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Atlas/Small molecules/Evrysdi/Efficacy evidence

Evrysdi: animal efficacy model or human cells?

risdiplam · SMN2 splicing

Check my plan vs. these

Efficacy evidence

SMNΔ7 and C/C SMA mouse models carrying the human SMN2 transgene

“The in vivo activity of RIS was investigated in 2 different SMA mouse models (SMNΔ7 and C/C), which both carry the human SMN2 transgene”

✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Why that model

SMN2 exists only in humans, so in vivo models require transgenic mice carrying human SMN2

“The intended pharmacological target, the SMN2 gene, exists only in humans, and thus a pharmacological responder species as requested by existing guidelines does not exist unless studies are conducted in transgenic mouse models.”

✓ VerifiedEMA assessment report, p. 48Source ↗

Reviewer's view of the efficacy data

EMA: the two SMA mouse models support SMN protein increase in brain and muscle, but the clinical SMN target could not be verified

“Since the applicant did not provide the baseline SMN levels in the two transgenic SMA mouse models, it is not possible to verify such clinical target, However, it is agreed that data from the two mouse SMA models suggest a positive correlation between FL SMN protein increases and increase in the brain and quadriceps.”

✓ VerifiedEMA assessment report, p. 25Source ↗

Same question, other small molecules

Accrufer

ferric maltol · Iron replacement

Radiolabeled iron studies in rats (confirmed in dogs): iron transferred to transferrin and ferritin; literature on iron

Adquey

difamilast · PDE4 (topical)

Mouse model of chronic contact dermatitis; in vitro PDE-4 inhibition and cytokine suppression in inflammatory cells

Agamree

vamorolone · Glucocorticoid receptor (dissociative)

mdx mouse (dystrophin-deficient) proof-of-concept studies with vamorolone

Alyftrek

vanzacaftor, tezacaftor and deutivacaftor · CFTR

CF patient-derived HBE cells (F508del/F508del, F508del/MF): increased F508del-CFTR processing and trafficking

Anzupgo

delgocitinib · Pan-JAK (topical)

Rat DNCB-induced dermatitis model (topical): dose-dependent suppression of ear swelling

Aqneursa

levacetylleucine · Neuronal metabolism (proposed)

Published data: Npc1-/- CHO cells, NPC patient fibroblasts and Npc1-/- mice

Artesunate

artesunate · Plasmodium (antimalarial)

Malaria infection models: P. berghei rodents, P. falciparum-infected immunocompromised mice, Plasmodium-infected nonhuman primates

Attruby

acoramidis · Transthyretin (stabiliser)

TTR stabilisation measured in serum from acoramidis-dosed dogs and monkeys (in vivo pharmacodynamics)

Augtyro

repotrectinib · ROS1/TRK

Mouse subcutaneous allograft/xenograft tumors (engineered NIH/3T3 or Ba/F3 cells expressing ROS1 mutants/fusions)

Avmapki Fakzynja Co-pack

avutometinib and defactinib · RAF/MEK clamp; FAK

LGSOC patient-derived xenograft mice: avutometinib plus FAK-inhibitor surrogate VS-4718

Ayvakit

avapritinib · KIT/PDGFRA

Mouse P815 mastocytoma (KIT exon 17) model and imatinib-resistant GIST patient-derived xenograft (KIT exon 11/17)

Azstarys

serdexmethylphenidate and dexmethylphenidate · Dopamine/norepinephrine reuptake

In vitro radioligand binding only: SDX showed no significant binding to human DAT, NET or SERT

Balversa

erdafitinib · FGFR1-4

Human tumor cell-line xenografts with FGFR1, 2 and 3 alterations (bladder, lung, GI, liver) in immune-deficient rodents

Barhemsys

amisulpride · Dopamine D2/D3 receptor

Ferret emesis models (apomorphine-, morphine- and cisplatin-induced)

Baxfendy

baxdrostat · Aldosterone synthase (CYP11B2)

Telemetered cynomolgus monkeys on low-sodium diet plus furosemide (maximal RAAS activation)

Beqalzi

sonrotoclax · BCL-2

MAVER-1 mantle cell lymphoma subcutaneous xenograft in immunocompromised mice

Blujepa

gepotidacin · Bacterial topoisomerases (gyrase/topo IV)

Neutropenic murine thigh infection models (Enterobacterales, S. aureus); in vitro E. coli chemostat model

