Ultomiris (ravulizumab): what safety margin did regulators accept?

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Ultomiris: what safety margin did regulators accept?

ravulizumab · Complement C5

Safety margin at NOAEL

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

“Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.”

✓ VerifiedUS prescribing informationSource ↗

NOAEL / key findings

Surrogate mouse 26-week study: NOAEL 60 mg/kg/week, the highest dose tested

“The No Observed Adverse Effect Level (NOAEL) for BB5.1 mAb administered to CD‐1 mice via IV injection twice weekly for 26 weeks was determined to be 60 mg/kg/week, the highest dose tested.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

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)

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

Zinplava

bezlotoxumab · C. difficile toxin B

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

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 →