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Precedia/Monoclonal antibodies/Enflonsia/Skipped studies

Enflonsia: genotox, carcinogenicity and repro: done or skipped?

clesrovimab · RSV F protein (site IV)
Check my plan vs. these
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
✓ VerifiedFDA integrated review, p. 179Source ↗
Carcinogenicity
Not conducted (ICH S1A, S6(R1)); administered as a single dose
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
✓ VerifiedFDA integrated review, p. 179Source ↗
Instead of carcinogenicity
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.
Instead of genotoxicity
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.
DRG histopathology
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.
Reproductive & developmental
No dedicated DART studies (exogenous target, ICH S6(R1)); no male or female reproductive toxicity in 2-week rat study
“In accordance with ICH S6(R1), DART studies are generally not needed for biologics to exogenous targets. In addition, no male or female reproductive toxicities were observed in the 2-week repeat-dose toxicology study in rats (Study TT #16-1029)”
✓ VerifiedFDA integrated review, p. 179Source ↗
Safety pharmacology
Assessed within the GLP 2-week rat toxicology study (FOB)
“Safety pharmacology of MK-1654 was assessed as a component of the GLP 2-week repeat dose toxicology study in Wistar Han rats (Study # TT #16-1029).”
✓ VerifiedFDA integrated review, p. 172Source ↗
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
✓ VerifiedFDA integrated review, p. 179Source ↗
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
✓ VerifiedFDA integrated review, p. 179Source ↗
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted with MK-1654. In accordance with ICH S6(R1), genotoxicity studies are not needed for biologics as they are not anticipated to interact with deoxyribonucleic acid (DNA) or other genetic material.”
✓ VerifiedFDA integrated review, p. 179Source ↗
Carcinogenicity model
Not conducted (single-dose administration; ICH S1A, S6(R1))
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
✓ VerifiedFDA integrated review, p. 179Source ↗
Carcinogenicity timing
Not required (single dose)
“In accordance with ICH S1A and ICH S6(R1), carcinogenicity studies are not needed because MK-1654 will be administered as a single dose.”
✓ VerifiedFDA integrated review, p. 179Source ↗
hERG / QT
No hERG study (absence justified by literature review)
“The absence of a hERG study was sufficiently justified based on the scientific review by Vargas et al, 2008, stating that no changes were noted for cardiovascular and respiratory endpoints assessed via routine clinical observations and comprehensive histopathological examination.”
✓ VerifiedEMA assessment report, p. 37Source ↗

Same question, other monoclonal antibodies

Actemra

tocilizumab · IL-6R
No special hazard in conventional genotoxicity studies

Adakveo

crizanlizumab · P-selectin
Not conducted (ICH S6)

Adbry

tralokinumab · IL-13
Not conducted (ICH S6(R1))

Aduhelm

aducanumab · Aggregated amyloid-β
Not conducted; antibodies unable to interact with genetic material

Aimovig

erenumab · CGRP receptor
Not conducted (ICH S6(R1))

Ajovy

fremanezumab · CGRP
Not conducted (ICH S6(R1))

Alhemo

concizumab · TFPI
Not conducted (ICH S6(R1))

Andembry

garadacimab · Factor XIIa
Not conducted (ICH S6(R1))

Anthim

obiltoxaximab · B. anthracis PA
Not conducted

Arzerra

ofatumumab · CD20
Not conducted (ICH S6)

Avastin

bevacizumab · VEGF-A
Not conducted

Bavencio

avelumab · PD-L1
Not conducted (ICH S6)

Benlysta

belimumab · BLyS (BAFF)
Not conducted; not required for a monoclonal antibody

Beovu

brolucizumab · VEGF-A
Not conducted (ICH S6(R1))

Beyfortus

nirsevimab · RSV F protein
Not conducted (ICH S6(R1))

Bimzelx

bimekizumab · IL-17A/IL-17F
Not conducted (ICH S6(R1))

Briumvi

ublituximab · CD20
Not recommended for biologics; an Ames assay was conducted and was negative

Cablivi

caplacizumab · von Willebrand factor (A1 domain)
Not conducted (ICH S6(R1))

Campath

alemtuzumab · CD52
Not conducted (ICH S6)

Cimzia

certolizumab pegol · TNF-α
Conducted: negative in Ames, human lymphocyte chromosomal aberration and mouse micronucleus assays

