Exploration of Asthma & Allergy

Table 3.

Small molecules in advanced clinical trials for AD

Target	Drug	Route	Status	Global endpoints achieved	Reported adverse effects	References
JAK1	Upadacitinib	Oral	Approved	EASI-75; EASI-90; EASI-100; IGA 0/1	Nasopharyngitis, acne, headache, oral herpes, diarrhea, eczema, herpes zoster	[111–114]
	Abrocitinib	Oral	Approved	IGA 0/1; EASI-50; EASI-75	Transient decreased platelet count, acne, dizziness, nasopharyngitis, acne, headache, oral herpes, vomiting, diarrhoea, eczema, herpes zoster, nausea, folliculitis	[115–120]
	LNK01001	Oral	Phase III	Ongoing	Ongoing	NCT06277245
	SHR0302	Oral	Phase II; Phase II/III	IGA 0/1; EASI-75	Blood pressure increased, upper respiratory tract infection, folliculitis, urinary tract infection, hyperlipidemia, hyperuricemia, headache	[121] NCT04717310
JAK1/2	Baricitinib	Oral	Approved	IGA 0/1; EASI-75	Headache, increased blood CPK, nasopharyngitis, herpes simplex, influenza, diarrhea, nausea, folliculitis, back pain, acne	[122–128]
JAK1/2	Ruxolitinib	Topical	Approved	IGA 0/1; EASI-75; EASI-90	Nasopharyngitis, headache	[129–131]
JAK1/3	Tofacitinib	Topical	Phase IIa	EASI-75	Viral upper respiratory tract infection, gastroenteritis, bronchitis, nausea	[132]
	ATI-1777	Topical	Phase IIa/b	mEASI-75	Blood CPK increased, headache	[133] NCT05432596
	ATI-502	Topical	Phase IIb	No significant efficacy	None reported	[134] NCT03585296
JAK1/TYK2	Brepocitinib	Topical	Phase IIb	EASI-90	Nasopharyngitis, erythema	[135]
JAK1/2/3/TYK2	Delgocitinib	Topical	Approved (Japan)	mEASI-50; mEASI-75; mEASI-90	Acne, folliculitis, gastroenteritis, herpes simplex, paronychia, nasopharyngitis	[136–140]
Pan-JAK	Jaktinib	Oral	Phase III	Ongoing	Ongoing	NCT05526222 NCT05676242
PDE4	Crisaborole	Topical	Approved	IGA 0/1	Application-site pain, upper respiratory tract infection, nasopharyngitis, headache, oropharyngeal pain, cough	[141–143]
PDE4	Lotamilast	Topical	Phase II	Not available	Not available	NCT03394677
PDE4	DRM02	Topical	Phase II	Not available	Not available	NCT01993420
PDE4	Difamilast	Topical	Approved (Japan)	IGA 0/1; EASI-75; EASI-90	Nasopharyngitis, folliculitis, gastroenteritis	[144–146] NCT05571943 NCT05372653
PDE4	Roflumilast	Topical	Phase III	IGA 0/1; EASI-75	Headache, nausea, application-site pain, nasopharyngitis, Covid-19, upper respiratory tract infection, diarrhea, vomiting	[147] NCT04773587 NCT04773600
P2X3	BLU-5937	Oral	Phase II	Not available	Not available	NCT04693195
NK1R	Serlopitant	Oral	Phase II	No significant efficacy	Nasopharyngitis, urinary tract infection	NCT02975206
NK1R	Tradipitant	Oral	Phase III	WI-NRS ≥ 4; IGA 0/1; SCORAD 50	Not available	[148] NCT04140695
KOR	Difelikefalin	Oral	Phase II	I-NRS ≥ 4	Abdominal pain/discomfort, nausea, dry mouth, headache, dizziness, hypertension, hyponatremia, nephrolithiasis, costochondritis	[149]
S1PR1	Vibozilimob	Oral	Phase II	Ongoing	Ongoing	NCT04684485
S1PR1	Udifitimod	Oral	Phase II	No significant efficacy	Skin mass, depression, upper respiratory tract infection, pyrexia	NCT05014438
S1PR1/S1PR4/S1PR5	Etrasimod	Oral	Phase IIb	EASI-50	Nausea, constipation, back pain, dizziness	[110]
H4R	Adriforant	Oral	Phase II	EASI-75	Headache, somnolence, nasopharyngitis, eczema, urinary tract infection	[150]
GPCR19	HY209	Topical	Phase II	Not available	Not available	NCT04530643
LXR	VTP-38543	Topical	Phase I/II	No significant efficacy	Upper respiratory tract infection, fatigue, cellulitis, dizziness, pruritus	[151]
LXR	ALX-101	Topical	Phase IIb	Not available	Not available	NCT03859986

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CPK: creatine phosphokinase; EASI: eczema area and severity index; EASI 50/75/90: ≥ 50/75/90% improvement in EASI from baseline; GPCR19: G protein-coupled receptor 19; H4R: type 4 histamine receptor; IGA: investigator global assessment; IGA 0/1: “clear or almost clear” with ≥ 2-point improvement in IGA from baseline; I-NRS: itch numeric rating scale; JAK: janus kinase; KOR: kappa opioid receptor; LXR: liver X receptor; mEASI: modified eczema area and severity index; mEASI 50/75/90: ≥ 50/75/90% improvement in mEASI from baseline; NCT: national clinical trial identifier consultable on www.clinicaltrials.gov (website consulted last time as of April 30, 2024), only clinical trials in advanced phases (Phase II onwards) are listed; NK1R: neurokinin 1 receptor; PDE4: phosphodiesterase 4; Pan-JAK: multiple janus kinases inhibitor; P2X3: purinergic receptor P2X; SCORAD: scoring atopic dermatitis; SCORAD 50: ≥ 50% improvement in SCORAD from baseline; S1PR1/4/5: sphingosine 1-phosphate receptor 1/4/5; TYK: tyrosine kinase; WI-NRS: worst itch numeric rating scale; WI-NRS/I-NRS ≥ 4: ≥ 4-point change in WI-NRS/I-NRS from baseline