Brenzavvy

bexagliflozin · SGLT2

Diabetic db/db mouse and ZDF rat models: dose-dependent HbA1c reduction

Brexafemme

ibrexafungerp · Fungal glucan synthase

In vitro antifungal activity against Candida species (MIC90 0.015-4 ug/mL)

Brinsupri

brensocatib · DPP1 (cathepsin C)

LPS-induced acute lung injury model (no established NCFB model)

Brukinsa

zanubrutinib · BTK

REC-1 mantle cell lymphoma subcutaneous xenograft in mice; dose-dependent growth suppression

Byfavo

remimazolam · GABA-A receptor (benzodiazepine site)

Sedation in normal animals (rodents, monkeys), reversed by flumazenil; GABA-A benzodiazepine-site binding in vitro

Bylvay

odevixibat · IBAT

Mdr2-/- mouse cholestasis model: reduced liver weight and serum markers of liver damage and cholestasis

Cabenuva

cabotegravir and rilpivirine · HIV-1 integrase; NNRTI

In vitro antiviral activity in human MT4 T-cell line and HIV-1 primary isolates (rilpivirine)

Camzyos

mavacamten · Cardiac myosin

Transgenic troponin T-mutant HCM mice dosed 6 months: improved diastolic function, preserved fractional shortening

Caplyta

lumateperone · 5-HT2A / D2 receptor

Rodent models of antipsychotic activity: head twitch, conditioned avoidance, amphetamine-induced hyperlocomotion

Cardamyst

etripamil · L-type calcium channel

Isolated rabbit hearts, spontaneously hypertensive rats and normotensive rabbits (BP, AV conduction, ECG)

Cibinqo

abrocitinib · JAK1

Adjuvant-induced arthritis rat model (paw swelling; ex vivo STAT phosphorylation)

Cobenfy

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

Rodent and monkey models of schizophrenia: conditioned avoidance, psychostimulant-induced hyperactivity, schedule-controlled behavior

Cosela

trilaciclib · CDK4/6

In vivo mouse studies of protection from chemotherapy-induced myelosuppression and of tumor protection

Crenessity

crinecerfont · CRF1 receptor

In vitro CRF1 binding, cAMP and ACTH assays; CRF- and stress-induced ACTH inhibition in normal rats

Cypsedo

cipepofol · GABA-A receptor

Anesthesia in normal rats, dogs and minipigs, similar depth to propofol with 6-fold higher potency

Daybue

trofinetide · IGF-1 tripeptide analogue

MeCP2 knockout mouse model of Rett syndrome (20 mg/kg IP daily, 5 or 20 weeks)

Dayvigo

lemborexant · Orexin OX1/OX2 receptors

Increased total sleep time in normal mice and rats (ED50 1 and 4.4 mg/kg)

Defencath

taurolidine and heparin · Antimicrobial catheter lock

In vitro antimicrobial activity of taurolidine against a panel of microorganisms

Dojolvi

triheptanoin · Anaplerotic energy substrate

Published studies: VLCAD-/- knockout mice fed triheptanoin diet (cardiac function), plus GLUT-1 KO and seizure mouse models

Duvyzat

givinostat · Histone deacetylase (class I/II)

B10.mdx (mild) and D2.mdx (severe) mouse models of DMD; DMD patient-derived fibroblasts

Egaten

triclabendazole · Fasciola (tubulin)

Published studies in animals experimentally infected with F. hepatica or F. gigantica; in vitro fluke motility and tegument assays

Ekterly

sebetralstat · Plasma kallikrein

Carrageenan-induced paw oedema in Sprague-Dawley rats (non-HAE acute inflammation model)

Ensacove

ensartinib · ALK

H3122 (EML4-ALK) human NSCLC xenograft in nude mice

Exblifep

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

Neutropenic murine thigh infection model (ESBL K. pneumoniae) and hollow-fiber infection model

Exkivity

mobocertinib · EGFR exon 20 insertion

Patient-derived NSCLC xenograft LU0387 (EGFR exon 20 insertion) in immunocompromised mice

Exxua

gepirone · 5-HT1A receptor

Active in animal models predictive of antidepressant and anxiolytic activity

Fabhalta

iptacopan · Complement factor B

PNH patient erythrocytes in vitro: inhibition of hemolysis and C3 deposition

Fetroja

cefiderocol · Penicillin-binding proteins

Murine thigh and lung infection models with Gram-negative strains (dose-ranging, PK/PD target)

