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Precedia/Small molecules/Koselugo/Flexibility

Koselugo: what flexibility did regulators accept, and why?

selumetinib · MEK1/2
Check my plan vs. these
Flexibility accepted
SpeciesVerdict not stated
Mouse instead of rat as the rodent for long-term toxicology and developmental studies
Why: Mouse forms detectable levels of the active N-desmethyl metabolite, giving toxicological coverage · Pharmacology or kinetics
“The Applicant chose the mouse as the rodent species for the long-term toxicology and developmental studies due to detectable levels of the active N-desmethyl metabolite in this species that allowed for toxicological coverage; there were no unique human metabolites or other metabolites that needed toxicological coverage in animals.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗
DARTAcceptedBeyond the letter
Embryo-fetal development tested in mouse only (no second species)
Why: Embryolethality and teratogenicity already shown in mice · Other reason
“A second species was not used for investigating the potential effects on embryo-foetal development, which is acceptable in view of the toxicological findings reported in mice (embryolethality, teratogenicity).”
✓ VerifiedEMA assessment report, p. 44Source ↗
Juvenile toxAcceptedBeyond the letter
No dedicated juvenile toxicity studies for a paediatric indication
Why: Studies in sexually immature primates and younger mice cover children from 12 years onwards · Weight of evidence
“No specific juvenile toxicity studies have been conducted but studies performed in sexually immature primates and younger mice cover the age of children from 12 years onwards.”
✓ VerifiedEMA assessment report, p. 44Source ↗
“Therefore, concerning pharmacokinetics, exposure assessments at dose levels investigated in adults are considered to be sufficient to evaluate exposures expected in the younger population, e.g. from 3 years onwards.”
✓ VerifiedEMA assessment report, p. 44Source ↗
GenotoxicityAcceptedBeyond the letter
Positive mouse micronucleus test via an aneugenic mode of action accepted for long-term paediatric use
Why: Aneugenicity is a known MEK-inhibitor pharmacological effect; carcinogenicity studies showed no neoplastic changes · Class precedent · Weight of evidence
“Aneugenic effects of selumetinb are known as pharmacological action of MEK inhibitors. However, no neoplastic changes were observed in carcinogenicity studies supporting the long-term treatment of children with selumetinib.”
✓ VerifiedEMA assessment report, p. 44Source ↗
Safety marginVerdict not stated
No NOAEL or safety margin for irreversible corneal mineralisation in the 1-month mouse study
“In 1-month study in mice, ophthalmology findings (oval opacities across the cornea, rough appearance to the surface of the cornea) were observed at all doses and histopathologic exam revealed a dose-dependent mineralisation of the cornea which is not reversible after cessation of treatment. No NOAEL and no safety margin could be determined.”
✓ VerifiedEMA assessment report, p. 43Source ↗

Same question, other small molecules

Accrufer

ferric maltol · Iron replacement
No carcinogenicity studies with ferric maltol; rodent carcinogenicity data on maltol relied on

Adquey

difamilast · PDE4 (topical)
39-week dermal minipig NOAEL at the maximum feasible dose gave only 0.38x (males) and 0.30x (females) MRHD by AUC

Agamree

vamorolone · Glucocorticoid receptor (dissociative)
No carcinogenicity studies before approval; mouse and rat studies deferred to postmarketing requirements

Alyftrek

vanzacaftor, tezacaftor and deutivacaftor · CFTR
Vanzacaftor 2-year rat carcinogenicity study not completed before approval; deferred to postmarketing

Anzupgo

delgocitinib · Pan-JAK (topical)
No toxicokinetics in safety pharmacology studies; margins derived from repeat-dose study exposures

Aqneursa

levacetylleucine · Neuronal metabolism (proposed)
No carcinogenicity studies before approval; 26-week rasH2 mouse and 2-year rat required postmarketing

Artesunate

artesunate · Plasmodium (antimalarial)
No adequate in vivo genotoxicity characterisation of IV artesunate at approval; GLP in vivo micronucleus test deferred

Attruby

acoramidis · Transthyretin (stabiliser)
No exposure margin at the NOEL for learning deficits in rat offspring of the pre- and postnatal development study

Augtyro

repotrectinib · ROS1/TRK
Only a non-GLP dose-range-finding rat EFD study; no definitive EFD study

Avmapki Fakzynja Co-pack

avutometinib and defactinib · RAF/MEK clamp; FAK
No embryo-fetal development study for avutometinib or defactinib; weight-of-evidence assessment instead

Ayvakit

avapritinib · KIT/PDGFRA
No dedicated fertility or pre- and postnatal development studies

