Nonclinical precedent Request an invite
Precedia/Monoclonal antibodies/Libtayo/Risks

Libtayo: which risks did reviewers probe?

cemiplimab · PD-1
Check my plan vs. these
Immune & cytokine safety
Anti-drug antibodies in 53% of monkeys in 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg)
“ADAs were detected in 19/36 (53%) monkeys dosed with REGN2810 including 11/12 (92%), 4/12 (33%), and 4/12 (33%) monkeys dosed with 2, 10, and 50 mg/kg REGN2810, respectively.”
✓ VerifiedFDA multi-discipline review, p. 40Source ↗
Biodistribution & persistence
No distribution, metabolism or excretion studies; tissue cross-reactivity study used to assess target distribution
“Traditional distribution, metabolism, and excretion studies were not conducted with cemiplimab because it is a monoclonal antibody; however, consistent with ICH S6(R1), the Applicant did include a tissue cross reactivity assay to assess distribution of the target”
✓ VerifiedFDA multi-discipline review, p. 38Source ↗
Modality-specific risk
Immune-mediated adverse reactions such as pneumonitis, predicted by PD-1 blockade
“Based on clinical trials done to support the approval of cemiplimab in the proposed patient population, toxicities associated with cemiplimab are primarily immune-mediated adverse reactions, such as pneumonitis, that are predicted by its mechanism of action.”
✓ VerifiedFDA multi-discipline review, p. 30Source ↗
Anti-drug antibodies: animals
ADA in 53% of monkeys in the 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg), inversely related to dose
“ADAs were detected in 19/36 (53%) monkeys dosed with REGN2810 including 11/12 (92%), 4/12 (33%), and 4/12 (33%) monkeys dosed with 2, 10, and 50 mg/kg REGN2810, respectively.”
✓ VerifiedFDA multi-discipline review, p. 40Source ↗
Anti-drug antibodies: patients
2% of patients developed anti-cemiplimab antibodies; no clinically significant effect on PK
“During a treatment period ranging from 8 to 19 months in 5 clinical studies, 2% (22/1029) of LIBTAYO-treated patients developed anti-cemiplimab-rwlc antibodies. There was no clinically significant effect of anti-cemiplimab-rwlc antibodies on PK of cemiplimab-rwlc.”
✓ VerifiedUS prescribing informationSource ↗

Same question, other monoclonal antibodies

Actemra

tocilizumab · IL-6R
Immunogenic in monkeys with inverse dose relationship (ADA lower at high doses)

Adakveo

crizanlizumab · P-selectin
ADA in 40% of treated monkeys in the 26-week study, with hypersensitivity reactions in some animals

Adbry

tralokinumab · IL-13
No significant modulation of CD4/CD8 T cells, NK cells or mature B cells in 26-week monkey study

Aduhelm

aducanumab · Aggregated amyloid-β
No anti-drug antibodies in the 4-week monkey study

Aimovig

erenumab · CGRP receptor
ADA in 3 low-dose monkeys reduced drug exposure (Cmax and AUC)

Ajovy

fremanezumab · CGRP
Ciliary vessel inflammation with immune complex deposition in a monkey study (hypersensitivity-type); not reproduced in the 6-month study

Alhemo

concizumab · TFPI
ADA induced in all monkey repeat-dose studies, causing loss of exposure without affecting study interpretation

Andembry

garadacimab · Factor XIIa
Mouse deaths and premature euthanasia, mainly at low IV dose, attributed to immunogenicity to the human protein

Anthim

obiltoxaximab · B. anthracis PA
Anti-drug antibodies in 8 of 12 monkeys (75%) after a single dose

Arzerra

ofatumumab · CD20
Monkey complement activation and IL-6 rise suggesting mild cytokine release; ADA in all studies; reduced KLH antibody response

Avastin

bevacizumab · VEGF-A
Rabbits developed anti-drug antibodies 8-11 days after start of dosing, limiting rabbit study duration

