Inqovi (decitabine and cedazuridine): what safety margin did regulators accept?

Atlas/Small molecules/Inqovi/Safety margin

Inqovi: what safety margin did regulators accept?

decitabine and cedazuridine · DNMT (decitabine); cytidine deaminase (cedazuridine)

Safety margin at NOAEL

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.

NOAEL / key findings

Reversible myelosuppression; reversible reproductive tract effects from cedazuridine

“In summary, the main repeat-dose toxicity findings from studies conducted in mice, rats, and monkeys were characterized by reversible myelosuppression (leukopenia, neutropenia, lymphopenia, and/or decreased platelet counts) due to decitabine, or both (ASTX727), reversible reproductive tract effects due to cedazuridine”

✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Same question, other small molecules

Accrufer

ferric maltol · Iron replacement

Maltol rat EFD: no adverse effects at 6x recommended human dose (no repeat-dose margin stated)

Adquey

difamilast · PDE4 (topical)

Dog 39-week SC NOAEL 36x (male) and 23x (female) MRHD by AUC

Agamree

vamorolone · Glucocorticoid receptor (dissociative)

No margin: NOAEL exposures negligible in mice and non-existent in dogs versus MRHD

Alyftrek

vanzacaftor, tezacaftor and deutivacaftor · CFTR

Vanzacaftor 6-month rat NOAEL 21x (male) and 59x (female) clinical exposure

Anzupgo

delgocitinib · Pan-JAK (topical)

Dermal minipig: no toxicity up to 20 mg/kg/day, 20x (male) and 11x (female) human exposure

Aqneursa

levacetylleucine · Neuronal metabolism (proposed)

NOAEL 2-3x (rat) and 6-9x (dog) human steady-state AUC at MRHD

Artesunate

artesunate · Plasmodium (antimalarial)

Rat NOAEL 3 mg/kg/day = 0.2x clinical dose (body surface area)

Attruby

acoramidis · Transthyretin (stabiliser)

Rat 26-week NOAEL approximately equal to (males) and 32x (females) human AUC at MRHD

Augtyro

repotrectinib · ROS1/TRK

Rat NOAEL: low to non-existing safety margins vs clinical exposure at 160 mg BID

Avmapki Fakzynja Co-pack

avutometinib and defactinib · RAF/MEK clamp; FAK

No margin: avutometinib rat myocardial degeneration/necrosis at ≥0.01 mg/kg/day, below human AUC at recommended dose

Ayvakit

avapritinib · KIT/PDGFRA

No margin: dog choroid plexus edema at >=7.5 mg/kg/day, ~0.4x human AUC at 300 mg; absent at 5 mg/kg/day (9-month)

Azstarys

serdexmethylphenidate and dexmethylphenidate · Dopamine/norepinephrine reuptake

No margin: rat NOAEL (25 mg/kg) exposure below human exposure at MRHD

Balversa

erdafitinib · FGFR1-4

No margin: repeat-dose exposure multiples much lower than human AUC at 8 or 9 mg

Barhemsys

amisulpride · Dopamine D2/D3 receptor

Rat EFD study: no adverse embryo-fetal effects up to 160 mg/kg/day, 43x human AUC at 10 mg

Baxfendy

baxdrostat · Aldosterone synthase (CYP11B2)

Monkey 39-week NOAEL: 11-fold (males) and 8.5-fold (females) vs 2 mg human dose

Beqalzi

sonrotoclax · BCL-2

13-week dog high dose ~11x human AUC at 320 mg once daily

Blujepa

gepotidacin · Bacterial topoisomerases (gyrase/topo IV)

13-week dog NOAEL 60 mg/kg/day ~2x and 13-week rat NOAEL ~4x human AUC (4-week rat NOAEL 0.3x)

Brenzavvy

bexagliflozin · SGLT2

NOAEL (highest dose) 78x (monkey) and 89x (rat) human AUC at 20 mg

Brexafemme

ibrexafungerp · Fungal glucan synthase

Rabbit EFD: NOAEL ~2x and LOAEL ~5x human AUC in fed patients

Brinsupri

brensocatib · DPP1 (cathepsin C)

NOAEL margins vs human AUC: 26-week dog ~1.4x, 39-week dog ~5.4x, 26-week rat ~20.6x

Brukinsa

zanubrutinib · BTK

NOAEL ~13x (rat, 100 mg/kg/day) and ~3x (dog, 10 mg/kg/day) human AUC

Byfavo

remimazolam · GABA-A receptor (benzodiazepine site)

No systemic toxicity beyond pharmacology up to 120 mg/kg/day in monkey and minipig: >100x human AUC at MRHD