Cinqair

reslizumab · IL-5
Not applicable for a protein; Ames and in vitro chromosomal aberration assays negative

Cosentyx

secukinumab · IL-17A
Not conducted (ICH S6(R1))

Crysvita

burosumab · FGF23
Not conducted (not appropriate for monoclonal antibodies)

Cyramza

ramucirumab · VEGFR2
Not conducted (ICH S6)

Danyelza

naxitamab · GD2
Not conducted (ICH S6/S9, advanced cancer)

Darzalex

daratumumab · CD38
Not conducted (ICH S6)

Dupixent

dupilumab · IL-4Ra
Not conducted (ICH S6)

Ebanga

ansuvimab · Zaire ebolavirus glycoprotein
Not conducted (ICH S6(R1))

Ebglyss

lebrikizumab · IL-13
Not conducted (ICH S6)

Emgality

galcanezumab · CGRP
Not conducted (ICH S6(R1))

Empliciti

elotuzumab · SLAMF7
Not conducted (ICH S6)

Enjaymo

sutimlimab · Complement C1s
Not conducted (monoclonal antibody, ICH S6)

Enspryng

satralizumab · IL-6R
Not conducted (antibodies unable to interact with genetic material)

Entyvio

vedolizumab · α4β7-integrin
Not conducted (ICH S6(R1))

Erbitux

cetuximab · EGFR
Conducted (partial): Ames test and rat micronucleus test negative

Evenity

romosozumab · Sclerostin
Not conducted (recombinant protein not expected to interact with DNA)

Evkeeza

evinacumab · ANGPTL3
Not conducted (ICH S6)

Exdensur

depemokimab · IL-5
Not conducted (ICH S6(R1))

Fasenra

benralizumab · IL-5Rα
Not conducted; not applicable to a therapeutic protein

Gamifant

emapalumab · IFN-γ
Not conducted (ICH S6)

Gazyva

obinutuzumab · CD20
Not conducted (ICH S6/S9)

Herceptin

trastuzumab · HER2
Conducted: Ames, E. coli, human lymphocyte chromosome aberration and mouse micronucleus; all negative

Humira

adalimumab · TNF-α
Limited tests (bacterial mutation, mouse micronucleus) negative; not needed for a monoclonal antibody (ICH S6)

Hympavzi

marstacimab · TFPI
Not conducted; not scientifically appropriate for a monoclonal antibody

Ilaris

canakinumab · IL-1β
Not conducted (protein; ICH S6)

Ilumya

tildrakizumab · IL-23 p19
Not conducted (ICH S6(R1))

Imaavy

nipocalimab · FcRn
Not conducted

Imfinzi

durvalumab · PD-L1
Not conducted

Imjudo

tremelimumab · CTLA-4
Not conducted (ICH S6(R1))

Jemperli

dostarlimab · PD-1
Not conducted; not warranted for a biotechnology-derived product

Kevzara

sarilumab · IL-6R
Not conducted (not applicable to a monoclonal antibody)

Keytruda

pembrolizumab · PD-1
Not conducted (ICH S6)

Kisunla

donanemab · Amyloid-β (N3pG)
Not conducted; antibodies unable to interact with genetic material

Lartruvo

olaratumab · PDGFRα
Not conducted (ICH S6)

Leqembi

lecanemab · Amyloid-β protofibrils
Not conducted (ICH S6)

Libtayo

cemiplimab · PD-1
Not conducted (ICH S6)

Loqtorzi

toripalimab · PD-1
Not conducted (ICH S6(R1))

Lucentis

ranibizumab · VEGF-A
Not conducted; acceptable given nature of compound

Margenza

margetuximab · HER2
Not conducted (ICH S6(R1))

Monjuvi

tafasitamab · CD19
Not conducted (ICH S6)

Nemluvio

nemolizumab · IL-31RA
Not conducted (ICH S6(R1))

Niktimvo

axatilimab · CSF-1R
Not conducted; antibodies not expected to interact with DNA

Nucala

mepolizumab · IL-5
Not conducted; not applicable to a therapeutic biologic protein

Ocrevus

ocrelizumab · CD20
Not conducted (ICH S6)

Omvoh

mirikizumab · IL-23 p19
Not conducted (ICH S6(R1))