Azstarys

serdexmethylphenidate and dexmethylphenidate · Dopamine/norepinephrine reuptake
Abbreviated program for an NME: 28-day repeat-dose studies in rat and dog only; no chronic adult toxicity studies

Balversa

erdafitinib · FGFR1-4
No exposure margin: animal-to-human exposure ratios below one at the highest doses in 3-month rat and dog studies

Barhemsys

amisulpride · Dopamine D2/D3 receptor
Repeat-dose toxicity limited to a single 28-day IV study in one species (rat)

Baxfendy

baxdrostat · Aldosterone synthase (CYP11B2)
Rat and transgenic mouse carcinogenicity studies likely did not achieve aldosterone synthase inhibition; treated as off-target assessment only

Blujepa

gepotidacin · Bacterial topoisomerases (gyrase/topo IV)
Positive in vitro micronucleus and mouse lymphoma assays; negative in vivo rat micronucleus and comet assays

Brexafemme

ibrexafungerp · Fungal glucan synthase
No carcinogenicity studies

Brinsupri

brensocatib · DPP1 (cathepsin C)
No juvenile animal studies; adolescent rat and dog repeat-dose studies used to support patients aged 12 years and older

Brukinsa

zanubrutinib · BTK
No carcinogenicity studies; absence justified by weight of evidence

Byfavo

remimazolam · GABA-A receptor (benzodiazepine site)
Rat fertility, EFD and PPND studies used short boluses giving exposures below human; DART battery incomplete

Bylvay

odevixibat · IBAT
Rabbit fetal cardiovascular malformations at all doses; low exposure multiple (about 2.1 times human AUC), no developmental NOAEL

Cabenuva

cabotegravir and rilpivirine · HIV-1 integrase; NNRTI
Pivotal cabotegravir toxicity studies used the oral route; IM/SC route covered only by a 3-month rat bridging study

Camzyos

mavacamten · Cardiac myosin
2-year rat carcinogenicity study still ongoing at approval; to be completed post-approval (rasH2 mouse study completed)

Caplyta

lumateperone · 5-HT2A / D2 receptor
Rat and dog used although neither matches human metabolism; dog and rat form aniline metabolites not quantifiable in humans

Cardamyst

etripamil · L-type calcium channel
No rodent carcinogenicity studies for a chronically used intranasal drug

Cibinqo

abrocitinib · JAK1
Cynomolgus monkey used as non-rodent species without initial cross-reactivity data; CHMP questioned its pharmacological relevance

Cobenfy

xanomeline and trospium · Muscarinic M1/M4 agonist; peripheral antagonist
No new nonclinical program for trospium; relies on prior FDA finding of safety for the approved trospium product

Cosela

trilaciclib · CDK4/6
No fertility, embryo-fetal or pre/postnatal development studies despite ovary and estrus-cycle findings in rats

Crenessity

crinecerfont · CRF1 receptor
Exposure multiples at the NOAELs in pivotal studies limited to one- to fourfold the MRHD because of exposure saturation

Cypsedo

cipepofol · GABA-A receptor
Juvenile rat toxicity and neonatal neurotoxicity studies deferred to postmarketing requirements

Daybue

trofinetide · IGF-1 tripeptide analogue
No carcinogenicity studies before approval; two-species carcinogenicity deferred to a postmarketing requirement

Defencath

taurolidine and heparin · Antimicrobial catheter lock
No adequate general toxicology study: rat study with diluted product did not reach doses that explore taurolidine toxicity

Dojolvi

triheptanoin · Anaplerotic energy substrate
No nonclinical toxicology studies submitted to the IND; only published pharmacology studies

Duvyzat

givinostat · Histone deacetylase (class I/II)
Mouse and two-year rat carcinogenicity studies deferred to after approval as postmarketing requirements

Egaten

triclabendazole · Fasciola (tubulin)
Nonclinical package consists of older studies conducted to support the veterinary product

Ekterly

sebetralstat · Plasma kallikrein
2-year rat carcinogenicity study still ongoing at approval; completion issued as a postmarketing requirement

Ensacove

ensartinib · ALK
No exposure margin for dog skin toxicity: severe skin lesions at exposures approximately equal to clinical AUC at 225 mg/day

Evrysdi

risdiplam · SMN2 splicing
Only a rasH2 mouse study before approval; 2-year rat carcinogenicity study deferred to a post-approval commitment

Exblifep

cefepime and enmetazobactam · PBPs; beta-lactamase (enmetazobactam)
No exposure margin for enmetazobactam liver effects; combination-study NOAELs below MRHD exposure in dogs and rats

Exkivity

mobocertinib · EGFR exon 20 insertion
Embryo-fetal development assessed only in a preliminary rat study; no definitive study and no second species