Bylvay

odevixibat · IBAT

Dog 39-week NOAEL 150 mg/kg: 31x (males) and 41x (females) human exposure

Cabenuva

cabotegravir and rilpivirine · HIV-1 integrase; NNRTI

Cabotegravir 39-week monkey NOAEL 3.7x human AUC at the oral dose

Camzyos

mavacamten · Cardiac myosin

NOAEL exposures in all toxicology and reproductive studies below human exposure at the MRHD

Caplyta

lumateperone · 5-HT2A / D2 receptor

Dog NOAEL 2x the MRHD of 42 mg (mg/m2 basis)

Cardamyst

etripamil · L-type calcium channel

No systemic toxicity at ~1-2x AUC and 1-4x Cmax at the MRHD (rat, monkey); local nasal toxicity at all doses

Cibinqo

abrocitinib · JAK1

Rat EFD: NOAEL 2.3x (skeletal effects) and 10x (embryo-fetal lethality) human AUC at 200 mg

Cobenfy

xanomeline and trospium · Muscarinic M1/M4 agonist; peripheral antagonist

Rat EFD (combination) NOAEL ~3x the xanomeline dose at the MRHD (BSA)

Cosela

trilaciclib · CDK4/6

Pivotal iv dog study: NOAEL 5 mg/kg = 0.5x MRHD; LOAEL 15 mg/kg = 1x MRHD

Crenessity

crinecerfont · CRF1 receptor

NOAEL exposures in pivotal nonclinical studies limited to 1- to 4-fold MRHD

Cypsedo

cipepofol · GABA-A receptor

At least 1x human AUC margin in 14- or 28-day rat/dog repeat-dose studies

Daybue

trofinetide · IGF-1 tripeptide analogue

No margin: 26-week rat AUC at highest dose (no adverse effects) similar to pediatric patient exposure

Dayvigo

lemborexant · Orexin OX1/OX2 receptors

Monkey NOAEL 10 mg/kg/day ~12x MRHD AUC

Dojolvi

triheptanoin · Anaplerotic energy substrate

Minipig NOAEL ~4x human heptanoate AUC at 1.25 g/kg/day (30% DCI)

Duvyzat

givinostat · Histone deacetylase (class I/II)

No relevant AUC- or Cmax-based margins at repeat-dose NOAELs (mouse, rat, monkey) vs human doses of 25 to 70 mg bid

Egaten

triclabendazole · Fasciola (tubulin)

EFD study: no embryotoxicity up to 1.6x (rat) and 0.3x (rabbit) the clinical dose (BSA)

Ekterly

sebetralstat · Plasma kallikrein

26-week monkey NOAEL (300 mg/kg biweekly) 1.20x human AUC; 26-week rat NOAEL 28.8x

Ensacove

ensartinib · ALK

No NOAEL margin stated; severe dog skin lesions at exposures ~equal to human AUC at 225 mg/day

Evrysdi

risdiplam · SMN2 splicing

Monkey 39-week NOAEL (1.5 mg/kg/day) AUC identical to targeted patient exposure (no margin)

Exblifep

cefepime and enmetazobactam · PBPs; beta-lactamase (enmetazobactam)

28-day dog: highest enmetazobactam dose without liver effects 2.8x MRHD exposure

Exkivity

mobocertinib · EGFR exon 20 insertion

Rat EFD: no embryo-fetal loss up to 5 mg/kg (~0.8x clinical AUC at 160 mg); no repeat-dose NOAEL margin stated

Exxua

gepirone · 5-HT1A receptor

Developmental NOAEL (EFD) 9x (rat) and 12x (rabbit) MRHD on mg/m2 basis; no repeat-dose margin stated

Fabhalta

iptacopan · Complement factor B

9-month dog NOAEL 0.5x (male) and 2.2x (female) human AUC; 6-month rat NOAEL 1.4x

Fetroja

cefiderocol · Penicillin-binding proteins

3-month monkey NOAEL 100 mg/kg/day: 0.3-fold human AUC (3-fold Cmax)

Fexinidazole

fexinidazole · Trypanosoma brucei

Rat NOAEL 200 mg/kg (males): 0.7 times clinical exposure; 800 mg/kg (females) similar to clinical

Filspari

sparsentan · Endothelin A / angiotensin II receptors

9-month monkey NOAEL 50 mg/kg/d: 0.2 (males) and 0.1 (females) times human AUC at 800 mg

Fotivda

tivozanib · VEGFR1-3

9-month monkey NOAEL ~0.5-fold RCC patient exposure; 6-month rat NOAEL ~2-fold

Foundayo

orforglipron · GLP-1 receptor (non-peptide)