Opdivo

nivolumab · PD-1
Not conducted (ICH S6)

Pasatru

garetosmab · Activin A
Not evaluated; monoclonal antibodies not expected to alter DNA or chromosomes

Penpulimab

penpulimab · PD-1
Not conducted (ICH S6)

Perjeta

pertuzumab · HER2
Not conducted (ICH S6)

Piasky

crovalimab · Complement C5
Not conducted (biotechnology-derived pharmaceutical)

Portrazza

necitumumab · EGFR
Not conducted (ICH S6)

Poteligeo

mogamulizumab · CCR4
Not conducted (ICH S6(R1))

Praluent

alirocumab · PCSK9
Not conducted (ICH S6); not expected to interact with DNA

Praxbind

idarucizumab · Dabigatran
Not conducted

Prolia

denosumab · RANKL
Not conducted; not necessary for a recombinant protein

Raxibacumab

raxibacumab · B. anthracis protective antigen
Not conducted

Remicade

infliximab · TNF-α
Complete battery performed despite limited value; no genotoxic activity

Repatha

evolocumab · PCSK9
Not conducted (ICH S6)

Rituxan

rituximab · CD20
Not conducted; omission considered justified

Rystiggo

rozanolixizumab · FcRn
Not conducted

Saphnelo

anifrolumab · IFNAR1
Not conducted (ICH S6(R1))

Sarclisa

isatuximab · CD38
Not conducted (ICH S6)

Siliq

brodalumab · IL-17RA
Not conducted (ICH S6)

Simponi

golimumab · TNF-α
Not conducted

Simulect

basiliximab · IL-2Rα (CD25)
Negative in Ames and V79 Chinese hamster cell chromosomal aberration assays

Skyrizi

risankizumab · IL-23 p19
Not conducted (ICH S6(R1))

Soliris

eculizumab · Complement C5
Not conducted (ICH S6)

Spevigo

spesolimab · IL-36R
Not conducted

Stelara

ustekinumab · IL-12/23 p40
Not conducted

Sylvant

siltuximab · IL-6
Not conducted (ICH S6)

Synagis

palivizumab · RSV F protein
Not conducted

Takhzyro

lanadelumab · Plasma kallikrein
Not conducted (ICH S6)

Taltz

ixekizumab · IL-17A
Not conducted (ICH S6)

Tecentriq

atezolizumab · PD-L1
Not conducted (ICH S6(R1))

Tepezza

teprotumumab · IGF-1R
Not conducted (ICH S6(R1))

Tevimbra

tislelizumab · PD-1
Not conducted (ICH S9)

Tezspire

tezepelumab · TSLP
Not conducted (ICH S6(R1))

Tremfya

guselkumab · IL-23 p19
Not conducted (ICH S6R1)

Trogarzo

ibalizumab · CD4
Not conducted (ICH S6(R1))

Tysabri

natalizumab · α4-integrin
Standard mutagenicity assays: no mutagenic potential

Tzield

teplizumab · CD3
Not conducted

Ultomiris

ravulizumab · Complement C5
Not conducted (ICH S6(R1))

Unituxin

dinutuximab · GD2
Not conducted (ICH S6)

Unloxcyt

cosibelimab · PD-L1
Not conducted (ICH S6(R1)); large molecule not expected to interact with DNA

Uplizna

inebilizumab · CD19
Not conducted (ICH S6)

Vectibix

panitumumab · EGFR
Not conducted

Veopoz

pozelimab · Complement C5
Not conducted (ICH S6(R1))

Voyxact

sibeprenlimab · APRIL
Not conducted (antibody lacks ability to interact directly with DNA)

Vyepti

eptinezumab · CGRP
Not conducted (ICH S6(R1))

Vyloy

zolbetuximab · Claudin 18.2
Not conducted (ICH S6 and S9)

Xolair

omalizumab · IgE
Ames test negative; full genotoxicity battery not conducted (no relevant species)

Yervoy

ipilimumab · CTLA-4
Not conducted

Zinbryta

daclizumab · IL-2Rα (CD25)
Not conducted; antibody not expected to interact directly with DNA

Zinplava

bezlotoxumab · C. difficile toxin B
Not conducted

Zynyz

retifanlimab · PD-1
Not conducted; not warranted

Summary across all 117 monoclonal antibodies →