Exxua

gepirone · 5-HT1A receptor
In vitro chromosome aberration assay inadequate: 5-hour treatment only, no ~24-hour continuous treatment without activation

Fabhalta

iptacopan · Complement factor B
Male dog NOAEL in the 9-month study at 0.5 times human AUC at the MRHD

Fetroja

cefiderocol · Penicillin-binding proteins
Cynomolgus monkey used as non-rodent species for general toxicology without species justification

Fexinidazole

fexinidazole · Trypanosoma brucei
Positive Ames assay, including nitroreductase-deficient strains; applicant argued no human relevance

Filspari

sparsentan · Endothelin A / angiotensin II receptors
No exposure margin at the 9-month monkey NOAEL: 0.2 (males) and 0.1 (females) times human AUC at 800 mg

Fotivda

tivozanib · VEGFR1-3
Exposure at the 9-month monkey NOAEL about 0.5-fold that of RCC patients (no margin)

Foundayo

orforglipron · GLP-1 receptor (non-peptide)
Lifetime rat and rasH2 mouse studies in pharmacologically inactive species; on-target thyroid C-cell tumor risk not assessable

Fruzaqla

fruquintinib · VEGFR1-3
Most single- and repeat-dose studies non-GLP; only two 13-week GLP bridging studies (rat, dog) considered pivotal

Gavreto

pralsetinib · RET
Embryo-fetal toxicity in rat only; no second-species EFD, pre/postnatal, juvenile or immunotoxicity studies

Gomekli

mirdametinib · MEK1/2
2-year rat carcinogenicity study ongoing at approval; final report required postmarketing (rasH2 mouse study completed)

Grafapex

treosulfan · DNA alkylation
No dedicated reproductive and developmental toxicity studies

Hernexeos

zongertinib · HER2 (mutant)
No dedicated fertility and early embryonic development studies; fertility assessed from repeat-dose reproductive organ histopathology

Hyrnuo

sevabertinib · HER2 (mutant)
Embryo-fetal development assessed in rat only; rabbit not usable as no relevant exposure achieved

Ibsrela

tenapanor · NHE3
Juvenile rat NOAEL gives no safety margin for patients under 12; additional juvenile study (from postnatal day 21) deferred to postmarketing

Ibtrozi

taletrectinib · ROS1
No pre- and postnatal development study despite concern for neurodevelopmental effects of Trk inhibition

Idvynso

doravirine and islatravir · NNRTI; NRTTI
Islatravir positive for chromosomal aberrations in vitro (CHO cells); accepted on mechanism and negative Ames and in vivo micronucleus

Inluriyo

imlunestrant · Estrogen receptor (SERD)
No fertility/early embryonic, pre- and postnatal development or juvenile toxicity studies

Inpefa

sotagliflozin · SGLT1/SGLT2
Major human metabolite sotagliflozin-3-O-glucuronide not qualified in animal studies (formed at much lower levels in rodents, absent in dog)

Inqovi

decitabine and cedazuridine · DNMT (decitabine); cytidine deaminase (cedazuridine)
Combination toxicology limited to one non-GLP 4-week (one-cycle) monkey study using separate capsules, not the fixed-dose tablet

Inrebic

fedratinib · JAK2
No long-term rodent carcinogenicity study; sponsor ICH S9 rationale rejected, waiver granted on low rodent exposure

Iqirvo

elafibranor · PPARα/δ
Most repeat-dose exposure margins for elafibranor below one (CHMP recalculation); findings considered likely clinically relevant

Isturisa

osilodrostat · 11β-hydroxylase (CYP11B1)
No toxicokinetics of major human metabolite M34.5 in pivotal rat studies; exposure only extrapolated from single-dose ADME data

Itovebi

inavolisib · PI3Kα (mutant-selective)
No exposure margins: NOAEL AUC margins in 4- and 13-week rat and dog studies and rat embryo-fetal study generally below 1

Jascayd

nerandomilast · PDE4B
In vitro hERG assay not conducted under GLP and had several deficiencies

Jaypirca

pirtobrutinib · BTK (non-covalent)
Aneugenic in in vitro human lymphocyte micronucleus assays; in vivo rat micronucleus negative

Jesduvroq

daprodustat · HIF prolyl hydroxylase
Major human metabolites M2, M3 and M13 not formed in rodents; given SC as a metabolite cocktail in mouse carcinogenicity and rat pre/postnatal studies

Jideytro

zidesamtinib · ROS1
No fertility or pre- and postnatal development studies, so neurodevelopmental effects of TRK inhibition were not assessed

Joenja

leniolisib · PI3Kδ
Carcinogenicity studies (6-month Tg-rasH2 mouse, 2-year rat) ongoing at approval; final reports deferred to postmarketing

