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Precedia/Monoclonal antibodies/Tepezza/Flexibility

Tepezza: what flexibility did regulators accept, and why?

teprotumumab · IGF-1R
Check my plan vs. these
Flexibility accepted
DARTAcceptedBeyond the letter
No definitive GLP embryofetal study; only a preliminary non-GLP monkey EFD study, GLP study waived
Why: Results of the preliminary non-GLP study · Weight of evidence
“This non-GLP study was intended as a preliminary EFD assay prior to the definitive GLP EFD study.”
✓ VerifiedFDA pharmacology/toxicology review, p. 122Source ↗
“Based on the results, the Applicant requested that the GLP EFD study be waived, and DTOP concurred for the TED indication.”
✓ VerifiedFDA pharmacology/toxicology review, p. 122Source ↗
DARTAcceptedBeyond the letter
No pre- and postnatal development study
Why: Mechanism-based teratogen with possible fetal loss; PPND study in monkeys not practical or feasible · Pharmacology or kinetics
“A PPND study was not performed. This is justified, because teprotumumab is a mechanism-based teratogen and potential increased foetal loss could not be ruled out, therefore studies evaluating PPND in cynomolgus monkeys would not be practical or feasible.”
✓ VerifiedEMA assessment report, p. 26Source ↗
“The Applicant did not submit a prenatal and postnatal development (PPND) study for teprotumumab, and P/T concurs that a PPND study is not warranted to support the TED indication at the labeled dose level.”
✓ VerifiedFDA pharmacology/toxicology review, p. 133Source ↗
DARTAccepted
No stand-alone fertility study; fertility assessed by reproductive organ histopathology in monkey repeat-dose studies
Why: Mating studies not practical in non-human primates · Within the guideline
“A formal fertility study with teprotumumab has not been performed, since mating studies are not practical for NHPs.”
✓ VerifiedEMA assessment report, p. 25Source ↗
“No stand-alone studies to assess fertility and early embryonic development (FEED) were conducted with teprotumumab, and P/T concurs that a stand-alone FEED study is not warranted to support the TED indication at the labeled dose level.”
✓ VerifiedFDA pharmacology/toxicology review, p. 121Source ↗
Safety marginVerdict not stated
No NOAEL in juvenile monkeys; lowest dose (3 mg/kg/week IV) was the LOAEL
“For juveniles, the low-dose (3 mg/kg/week IV) is the lowest adverse effect level (LOAEL), and no NOAEL was identified.”
✓ VerifiedFDA pharmacology/toxicology review, p. 22Source ↗

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

Exdensur

depemokimab · IL-5
No carcinogenicity study for a chronic non-oncology indication; weight-of-evidence assessment using mepolizumab and literature data

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

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 →