Bavencio

avelumab · PD-L1
Human PBMC cytokine release limited to a 5-7 fold TNFα increase at 24 hours

Benlysta

belimumab · BLyS (BAFF)
ADA in 12 of 124 monkeys (6 with reduced exposure)

Beovu

brolucizumab · VEGF-A
Weakly immunogenic; ADA in all groups (including pre-existing) without effect on exposure

Beyfortus

nirsevimab · RSV F protein
No ADA during dosing; ADA in 4 (22.2%) recovery monkeys; no evidence of immunotoxicity

Bimzelx

bimekizumab · IL-17A/IL-17F
Increased infection risk from reduced muco-epidermal immunity in single and repeat-dose monkey studies

Briumvi

ublituximab · CD20
No significant changes in serum IL-6, IL-8, IFN-γ or TNF-α in monkeys after repeated dosing

Cablivi

caplacizumab · von Willebrand factor (A1 domain)
Anti-drug antibodies observed but did not affect exposure except in one 26-week monkey

Campath

alemtuzumab · CD52
IL-6, IL-10, MCP-1 and TNF-α elevated 2-4 hours after dosing in huCD52 transgenic mice

Cimzia

certolizumab pegol · TNF-α
Anti-drug antibody incidence 10-20% in main monkey toxicity studies

Cinqair

reslizumab · IL-5
ADA in 3 monkeys in pivotal study; one at 25 mg/kg had repeated hypersensitivity-type infusion reactions

Cosentyx

secukinumab · IL-17A
Immunotoxicity in one high-dose female: skin lesions, splenic lymphocytic atrophy, decreased NK cell activity and TDAR

Crysvita

burosumab · FGF23
ADA in some monkeys reduced burosumab exposure and attenuated phosphate and vitamin D increases

Cyramza

ramucirumab · VEGFR2
ADA in 5/7 monkeys at 5 mg/kg and 3/9 at 16 mg/kg; none at the high dose

Danyelza

naxitamab · GD2
In vitro ADCC with nude rat effector cells ~22% vs 55% with human NK cells, underpredicting human activity

Darzalex

daratumumab · CD38
Cytokine release (TNF-α, IL-6, IFN-γ) caused one chimpanzee death at 5 mg/kg shortly after dosing

Dupixent

dupilumab · IL-4Ra
No effect of REGN646 on antibody response to KLH immunization

Ebanga

ansuvimab · Zaire ebolavirus glycoprotein
No exposure or activity changes suggesting meaningful anti-drug antibody formation in monkeys

Ebglyss

lebrikizumab · IL-13
Low-level ADA in several monkeys without appreciable impact on exposure

Emgality

galcanezumab · CGRP
Decreased plasma drug levels after repeat dosing attributed to ADA formation

Empliciti

elotuzumab · SLAMF7
In vitro human whole-blood assay: elevated levels of 10 cytokines with elotuzumab

Enflonsia

clesrovimab · RSV F protein (site IV)
In vitro interleukin release by human white blood cells prompted a clinical hold for potential cytokine release syndrome

Enjaymo

sutimlimab · Complement C1s
Minimally immunogenic: ADA in 2/10 animals at 60 and 1/10 at 180 mg/kg/week, increased clearance, no immune complex disease

Enspryng

satralizumab · IL-6R
Low cytokine release syndrome risk in human whole-blood cytokine assay

Entyvio

vedolizumab · α4β7-integrin
No T-lymphocyte activation or cytokine release in human whole blood in vitro

Erbitux

cetuximab · EGFR
Anti-drug antibodies in 3/22 monkeys (13.6%), affecting serum concentration in one

Evenity

romosozumab · Sclerostin
No adverse consequences of ADAs in rats and monkeys; immune complex disease in a few rabbits

Evkeeza

evinacumab · ANGPTL3
Low ADA responses in rats and monkeys; highly immunogenic in rabbits

