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Atopic dermatitis

Disease ID:94
Name:Atopic dermatitis
Associated with:2 targets
1 immuno-relevant target
15 immuno-relevant ligands
Database Links
Disease Ontology: DOID:3310
OMIM: 603165

Targets

BLT1 receptor
References:  12
INPP5D
Comments:  Target of activating compounds with potential immunosuppressant action. Phase 2 with rosiptor has been completed for atopic dermatitis.
Ligand interactions: 
Ligand Comments
rosiptor
Phase 2 clinical trial NCT02324972 completed.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
tralokinumab
Immuno Disease Comments: Phase 3 clinical candidate for atopic dermatitis (see NCT03131648).
Clinical Use: Tralokinumab reached Phase 3 clinical trials for uncontrolled asthma, and atopic dermatitis, and Phase 2 for alopecia areata. Click here to link to ClinicalTrials.gov's listing of Phase III tralokinumab trials. In addition, Phase 2 trials are investigating tralokinumab as a treatment for idiopathic pulmonary fibrosis (IPF, NCT01629667 and NCT02036580). Business reports online indicate that AstraZeneca have discontinued tralokinumab development as it showed no benefit over placebo in their STRATOS 2 and TROPOS late-stage asthma trials [1]. | View clinical data
asivatrep
Immuno Disease Comments: Phase 3 clinical candidate for atopic dermatitis.
Clinical Use: A Phase 3 clinical study evaluating PAC-14028 vs. atopic dermatitis is underway (see NCT02965118). Phase 2 studies for rosacea, seborrheic dermatitis and skin pruritus have been completed. | View clinical data
rovazolac
Immuno Disease Comments: Phase 2 clinical candidate for atopic dermatitis.
Clinical Use: A Phase 2 clinical trial evaluating ALX-101 as a topical treatment for moderate atopic dermatitis is underway (see NCT03175354). | View clinical data
tapinarof
Immuno Disease Comments: Phase 1 clinical candidate for atopic dermatitis- NCT02466152
Clinical Use: Topically applied tapinarof (research code GSK2894512) has shown clinical efficacy in Phase 2 clinical trial in patients with plaque psoriasis [4] (NCT02564042). A Phase 3 trial (NCT03202004) is ready to recruit subjects (Oct 2017). Tapinarof has also completed Phase 1 studies for atopic dermatitis. | View clinical data
Bioactivity Comments: Tapinarof inhibits proinflammatory cytokine expression in vitro and exhibits anti-inflammatory effects in vivo [14]. | View biological activity
OPA-15406
Immuno Disease Comments: Phase 2 clinical candidate for atopic dermatitis- see NCT02914548
Clinical Use: OPA-15406 has completed Phase 2 clinical trials in adult and pediatric patients with atopic dermatitis. Click here to view ClinicalTrials.gov's registered OPA-15406 trials. Positive Phase 2 trial results are published by Hanifin et al. (2016) [7]. | View clinical data
Bioactivity Comments: OPA-15406 exhibits high selectivity for the PDE4B isoform [7]. | View biological activity
cortisol
Immuno Disease Comments: Glucocorticoid drug used to treat many inflammatory condtions including allergic dermatitis.
Clinical Use: Hydrocortisone is used to treat many immune and allergic disorders, adrenal insufficiency disorders (eg Addison's disease) and corticosteroid-responsive dermatological disorders (eg psoriasis, atopic dermatitis, and contact dermatitis). | View clinical data
IL-31
Immuno Disease Comments: IL-31 expression is elevated in inflammatory cells in atopic dermatitis.
dupilumab
Immuno Disease Comments: Dupilumab is approved to treat atopic dermatitis (eczema).
Clinical Use: Dupilumab is being clinically assessed as a treatment for atopic allergic conditions, including asthma, atopic dermatitis (AD) and nasal polyposis. A list of trials registered at ClinicalTrials.gov is available here.
Preliminary results from one clinical trial in patients with persistent asthma, reports significant improvements in measures of lung function and asthma control when treated with dupilumab [17].
Results from a Phase II study in patients with nasal polyposis and chronic symptoms of sinusitis (NCT01920893) are reported by Bachert et al. (2016) [3]. Patients in this study were given dupilumab + or mometasone + dupilumab placebo. Dupilumab + mometasone reduced nasal polyp burden and improved symptoms of sinusitis to a greater extent than the mometasone + placebo treatment.
