Existing and upcoming small molecules in psoriasis

Small molecules act on intracellular signalling pathways; thus, indirectly acting on key proinflammatory cytokines in psoriasis. They are less specific than biologics but have the advantage of oral or topical administration. Roflumilast, deucravacitinib, and tapinarof have shown promising data in phase 2 and phase 3 trials.

Dr Enikö Sonkoly (Karolinska University Hospital, Sweden) pointed out that the immunological changes and gene expression alterations behind the pathogenesis of psoriasis have been identified through extensive laboratory experiments and clinical drug trials [1]. IL-23 and IL-17 are thought to play a central role in initiating a keratinocyte response and maintaining the inflammatory process.

Conventional treatment options for psoriasis are limited and include corticosteroids and vitamin D analogues. Currently on the rise are new and targeted treatments such as biologics and small molecules. A fundamental difference between the two is that biologics target single cytokines like TNF, IL-17, and IL-23 and their receptors in the intercellular signalling pathways, while small molecules target intracellular signalling pathways that contribute to the pathogenesis of psoriasis (see Table).

Small molecules are synthesised chemically and thus cheaper. Also, they are less cell-specific compared with biologics, and due to their low molecular weight, they can be administered orally and topically. A few small molecules, such as apremilast, have already been approved for the treatment of psoriasis, and several others are currently undergoing clinical trials (see Table).

Table: Existing and upcoming small molecules in psoriasis [1]
AD, atopic dermatitis; cAMP, cyclic adenosine monophosphate; IL, interleukin; JAK, Janus kinase; PDE4, phosphodiesterase 4; PsA, psoriatic arthritis; Pso, plaque psoriasis; RA, rheumatoid arthritis; STAT, signal transducers and activators of transcription; TYK, tyrosine kinase.

Apremilast is an oral PDE4 inhibitor, which acts on the PDE4/cAMP pathway and decreases proinflammatory cytokines while increasing anti-inflammatory cytokines. It has been approved for psoriasis and psoriatic arthritis and has demonstrated good efficacy, also in-difficult-to treat areas such as the scalp, nails, and palmoplantar area. “It is also suitable for patients with many comorbidities, such as malignancy,” Dr Sonkoly said. New phase 3 data also demonstrated apremilast’s efficacy in mild-to-moderate plaque psoriasis [2].

Roflumilast, a topical PDE4 inhibitor that has already completed phase 2b trials, is thought to have the same efficacy as high-potency topical steroids. It has shown an at least 2-point improvement from baseline in the intertriginous Investigator’s Global Assessment (IGA) score in 86% of patients, compared to 29% in controls. Due to the absence of topical corticosteroids side effects, it could be a promising option to treat intertriginous psoriasis.

Dr Sonkoly also pointed out that of the many existing Janus kinase (JAK) inhibitors, only tyrosine kinase (TYK)2 inhibitors were further developed for the treatment of psoriasis due to the adverse events caused by JAK inhibitors. TYK2 receptors are important for IL-23 signalling. Deucravacitinib is an oral, small molecule TYK2 inhibitor that was recently assessed in the trials POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) [3]. It showed superiority over apremilast and placebo across multiple efficacy endpoints. A quick onset of action is another advantage of this agent.

Tapinarof is a topical, small molecule, aryl hydrocarbon receptor agonist that works by decreasing inflammatory cytokines and normalising the skin barrier. There are published phase 2b and 3 trials demonstrating its efficacy. Phase 2b trials showed an improvement in the Physician’s Global Assessment (PGA) response, change in PGA, and total target grading scores with the use of 0.5% or 1% tapinarof cream twice daily compared with vehicle once or twice daily for 12 weeks [4]. The recently published phase 3 trials PSOARING 1 and 2 (NCT03956355 and NCT03983980) revealed similar results [5].

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   1. Sonkoly E. Existing and upcoming small molecules. D1T03.2A, EADV Congress 2021, 29 Sept–2 Oct.
   2. Stein Gold L, et al. J Am Acad Dermatol. 2021;Jul 31. DOI:1016/j.jaad.2021.07.040.
   3. Armstrong A, et al. Ann Rheum Dis. 2021;80 (suppl 1):795–796.
   4. Stein Gold L, et al. J Am Acad Dermatol. 2021;84(3):624-631.
   5. Lebwohl M, et al. Skin. 2020;4:s75.

 

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Posted on 18 November 202116 February 2024