Exdensur

depemokimab · IL-5
ADA in 6 monkeys, exposure reduced in one high-titer animal; immune-complex vasculitis in one monkey; no dedicated immunotoxicity studies

Fasenra

benralizumab · IL-5Rα
ADA in 8.3%, 25% and 5.5% of monkeys in the 9-, 15- and 39-week studies

Gamifant

emapalumab · IFN-γ
Transient impairment of primary anti-KLH IgG response (TDAR) in monkeys; robust response after second challenge

Gazyva

obinutuzumab · CD20
In vitro whole-blood assays: cytokine release (IL-6, IL-8, TNF) predicting first-infusion reactions; monkey ADA with hypersensitivity; opportunistic infections

Herceptin

trastuzumab · HER2
Anti-drug antibodies rare: 1/84 animals in repeat-dose studies

Humira

adalimumab · TNF-α
Anti-drug antibodies (MAHA, PAHA) after single doses in mice and monkeys; PAHA neutralising

Hympavzi

marstacimab · TFPI
Non-neutralizing ADA in ~28% of rats in 3-month study; no ADA in 3-month monkey or 6-month rat studies

Ilaris

canakinumab · IL-1β
No anti-drug antibodies detected in marmoset or mouse surrogate toxicity studies

Ilumya

tildrakizumab · IL-23 p19
No tildrakizumab-related changes in infant lymphocyte counts or TDAR responses (PPND study)

Imaavy

nipocalimab · FcRn
KLH TDAR suppressed as expected from mechanism; tetanus toxoid response preserved during recovery in monkeys

Imfinzi

durvalumab · PD-L1
No cytokine release in a human whole blood assay

Imjudo

tremelimumab · CTLA-4
No TNF-α, IL-6 or IL-1β release from unstimulated human PBMC or whole blood in vitro

Jemperli

dostarlimab · PD-1
No in vitro cytokine release from human PBMCs at up to 400 µg/well

Kevzara

sarilumab · IL-6R
Small decreases in primary and secondary IgG TDAR responses to KLH at >=5 mg/kg/week, attributed to immunosuppression

Keytruda

pembrolizumab · PD-1
No cytokine release (IL-2) from hPBMCs cultured on immobilized pembrolizumab

Kisunla

donanemab · Amyloid-β (N3pG)
ADA in 1/6 low, 1/6 mid, 4/12 high-dose monkeys (1/12 controls); reduced exposure only in 2 high-titer recovery animals

Lartruvo

olaratumab · PDGFRα
ADA in at least 22% of monkeys causing variable exposure; peripheral blood immunophenotyping unremarkable

Leqembi

lecanemab · Amyloid-β protofibrils
No ADAs detected in monkey IV repeat-dose and SC local irritation studies

Loqtorzi

toripalimab · PD-1
In vitro cytokine release with immobilized or soluble antibody similar to negative control; cytokine release unlikely

Lucentis

ranibizumab · VEGF-A
Highly immunogenic in rabbits; significant antigenicity in monkeys, even within the eye

Margenza

margetuximab · HER2
No serum IFN-γ, IL-2, IL-5, IL-6, IL-10 or TNF-α increase in monkeys; partially reversible NK-cell decreases

Monjuvi

tafasitamab · CD19
B-cell depletion with reduced serum IgG and reduced TDAR (KLH primary, tetanus toxoid secondary response)

Nemluvio

nemolizumab · IL-31RA
In vitro whole-blood cytokine release far below alemtuzumab/TGN1412 controls; no effects on monkey TDAR, lymphocyte subsets or serum cytokines; ADA in some monkeys

Niktimvo

axatilimab · CSF-1R
ADA inversely related to dose (6/12, 3/12, 1/12 animals in 13-week study), reducing exposure and PD effect

Nucala

mepolizumab · IL-5
No effect on infant vaccine (Tripedia) titers in monkey PPND; ADA in one mother and its infant at 10 mg/kg