Journavx

suzetrigine · NaV1.8
No in vitro chromosomal aberration test with the major human metabolite M6-SUZ; clastogenicity covered by parent in vivo micronucleus assay

Kerendia

finerenone · Mineralocorticoid receptor
No finerenone MR binding data in mouse or rabbit (carcinogenicity and EFD species); relevance argued by receptor homology

Klisyri

tirbanibulin · Tubulin / Src
Positive genotoxicity (clastogenic in vitro and in vivo, weakly mutagenic in mouse lymphoma) accepted for a topical product

Komzifti

ziftomenib · Menin-KMT2A
Mouse embryo-fetal skeletal malformations at all doses; lowest dose about 0.3 times human AUC

Krazati

adagrasib · KRAS G12C
Low exposure margins (0.3 to 2.4) in 28-day and 13-week rat and dog studies; NOAEL exposures similar to or below human exposure

Kygevvi

doxecitine and doxribtimine · Pyrimidine nucleoside replacement (TK2 deficiency)
No 2-year rat carcinogenicity study; weight-of-evidence assessment instead, with 26-week Tg-rasH2 mouse study postapproval

Lampit

nifurtimox · Trypanosoma cruzi
Most nonclinical studies, including all repeat-dose toxicity studies, decades old, non-GLP and reported in literature publications

Lazcluze

lazertinib · EGFR (mutant-selective)
Low exposure margins: NOAEL or LOAEL exposures at or below clinical exposure at the recommended dose

Leqselvi

deuruxolitinib · JAK1/JAK2
Juvenile rat toxicity study deferred to a postmarketing requirement

Lifyorli

relacorilant · Glucocorticoid receptor (antagonist)
Predominant human metabolite CORT125295 absent in rodents; qualified by weight-of-evidence assessment instead of dedicated toxicity studies

Litfulo

ritlecitinib · JAK3/TEC kinases
Dog axonal dystrophy margin only 6.0-fold (Cmax) and 7.4-fold (AUC); lowest affected dog dose 10 mg/kg/day

Livdelzi

seladelpar · PPARδ
Cardiovascular/respiratory safety pharmacology in dogs without data showing dog relevance; female dog and guinea pig studies non-GLP

Livmarli

maralixibat · IBAT (ASBT)
Only the Tg.RasH2 mouse study completed before approval; 2-year rat carcinogenicity study in progress and made a postmarketing requirement

Livtencity

maribavir · CMV UL97 protein kinase
In vivo safety pharmacology studies not GLP-compliant (conducted before ICH S7A)

Lumakras

sotorasib · KRAS G12C
Exposure to major human metabolite M10 not measured in any GLP toxicology study; extrapolated from rat mass balance data

Lupkynis

voclosporin · Calcineurin
Most toxicology studies used a cis/trans isomer mixture (mix-ISA247) rather than the clinical product, with a limited bridging programme

Lybalvi

olanzapine and samidorphan · D2/5-HT2A; opioid receptors (samidorphan)
No new olanzapine nonclinical studies; olanzapine pharmacology, genotoxicity, carcinogenicity and DART data taken from the approved Zyprexa label

Lynavoy

linerixibat · IBAT
No PBC or cholestatic pruritus model; bile acid excretion in healthy mice and dogs and a rat NEC model instead

Lynkuet

elinzanetant · NK1/NK3 receptors
No margin at 39-week monkey NOAEL: females below 1x and males 1x MRHD AUC

Lytgobi

futibatinib · FGFR1-4 (covalent)
No exposure margin: rat severely toxic dose (cardiac mineralisation) exposure approximately equals clinical exposure

Mayzent

siponimod · S1P1/S1P5 receptor
Human metabolites M3 and M17 not measured in pivotal repeat-dose studies; exposure inferred from non-GLP metabolite-to-parent ratios with unvalidated assays

Miebo

perfluorohexyloctane · Tear film evaporation barrier
Safety pharmacology limited to a CNS Irwin test within a short oral rat study; no other endpoints assessed

Miplyffa

arimoclomol · Heat-shock response amplifier
Nonclinical efficacy and mechanism data for arimoclomol alone in patient-derived cells and NPC animal models judged unconvincing

Modeyso

dordaviprone · DRD2 antagonist / ClpP agonist
Embryo-fetal development assessed only in non-GLP dose-range-finding studies in rats and rabbits; no definitive GLP studies

Myqorzo

aficamten · Cardiac myosin
Chronic rat and dog exposure margins below ICH M3(R2) expectations because exaggerated pharmacology limited dosing

Nereus

tradipitant · NK1 receptor
No ≥6-month nonrodent toxicity study for unrestricted, repeated intermittent lifetime use; dog studies subchronic only