Fexinidazole

fexinidazole · Trypanosoma brucei

Acute and chronic murine T. brucei infection models of HAT

Filspari

sparsentan · Endothelin A / angiotensin II receptors

gddY and passive (EIC-induced) mouse IgAN models; anti-Thy-1 rat mesangioproliferative glomerulonephritis model

Fotivda

tivozanib · VEGFR1-3

Human and murine tumor xenografts in mice and rats (tumor growth inhibition, anti-angiogenesis)

Foundayo

orforglipron · GLP-1 receptor (non-peptide)

Cynomolgus monkeys and humanized GLP-1R knock-in (Glp1rS33W) rats, including diet-induced obese

Fruzaqla

fruquintinib · VEGFR1-3

Human tumor xenografts in BALB/c nude mice (BGC-823, HT-29, Caki-1, NCI-H460)

Gavreto

pralsetinib · RET

RET-mutant and patient-derived RET-fusion (NSCLC, CRC) xenografts in mice

Gemtesa

vibegron · β3-adrenergic receptor

Acetic acid-induced bladder overactivity model (rat)

Gomekli

mirdametinib · MEK1/2

Genetically engineered Nf1fl/fl;Dhh-Cre neurofibroma mouse model

Grafapex

treosulfan · DNA alkylation

Murine allogeneic bone marrow transplant model (myeloablation, immunosuppression)

Hernexeos

zongertinib · HER2 (mutant)

Mice implanted with patient-derived lung cancer cells (ST-3107, HER2 exon 20-YVMA): dose-dependent tumor growth inhibition

Hyrnuo

sevabertinib · HER2 (mutant)

NSCLC patient-derived xenograft models with HER2 exon 20 insertion YVMA: antitumor activity

Ibsrela

tenapanor · NHE3

Stress-induced IBS-C rat model, mouse opioid-induced constipation model, neonatal acetic-acid IBS-like rat model

Ibtrozi

taletrectinib · ROS1

Subcutaneous ROS1-fusion xenografts (Ba/F3, NSCLC) and intracranial patient-derived NSCLC xenograft in mice

Idvynso

doravirine and islatravir · NNRTI; NRTTI

Islatravir anti-HIV-1 activity in human PBMCs (IC50 0.21 nM)

Inluriyo

imlunestrant · Estrogen receptor (SERD)

ER+ breast cancer xenograft and PDX mouse models, including ESR1-Y537S mutant PDX

Inpefa

sotagliflozin · SGLT1/SGLT2

Metabolic rat model of HFpEF: improved diastolic dysfunction markers (LVEDP, left atrial remodeling, IVRT)

Inqovi

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

L1210 and KG-1 disseminated leukemia mouse models (oral cedazuridine plus oral decitabine)

Inrebic

fedratinib · JAK2

Mouse models of JAK2V617F-driven myeloproliferative disease: survival up to 100% at 42 days; reduced WBC, hematocrit, splenomegaly, fibrosis

Iqirvo

elafibranor · PPARα/δ

NASH in db/db mice on MCD diet and chemically induced (CCl4) liver fibrosis in rats; no PBC model

Isturisa

osilodrostat · 11β-hydroxylase (CYP11B1)

In vitro human CYP11B1 inhibition; cortisol synthesis inhibition in ACTH-stimulated normal monkeys

Itovebi

inavolisib · PI3Kα (mutant-selective)

PIK3CA-mutant human breast cancer xenografts in mice (KPL-4, HCC1954X1, MCF7)

Jascayd

nerandomilast · PDE4B

Bleomycin lung fibrosis in mice and rats; IPF patient lung fibroblasts in vitro

Jaypirca

pirtobrutinib · BTK (non-covalent)

Mouse xenograft models of lymphoma with WT or C481S mutant BTK

Jesduvroq

daprodustat · HIF prolyl hydroxylase

Normal Sprague-Dawley rats: dose-related increases in RBC, hemoglobin and hematocrit

Jideytro

zidesamtinib · ROS1

Patient-derived xenograft (PDX) mouse models of ROS1-fusion NSCLC (SDC4-ROS1, CD74-ROS1 G2032R)

Joenja

leniolisib · PI3Kδ

Pik3cd E1020K/+ mouse model of APDS; rat TDAR and induced inflammation models

Journavx

suzetrigine · NaV1.8

Primary human DRG neurons in vitro (NaV1.8 current and action potential firing inhibition); no in vivo model

Kerendia

finerenone · Mineralocorticoid receptor

Animal models of heart failure and chronic kidney disease: heart and kidney protection