6-month rat (pharmacologically inactive species): no adverse effects up to 35-fold MRHD AUC

Fruzaqla

fruquintinib · VEGFR1-3

13-week NOAEL AUC margins: rat 0.3x, dog 0.05x human exposure

Gavreto

pralsetinib · RET

13-week rat and monkey NOAEL (10 mg/kg/day) ~1x human AUC

Gemtesa

vibegron · β3-adrenergic receptor

Rat NOAEL ~21.3x AUC; monkey NOEL (ECG findings) 2.1x AUC, 6.4x Cmax at 75 mg

Gomekli

mirdametinib · MEK1/2

4-week dog NOAEL 0.1 mg/kg/day at 0.35x clinical exposure

Hernexeos

zongertinib · HER2 (mutant)

Dog NOAEL approximately at clinical AUC; rat NOAEL ~1.5 to 3-fold (applicant)

Hyrnuo

sevabertinib · HER2 (mutant)

No NOAEL margin stated; monkey lens degeneration at 5 mg/kg (0.1x human AUC)

Ibsrela

tenapanor · NHE3

Rat NOAEL 1.8x (males) and 5.9x (females) the 100 mg/day clinical dose (mg/kg basis)

Ibtrozi

taletrectinib · ROS1

Rabbit EFD: pregnancy loss at lowest dose 15 mg/kg/day (0.04x human AUC); no margin

Idvynso

doravirine and islatravir · NNRTI; NRTTI

Islatravir NOAEL: rat 119x and monkey 539x human AUC at the recommended dose

Inluriyo

imlunestrant · Estrogen receptor (SERD)

No NOAEL margin: female reproductive tract effects in monkeys at ≥15 mg/kg/day (≥1x human AUC)

Inpefa

sotagliflozin · SGLT1/SGLT2

Rat 26-week NOAEL 30 mg/kg/day (males) ~8x human AUC at MRHD

Inrebic

fedratinib · JAK2

No safety margin: exposures in mice, rats and dogs were below human exposure

Iqirvo

elafibranor · PPARα/δ

No margin: most repeat-dose exposure margins for elafibranor <1 (CHMP); findings likely clinically relevant

Isturisa

osilodrostat · 11β-hydroxylase (CYP11B1)

Rat 26-week and dog 39-week NOAELs ~14-16x clinical AUC (~4x Cmax)

Itovebi

inavolisib · PI3Kα (mutant-selective)

Rat and dog 4- and 13-week NOAELs generally below clinical AUC; no exposure margin

Jascayd

nerandomilast · PDE4B

Rat 26-week NOAEL ~1x human AUC and Cmax at MRHD

Jaypirca

pirtobrutinib · BTK (non-covalent)

Dog 3-month: corneal lesions at 0.42-fold human AUC at 200 mg; toxicity below clinical exposure

Jesduvroq

daprodustat · HIF prolyl hydroxylase

Rat embryo-fetal NOAEL 7 mg/kg/day = 3x MRHD (body surface area); no repeat-dose margin stated

Jideytro

zidesamtinib · ROS1

Rat lymphoid depletion at exposures comparable to human AUC (males) and ~1.7x (females); no NOAEL multiple stated

Joenja

leniolisib · PI3Kδ

NOAEL margins 0.8x (rat, 15 mg/kg/day) and 1.0x (monkey, 20 mg/kg/day)

Journavx

suzetrigine · NaV1.8

91-day rat female NOAEL 1.3x and 13-week monkey NOAEL 2.1x human AUC

Kerendia

finerenone · Mineralocorticoid receptor

Dog chronic study male NOAEL 0.5 mg/kg: 3x human total AUC (2x unbound)

Klisyri

tirbanibulin · Tubulin / Src

5-day topical minipig NOAEL (highest dose tested): 9x (females) and 20x (males) clinical AUC

Komzifti

ziftomenib · Menin-KMT2A

No margin: EFD skeletal malformations at all doses, lowest ~0.3x human AUC at 600 mg QD

Koselugo

selumetinib · MEK1/2

3-month rat NOAEL (males, 2.5 mg/kg/day) 15x clinical total AUC; no NOAEL in 26-week mouse

Krazati

adagrasib · KRAS G12C

Rat and dog 28-day/13-week exposure margins 0.3 to 2.4; NOAEL exposures similar to or below MRHD exposure

Kygevvi

doxecitine and doxribtimine · Pyrimidine nucleoside replacement (TK2 deficiency)