Dupilumab received full FDA approval for moderate-to-severe eczema (atopic dermatitis) in March 2017, and the EMA granted this same approval in August 2017. | View clinical data
Bioactivity Comments: Affinity data in the table below is taken from patent US7608693 [9], using antibody clone H4H098P as a representative example of the embodiment of the patent. The clone becoming dupilumab is not reported. | View biological activity
tezepelumab
Immuno Disease Comments: Clinical candidate for atopic dermatitis (Phase 1).
Clinical Use: Tezepelumab is being evaluated in clinical trials as a potential immunomodulatory agent for uncontrolled (especially noneosinophilic type) asthma (Phase 2- results of NCT02054130 published in [5]) and atopic dermatitis (AD; Phase 1). Click here to link to ClinicalTrials.gov's full listing of tezepelumab (research coded AMG 157 or MEDI9929) trials. | View clinical data
JNJ-39758979 8,10
Immuno Disease Comments: Failed to show clinical efficiency in Phase 2 trial.
Clinical Use: Phase 2a clinical trial results in patients with moderate atopic dermatitis are published in [10] which indicate that the study did not meet its primary end-point, and produced drug-induced agranulocytosis, explaining its termination. Phase 2 trial NCT00946569 in asthma patients has been completed. | View clinical data
Bioactivity Comments: Preclinical data are reported in [16]. | View biological activity
ZPL-3893787
Immuno Disease Comments: Completed Phase 2 trial in atopic dermatitis (see NCT02424253).
Clinical Use: ZPL-3893787 has reached Phase 2 clinical trial for evaluation as an antiinflammatory agent in patients with plaque psoriasis (see NCT02618616), and a Phase 1 in atopic dermatitis has been completed. | View clinical data
crisaborole
Immuno Disease Comments: Approved drug for atopic dermatitis.
Clinical Use: Crisaborole (with research code AN2728) has completed Phase 3 clinical trials as a monotherapy for atopic dermatitis (NCT02118792 and NCT02118766) and has received FDA approval for treatment of mild-to-moderate atopic dermatitis in December 2016. | View clinical data
Bioactivity Comments: Inhibits partially purified human PDE4 with an IC50 of 490nM, and inhibits cytokine release in vitro and in vivo [2]. | View biological activity
rosiptor
Immuno Disease Comments: Phase 2 clinical trial NCT02324972 completed.
Clinical Use: AQX-1125 has reached Phase 2 clinical trial in chronic inflammatory conditions such as unstable chronic obstructive pulmonary disease (COPD) and atopic dermatitis, and Phase 3 for interstitial cystitis/bladder pain syndrome [11] (see NCT02858453). Click here to link to ClinicalTrials.gov's full list of AQX-1125 trials. | View clinical data
Bioactivity Comments: AQX-1125 activates INPP5D enzyme activity by 20% (reducing the KM from 214 (control) to 180 [15]. This reduction in KM is concentration-dependent, but the compound has no effect on the enzyme's turnover constant (kcat) or maximum velocity (Vmax), which is indicative of allosteric modulation [15]. | View biological activity
timapiprant
Immuno Disease Comments: Phase 2 clinical candidate for atopic dermatitis.
Clinical Use: OC000459 is being evaluated in several Phase 2 clinical trials in various inflammatory and allergic conditions including asthma, allergic rhinitis and atopic dermatitis. Click here to link to a list of Phase 2 OC000459 trials registered with ClinicalTrials.gov. | View clinical data
Bioactivity Comments: OC000459 inhibits mast cell-dependent activation of human Th2 lymphocytes and eosinophils [13]. It does not antagonise ligand binding at any of the other prostanoid receptors [13]. | View biological activity
fezakinumab
Immuno Disease Comments: Active Phase 2 study NCT01941537.
Clinical Use: Fezakinumab (ILV-094) has reached Phase 2 for atopic dermatitis (NCT01941537 ongoing), rheumatoid arthritis (NCT00883896 completed) and Phase 1 for psoriasis (NCT00563524 completed). | View clinical data
Bioactivity Comments: Fezakinumab shows cross-species reactivity, blocking IL-22 receptor activation and cellular proliferation induced by murine, monkey and rat IL-22 in addition to the human cytokine [6]. | View biological activity