Klisyri

tirbanibulin · Tubulin / Src

Cultured keratinocytes in vitro: proliferation reduced 50% at 40 nM

Komzifti

ziftomenib · Menin-KMT2A

AML xenografts (MV4-11, MOLM-13 cell lines and patient-derived cells) in immunocompromised mice and rats

Koselugo

selumetinib · MEK1/2

Nf1fl/fl;DhhCre neurofibroma knockout mouse: reduced nerve root size and tumor number/size

Krazati

adagrasib · KRAS G12C

KRAS G12C-mutant human tumor xenografts in mice: activity in 14 of 17 lung xenograft models, none in G12C-negative models

Kygevvi

doxecitine and doxribtimine · Pyrimidine nucleoside replacement (TK2 deficiency)

Tk2 knock-in (Tk2KI) and knockout (Tk2KO) mouse models of TK2 deficiency

Lampit

nifurtimox · Trypanosoma cruzi

Acute and chronic T. cruzi infection models in mice, rats, hamsters, guinea pigs, rabbits and dogs

Lazcluze

lazertinib · EGFR (mutant-selective)

Human NSCLC xenografts (EGFR del19, L858R/T790M) in nude mice, including intracranial model

Leqselvi

deuruxolitinib · JAK1/JAK2

In vitro kinase assays and IL-6-stimulated STAT3 inhibition, benchmarked against ruxolitinib

Lifyorli

relacorilant · Glucocorticoid receptor (antagonist)

Mouse xenografts of human ovarian, endometrial and cervical cancer with relacorilant plus paclitaxel

Litfulo

ritlecitinib · JAK3/TEC kinases

C3H/HeJ skin-grafted alopecia areata mice: IV ritlecitinib prevented AA onset and hair loss

Livdelzi

seladelpar · PPARδ

Carbon tetrachloride (CCl4) liver fibrosis model in mice

Livmarli

maralixibat · IBAT (ASBT)

Rat partial bile duct ligation (pBDL) cholestasis model: reduced serum bile acids, liver enzymes and bilirubin

Livtencity

maribavir · CMV UL97 protein kinase

In vivo HCMV models using transplanted human tissue or surrogate animal viral strains, compared with ganciclovir

Lumakras

sotorasib · KRAS G12C

Mice bearing KRAS G12C human tumor cell line xenografts (incl. NSCLC): ERK inhibition and tumor growth inhibition

Lupkynis

voclosporin · Calcineurin

Animal models of autoimmune uveitis, arthritis and organ transplantation; calcineurin inhibition in monkeys

Lybalvi

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

Olanzapine-induced weight gain and adiposity in rats and nonhuman primates mitigated by samidorphan

Lynavoy

linerixibat · IBAT

Fecal bile acid excretion in healthy mice and dogs; rat necrotizing enterocolitis model; no PBC model

Lynkuet

elinzanetant · NK1/NK3 receptors

Mongolian gerbil model: elinzanetant reduced NK-1 agonist (GR-73632)-induced foot tapping

Lytgobi

futibatinib · FGFR1-4 (covalent)

Human tumor xenografts with FGFR2 alterations: AN3 CA endometrial carcinoma in nude mice and SNU-16 gastric carcinoma in nude rats

Mayzent

siponimod · S1P1/S1P5 receptor

Rodent EAE (experimental autoimmune encephalomyelitis) models; oral and ICV siponimod reduced clinical signs

Miebo

perfluorohexyloctane · Tear film evaporation barrier

Normal NZW rabbits: 7-day ocular dosing showed a trend to increased tear film breakup time (TFBUT)

Miplyffa

arimoclomol · Heat-shock response amplifier

NPC patient fibroblasts and Npc1-/- mutant mice (hepatic GSL, motor deficits)

Modeyso

dordaviprone · DRD2 antagonist / ClpP agonist

Orthotopic intracranial (brainstem) tumor-bearing mice; survival and pharmacodynamic endpoints

Myqorzo

aficamten · Cardiac myosin

Transgenic MYH7 R403Q HCM mouse and A31P MYBPC3 cat model of hereditary obstructive HCM

Nereus

tradipitant · NK1 receptor

Apomorphine-induced emesis in Beagle dogs (single oral dose reduced emesis incidence)