NOAELs in 26-week rat and 13-week dog studies at least 25-fold human baseline-adjusted AUC

Lampit

nifurtimox · Trypanosoma cruzi

Low: rat and dog NOAEL HEDs 0.2-1.7x the 10-20 mg/kg/day clinical dose (body surface area)

Lazcluze

lazertinib · EGFR (mutant-selective)

Low: NOAEL/LOAEL exposures at or below clinical exposure at the recommended dose

Leqselvi

deuruxolitinib · JAK1/JAK2

NOAEL ~0.8x (26-week rat) and ~1.4x (52-week dog) human AUC at MRHD

Lifyorli

relacorilant · Glucocorticoid receptor (antagonist)

No repeat-dose margin stated; rabbit EFD skeletal variations at ≥1 mg/kg/day, below human AUC

Litfulo

ritlecitinib · JAK3/TEC kinases

Dog study 20099163 at 10 mg/kg/day: 7.4-fold human AUC (6.0-fold Cmax); axonal dystrophy still seen at this dose

Livdelzi

seladelpar · PPARδ

NOAEL AUC margins ~2x (male) / 11x (female) in 52-week monkey; ~5x / 13x in 26-week rat

Livmarli

maralixibat · IBAT (ASBT)

1-year dog NOAEL 5 mg/kg/day: 96- to 358-fold human AUC

Livtencity

maribavir · CMV UL97 protein kinase

26-week rat NOAEL 25 mg/kg/day: ~0.1x total (0.5x unbound) human AUC; no NOAEL in 52-week monkey

Lumakras

sotorasib · KRAS G12C

Clinical exposures exceed those at the dog HNSTD (1000 mg/kg/day) but are below the rat STD10 (180 mg/kg)

Lupkynis

voclosporin · Calcineurin

NOAEL exposure margins lower than the optimal 10x; toxicology similar to cyclosporine

Lybalvi

olanzapine and samidorphan · D2/5-HT2A; opioid receptors (samidorphan)

Rat samidorphan NOAEL 5 mg/kg/day: 0.4x (males) and 5x (females) MRHD AUC

Lynavoy

linerixibat · IBAT

Rat and dog NOAEL AUC 140- to 145-fold above exposure in moderate hepatic impairment at 40 mg

Lynkuet

elinzanetant · NK1/NK3 receptors

39-week monkey NOAEL: 0.35x (females, 30 mg/kg/day) and 1x (males, 80 mg/kg/day) MRHD AUC

Lytgobi

futibatinib · FGFR1-4 (covalent)

No NOAEL; rat STD10 (10 mg/kg QOD) exposure approximately equals clinical exposure, no margin

Mayzent

siponimod · S1P1/S1P5 receptor

52-week monkey NOAEL (low dose) AUC >50-fold human exposure at recommended daily dose

Miebo

perfluorohexyloctane · Tear film evaporation barrier

26-week rabbit ocular study: ocular NOAEL 3.6X ocular MRHD; systemic NOAEL 39X MRHD (dose-based)

Miplyffa

arimoclomol · Heat-shock response amplifier

Rat NOAEL 200 mg/kg/day ~2-fold, dog NOAEL 160 mg/kg/day ~10-fold the 600 mg/day clinical dose

Modeyso

dordaviprone · DRD2 antagonist / ClpP agonist

Rat NOAEL AUC 75% of clinical AUC (dog LOAEL 70%)

Myqorzo

aficamten · Cardiac myosin

No margin: no adverse effects at clinical free AUC exposure; no adverse findings in dogs only at exposures below clinical total AUC

Nereus

tradipitant · NK1 receptor

Han Wistar rat repeat-dose study (liver necrosis): male NOAEL 15 mg/kg/day below maximum clinical dose (HED); female NOAEL 8.5-fold

Nexletol

bempedoic acid · ATP citrate lyase

52-week monkey NOAEL 13x human AUC at 180 mg; 26-week rat NOAEL <1x

Nextstellis

drospirenone and estetrol · Estrogen / progestin receptors

Estetrol NOAEL 3.3x (chronic rat) and 2.1x (chronic monkey) the MRHD by AUC

Nourianz

istradefylline · Adenosine A2A receptor

Rat embryo-fetal NOAEL (200 mg/kg/day) ~4x human AUC at MRHD 40 mg; no repeat-dose margin stated

Nubeqa

darolutamide · Androgen receptor

No NOAEL margin stated; male reproductive toxicity at 0.6x (rat) and 1x (dog) human AUC

Nulibry

fosdenopterin · cPMP replacement (MoCD type A)

No adverse effects up to 17.8x (juvenile rat) and 6.2x (juvenile dog) the MRHD, HED basis