Nexletol

bempedoic acid · ATP citrate lyase
26-week rat NOAEL below clinical exposure (<1x AUC); 52-week monkey NOAEL 13x

Nextstellis

drospirenone and estetrol · Estrogen / progestin receptors
No new nonclinical program for drospirenone; relies on FDA's previous findings of safety for the listed drug YAZ

Nourianz

istradefylline · Adenosine A2A receptor
Brain not adequately evaluated in pivotal dog toxicity studies despite rat brain mineralization; nonclinical deficiency in first-cycle Not Approvable letter

Nubeqa

darolutamide · Androgen receptor
No carcinogenicity studies before approval (advanced cancer); EMA required a 6-month Tg-rasH2 mouse study post-approval

Nulibry

fosdenopterin · cPMP replacement (MoCD type A)
No carcinogenicity study before approval; single-species study deferred to a postmarketing requirement

Nurtec ODT

rimegepant · CGRP receptor
Rat pre- and postnatal development study deficient (too few offspring, weak neurobehavioral assessment); repeat required postmarketing

Nuzolvence

zoliflodacin · Bacterial topoisomerase II
No sperm count or viability analyses in animals despite testicular toxicity and incomplete reversibility of epididymal findings

Ogsiveo

nirogacestat · Gamma secretase
No 2-year rat carcinogenicity study; only 26-week Tg rasH2 mouse study plus weight-of-evidence assessment

Ojemda

tovorafenib · RAF (type II pan-RAF)
No juvenile toxicity studies for a paediatric indication; youngest animals corresponded to 12 to 16 years of human age

Ojjaara

momelotinib · JAK1/JAK2/ACVR1
Major active metabolite M21 not covered by animal exposure; no safety margins for M21

Olinvyk

oliceridine · μ-opioid receptor (G-protein biased)
Major human metabolite TRV0109662 not shown qualified in EFD studies (failed ISR); no dedicated metabolite study, original EFD samples reanalysed instead

Omlonti

omidenepag isopropyl · EP2 receptor
No rodent carcinogenicity bioassays; applicant cited the ICH S1A ocular-route provision

Ongentys

opicapone · COMT
Rabbit embryofetal study: no exposure margin for maternal or developmental toxicity (<1 to 1 times human AUC)

Orgovyx

relugolix · GnRH receptor
Rat reproductive and developmental data discounted because of low relugolix affinity for rat GnRH receptors; rabbit EFD used for labeling

Orladeyo

berotralstat · Plasma kallikrein
Narrow NOAEL exposure margins in chronic studies: 3.8 in rat and 1.5 in monkey

Orlynvah

sulopenem etzadroxil and probenecid · Penicillin-binding proteins
Positive in vitro clastogenicity for sulopenem etzadroxil and sulopenem; judged non-genotoxic on negative in vivo micronucleus and Ames results

Orserdu

elacestrant · Estrogen receptor (SERD)
No exposure margin for rat embryo-fetal toxicity: maternal toxicity and embryo-fetal mortality at about 0.1 times human AUC

Orzeyful

oveporexton · Orexin OX2 receptor agonist
Positive in vitro micronucleus assay after continuous treatment; overall judged non-genotoxic on negative Ames and in vivo micronucleus

Oxbryta

voxelotor · HbS polymerisation
Adverse effects in animals at exposures comparable to or below anticipated clinical exposure

Palsonify

paltusotine · Somatostatin receptor 2
Rat carcinogenicity study terminated early (Week 91 males, Week 89 females) due to low control survival

Paxlovid

nirmatrelvir and ritonavir · SARS-CoV-2 Mpro (3CL protease)
No combination toxicity studies of nirmatrelvir with ritonavir

Pemazyre

pemigatinib · FGFR1-3
Embryo-fetal development assessed only in a non-GLP dose range-finding rat study

Piqray

alpelisib · PI3Kα
In vitro genotoxicity concentrations below ICH S2 requirements; in vivo micronucleus exposure only 2-fold or 1.4-fold human exposure

Pizensy

lactitol · Osmotic laxative
No GLP chronic toxicity studies by the applicant; chronic toxicity supported by published literature

Ponvory

ponesimod · S1P1 receptor
Lung toxicity NOAEL in rats below human exposure (0.7-fold based on plasma exposure)

Pretomanid

pretomanid · Mycobacterial cell wall / respiration
2-year rat carcinogenicity study ongoing at approval and deferred post-marketing, despite mutagenic circulating metabolite M50

Pyrukynd

mitapivat · Pyruvate kinase (activator)
No in vivo pyruvate kinase deficiency model; efficacy shown in a β-thalassemia mouse model, normal mice and patient RBCs ex vivo

