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Atlas/Small molecules/Ohtuvayre/Safety margin

Ohtuvayre: what safety margin did regulators accept?

ensifentrine · PDE3/PDE4
Check my plan vs. these
Safety margin at NOAEL
Dog NOAEL provided adequate margins (no multiple stated in text)
“While the no observed adverse effect level in dogs provided adequate nonclinical safety margins, cardiac and vascular disorders were evaluated as safety topics of interest.”
✓ VerifiedFDA integrated review, p. 68Source ↗
NOAEL / key findings
Rat: salivary gland acinar hypertrophy, testis atrophy, epididymal germ cell debris; dog: coronary artery vasculopathy
“Target organs of toxicity were identified as mandibular and parotid salivary glands (acinar cell hypertrophy), testis (tubular degeneration/atrophy), and epididymis (intraluminal germ cell debris) in rats, and heart (coronary artery vasculopathy) in dogs.”
✓ VerifiedFDA integrated review, p. 79Source ↗

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

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 →