Nurtec ODT

rimegepant · CGRP receptor

Monkey: ≥16x (males) and ≥24x (females) human AUC at clinical dose

Nuzolvence

zoliflodacin · Bacterial topoisomerase II

4-week oral rat NOAEL 200 mg/kg/day ~3x MRHD AUC

Ogsiveo

nirogacestat · Gamma secretase

No margin: NOAEL/LOAEL exposures in 1- and 3-month studies below human exposure at 150 mg BID

Ohtuvayre

ensifentrine · PDE3/PDE4

Dog NOAEL provided adequate margins (no multiple stated in text)

Ojemda

tovorafenib · RAF (type II pan-RAF)

No margin: NOAEL exposure 0.39x (rat) and 0.41x (monkey) adult clinical exposure

Ojjaara

momelotinib · JAK1/JAK2/ACVR1

39-week dog NOAEL 20 mg/kg/day <0.6x MRHD (combined momelotinib + M21 AUC)

Olinvyk

oliceridine · μ-opioid receptor (G-protein biased)

Rat and rabbit EFD: no effect at 7x and 8x MRHD AUC (no repeat-dose NOAEL margin stated)

Omlonti

omidenepag isopropyl · EP2 receptor

No NOAEL in monkey topical ocular studies; LOAEL 0.9 µg/eye/day (nasal cavity findings)

Ongentys

opicapone · COMT

6-month rat NOAEL ≥21x human AUC at MRHD; 28-day studies ≥7x

Orgovyx

relugolix · GnRH receptor

39-week monkey NOAEL (liver toxicity) 15 mg/kg ~9.3x human exposure

Orladeyo

berotralstat · Plasma kallikrein

Monkey chronic NOAEL (30 mg/kg/day) ~1.5x human AUC at 150 mg QD

Orlynvah

sulopenem etzadroxil and probenecid · Penicillin-binding proteins

No repeat-dose NOAEL multiple stated; rabbit EFD maternal toxicity and reduced fetal weights at ~0.1 and 0.2x clinical exposure

Orserdu

elacestrant · Estrogen receptor (SERD)

No repeat-dose NOAEL established; rat EFD maternal toxicity and embryo-fetal mortality at ~0.1x human AUC

Orzeyful

oveporexton · Orexin OX2 receptor agonist

Rat 26-week NOAEL ~311x (males) and 455x (females) human AUC at MRHD

Oxbryta

voxelotor · HbS polymerisation

No margin: adverse effects in animals at exposures comparable to or below anticipated clinical exposure

Palsonify

paltusotine · Somatostatin receptor 2

Dog 39-week NOAEL (10 mg/kg/day) ~3x human AUC at 60 mg/day

Paxlovid

nirmatrelvir and ritonavir · SARS-CoV-2 Mpro (3CL protease)

NOAEL ~8.0x (rat) and ~14x (monkey) predicted human AUC24 at 300/100 mg BID

Pemazyre

pemigatinib · FGFR1-3

No safety margin for soft tissue mineralisation and ocular findings in rats and monkeys

Piqray

alpelisib · PI3Kα

No margin: repeat-dose effects occurred below human exposure at the maximum recommended dose

Pizensy

lactitol · Osmotic laxative

Mouse and rat NOAEL 0.7- to 1.5-fold human AUC (fasted), 1.8- to 3.7-fold (fed)

Ponvory

ponesimod · S1P1 receptor

Lung toxicity NOAEL margins: rat 0.7-fold, dog 4.4-fold, mouse 12-/2.4-fold (M/F), based on plasma exposure

Pretomanid

pretomanid · Mycobacterial cell wall / respiration

26-week rat: NOAEL exposure below predicted human exposure (testicular toxicity)

Pyrukynd

mitapivat · Pyruvate kinase (activator)

Chronic monkey NOAEL 1.2x (males) and 2.2x (females) MRHD AUC

Qelbree

viloxazine · Norepinephrine reuptake

No safety margin between NOAEL exposures for seizures in animals and clinical blood levels

Qinlock

ripretinib · KIT/PDGFRA

Rat and dog NOAEL exposures below patient exposure (margins below 1)

Qulipta

atogepant · CGRP receptor

9-month monkey NOAEL (300 mg/kg) 10-fold human AUC at MRHD

Quviviq

daridorexant · Orexin OX1/OX2 receptors

39-week dog NOAEL ~1.5x human exposure at MRHD 50 mg (Cmax and AUC)

