Zinplava (bezlotoxumab): what safety margin did regulators accept?

Mouse NOAEL >=125 mg/kg/dose up to 5-fold human exposure at 10 mg/kg (Source: EMA assessment report, p. 19.)

Atlas/Monoclonal antibodies/Zinplava/Safety margin

Zinplava: what safety margin did regulators accept?

bezlotoxumab · C. difficile toxin B

Safety margin at NOAEL

Mouse NOAEL >=125 mg/kg/dose up to 5-fold human exposure at 10 mg/kg

“The no-observed-adverse-effect-level (NOAEL) for bezlotoxumab alone or in combination with actoxumab was ≥125 mg/kg/dose. This is up to 5 fold over the exposure in humans at the clinically recommended dose (10mg/Kg).”

✓ VerifiedEMA assessment report, p. 19Source ↗

NOAEL / key findings

NOAEL >=125 mg/kg/dose alone or with actoxumab (up to 5-fold clinical exposure); no findings of toxicological significance

✓ VerifiedEMA assessment report, p. 19Source ↗

Same question, other monoclonal antibodies

Actemra

tocilizumab · IL-6R

Monkey steady-state trough exposure 8- to 10-fold above maximum human exposure

Adakveo

crizanlizumab · P-selectin

Monkey 50 mg/kg (dose with vascular inflammation) ~13.5x human AUC at 5 mg/kg

Adbry

tralokinumab · IL-13

Monkey 26-week IV NOAEL 100 mg/kg/week = 18x human AUC at MRHD (10x on mg/kg basis)

Aduhelm

aducanumab · Aggregated amyloid-β

Monkey NOAEL (high dose) 9x human AUC at 10 mg/kg; ~35x after adjusting QW vs Q4W dosing

Aimovig

erenumab · CGRP receptor

Monkey 3/6-month NOAEL (150 mg/kg twice weekly) >100x human AUC at 140 mg QM; ePPND NOAEL ~17x

Ajovy

fremanezumab · CGRP

Cmax exposure multiples 2.3-43x (IV) and 2.2-227x (SC) vs human; may be overestimated due to animal accumulation

Alhemo

concizumab · TFPI

52-week monkey NOAEL 0.5 mg/kg/day SC: 74x human AUC at 0.20 mg/kg

Andembry

garadacimab · Factor XIIa

Monkey SC NOAEL AUC ~37x clinical AUC at 200 mg once monthly

Anthim

obiltoxaximab · B. anthracis PA

Rabbit EFD NOEL: AUC 0.62x and Cmax ~3x human exposure at 16 mg/kg

Arzerra

ofatumumab · CD20

Monkey EFD maternal exposure at no-effect dose ~2.4x clinical exposure at 2 g

Avastin

bevacizumab · VEGF-A

Monkey physeal dysplasia at exposures ~1.5- to 2.0-fold below expected human exposure (average serum concentration)

Bavencio

avelumab · PD-L1

No NOAEL in 13-week monkey study (CNS perivascular infiltrates at all doses); LOAEL 1.5-fold human AUC; high dose 10- to 15-fold

Benlysta

belimumab · BLyS (BAFF)

Monkey 4-week high dose: 12x human AUC, 5x Cmax

Beovu

brolucizumab · VEGF-A

Monkey NOAEL 6 mg/eye: 6-fold human AUC, 12-fold Cmax (systemic); 2-fold ocular

Beyfortus

nirsevimab · RSV F protein

Monkey IM NOAEL 300 mg/week: 8-fold infant AUC, 44-fold Cmax (50/100 mg IM)

Bimzelx

bimekizumab · IL-17A/IL-17F

Monkey ePPND NOAEL exposure 27-fold clinical exposure (AUC); no NOAEL in 26-week study

Briumvi

ublituximab · CD20

Monkey 26-week study at only dose (30 mg/kg): Cave ~24x human at 450 mg MRHD; no NOAEL defined

Cablivi

caplacizumab · von Willebrand factor (A1 domain)

Not definable per EMA: dose-dependent bleeding at all doses precludes a NOAEL and clinical exposure margin

Campath

alemtuzumab · CD52

huCD52 mouse developmental NOAEL: below clinical exposure by Cmax; 0.6- to 4.4-fold by AUC

Cimzia

certolizumab pegol · TNF-α

Monkey single-dose IV NOAEL 400 mg/kg: maximal exposure ~200-fold the plasma level at the maximal recommended human dose (~50 µg/ml)

Cinqair

reslizumab · IL-5

Mouse and monkey NOAEL ~3-fold human AUC at 3 mg/kg IV q4w

Cosentyx

secukinumab · IL-17A

Monkey exposure 48-108-fold human AUC (53-100-fold Cmax) at doses giving maximal IL-17A neutralization