Ocrevus

ocrelizumab · CD20
ADAs at all dose levels, most evident at 10 mg/kg or lower

Omvoh

mirikizumab · IL-23 p19
No effect on immunophenotyping, T-dependent antibody response or NK-cell cytotoxicity in monkeys

Opdivo

nivolumab · PD-1
No CDC, ADCC or direct cytokine release in the absence of TCR activation

Pasatru

garetosmab · Activin A
Systemic hypersensitivity reactions and immunogenicity considered potential risks of treatment

Penpulimab

penpulimab · PD-1
ADA incidence 63.33% (6-week study) and 93.33% (13-week study) in monkeys

Perjeta

pertuzumab · HER2
No anti-pertuzumab antibodies detected in 7- and 26-week monkey studies; not immunogenic

Piasky

crovalimab · Complement C5
ADA in 21/30 SC and 8/10 IV monkeys in the 26-week study

Portrazza

necitumumab · EGFR
Monkey immunogenicity could not be assessed reliably (drug interference with ADA assay); exposure maintained on repeat dosing

Poteligeo

mogamulizumab · CCR4
In vitro cytokine release (IL-6, TNF-α, IFN-γ) varied by assay format, greatest in solid-phase PBMC assays

Praluent

alirocumab · PCSK9
Low anti-drug antibody incidence; neutralizing antibodies low in rats and negligible in monkeys

Praxbind

idarucizumab · Dabigatran
No anti-dabigatran antibodies; circulating immune complexes normal; no renal immune complex deposition in monkeys

Prolia

denosumab · RANKL
Highly immunogenic in monkeys (ADA in most studies); no major immunomodulatory changes; no dedicated immunotoxicity studies

Remicade

infliximab · TNF-α
Anti-TNF-α antibodies reduce host defence in intracellular infection models, increasing infection-induced mortality

Repatha

evolocumab · PCSK9
Apparent TDAR suppression in monkeys was no longer significant after restricting analysis to KLH-naive animals

Rituxan

rituximab · CD20
B-cell depletion only; T-cells unaffected, no infections; monkey anti-chimeric antibodies formed

Rystiggo

rozanolixizumab · FcRn
No cytokine release in any of four in vitro assay formats

Saphnelo

anifrolumab · IFNAR1
Arteritis in high-dose males attributed to ADA-mediated immune complex deposition (anifrolumab, IgM, C3b)

Sarclisa

isatuximab · CD38
No significant cytokine release from human PBMCs or WBCs in vitro

Siliq

brodalumab · IL-17RA
No significant effects on standard immune endpoints, immunophenotyping or KLH TDAR in adult and juvenile monkeys

Simponi

golimumab · TNF-α
Monkey anti-drug antibodies more frequent at lower doses (3-10 mg/kg) than at 25-50 mg/kg

Simulect

basiliximab · IL-2Rα (CD25)
Anti-idiotype antibodies in 75% of low-dose monkeys after four weeks, increasing clearance; offspring immunotoxicity not studied

Skyrizi

risankizumab · IL-23 p19
No immunosuppression (TDAR) or T-cell depletion in monkey toxicity studies

Soliris

eculizumab · Complement C5
No lymph node findings with surrogate in 26-week mouse study; no dedicated immunotoxicity or cytokine studies

Spevigo

spesolimab · IL-36R
Human whole-blood cytokine release assay: no IL-2, IL-6, TNF-α or IFN-γ release; low cytokine release potential

Stelara

ustekinumab · IL-12/23 p40
No adverse effects on functional immune responses, circulating lymphocyte subsets or lymphoid T- and B-cell distribution

Sylvant

siltuximab · IL-6
Lower anti-KLH IgM/IgG (TDAR), reduced splenic germinal centers, lower globulin; first-dose infusion reaction (facial swelling) in 1/52 monkeys

Synagis

palivizumab · RSV F protein
Immunogenic in cynomolgus monkeys: anti-drug antibodies in low- and high-dose groups

Takhzyro

lanadelumab · Plasma kallikrein
Neutralizing ADA in nearly all rats in the 4-week SC study