Rapiblyk

landiolol · β1-adrenergic receptor

4-week dog continuous infusion NOAEL (1 mg/kg/min) ~136-fold human AUC at MRHD

Rasonque

daraxonrasib · RAS(ON) multi-selective

13-week mouse and monkey studies: margin ~1x human AUC at recommended dose

Recarbrio

imipenem, cilastatin and relebactam · Beta-lactamase (relebactam)

Rat NOAEL ~2x expected clinical relebactam exposure

Relyvrio

sodium phenylbutyrate and taurursodiol · ER stress / mitochondrial (proposed)

No margin: highest pivotal doses gave Cmax and AUC below human clinical exposure

Retevmo

selpercatinib · RET

91-day minipig HNSTD/NOAEL 5 mg/kg/day: ~0.2–0.3x human AUC

Revtorpyk

gedatolisib · PI3K/mTOR

No margin: reproductive organ findings in rats and dogs at exposures ≤0.2x human AUC

Revuforj

revumenib · Menin-KMT2A

13-week dog HNSTD ~3.1x human AUC

Reyvow

lasmiditan · 5-HT1F receptor

39-week dog NOAEL (30 mg/kg/day) ~7x human AUC at MRHD

Rezdiffra

resmetirom · Thyroid hormone receptor β

Dog NOAEL (45 mg/kg/day) ~7-fold human AUC at MRHD

Rezlidhia

olutasidenib · IDH1 (mutant)

Toxicology-study AUC margins 1- to 12-fold vs pivotal clinical study (unbound drug)

Rezurock

belumosudil · ROCK2

Dog 9-month NOAEL margins 0.2-0.4x clinical exposure (rabbit EFD NOAEL 0.08x)

Rezzayo

rezafungin · Fungal glucan synthase

26-week NOAELs: rat (45 mg/kg) ~4-fold and monkey (30 mg/kg) ~6-fold human AUC

Rhapsido

remibrutinib · BTK

Repeat-dose toxicity (26-week rat, 39-week dog) exposure multiples 15- to 146-fold human steady-state AUC

Rinvoq

upadacitinib · JAK1

Chronic dog NOAEL exposure ~2x the clinical dose (rat ~13x)

Romvimza

vimseltinib · CSF1R

No exposure margin at the 13-week dog NOAEL; rat NOAEL margin around 4

Rozlytrek

entrectinib · TRK/ROS1/ALK

No margin: CNS toxicity at ≥0.2x human Cmax and skin/RBC effects at ≥0.1x human AUC

Rukobia

fostemsavir · HIV-1 gp120 (attachment)

9-month dog NOAEL (liver findings) 10 mg/kg/day, ~2.6x human AUC

Scemblix

asciminib · BCR-ABL1 (STAMP, myristoyl pocket)

No rat NOAEL: hepatocellular necrosis at lowest dose (15 mg/kg/day), exposure equivalent to or below 80 mg QD

Sephience

sepiapterin · Tetrahydrobiopterin precursor

26-week rat NOAEL 30 mg/kg/day, 1.5-fold human exposure at MRHD (kidney findings above)

Simtriyo

centanafadine · Triple monoamine reuptake

26-week rat NOAEL: male AUC ~0.1x, female ~0.8x human AUC at MRHD

Skyclarys

omaveloxolone · Nrf2 activator

Rabbit EFD (no repeat-dose margin stated): maternal NOAEL 0.3x, developmental NOAEL 0.7x clinical exposure

Sofdra

sofpironium · Muscarinic receptors (topical)

Adequate systemic safety margins at pivotal NOAELs; dermal NOAEL generally 20% gel vs 15% clinical

Sohonos

palovarotene · RARγ

No safety margin: NOAELs <0.03 mg/kg/day (26-week rat) and <12 mg/kg/day (39-week dog) due to exaggerated pharmacology

Sotyktu

deucravacitinib · TYK2

NOAEL 5 mg/kg/day ~9x RHD AUC

Sunlenca

lenacapavir · HIV-1 capsid

NOAEL 6- to 8-fold human exposure at RHD in 6-month rat (32-fold in 2-month rat)

Sunosi

solriamfetol · Dopamine/norepinephrine reuptake

NOAEL margins ~1x MRHD in dog and <1x in mouse and rat (AUC)

Tabrecta

capmatinib · MET

Small margins: NOAEL AUC in nonclinical species within the same range as human exposure

Tavneos

avacopan · C5a receptor (C5aR1)

Pivotal toxicology AUC margins ~4x (hamster, monkey) and ~15x (rat) human AUC at 30 mg b.i.d.