Qelbree

viloxazine · Norepinephrine reuptake
General and reproductive toxicity largely from 1970s legacy studies not in full GLP compliance, many without toxicokinetics

Qinlock

ripretinib · KIT/PDGFRA
No in vivo phototoxicity follow-up after a positive in vitro 3T3 NRU assay, contrary to ICH S10 and CHMP advice

Qulipta

atogepant · CGRP receptor
Female mouse carcinogenicity study inadequate: high dose not an MTD or MFD and below 25-fold human exposure

Quviviq

daridorexant · Orexin OX1/OX2 receptors
Tg.rasH2 mouse high dose gave only 4.37- to 8.5-fold AUC multiples, below the 50-fold ICH S1 criterion

Rapiblyk

landiolol · β1-adrenergic receptor
Core nonclinical package taken from published literature on the Japanese landiolol product ONO-1101 (Onoact) rather than new studies

Rasonque

daraxonrasib · RAS(ON) multi-selective
Embryo-fetal assessment limited to a dose-range-finding study in mice; no definitive or second-species study

Recarbrio

imipenem, cilastatin and relebactam · Beta-lactamase (relebactam)
No carcinogenicity studies with relebactam or imipenem/cilastatin

Relyvrio

sodium phenylbutyrate and taurursodiol · ER stress / mitochondrial (proposed)
No carcinogenicity studies before approval; mouse and rat studies deferred to post-marketing requirements

Retevmo

selpercatinib · RET
No carcinogenicity studies before approval although MTC patients can live long; rat and mouse studies required postmarketing

Revtorpyk

gedatolisib · PI3K/mTOR
No embryo-fetal development studies; drug is given with palbociclib and fulvestrant, both known embryo-fetal toxicants

Revuforj

revumenib · Menin-KMT2A
Single preliminary rat embryo-fetal study only; no definitive or second-species embryo-fetal study

Reyvow

lasmiditan · 5-HT1F receptor
In vivo mouse micronucleus assay judged inadequate by the primary reviewer: exposure to major human metabolites not demonstrated

Rezdiffra

resmetirom · Thyroid hormone receptor β
Rat pre/postnatal study lacked behavior, motor activity, sensory function and reflex development testing

Rezurock

belumosudil · ROCK2
No carcinogenicity studies at US approval; waiver for chronic GVHD refused and rodent studies deferred to postmarketing requirements

Rezzayo

rezafungin · Fungal glucan synthase
No carcinogenicity studies

Rhapsido

remibrutinib · BTK
No NOAEL in 26-week rat study: endocrine pancreas fibrosis, haemorrhage and pigment at all doses

Rinvoq

upadacitinib · JAK1
No exposure margin for teratogenicity: rat and rabbit embryo-fetal NOAELs at exposures similar to or below the clinical dose

Romvimza

vimseltinib · CSF1R
2-year rat carcinogenicity study ongoing at approval; report deferred to post-marketing

Rozlytrek

entrectinib · TRK/ROS1/ALK
No exposure margins: CNS toxicity at 0.2 times human Cmax and skin, red-cell effects at 0.1 times human AUC

Rukobia

fostemsavir · HIV-1 gp120 (attachment)
No stand-alone CNS or respiratory safety pharmacology studies; assessed within toxicity studies

Scemblix

asciminib · BCR-ABL1 (STAMP, myristoyl pocket)
No carcinogenicity studies submitted for chronic-phase CML in patients pretreated with two or more TKIs

Sephience

sepiapterin · Tetrahydrobiopterin precursor
No 2-year rat carcinogenicity study before approval; weight-of-evidence waiver refused and study deferred to a postmarketing requirement

Simtriyo

centanafadine · Triple monoamine reuptake
26-week rat NOAEL exposure below human AUC at the MRHD (~0.1x males, ~0.8x females)

Skyclarys

omaveloxolone · Nrf2 activator
Carcinogenicity studies (26-week Tg.rasH2 mouse, 2-year rat) deferred to post-marketing requirements

Sohonos

palovarotene · RARγ
No rodent carcinogenicity studies before approval for chronic use; weight-of-evidence assessment submitted; two-species studies required postmarketing

Sotyktu

deucravacitinib · TYK2
Low margin in GLP monkey cardiovascular telemetry study: NOEL at 3x clinical Cmax

Sunlenca

lenacapavir · HIV-1 capsid
No completed carcinogenicity studies at submission; rasH2 mouse and 2-year rat studies ongoing, submitted post-approval

Sunosi

solriamfetol · Dopamine/norepinephrine reuptake
No exposure margin at general toxicology NOAELs: about 1 in dog and below 1 in mouse and rat (AUC)