Nexletol

bempedoic acid · ATP citrate lyase

LDLR+/- and LDLR-/- Yucatan miniature pigs (160 days): LDL-C lowered vs vehicle

Nextstellis

drospirenone and estetrol · Estrogen / progestin receptors

Ovulation and implantation inhibition in normal rabbits

Nourianz

istradefylline · Adenosine A2A receptor

MPTP mouse and primate Parkinson's models, 6-OHDA-lesioned rat, haloperidol catalepsy

Nubeqa

darolutamide · Androgen receptor

Mouse xenograft models of human prostate cancer: tumor growth inhibition and suppressed PSA rise

Nulibry

fosdenopterin · cPMP replacement (MoCD type A)

Knockout mouse model of MoCD Type A: reduced plasma and brain SSC, improved survival vs controls

Nurtec ODT

rimegepant · CGRP receptor

Marmoset hCGRP-induced facial blood flow: 75-80% inhibition (target engagement in normal animals)

Nuzolvence

zoliflodacin · Bacterial topoisomerase II

In vitro hollow fiber infection model (HFIM) with N. gonorrhoeae strains WHO-F and WHO-X; no animal infection studies

Ogsiveo

nirogacestat · Gamma secretase

Patient-derived desmoid tumor cell lines in vitro; in vivo only in non-desmoid Notch-driven xenografts (e.g., T-ALL)

Ohtuvayre

ensifentrine · PDE3/PDE4

Exploratory in vivo models of allergic conditions and asthma; no COPD animal model

Ojemda

tovorafenib · RAF (type II pan-RAF)

Mouse tumour xenografts (BRAF-mutant WM-266-4 melanoma; Calu-6, BxPC-3): tumour growth inhibition or regression

Ojjaara

momelotinib · JAK1/JAK2/ACVR1

Mouse model of myeloproliferative neoplasms and rat model of anemia of chronic disease

Olinvyk

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

Rodent (mouse, rat) spinal reflexive and supraspinal affective nociceptive pain models

Omlonti

omidenepag isopropyl · EP2 receptor

IOP lowering in normotensive rabbits and monkeys and in a monkey model of ocular hypertension

Ongentys

opicapone · COMT

MPTP-lesioned cynomolgus monkeys: augmented L-DOPA/benserazide effects on motor activity

Orgovyx

relugolix · GnRH receptor

Human GnRH receptor knock-in mice (testosterone reduction) and castrated monkeys (LH decrease)

Orladeyo

berotralstat · Plasma kallikrein

Ex vivo kallikrein inhibition in plasma from HAE patients

Orlynvah

sulopenem etzadroxil and probenecid · Penicillin-binding proteins

Neutropenic and immune-competent murine thigh infection models plus in vitro hollow-fiber infection model

Orserdu

elacestrant · Estrogen receptor (SERD)

ER+ breast cancer xenograft and patient-derived xenograft mouse models (≥96% TGI at ≥30 mg/kg/day)

Orzeyful

oveporexton · Orexin OX2 receptor agonist

OX/ataxin-3 transgenic NT1 mouse model (loss of orexin neurons): increased wakefulness

Oxbryta

voxelotor · HbS polymerisation

SCD (SS) mouse model: increased Hb-O2 affinity and reduced ex vivo RBC sickling

Palsonify

paltusotine · Somatostatin receptor 2

GHRH-challenged rats: dose-dependent suppression of GH elevation

Paxlovid

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

Mouse-adapted SARS-CoV-2 (MA10) infection in BALB/c and 129 mice: reduced lung viral titres and disease

Pemazyre

pemigatinib · FGFR1-3

Human tumour xenografts in mice with FGFR1-3 activation, incl. patient-derived FGFR2-TRA2B cholangiocarcinoma xenografts

Piqray

alpelisib · PI3Kα

Breast cancer xenografts in mice, incl. ER-positive PIK3CA-mutant models and PDX

Pizensy

lactitol · Osmotic laxative

Normal rats: increased small intestine contents (osmotic effect), independent of fermentation

Ponvory

ponesimod · S1P1 receptor

Mouse MOG-peptide experimental autoimmune encephalomyelitis (EAE) model

Pretomanid

pretomanid · Mycobacterial cell wall / respiration

Acute, chronic and latent murine TB infection models (lung/spleen CFU, relapse)

Pyrukynd

mitapivat · Pyruvate kinase (activator)

Hbbth3/+ β-thalassemia mouse (another hemolytic anemia), normal mice, and RBCs from PKD patients ex vivo

Qelbree

viloxazine · Norepinephrine reuptake

Normal rats: increased brain norepinephrine (and 5-HT, DA) levels

Qinlock

ripretinib · KIT/PDGFRA

Mouse tumour xenografts: KIT exon 11 GIST T1, imatinib-resistant exon 17 GIST patient-derived xenograft