Tazverik

tazemetostat · EZH2

No NOAEL margin; juvenile rat deaths at 50 mg/kg, approximately equal to adult human exposure at 800 mg BID

Tepmetko

tepotinib · MET

No margin: NOAEL AUC ~4% of human exposure at 500 mg in rats and dogs

Trikafta

elexacaftor, tezacaftor and ivacaftor · CFTR

Elexacaftor 26-week rat NOAEL 15 mg/kg/day: 4x (males) to 12x (females) human AUC

Truqap

capivasertib · AKT1-3

No margin: toxicities at ≥30 mg/kg in rats and ≥10 mg/kg in dogs, ~0.4x and 0.6x human AUC at 400 mg BID

Truseltiq

infigratinib · FGFR1-3

Margins <1 at all doses in rat and dog toxicity studies vs human exposure at 125 mg QD

Tryptyr

acoltremon · TRPM8 agonist

Rabbit and dog ocular NOAELs: ~3x RHOD ocular; 29x and 9x systemic (mg/m2)

Tryvio

aprocitentan · Endothelin A/B receptors

Rat and dog NOAELs ~14x and 11x human AUC at the MRHD

Tukysa

tucatinib · HER2

Rat and monkey liver and GI toxicity at safety margins below 1 (clinically relevant doses)

Turalio

pexidartinib · CSF1R

Rat liver toxicity at ≥20 mg/kg (~0.6x clinical exposure at 800 mg)

Ubrelvy

ubrogepant · CGRP receptor

No adverse findings at highest doses: 34x (6-month rat) and 78x (9-month monkey) human AUC at MRHD 200 mg/day

Ukoniq

umbralisib · PI3Kδ / CK1ε

No NOAEL margin stated; dog testicular toxicity at ≥100 mg/kg, about 0.1x human AUC at 800 mg

Utebzi

tebipenem pivoxil · Penicillin-binding proteins

Monkey 28-day GLP NOAEL 300 mg/kg/day ~1.5x MRHD exposure (13-week monkey NOAEL 0.9x)

Vafseo

vadadustat · HIF prolyl hydroxylase

No margin: NOAEL exposures in all species below human exposure at 600 mg QD

Vanflyta

quizartinib · FLT3

13-week NOAELs for haematopoietic inhibition: monkey MOE 0.07-0.10, dog 0.41-0.54, rat 1.42-1.51

Vanrafia

atrasentan · Endothelin A receptor

No NOAEL established in chronic rat or dog studies

Veklury

remdesivir · SARS-CoV-2 RNA polymerase

Rat 4-week NOAEL 0.1–0.2x human AUC (GS-441524); below clinical exposure

Velsipity

etrasimod · S1P1/S1P4/S1P5 receptors

No adverse effects in rats and dogs up to 738x and 446x human AUC at MRHD

Veozah

fezolinetant · Neurokinin-3 receptor

26-week rat and 39-week monkey NOAELs ~148x and 43x human AUC at MRHD

Veppanu

vepdegestrant · Estrogen receptor (PROTAC degrader)

Repeat-dose: female reproductive organ toxicity at ≥30 mg/kg/day, 0.3x human AUC (below clinical exposure)

Verquvo

vericiguat · Soluble guanylate cyclase

9-month dog NOAEL 5 mg/kg: 2.4x human AUC at MRHD

Vivjoa

oteseconazole · Fungal CYP51

Rat 26-week NOAEL 0.5 mg/kg: ~0.2x human AUC at MRHD

Vizz

aceclidine · Muscarinic agonist (miotic)

Rat/rabbit EFD at 1.5 mg/kg/day (no maternal or fetal toxicity): ~110x and 70x human 3-quinuclidinol exposure

Vonjo

pacritinib · JAK2/FLT3

NOAEL below clinical exposure: 6-month mouse 0.02x, 9-month dog 0.02–0.06x human AUC

Voquezna

vonoprazan · H+/K+-ATPase (potassium-competitive)

Rat EFD NOAEL 100 mg/kg: ~27x clinical exposure

Voranigo

vorasidenib · IDH1/IDH2

Monkey 13-week NOAEL 2 mg/kg/day; safety margin around 2

Voydeya

danicopan · Complement factor D

Dog 39-week NOAEL: 5x the AUC at the MRHD (200 mg TID)

Vtama

tapinarof · Aryl hydrocarbon receptor

General toxicity NOAELs: modest (dermal) to large (subcutaneous) margins over topical human exposure

Vyndaqel

tafamidis · Transthyretin (stabiliser)

Dog 39-week no-effect level: at least 9-fold (females) and 11-fold (males) human steady-state AUC