Tabrecta

capmatinib · MET
NOAEL exposures in rat and dog within the range of human exposure; below 1 in female monkeys

Tavneos

avacopan · C5a receptor (C5aR1)
Respiratory, renal, CNS safety pharmacology and TDAR studies done only in rats, a pharmacologically non-relevant species

Tazverik

tazemetostat · EZH2
No NOAEL in the juvenile rat study: deaths, mostly from malignant lymphoma, even at 50 mg/kg, approximately equal to adult human exposure at 800 mg BID

Tepmetko

tepotinib · MET
No exposure margin: NOAEL AUC in chronic rat and dog studies about 4% of human exposure at 500 mg

Trikafta

elexacaftor, tezacaftor and ivacaftor · CFTR
2-year rat carcinogenicity study of elexacaftor ongoing at approval; completed as a postmarketing requirement

Truqap

capivasertib · AKT1-3
Only preliminary rat embryo-fetal studies; no definitive or second-species embryo-fetal study

Truseltiq

infigratinib · FGFR1-3
Safety margins below 1 at all dose levels in rat and dog toxicity studies versus human exposure at 125 mg QD

Tryptyr

acoltremon · TRPM8 agonist
Rodent carcinogenicity studies waived for a chronic topical ocular drug; reviewer noted unexplored literature on TRPM8 in cancer

Tryvio

aprocitentan · Endothelin A/B receptors
No dedicated carcinogenicity studies with aprocitentan; mouse and rat studies of parent drug macitentan used instead

Tukysa

tucatinib · HER2
No exposure margin: liver and GI toxicity in rats and monkeys at safety margins below 1 (clinically relevant doses)

Turalio

pexidartinib · CSF1R
Major human metabolite ZAAD-1006a not measured in rat and dog toxicity studies; off-target screening deferred to a postmarketing commitment

Ubrelvy

ubrogepant · CGRP receptor
Mouse 104-week carcinogenicity study inadequate: AUC margin at highest dose below 25-fold the MRHD

Ukoniq

umbralisib · PI3Kδ / CK1ε
Rabbit embryo-fetal study exposures only 0.03 to 0.08 times clinical exposure, with high variability and no dose-dependence

Utebzi

tebipenem pivoxil · Penicillin-binding proteins
Prodrug tebipenem pivoxil positive in vitro (mammalian gene mutation, CHO chromosomal aberration); in vivo micronucleus negative

Vafseo

vadadustat · HIF prolyl hydroxylase
No exposure margin: NOAEL exposures in all species below human exposure at 600 mg QD

Vanflyta

quizartinib · FLT3
No exposure margin at NOAELs for severe haematopoietic inhibition in monkeys (MOE 0.07-0.10) and dogs (MOE 0.41-0.54)

Vanrafia

atrasentan · Endothelin A receptor
No NOAEL established in chronic rat or dog toxicity studies

Veklury

remdesivir · SARS-CoV-2 RNA polymerase
No recovery phase in the 4-week rat and monkey toxicity studies

Velsipity

etrasimod · S1P1/S1P4/S1P5 receptors
Exposure to major human metabolites M3 and M6 not investigated in mice and dogs; coverage shown in rats only

Veozah

fezolinetant · Neurokinin-3 receptor
Sub-chronic and chronic toxicity studies conducted in female animals only

Veppanu

vepdegestrant · Estrogen receptor (PROTAC degrader)
Only a preliminary rat embryo-fetal study; no definitive or second-species embryo-fetal study

Verquvo

vericiguat · Soluble guanylate cyclase
In vitro hERG assay deviated from ICH S7B Q&A best practices (voltage protocol, no concentration verification or positive controls)

Vivjoa

oteseconazole · Fungal CYP51
26-week rat NOAEL exposure about 0.2 times the MRHD by AUC

Vizz

aceclidine · Muscarinic agonist (miotic)
Potential mutagenic drug-substance impurity specified above the default ICH M7 acceptable intake, without impurity-specific safety data

Vonjo

pacritinib · JAK2/FLT3
Chronic dog NOAEL exposure only 0.06x (males) and 0.02x (females) the clinical AUC

Voranigo

vorasidenib · IDH1/IDH2
No chronic toxicity study, although the long-life-expectancy indication falls outside ICH S9

Voydeya

danicopan · Complement factor D
Rat (pharmacologically inactive) used only for off-target toxicity; DART conducted in rabbit, a pharmacologically active species

Vtama

tapinarof · Aryl hydrocarbon receptor
Male arm of the subcutaneous rat carcinogenicity study of inadequate duration; only female rat data adequate