Crysvita

burosumab · FGF23

Adult monkey NOAEL 0.3 mg/kg at 0.9x adult human AUC

Cyramza

ramucirumab · VEGFR2

No NOAEL-based multiple stated; end-of-study 39-week monkey exposures 0.2-5.6x human exposure at 8 mg/kg

Danyelza

naxitamab · GD2

Nude rat 50 mg/kg exposure 32x (males) and 25x (females) human AUC at 9 mg/kg

Dupixent

dupilumab · IL-4Ra

Monkey ePPND NOAEL (surrogate REGN646) 100 mg/kg/week = 10x MRHD on a mg/kg basis

Ebanga

ansuvimab · Zaire ebolavirus glycoprotein

Rhesus 4-week NOAEL 500 mg/kg/dose (AUC 222664 µg.day/mL) = 7.6x human exposure

Ebglyss

lebrikizumab · IL-13

Monkey IV 25 mg/kg/week for 37 weeks (no fertility effects): Cavg,ss ~15x human exposure at MRHD

Emgality

galcanezumab · CGRP

General tox NOAELs: rat 20 mg/kg ~1x human AUC (7x Cmax); monkey 100 mg/kg 21x AUC (143x Cmax)

Enflonsia

clesrovimab · RSV F protein (site IV)

Rat NOAEL 300 mg/kg: >40-fold infant exposure (AUC0-72h and Cmax)

Enjaymo

sutimlimab · Complement C1s

Monkey 26-week NOAEL 180 mg/kg: ~3- or 5-fold human AUC at 6.5 g or 7.5 g

Enspryng

satralizumab · IL-6R

Monkey NOAEL (26-week and ePPND maternal) ~26x human steady-state AUC

Entyvio

vedolizumab · α4β7-integrin

Monkey NOAEL 100 mg/kg ~18x human AUC at 300 mg

Erbitux

cetuximab · EGFR

No margin: lowest monkey dose (12 then 7.5 mg/kg weekly) equals the human therapeutic dose

Evenity

romosozumab · Sclerostin

No adverse effects at 100 mg/kg weekly for 26 weeks: 37x (rat) and 90x (monkey) human AUC at 210 mg monthly

Evkeeza

evinacumab · ANGPTL3

NOAEL 100 mg/kg/week IV: ~1x (rat) and 4x (monkey) MRHD AUC at 15 mg/kg IV every 4 weeks

Exdensur

depemokimab · IL-5

Monkey NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg): 8.48x (asthma) and 9.65x (CRSwNP) human AUC; 10.9-12.0x Cmax

Fasenra

benralizumab · IL-5Rα

Monkey NOAEL AUC 153- to 271-fold the exposure at the recommended clinical dose

Gazyva

obinutuzumab · CD20

No off-target toxicity in monkeys at AUC up to 6-fold human exposure at 1000 mg

Herceptin

trastuzumab · HER2

Monkey fertility study: no impaired fertility at up to 25x the weekly human dose of 2 mg/kg

Humira

adalimumab · TNF-α

Monkey embryo-fetal/perinatal study: no fetal harm at up to 373x MRHD exposure (AUC)

Hympavzi

marstacimab · TFPI

NOAELs (rat 1000, monkey 500 mg/kg/week IV) ~200x human AUC at the MRHD

Ilaris

canakinumab · IL-1β

Marmoset EFD doses ~11x human AUC at MRHD and greater; no embryotoxicity or malformations

Ilumya

tildrakizumab · IL-23 p19

Monkey NOAEL 140 mg/kg Q2W (3 months): 133x (SC) or 155x (IV) MRHD by AUC

Imaavy

nipocalimab · FcRn

Monkey 26-week NOAEL lowered to 100 mg/kg by EMA: 10.8x (AUC) and 6.7x (Cmax) human exposure

Imfinzi

durvalumab · PD-L1

Monkey highest repeat-dose exposure 19.6x human AUC0-14 day at 10 mg/kg every two weeks

Imjudo

tremelimumab · CTLA-4

Chronic monkey study: no NOAEL; lowest dose 5 mg/kg/week gave exposure margin of 1-2 (potency-adjusted)

Jemperli

dostarlimab · PD-1

No NOAEL in 13-week monkey study; lowest dose 10 mg/kg AUC ~6x and 5x human exposure at 500 mg Q3W/Q6W

Kevzara

sarilumab · IL-6R

Monkey 6-month NOAEL 50 mg/kg/week >80x human systemic exposure at recommended doses

Keytruda

pembrolizumab · PD-1

Monkey exposure at all doses tested exceeded human exposure at 2 mg/kg Q3W

Kisunla

donanemab · Amyloid-β (N3pG)