Qulipta

atogepant · CGRP receptor

Capsaicin-induced dermal vasodilatation (CIDV) inhibition as surrogate pharmacodynamic marker; no animal migraine model

Quviviq

daridorexant · Orexin OX1/OX2 receptors

Sleep-wake EEG studies in naive rats and dogs (decreased wake, increased REM/non-REM sleep); no disease model

Rapiblyk

landiolol · β1-adrenergic receptor

Dog halothane-epinephrine, electrical stimulation and aconitine-induced arrhythmia/tachycardia models

Rasonque

daraxonrasib · RAS(ON) multi-selective

KRAS G12X PDAC cell-line xenografts in mice (mean regressions 53%–93% at 25 mg/kg daily)

Recarbrio

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

Neutropenic mouse infection models with relebactam plus imipenem

Relyvrio

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

SOD1 G93A transgenic mouse model of ALS (no effect on lifespan or disease progression)

Retevmo

selpercatinib · RET

TT medullary thyroid carcinoma and LC-2/ad lung adenocarcinoma xenografts in mice

Revtorpyk

gedatolisib · PI3K/mTOR

ER+ breast cancer PDX models and MCF7 orthotopic xenograft (triplet with palbociclib and fulvestrant)

Revuforj

revumenib · Menin-KMT2A

MV4;11 and MOLM-13 human AML xenografts in rats and immunocompromised mice

Reyvow

lasmiditan · 5-HT1F receptor

Rat trigeminovascular models: dural protein extravasation, c-fos induction, dural-evoked nociception, dural vasodilation

Rezdiffra

resmetirom · Thyroid hormone receptor β

High-fat diet-induced obese (DIO) mice for 25 weeks: reduced liver weight and vacuolation

Rezlidhia

olutasidenib · IDH1 (mutant)

Mouse xenografts of cell lines engineered to express mutant IDH1 (tumor 2-HG measured)

Rezurock

belumosudil · ROCK2

cGVHD mouse models (lung and skin endpoints) and murine pulmonary fibrosis model

Rezzayo

rezafungin · Fungal glucan synthase

Neutropenic murine candidiasis model (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. dubliniensis)

Rhapsido

remibrutinib · BTK

Mouse reverse passive Arthus and passive cutaneous anaphylaxis models of skin mast cell degranulation

Rinvoq

upadacitinib · JAK1

Rat adjuvant-induced arthritis model (paw swelling, bone erosion, ankle histology)

Romvimza

vimseltinib · CSF1R

CSF1R-dependent in vivo primary PD models; no TGCT models

Rozlytrek

entrectinib · TRK/ROS1/ALK

Mouse xenograft models (cell line- and patient-derived) with TRK, ROS1 and ALK fusions, including an orthotopic glioma model

Rukobia

fostemsavir · HIV-1 gp120 (attachment)

Cell-culture antiviral activity of temsavir against HIV-1 clinical isolates in PBMCs

Scemblix

asciminib · BCR-ABL1 (STAMP, myristoyl pocket)

KCL-22 CML xenograft mice, including a T315I-mutant model

Sephience

sepiapterin · Tetrahydrobiopterin precursor

Pah-R261Q PKU mouse (single dose) plus COS-7 cells expressing PAH variants

Simtriyo

centanafadine · Triple monoamine reuptake

Microdialysis in normal rats: increased cortical NE, DA and 5-HT

Skyclarys

omaveloxolone · Nrf2 activator

Nrf2 target-gene induction in healthy mice, rats and monkeys; no FA animal model

Sofdra

sofpironium · Muscarinic receptors (topical)

Pilocarpine-induced perspiration in normal SD rats inhibited by topical 20% gel

Sohonos

palovarotene · RARγ

Injury-induced HO and FOP mouse models: BMP-2 implant, ALK2Q207D and ALK2R206H transgenic mice

Sotyktu

deucravacitinib · TYK2

Mouse IL-23-induced acanthosis (psoriasis), anti-CD40 and T-cell transfer colitis, NZB/W lupus nephritis

Sunlenca

lenacapavir · HIV-1 capsid

Cell-culture antiviral activity in human MT-4 T-cell line (EC50 0.19 nM)

Sunosi

solriamfetol · Dopamine/norepinephrine reuptake

Hypocretin/ataxin-3 transgenic narcolepsy mice: continuous wakefulness induced

Tabrecta

capmatinib · MET

Patient-derived NSCLC xenografts (MET exon 14 skipping or MET amplification) in nude mice