Vyndaqel

tafamidis · Transthyretin (stabiliser)
No in vivo pharmacology studies; efficacy supported by in vitro TTR stabilisation only

Wakix

pitolisant · Histamine H3 receptor
No safety margin in the monkey (convulsions) at the NOAEL, whether based on Cmax or AUC

Wayrilz

rilzabrutinib · BTK (reversible covalent)
Chronic rat NOAEL exposure only approximated clinical AUC at the maximum recommended dose

Welireg

belzutifan · HIF-2α
No carcinogenicity studies before US approval for chronic use in VHL disease; mouse and rat studies required postmarketing

Winlevi

clascoterone · Androgen receptor (topical)
No developmental NOAEL in the rat embryo-fetal study: malformations at all doses

Xacduro

sulbactam and durlobactam · PBPs; beta-lactamase (durlobactam)
Repeat-dose juvenile toxicity study (to inform dosing from birth to under one year) still ongoing at approval; completion under a postmarketing commitment

Xcopri

cenobamate · Sodium channel / GABA-A
Rat embryo-fetal study inadequate: high embryofetal death left too few fetuses to evaluate teratogenic potential; repeat study required postmarketing

Xdemvy

lotilaner · Mite GABA-Cl channel
Carcinogenicity studies waived on a weight-of-evidence basis

Xeglyze

abametapir · Lice metalloproteinases
Cardiovascular telemetry study in minipigs too flawed for regulatory use

Xocova

ensitrelvir · SARS-CoV-2 3CL protease
Eight drug-substance impurities with carcinogenic concern classified as ICH M7 Class 5 on lack of mutagenicity

Xolremdi

mavorixafor · CXCR4
No carcinogenicity studies before approval; rat and mouse carcinogenicity studies deferred to postmarketing requirements

Xpovio

selinexor · XPO1
No safety margin: toxicity in rats and monkeys at exposures below clinical exposure

Zavzpret

zavegepant · CGRP receptor
Juvenile animal toxicology study deferred to a post-marketing requirement to support pediatric development

Zaynich

cefepime and zidebactam · PBPs; beta-lactam enhancer (zidebactam)
Bacterial reverse mutation assay of a (redacted) test article limited to low concentrations because of antibacterial cytotoxicity

Zegfrovy

sunvozertinib · EGFR exon 20 insertion
No exposure margin: persistent ocular toxicity in rats at about 0.8 times the clinical AUC at 200 mg

Zenbexus

iberdomide · Cereblon (CELMoD)
No exposure margin at the 9-month monkey NOAEL (0.95-fold human steady-state AUC at 1 mg QD)

Zeposia

ozanimod · S1P1/S1P5 receptor
Major active human metabolites CC112273 and CC1084037 under-represented in pivotal toxicity, carcinogenicity and DART studies

Zepzelca

lurbinectedin · DNA minor groove (transcription)
Margins based on MTDs rather than NOAELs; exposure margins well below one in all studies and species

Zevtera

ceftobiprole medocaril · Penicillin-binding proteins
Animal data support only up to one month of dosing, while clinical treatment up to six weeks was permitted

Zokinvy

lonafarnib · Farnesyltransferase
No carcinogenicity study before approval; deferred to a postapproval study as agreed at the pre-IND meeting

Ztalmy

ganaxolone · GABA-A receptor (positive modulator)
Mouse and rat carcinogenicity studies not conducted before approval; deferred to postmarketing requirements as agreed with the Division

Zulresso

brexanolone · GABA-A receptor (positive modulator)
No carcinogenicity studies

Zurzuvae

zuranolone · GABA-A receptor (positive modulator)
Rabbit embryofetal study inadequate (plasma exposure below detection in some dams); second-species study required postapproval

Zycubo

copper histidinate · Copper replacement (Menkes disease)
No chronic repeat-dose toxicity studies in rodents or nonrodents, and no safety pharmacology studies

Beqalzi

sonrotoclax · BCL-2
Not stated in public reviews

Brenzavvy

bexagliflozin · SGLT2
Not stated in public reviews

Dayvigo

lemborexant · Orexin OX1/OX2 receptors
Not stated in public reviews

Gemtesa

vibegron · β3-adrenergic receptor
Not stated in public reviews

Ohtuvayre

ensifentrine · PDE3/PDE4
Not stated in public reviews

Rezlidhia

olutasidenib · IDH1 (mutant)
Not stated in public reviews

Sofdra

sofpironium · Muscarinic receptors (topical)
Not stated in public reviews

Voquezna

vonoprazan · H+/K+-ATPase (potassium-competitive)
Not stated in public reviews

Xenleta

lefamulin · Bacterial ribosome (50S PTC)
Not stated in public reviews

Summary across all 211 small molecules →