-fold lower potency for cynomolgus TNFα

Simulect

basiliximab · IL-2Rα (CD25)
Monkey embryo-fetal study without immunotoxicology assessment of the offspring

Skyrizi

risankizumab · IL-23 p19
No carcinogenicity study for chronic inflammatory indications; weight-of-evidence assessment with ECAC concurrence

Soliris

eculizumab · Complement C5
No relevant species for eculizumab; all toxicology in mice with surrogate anti-mouse C5 antibody BB5.1, cross-reactivity profile not compared

Spevigo

spesolimab · IL-36R
No pharmacologically relevant species; repeat-dose and DART toxicology done only with a mouse-specific surrogate antibody (BI674304)

Stelara

ustekinumab · IL-12/23 p40
No carcinogenicity or rodent tumour immune surveillance studies; ustekinumab does not bind mouse or rat IL-12/IL-23

Sylvant

siltuximab · IL-6
No rodent carcinogenicity study; carcinogenic risk assessed by weight of evidence including murine tumour surveillance studies with surrogate

Synagis

palivizumab · RSV F protein
No repeat-dose toxicity studies (including reproductive toxicity); single-dose studies only

Takhzyro

lanadelumab · Plasma kallikrein
No rodent carcinogenicity study for chronic HAE prophylaxis (neutralising ADA in rats); weight-of-evidence assessment instead

Taltz

ixekizumab · IL-17A
No carcinogenicity studies for chronic psoriasis use; weight-of-evidence review of nonclinical data and IL-17A literature instead

Tecentriq

atezolizumab · PD-L1
No reproductive and developmental toxicity studies; non-product-specific literature-based assessment of pregnancy risk instead

Tepezza

teprotumumab · IGF-1R
No definitive GLP embryofetal study; only a preliminary non-GLP monkey EFD study, GLP study waived

Tevimbra

tislelizumab · PD-1
Pivotal 13-week monkey toxicology study failed GLP inspection; a new GLP-compliant 13-week study was run during the procedure

Tezspire

tezepelumab · TSLP
No carcinogenicity studies; weight-of-evidence risk assessment from chronic monkey data and TSLP literature

Tremfya

guselkumab · IL-23 p19
No carcinogenicity studies for chronic psoriasis use; literature and monkey-data weight-of-evidence assessment instead

Trogarzo

ibalizumab · CD4
No carcinogenicity studies for a chronic HIV therapy; risk addressed by clinical monitoring and post-marketing surveillance

Tysabri

natalizumab · α4-integrin
No standard carcinogenicity studies; in vitro and SCID/nude mouse xenograft studies with human alpha-4 expressing tumour cells instead

Tzield

teplizumab · CD3
Teplizumab tested only in a single-dose chimpanzee study; repeat-dose and DART studies used a mouse surrogate anti-CD3 antibody

Ultomiris

ravulizumab · Complement C5
No toxicity studies with ravulizumab (no relevant species); reliance on surrogate BB5.1 mouse studies from the eculizumab application

Unituxin

dinutuximab · GD2
Only a 28-day rat repeat-dose study; chronic toxicity and peripheral neuropathy to be investigated after approval

Unloxcyt

cosibelimab · PD-L1
No developmental and reproductive toxicity studies; literature-based risk assessment instead

Uplizna

inebilizumab · CD19
No cross-reactive animal species; all toxicology in human CD19 transgenic mice

Vectibix

panitumumab · EGFR
No NOAEL in the monkey embryo-fetal study: abortions or fetal death and maternal toxicity at the lowest dose

Veopoz

pozelimab · Complement C5
No carcinogenicity studies for chronic use; weight-of-evidence risk assessment reviewed by ECAC

Voyxact

sibeprenlimab · APRIL
No rodent carcinogenicity studies for a chronic IgA nephropathy indication; carcinogenicity risk assessment instead

Vyepti

eptinezumab · CGRP
Chronic toxicity in cynomolgus monkey only; no chronic rat study because rat anti-drug antibodies precluded meaningful long-term studies

Vyloy

zolbetuximab · Claudin 18.2
Embryo-fetal development studied in one species only (mouse)

Xolair

omalizumab · IgE
No carcinogenicity study for chronic asthma use; carcinogenic potential to be judged from clinical safety data

Yervoy

ipilimumab · CTLA-4
No reproductive toxicity data at approval; monkey combined embryo-fetal/pre-postnatal study still ongoing

Zinbryta

daclizumab · IL-2Rα (CD25)
Carcinogenic potential not assessed at all (no studies, no weight-of-evidence assessment) for a chronic MS immunomodulator

Zinplava

bezlotoxumab · C. difficile toxin B
Foreign bacterial toxin target: no species for target-mediated toxicity; only short-term mouse toxicity studies

Zynyz

retifanlimab · PD-1
No animal reproductive or developmental toxicity studies; weight-of-evidence assessment instead

Yartemlea

narsoplimab · MASP-2
Not stated in public reviews

Summary across all 117 monoclonal antibodies →