Monkey high dose (no adverse effects) ~10x human AUC at 1400 mg/month, adjusted for dosing frequency

Lartruvo

olaratumab · PDGFRα

Monkey 75 mg/kg weekly up to 39 weeks (no mortality) AUC ~6-9.5x human steady-state AUC at recommended dose

Leqembi

lecanemab · Amyloid-β protofibrils

Monkey NOAEL (39-week, weekly dosing): 27-fold (AUC) and 14-fold (Cmax) human exposure

Libtayo

cemiplimab · PD-1

Monkey 50 mg/kg/week (highest dose, NOAEL): ~5.5 to 25.5x human AUC at 350 mg Q3W

Loqtorzi

toripalimab · PD-1

Monkey 100 mg/kg weekly (NOAEL, 26-week): 13 to 23-fold human AUC at 240 mg Q3W or 3 mg/kg Q2W

Lucentis

ranibizumab · VEGF-A

No ocular NOAEL; only the lowest dose (1.0-fold the clinical 0.5 mg dose, vitreous mg/ml) gave inflammation subsiding to vehicle levels

Margenza

margetuximab · HER2

Monkey 100 mg/kg/dose (13-week high dose): 8.6x (males) and 6.6x (females) human steady-state Cmax

Monjuvi

tafasitamab · CD19

Monkey NOAEL 100 mg/kg/week ~9x human AUC at 12 mg/kg/week

Nemluvio

nemolizumab · IL-31RA

Monkey NOAEL 25 mg/kg Q2W (6 months) 53x MRHD for PN and 72x for AD (AUC)

Nucala

mepolizumab · IL-5

Monkey NOAEL 100 mg/kg q4 weeks >90x human AUC at 100 mg SC q4 weeks

Ocrevus

ocrelizumab · CD20

Monkey doses tested were 2x and 10x the human 600 mg dose (mg/kg basis); no developmental no-effect dose identified

Omvoh

mirikizumab · IL-23 p19

No adverse effects in monkeys up to 30x MRHD (300 mg Q4W IV), AUC-based

Opdivo

nivolumab · PD-1

Monkey exposures up to 42x clinical AUC at 3 mg/kg Q2W without autoimmune disease

Pasatru

garetosmab · Activin A

Monkey 26-week NOAEL 50 mg/kg ~5x maximum clinical AUC

Penpulimab

penpulimab · PD-1

Monkey highest dose 60 mg/kg ≥4.7x human AUC at the 200 mg clinical dose

Perjeta

pertuzumab · HER2

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

Piasky

crovalimab · Complement C5

Monkey NOAEL 3.3- and 2.6-times patient exposure at maximum recommended human dose (males, females)

Portrazza

necitumumab · EGFR

No NOAEL in 26-week monkey study; 5-week NOAEL (40 mg/kg) exposure approximately equal to median human exposure at maximum clinical dose

Poteligeo

mogamulizumab · CCR4

Monkey EFD study at 40 mg/kg (no adverse findings) approximately 27 times patient exposure at recommended dose (AUC)

Praluent

alirocumab · PCSK9

No significant adverse findings at up to 11-fold (rat) and 103-fold (monkey) human exposure at 150 mg Q2W

Praxbind

idarucizumab · Dabigatran

Rhesus NOAEL 500 mg/kg/day: approx. 3-6x human AUC and 5-7x Cmax across human populations

Prolia

denosumab · RANKL

No effect on fertility or male reproductive organs in monkeys at 13- to 50-fold the 60 mg human dose (mg/kg)

Raxibacumab

raxibacumab · B. anthracis protective antigen

Rabbit EFD at 120 mg/kg (no harm): Cmax more than 3 and 4 times mean human Cmax

Repatha

evolocumab · PCSK9

Monkey NOAEL 744x, 300x and 134x human exposure at 140 mg Q2W, 420 mg QM and 420 mg Q2W (hamster 112x, 48x, 20x)

Rituxan

rituximab · CD20

No margin: monkey exposure about equal to human exposure (1:1)

Rystiggo

rozanolixizumab · FcRn

Monkey toxicity-study exposure 36-228x model-predicted human exposure

Saphnelo

anifrolumab · IFNAR1

General toxicity NOAEL >59x human AUC at MRHD (ePPND NOAEL 28x)

Siliq

brodalumab · IL-17RA

6-month monkey 90 mg/kg (NOAEL) AUC 47x human at 210 mg Q2W

Simponi

golimumab · TNF-α

Chronic SC monkey NOAEL 50 mg/kg: ~50x human AUC (~600x Cmax)

Simulect

basiliximab · IL-2Rα (CD25)

Cynomolgus embryo-fetal study: no maternal toxicity or teratogenicity at blood levels 13-fold human