Taltz

ixekizumab · IL-17A
No effects on lymphocyte subsets or KLH TDAR; neutralizing ADA in one high-dose monkey after recovery

Tecentriq

atezolizumab · PD-L1
No cytokine release from human PBMCs up to 250 µg/mL; minimal Fcγ receptor binding, no ADCC up to 10 µg/mL

Tepezza

teprotumumab · IGF-1R
Reversible thymic atrophy/lymphoid depletion without peripheral T-cell depletion or infections; juvenile TDAR (KLH) unimpaired; ADA accelerated clearance

Tevimbra

tislelizumab · PD-1
In vitro immunotoxicity/cytokine release assays: only neutralising ADA and possible enhanced recall response

Tezspire

tezepelumab · TSLP
Mild to moderate decrease in anti-KLH IgG titers (TDAR) at 300 mg/kg

Tremfya

guselkumab · IL-23 p19
No effect on hematology, immunophenotyping, TDAR, immune tissue histopathology or T/B-cell distribution in monkeys or offspring

Trogarzo

ibalizumab · CD4
Anti-drug antibodies in 83% (25 mg/kg) and 58% (50 mg/kg) of cynomolgus monkeys

Tysabri

natalizumab · α4-integrin
ADA-driven shock-like reactions with complement activation and immune complexes in some monkeys

Tzield

teplizumab · CD3
Transient cytokine increases (TNF, IL-6, IL-10, IFN-gamma) in chimpanzees; slight IL-6/IL-12 rise with surrogate in mice; anaphylaxis on intermittent surrogate dosing

Ultomiris

ravulizumab · Complement C5
Repeat SC dosing in rabbits caused severe systemic immune-complex (type III) hypersensitivity; ADA in monkeys and rabbits

Unituxin

dinutuximab · GD2
Rats: increased lymphocytes, neutrophils and NK cells; anti-drug antibodies affected exposure

Unloxcyt

cosibelimab · PD-L1
ADA in 10-50% of monkeys during dosing or recovery, incidence decreasing with dose

Uplizna

inebilizumab · CD19
Anti-drug antibodies mainly at lowest doses, correlated with B-cell depletion/recovery kinetics

Vectibix

panitumumab · EGFR
Anti-panitumumab antibodies (MAHA) in 9/10 low-dose, 2/10 mid-dose and 1/10 high-dose monkeys

Veopoz

pozelimab · Complement C5
ADA in 9 of 36 treated monkeys (26-week study); ADA did not notably affect exposure

Voyxact

sibeprenlimab · APRIL
ADAs in 20% of monkeys at 25 and 50 mg/kg SC, none at high dose, no exposure effect

Vyepti

eptinezumab · CGRP
Anaphylactoid reaction in a monkey associated with high ADA; animal immunogenicity not considered predictive of clinical risk

Vyloy

zolbetuximab · Claudin 18.2
ADA in 13/18 monkeys after a single dose; none detected in the 4-week monkey toxicity study

Xolair

omalizumab · IgE
Omalizumab:IgE complexes without immune complex disease; anti-drug antibodies in monkeys (all positive after inhalation), non-neutralizing

Yartemlea

narsoplimab · MASP-2
ADA in 2 of 40 treated monkeys, with no effect on exposure

Yervoy

ipilimumab · CTLA-4
Generally not immunogenic in monkeys; ADA in 12% including weak responders

Zinbryta

daclizumab · IL-2Rα (CD25)
ADA detected in monkeys, reducing exposure in some animals without compromising study adequacy

Zinplava

bezlotoxumab · C. difficile toxin B
No anti-drug antibodies detected in treated mice

Zynyz

retifanlimab · PD-1
No cytokine production by human PBMCs with soluble or immobilized antibody at 10-100 µg/mL

Raxibacumab

raxibacumab · B. anthracis protective antigen
Not stated in public reviews

Summary across all 117 monoclonal antibodies →