Tavneos

avacopan · C5a receptor (C5aR1)

Anti-MPO ANCA glomerulonephritis model in hC5aR knock-in mice

Tazverik

tazemetostat · EZH2

Patient-derived synovial sarcoma (SS18 fusion) xenografts in nude mice

Tepmetko

tepotinib · MET

Mouse xenografts of human METex14-skipping tumor cell lines; complete regression at 6 mg/kg with MET amplification

Trikafta

elexacaftor, tezacaftor and ivacaftor · CFTR

CF patient-derived human bronchial epithelial (HBE) cells; increased CFTR processing and chloride transport

Truqap

capivasertib · AKT1-3

Human cancer xenografts including ER+ breast cancer models with PIK3CA, AKT1 or PTEN alterations

Truseltiq

infigratinib · FGFR1-3

Mouse and rat xenografts of human FGFR2/3-altered tumors, including cholangiocarcinoma PDX with FGFR2 fusions

Tryptyr

acoltremon · TRPM8 agonist

Increased blink rate after a single topical ocular dose in guinea pigs (EC50 9.1 µM)

Tryvio

aprocitentan · Endothelin A/B receptors

Hypertensive rat models: DOCA-salt, Dahl-S and SHR rats

Tukysa

tucatinib · HER2

Mouse xenograft models of HER2-expressing tumors (anti-tumor activity, HER2 phosphorylation inhibition)

Turalio

pexidartinib · CSF1R

Mouse model of splenomegaly from injected CSF1R signaling-dependent cells: inhibited 79%

Ubrelvy

ubrogepant · CGRP receptor

Capsaicin-induced dermal vasodilation in rat, rabbit and monkey; CGRP-induced relaxation of human cranial arteries ex vivo

Ukoniq

umbralisib · PI3Kδ / CK1ε

MOLT-4 xenograft mice (150 mg/kg/day oral) plus 13 leukemia/lymphoma cell lines

Utebzi

tebipenem pivoxil · Penicillin-binding proteins

Neutropenic mouse and immunocompetent rat pyelonephritis infection models

Vafseo

vadadustat · HIF prolyl hydroxylase

Healthy normoxic mice and rats (EPO and erythropoiesis increases); no anemia model

Vanflyta

quizartinib · FLT3

MV4-11 (FLT3-ITD) mouse xenograft: tumor growth inhibition and increased lifespan

Vanrafia

atrasentan · Endothelin A receptor

Spontaneous IgAN mouse (grouped-ddY): dose-dependent albuminuria reduction

Veklury

remdesivir · SARS-CoV-2 RNA polymerase

Infection challenge: mouse SARS-CoV/MERS-CoV and non-human primate SARS-CoV-2/MERS-CoV models

Velsipity

etrasimod · S1P1/S1P4/S1P5 receptors

T-cell transfer colitis in SCID mice: reduced colonic T-cell and monocyte markers

Veozah

fezolinetant · Neurokinin-3 receptor

Ovariectomized rat (postmenopause model): attenuated hot flash-like symptoms

Veppanu

vepdegestrant · Estrogen receptor (PROTAC degrader)

MCF7 xenograft mice: tumor shrinkage (124% TGI) and >94% ER reduction at 30 mg/kg/day

Verquvo

vericiguat · Soluble guanylate cyclase

Spontaneously hypertensive rats, renin-transgenic rat heart failure model, dog/minipig PAH and dog PH-LVD models

Vivjoa

oteseconazole · Fungal CYP51

Estrogen-dependent murine model of vaginal candidiasis (C. albicans infection)

Vizz

aceclidine · Muscarinic agonist (miotic)

Pupil response (miosis) in normal New Zealand White rabbits after topical aceclidine 1.75%

Vonjo

pacritinib · JAK2/FLT3

Two murine myelofibrosis models driven by excessive JAK2 activity (nude mice bearing Ba/F3-JAK2 cells)

Voquezna

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

Rat NSAID-induced gastric lesion and experimental reflux esophagitis models

Voranigo

vorasidenib · IDH1/IDH2

Mouse xenografts: subcutaneous U87 IDH2-R140Q and orthotopic TS603 IDH1-R132H glioma (tumor 2-HG reduction)

Voydeya

danicopan · Complement factor D

Ex vivo alternative-pathway inhibition (80-90%) in serum of orally dosed cynomolgus monkeys

