Table Info

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

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

Declarations

Author contributions

GTS: Conceptualization, Writing—original draft, Writing—review & editing. EAF and MM: Writing—original draft. KN: Writing—review & editing. SB: Conceptualization, Writing—review & editing, Supervision, Funding acquisition. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This research was funded by the South African Research Chairs Initiative of the Department of Science and Technology (DST) and the National Research Foundation (NRF) [47904] of South Africa. The NRF and the South African Research Chair in Cancer Biotechnology have provided bursaries to support students contributing to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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