References

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1. Adams B. Sanofi ditches IL-4/IL-13 antibody drug in lung-scarring disease. Accessed on 09/02/2018. Modified on 09/02/2018. fiercebiotech.com, https://www.fiercebiotech.com/biotech/sanofi-ditches-il4-il13-antibody-drug-lung-scarring-disease

2. Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, Freund Y, Kimura R, Maples KR, Plattner JJ. (2009) Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg. Med. Chem. Lett., 19 (8): 2129-32. [PMID:19303290]

3. Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, Hellings P, Jiao L, Wang L, Evans RR et al.. (2016) Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial. JAMA, 315 (5): 469-79. [PMID:26836729]

4. Bissonnette R, Bolduc C, Maari C, Nigen S, Webster JM, Tang L, Lyle M. (2012) Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial. J Eur Acad Dermatol Venereol, 26 (12): 1516-21. [PMID:22077962]

5. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, van der Merwe R. (2017) Tezepelumab in Adults with Uncontrolled Asthma. N. Engl. J. Med., 377 (10): 936-946. [PMID:28877011]

6. Fouser LA, Hegen M, Luxenberg DP, O'Toole M. (2010) Methods of using antibodies against human IL-22. Patent number: US7811567. Assignee: Wyeth Llc. Priority date: 21/02/2006. Publication date: 12/10/2010.

7. Hanifin JM, Ellis CN, Frieden IJ, Fölster-Holst R, Stein Gold LF, Secci A, Smith AJ, Zhao C, Kornyeyeva E, Eichenfield LF. (2016) OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study. J. Am. Acad. Dermatol., 75 (2): 297-305. [PMID:27189825]

8. Kollmeier A, Francke K, Chen B, Dunford PJ, Greenspan AJ, Xia Y, Xu XL, Zhou B, Thurmond RL. (2014) The histamine H₄ receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects. J. Pharmacol. Exp. Ther., 350 (1): 181-7. [PMID:24817035]

9. Martin JH, Huang TT, Fairhurst JL, Papadopoulos NJ. (2009) Cytokine specific immunoglobulin for use in diagnosis, prevention and treatment ,of cell proliferative, inflammatory, allergic, respiratory, autoimmune and arthritic disorders. Patent number: US7608693. Assignee: Regeneron Pharmaceuticals, Inc.. Priority date: 02/10/2006. Publication date: 27/10/2009.

10. Murata Y, Song M, Kikuchi H, Hisamichi K, Xu XL, Greenspan A, Kato M, Chiou CF, Kato T, Guzzo C et al.. (2015) Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis. J. Dermatol., 42 (2): 129-39. [PMID:25491792]

11. Nickel JC, Egerdie B, Davis E, Evans R, Mackenzie L, Shrewsbury SB. (2016) A Phase II Study of the Efficacy and Safety of the Novel Oral SHIP1 Activator AQX-1125 in Subjects with Moderate to Severe Interstitial Cystitis/Bladder Pain Syndrome. J. Urol., 196 (3): 747-54. [PMID:26968644]

12. Oyoshi MK, He R, Li Y, Mondal S, Yoon J, Afshar R, Chen M, Lee DM, Luo HR, Luster AD et al.. (2012) Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation. Immunity, 37 (4): 747-58. [PMID:23063331]

13. Pettipher R, Vinall SL, Xue L, Speight G, Townsend ER, Gazi L, Whelan CJ, Armer RE, Payton MA, Hunter MG. (2012) Pharmacologic profile of OC000459, a potent, selective, and orally active D prostanoid receptor 2 antagonist that inhibits mast cell-dependent activation of T helper 2 lymphocytes and eosinophils. J. Pharmacol. Exp. Ther., 340 (2): 473-82. [PMID:22106101]

14. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D et al.. (2017) Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J. Invest. Dermatol., 137 (10): 2110-2119. [PMID:28595996]

15. Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Wu J, Ogden N, MacRury T et al.. (2013) Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br. J. Pharmacol., 168 (6): 1506-18. [PMID:23121445]

16. Thurmond RL, Chen B, Dunford PJ, Greenspan AJ, Karlsson L, La D, Ward P, Xu XL. (2014) Clinical and preclinical characterization of the histamine H(4) receptor antagonist JNJ-39758979. J. Pharmacol. Exp. Ther., 349 (2): 176-84. [PMID:24549371]

17. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B et al.. (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med., 368 (26): 2455-66. [PMID:23688323]