Wakix

pitolisant · Histamine H3 receptor

Monkey NOAEL 12 mg/kg/day: 0.4x human AUC (rat 30 mg/kg/day 1x; mouse 75 mg/kg/day 9x)

Wayrilz

rilzabrutinib · BTK (reversible covalent)

Chronic rat NOAEL (50 mg/kg/day) exposure approximated clinical AUC at MRHD 400 mg BID

Welireg

belzutifan · HIF-2α

Dog 30 mg/kg/day (no testicular findings) ~1-fold human AUC; rat testis degeneration at 0.13-fold

Winlevi

clascoterone · Androgen receptor (topical)

NOAEL margin 4.6x (26-week SC rat) and 7x (39-week dermal minipig) vs clinical systemic exposure

Xacduro

sulbactam and durlobactam · PBPs; beta-lactamase (durlobactam)

Durlobactam rat male fertility study: NOAEL 1000 mg/kg/day ~3x clinical AUC

Xcopri

cenobamate · Sodium channel / GABA-A

Acute neurotoxicity dose-limiting in all species, with minimal to no safety margins to clinical exposure

Xdemvy

lotilaner · Mite GABA-Cl channel

Rabbit and dog ocular NOAEL ~2.66x clinical dose (direct dose comparison)

Xeglyze

abametapir · Lice metalloproteinases

Rabbit EFD NOAEL (40 mg/kg/day) ~1x MRHD (Cmax)

Xenleta

lefamulin · Bacterial ribosome (50S PTC)

Monkey IV NOAEL (120 mg/kg/day) 2.8x (IV) and 2.4x (oral) human AUC

Xocova

ensitrelvir · SARS-CoV-2 3CL protease

Monkey NOAEL 10 mg/kg/day: 3x (shorter study) and 4x (4-week study) human exposure

Xolremdi

mavorixafor · CXCR4

39-week dog female NOAEL 3.8 mg/kg/day ~0.3x MRHD exposure; no NOAEL in males

Xpovio

selinexor · XPO1

No margin: monkey 13-week NOAEL exposure below human exposure at 80 mg

Zavzpret

zavegepant · CGRP receptor

Monkey 39-week intranasal, highest dose: ~8-fold (systemic) and ~12-fold (local) vs human at MRHD

Zaynich

cefepime and zidebactam · PBPs; beta-lactam enhancer (zidebactam)

Dog 13-week renal NOAEL (250 mg/kg/day zidebactam): 1.1-1.3x human AUC

Zegfrovy

sunvozertinib · EGFR exon 20 insertion

No NOAEL margin stated; rat ocular toxicity at 35 mg/kg, ~0.8x clinical AUC at 200 mg

Zenbexus

iberdomide · Cereblon (CELMoD)

9-month monkey NOAEL 0.12 mg/kg/day: 0.95-fold human steady-state AUC at 1 mg QD

Zeposia

ozanimod · S1P1/S1P5 receptor

Chronic NOAEL: rat ozanimod 10.4x, total active drug 0.62x; monkey ozanimod 3.73x, total active drug 0.515x human AUC

Zepzelca

lurbinectedin · DNA minor groove (transcription)

No margin: highest doses in rat and monkey 8-cycle studies gave exposures ~8 times lower than human exposure at 3.2 mg/m2

Zevtera

ceftobiprole medocaril · Penicillin-binding proteins

13-week dog NOAEL 8 mg/kg/day, ~0.1-fold the maximum human dose

Zokinvy

lonafarnib · Farnesyltransferase

Chronic rat NOAEL 15 mg/kg/day: 0.06x (males) and 0.36x (females) human AUC at 150 mg/m2 BID

Ztalmy

ganaxolone · GABA-A receptor (positive modulator)

Exposure 6.01-7.85-fold clinical at highest tested dose (15 mg/kg/day) in 12-month dog study

Zulresso

brexanolone · GABA-A receptor (positive modulator)

Rat NOAEL 60 mg/kg/day ~5x human AUC at MRHD (90 µg/kg/h)

Zurzuvae

zuranolone · GABA-A receptor (positive modulator)

Rat NOAEL 3x (males) and 2x (females) MRHD exposure (50 mg)

Zycubo

copper histidinate · Copper replacement (Menkes disease)

No NOAEL: juvenile rat kidney, liver, spleen findings at 1 mg/kg/day, equivalent to human Cmax at recommended dose

Defencath

taurolidine and heparin · Antimicrobial catheter lock

Not stated in public reviews

Grafapex

treosulfan · DNA alkylation

Not stated in public reviews; no NOAEL in adult repeat-dose studies (adverse effects at lowest dose)

Summary across all 211 small molecules →