Skyrizi

risankizumab · IL-23 p19

26-week monkey NOAEL 50 mg/kg/week: exposure 69-fold highest human exposure (AUC0-168hr)

Soliris

eculizumab · Complement C5

Surrogate mouse fertility study: no effect on mating or fertility at up to 4-8 times the clinical dose

Spevigo

spesolimab · IL-36R

No margin to clinical exposure calculated for the surrogate antibody

Stelara

ustekinumab · IL-12/23 p40

Monkey 45 mg/kg twice-weekly SC: steady-state Cmax ~116-fold human Cmax at 90 mg SC

Sylvant

siltuximab · IL-6

Monkey chronic-study AUC ~7-fold human AUC in cancer patients

Takhzyro

lanadelumab · Plasma kallikrein

Monkey 6-month NOAEL: AUC 23-fold and Cmax 21-fold over MRHD of 300 mg

Taltz

ixekizumab · IL-17A

Monkey 39-week NOAEL 5 mg/kg: AUC 6.5x human steady-state (61x at 50 mg/kg LOAEL)

Tecentriq

atezolizumab · PD-L1

No margin: toxicity studies provide no margin to exposure at the proposed clinical dose

Tepezza

teprotumumab · IGF-1R

Monkey repeat-dose exposure ~8x human AUC (schedule-normalised)

Tevimbra

tislelizumab · PD-1

Monkey no-toxicity dose 30 mg/kg Q2W: 4.3-6.6x human exposure at 200 mg

Tezspire

tezepelumab · TSLP

Monkey 6-month SC NOAEL 300 mg/kg: ~134x MRHD (210 mg Q4W) on AUC, 128x on Cmax

Tremfya

guselkumab · IL-23 p19

Monkey NOAEL AUC ~49.9x human AUC after a single 100 mg SC dose

Trogarzo

ibalizumab · CD4

Cynomolgus NOAEL (ADA-negative animals) ~4x exposure at MRHD

Tzield

teplizumab · CD3

Chimpanzee single-dose NOAEL ~4x total human dose per treatment cycle (BSA)

Ultomiris

ravulizumab · Complement C5

Mouse surrogate fertility study: no effects at up to 0.8-2.2x the clinical dose equivalent

Unituxin

dinutuximab · GD2

No NOAEL identified in the 28-day rat study; no margin stated

Uplizna

inebilizumab · CD19

huCD19 Tg mouse 6-month NOAEL 30 mg/kg/week: 55-fold exposure margin (6.9-fold HED-based)

Vectibix

panitumumab · EGFR

No NOAEL margin stated; monkey EFD embryolethality/abortions at 1.25-5x human dose (no NOAEL)

Veopoz

pozelimab · Complement C5

Monkey NOAEL 100 mg/kg/week (13-week SC, 26-week IV): 12-15x predicted clinical exposure

Voyxact

sibeprenlimab · APRIL

Monkey 6-month IV and SC studies, highest doses tested: 13-fold (IV) and 10-fold (SC) AUC margins at MRHD of 400 mg

Vyepti

eptinezumab · CGRP

Monkey chronic study, high dose: exposure >100x maximum clinical exposure

Vyloy

zolbetuximab · Claudin 18.2

NOAEL serum AUC 11-12x human exposure (clinical PK) or 6-7x (Pop-PK model)

Xolair

omalizumab · IgE

Monkey EFD study: no maternal or fetal toxicity at ~5x MRHD (mg/kg, up to 75 mg/kg/week)

Yartemlea

narsoplimab · MASP-2

Monkey 26-week SC NOAEL 300 mg/kg/week: 38-fold the MRHD

Yervoy

ipilimumab · CTLA-4

No safety margin could be determined for serious irAEs (colitis, dermatitis) in monkeys

Zinbryta

daclizumab · IL-2Rα (CD25)

Monkey NOAEL 10 mg/kg for CNS microglial aggregates: ~7x human exposure at recommended dose

Zynyz

retifanlimab · PD-1

Monkey top dose 150 mg/kg corresponds to 26-fold the proposed MRHD exposure

Darzalex

daratumumab · CD38

Not stated in public reviews

Empliciti

elotuzumab · SLAMF7

Not stated in public reviews

Gamifant

emapalumab · IFN-γ

Not stated in public reviews

Niktimvo

axatilimab · CSF-1R

Not stated in public reviews

Remicade

infliximab · TNF-α

Not stated in public reviews

Sarclisa

isatuximab · CD38

Not stated in public reviews

Synagis

palivizumab · RSV F protein

Not stated in public reviews

Tysabri

natalizumab · α4-integrin

Not stated in public reviews

Unloxcyt

cosibelimab · PD-L1

Not stated in public reviews

Summary across all 117 monoclonal antibodies →