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Review
. 2024 Feb 6;16(2):239.
doi: 10.3390/pharmaceutics16020239.

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis

Elena Carmona-Rocha  1   2   3 , Lluís Rusiñol  1   2   3 , Lluís Puig  1   2   3
Affiliations
Review

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis

Elena Carmona-Rocha et al. Pharmaceutics. .

Abstract

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis.

Keywords: IL-17 inhibitors; IL-23 inhibitors; Jak inhibitors; PDE4 inhibitors; biologics; oral therapies; psoriasis; roflumilast; systemic treatment; tapinarof; topical therapies.

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Conflict of interest statement

E.C.-R. has perceived the speaker’s honoraria from Boehringer-Ingelheim and Amgen. L.R. declares no conflicts of interest for the related topic. L.P. has perceived consultancy/speaker’s honoraria from and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Fresenius-Kabi, Gebro, Janssen, JS BIOCAD, Leo-Pharma, Lilly, Novartis, Pfizer, Samsung-Bioepis, and UCB.

Figures

Figure 1
Figure 1
Main inflammatory pathways involved in psoriasis pathogenesis and current and potential therapeutic targets. Adapted from Rusiñol et al. [3]. (1) PDE4 inhibition increases intracellular levels of cAMP, activating PKA-mediated phosphorylation of the transcription factors CREB and ATF-1; this results in increased gene expression of anti-inflammatory cytokines and inhibition of NF-κB due to interaction with the coactivators CBP and p300. (2) Binding of A3AR agonist to its receptor (A3AR) inhibits the activity of PKB/Akt and reduces NF-κB activity. (3) Binding of TNF to TNFR activates the complex of TAK1 with its binding proteins; TAK1 phosphorylates the IKK complex and MAPKs JNK and p38, leading to activation of NF-κB and AP1, respectively, and proinflammatory gene expression. (4) Activation of the IL-17 receptor complex by IL-17A/F leads to recruitment of Act1, followed by TRAFs. TRAF6 activates the TAK1 pathway, resulting in activation of NF-κB and AP1. Inhibition of the chaperone HSP90 leads to reduced function of the Act1 adaptor protein, which is essential in IL-17 receptor signal transduction. (5) Activation of IL-36R recruits IRAK proteins and MyD88, which activate the IKK complex and MAPK. The latter activates AP1 in the nucleus, increasing pro-inflammatory gene expression. (6) Upon binding of IL-23 to its receptor complex, Tyk2 and JAK2 activate and phosphorylate STAT3, which dimerizes, enters the nucleus, and promotes the expression of proinflammatory genes and RORγt. JAK inhibitors disrupt this signaling by targeting Tyk2/JAK2. RORγt inhibition leads to decreased Th17 differentiation and response. (7) Sphingosine-1-phosphate signals through its G-protein-coupled receptors (S1P1-5R), activating multiple guanine nucleotide-binding proteins (G proteins) bound to the receptors. Gi activates PLC, cAMP, AKT, Rac, and Ras. The latter leads to downstream signaling via Raf, MEK, and ERK. Gq also activates PLC. PLC leads to PKC activation. G12/13 activates the small GTPase Rho, which binds and activates ROCK/ROK complex. (8) Tapinarof binds to AhR, forming a complex that heterodimerizes with ARNT, leading to downregulation of inflammatory cytokines and upregulation of skin barrier proteins. Created with BioRender.com (accessed on 31 January 2024). Abbreviations: A3AR, A3 adenosine receptor; AhR, aryl hydrocarbon receptor; Akt, Protein kinase B (PKB); ARNT, AhR nuclear translocator; AP1, activator protein 1; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CBP, CREB-binding protein; C/EBPs, CCAAT/enhancer binding proteins; CREB, cAMP-response element-binding protein; ERK, extracellular signal-regulated kinase; G12/13, protein G12/13; Gi, protein Gi; Gq, protein Gq; GPCR, G-protein coupled receptor; GTP, guanosine triphosphate; HSP90, heat shock protein 90; IKK, inhibitor of κB (IκB) kinase complex; JAK2, janus kinase 2; JNK, c-JUN N terminal kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MyD88, innate immune signal transduction adaptor; NF-kB, nuclear factor kappa light-chain enhancer of activated B cells; PKA, protein kinase A; PKC, protein kinase C; PDE, phosphodiesterase; ROR, retinoic acid-related orphan nuclear receptor; RAS, Rat sarcoma virus; Raf, rapidly accelerated fibrosarcoma; Rho, Ras homologous; ROCK/ROK, Rho-associated protein kinase; TAK1, transforming growth factor-beta (TGFβ)-activated kinase 1; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TRAF, TNF associated factors; TYK2, tyrosine kinase 2; S1P1-5R, sphingosine 1 phosphate receptor 1–5; STAT, signaling transducers and activators of transcription.
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