Vtama

tapinarof · Aryl hydrocarbon receptor

Imiquimod mouse psoriasis model: reduced epidermal thickness and IL-17a/IL-17f/IL-19/IL-1β/IL-23a mRNA

Vyndaqel

tafamidis · Transthyretin (stabiliser)

In vitro only: TTR binding and tetramer stabilisation under acid/urea denaturation and physiologic conditions

Wakix

pitolisant · Histamine H3 receptor

Orexin-/- narcolepsy mouse: fewer narcoleptic attacks and shorter total narcolepsy duration

Wayrilz

rilzabrutinib · BTK (reversible covalent)

Mouse anti-CD41 antibody-induced ITP model; also rat collagen-induced arthritis and canine pemphigus

Welireg

belzutifan · HIF-2α

VHL-deficient 786-O ccRCC xenograft and patient-derived ccRCC xenograft in immunodeficient mice

Winlevi

clascoterone · Androgen receptor (topical)

Golden Syrian hamster flank organ (testosterone-induced) model with topical clascoterone

Xacduro

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

Neutropenic murine thigh and lung (pneumonia) infection models with MDR A. baumannii

Xcopri

cenobamate · Sodium channel / GABA-A

Rodent seizure models (battery); antiepileptic effects in mice and rats at 0.3-30 mg/kg

Xdemvy

lotilaner · Mite GABA-Cl channel

No proof-of-concept studies for Demodex blepharitis; mechanism (mite GABA-Cl inhibition) only

Xeglyze

abametapir · Lice metalloproteinases

In vitro ovicidal assay on resistant head lice eggs (SF-HL strain) with the lotion

Xenleta

lefamulin · Bacterial ribosome (50S PTC)

Animal infection models of S. pneumoniae and S. aureus pneumonia (PK-PD index fAUC/MIC)

Xolremdi

mavorixafor · CXCR4

Human K562 cells expressing WT and WHIM-mutant CXCR4 (CXCL12-binding IC50 6.1 nM WT; 3.2-11 nM mutants)

Xpovio

selinexor · XPO1

Mouse xenograft models of multiple myeloma (selinexor alone and with dexamethasone)

Zavzpret

zavegepant · CGRP receptor

Suppression of CGRP-induced facial blood flow in cynomolgus monkeys; in vitro receptor binding

Zaynich

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

Neutropenic mouse lung, thigh and cUTI infection models with human-simulated regimens

Zegfrovy

sunvozertinib · EGFR exon 20 insertion

Patient-derived NSCLC xenografts with EGFR exon20ins (LU0387, LU3075) and A431 WT EGFR xenograft in nude mice

Zenbexus

iberdomide · Cereblon (CELMoD)

Multiple myeloma xenograft models in mice, including lenalidomide-resistant models

Zeposia

ozanimod · S1P1/S1P5 receptor

Mouse EAE model and cuprizone demyelination model; lymphocyte reduction in rats, mice, dogs and monkeys

Zepzelca

lurbinectedin · DNA minor groove (transcription)

Subcutaneous/orthotopic human CDX and PDX tumour xenografts in mice (lung, breast, prostate, ovary, pancreas, sarcoma and others)

Zevtera

ceftobiprole medocaril · Penicillin-binding proteins

Infection models: murine septicemia and acute pneumonia, rat/rabbit endocarditis and osteomyelitis (MSSA, MRSA, S. pneumoniae)

Zokinvy

lonafarnib · Farnesyltransferase

Hutchinson-Gilford progeria mouse model (homozygous LmnaG609G/G609G): lonafarnib prolonged survival

Ztalmy

ganaxolone · GABA-A receptor (positive modulator)

Traditional rodent seizure models (chemically induced convulsions, corneal kindling); not tested in a Cdkl5 disease model

Zulresso

brexanolone · GABA-A receptor (positive modulator)

Behavioral depressant effects (sedation, muscle relaxation, decreased locomotion) in rats, dogs and mice; no PPD model

Zurzuvae

zuranolone · GABA-A receptor (positive modulator)

Rodent anticonvulsant, EEG, anxiolytic-like and sedation models (target engagement)

Zycubo

copper histidinate · Copper replacement (Menkes disease)

Published Menkes mouse model only (CuHis with AAV9-ATP7A); CuHis alone gave no survival benefit

Xocova

ensitrelvir · SARS-CoV-2 3CL protease

Not stated in public reviews

Summary across all 211 small molecules →