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Precedia/Small molecules/Balversa/Flexibility

Balversa: what flexibility did regulators accept, and why?

erdafitinib · FGFR1-4
Check my plan vs. these
Flexibility accepted
Safety marginQuestioned
No exposure margin: animal-to-human exposure ratios below one at the highest doses in 3-month rat and dog studies
“The animal-to-human exposure ratios at the highest daily dose of 8 mg/kg and 0.75 mg/kg tested in the 3-month rat and dog study, respectively, are low (<1). Thus, interpretation of the observed adverse effects is difficult since the exposure multiples following repeat dose administration of erdafitinib are much lower than the AUC in humans at the intended clinical dose of 8 or 9 mg.”
✓ VerifiedEMA assessment report, p. 40Source ↗
Safety pharmacologyAccepted with a conditionBeyond the letter
Dog cardiovascular NOAEL only 2.4-fold clinical exposure; QT effect within clinical exposure range
Why: Risk addressed in the RMP and SmPC section 5.3
“The NOAEL was 2.5 mg/kg with Cmax of 12.4 ng/ml representing 2.4-fold of the expected clinical exposure which is not considered acceptable as a safety margins. As this effect appears in the clinical exposure range it is included in the RMP part II module SII and the SmPC section 5.3.”
✓ VerifiedEMA assessment report, p. 39Source ↗
DARTAccepted
No fertility or pre- and postnatal development studies; embryo-fetal studies in rats only
Why: ICH S9 and ICH S5(R3) for an advanced cancer indication · Within the guideline · Serious disease
“In accordance with ICHS9 and ICHS5 (R3) guidelines no studies on fertility and early development and on pre- and postnatal development have been performed.”
✓ VerifiedEMA assessment report, p. 34Source ↗
“Fertility and early embryonic development studies were not conducted or required to support an advanced cancer indication.”
✓ VerifiedFDA multi-discipline review, p. 78Source ↗
Safety pharmacologyVerdict not stated
No dedicated CNS safety pharmacology study; CNS endpoints included in toxicology studies
Why: CNS endpoints included in the toxicology studies
“No dedicated safety pharmacology study was performed to evaluate CNS effects of erdafitinib. CNS endpoints were included in the toxicology studies and the effects are described in Toxicology section.”
✓ VerifiedEMA assessment report, p. 27Source ↗
Impurity or metaboliteAccepted
Potential genotoxic impurities controlled to non-mutagenic impurity limits (ICH Q3A) under ICH S9
Why: Erdafitinib not genotoxic; advanced cancer indication within ICH S9 · Within the guideline · Serious disease
“Erdafitinib (itself not genotoxic) is indicated for the treatment of patients with unresectable or metastatic urothelial carcinoma, to which ICH S9 applies. As such, potential genotoxic impurities may be controlled according to the limits for non-mutagenic impurities in ICH Q3A.”
✓ VerifiedEMA assessment report, p. 18Source ↗

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

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

Koselugo

selumetinib · MEK1/2
Mouse instead of rat as the rodent for long-term toxicology and developmental studies

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 →