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Precedia/Monoclonal antibodies/Enflonsia/Risks

Enflonsia: which risks did reviewers probe?

clesrovimab · RSV F protein (site IV)
Check my plan vs. these
Immune & cytokine safety
In vitro interleukin release by human white blood cells prompted a clinical hold for potential cytokine release syndrome
“The Agency placed the application on full clinical hold on January 6, 2017, due to the potential risk of cytokine release syndrome (based on demonstration of release of interleukins induced in human white blood cells in an in vitro cytokine release assay).”
✓ VerifiedFDA integrated review, p. 168Source ↗
Biodistribution & persistence
No off-target binding in tissue cross-reactivity study of adult, juvenile and neonatal human tissues
“No off-target binding was observed with MK-1654 in any tissue observed under the conditions of this study.”
✓ VerifiedFDA integrated review, p. 180Source ↗
Modality-specific risk
Possible FcRn competition with maternal IgG from YTE modification, potentially reducing passive immunity in infants
“It is unknown if competition could exist between maternal antibodies and clesrovimab for FcRn binding sites/IgG-recycling and if clesrovimab is preferentially recycled over endogenous maternal IgG due to the increased affinity for FcRn through the YTE modification”
✓ VerifiedEMA assessment report, p. 36Source ↗
Anti-drug antibodies: animals
ADA in 1 female rat (30 mg/kg) from day 28 with markedly reduced individual exposure; no impact on group toxicokinetics
“Anti-drug antibodies (ADA) were detected in one female animal in the 30 mg/kg dose group from day 28 post the first dosing. Even though the individual exposure of the animal was highly diminished, suggesting strong neutralising ADA potential, no substantial impact on overall group mean concentration and toxicokinetic values were noted.”
✓ VerifiedEMA assessment report, p. 40Source ↗
Anti-drug antibodies: patients
Day 150: 6% (Trial 004) and 5% (Trial 007); through Day 240: 12% and 13%
“In Trial 004 and Trial 007, after receiving the approved recommended dose in RSV season 1, 6% (120/2112) and 5% (13/291) of participants were ADA-positive on Day 150, respectively; and 12% (124/1033) and 13% (34/261) of participants were ADA-positive through Day 240, respectively.”
✓ VerifiedUS prescribing informationSource ↗

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Risks for Enflonsia, each with the regulator's own words, the page and a link. Ready to paste into a briefing document or send to your team.

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

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

Libtayo

cemiplimab · PD-1
Anti-drug antibodies in 53% of monkeys in 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg)

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 →