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Atlas/Small molecules/Hernexeos/Safety margin

Hernexeos: what safety margin did regulators accept?

zongertinib · HER2 (mutant)
Check my plan vs. these
Safety margin at NOAEL
Dog NOAEL approximately at clinical AUC; rat NOAEL ~1.5 to 3-fold (applicant)
“When comparing animal exposure at the NOAELs with preliminary available clinical exposure (AUCꚍ,ss at the 120 mg dose), there are reasonable exposure multiples in rats (~ 1.5 to 3 fold) while there are low exposure multiples in dogs (approximately the clinical exposure).”
✓ VerifiedFDA multi-discipline review, p. 68Source ↗
NOAEL / key findings
Target organs in rats and/or dogs: GI tract, adrenal gland and oral mucosa
“The major target organs of zongertinib in rats and/or dogs included the gastrointestinal (GI) tract, adrenal gland, and oral mucosa.”
✓ VerifiedFDA multi-discipline review, p. 47Source ↗

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

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)

Inqovi

decitabine and cedazuridine · DNMT (decitabine); cytidine deaminase (cedazuridine)
Not stated in public reviews

Summary across all 211 small molecules →