Multiple novel oral agents show promise in psoriasis

Although biologics are known to offer high response rates in patients with psoriasis, novel upcoming agents show promise with good efficacy and the advantage of oral administration. Prof. April Armstrong (University of California Los Angeles, CA, USA) reviewed upcoming agents targeting the IL-23/IL-17 axis, as well as PDE4 and TYK2 inhibitors.

JNJ-77242113, an oral peptide that inhibits IL-23 signalling through blocking the IL-23 receptor, was assessed in the long-term extension phase 2b FRONTIER 2 trial (NCT05364554) [1]. Recently presented 1-year data showed that JNJ-77242113 100 mg twice daily led to 76.2% of participants achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI75) scores, with 64.3% of participants achieving PASI90. Furthermore, 52 weeks of treatment with the 100 mg twice daily dose led to scalp clearance in 67% of participants who experienced scalp involvement. The most commonly reported adverse events included nasopharyngitis, upper respiratory tract infection, COVID-19, and headache, but, importantly, no increase in gastrointestinal toxicities was observed with increasing doses of JNJ-77242113.

Prof. Armstrong provided a list of PDE4 inhibitors in development for inflammatory skin diseases, including orismilast, ME3183, zatolmilast, PF-07038124, and roflumilast [2]. In particular, ME3183 was assessed in a phase 2a study showing that the 7.5 mg twice daily dose can lead to 61.5% of participants achieving PASI75, with 53.8% achieving PASI90 after 16 weeks of treatment [3]. Overall, the agent was well tolerated, but some gastrointestinal adverse events were still present at the higher doses assessed in this trial [2,3].

Of the novel TYK2 inhibitors for the treatment of psoriasis, TAK-279 led to high rates of PASI75 (~70%) in a recent phase 2b trial (NCT04999839) [5]. Furthermore, when assessing the gene expression of psoriasis genes, 12 weeks of treatment with TAK-279 resulted in psoriasis lesional skin reverting to gene expression levels which were more similar to non-lesional skin. Another novel TYK2 inhibitor is ESK-001, which was assessed in the phase 2 STRIDE study in participants with moderate-to-severe plaque psoriasis (NCT05600036) [6]. In this trial, 64.1% of participants receiving 40 mg twice daily ESK-001 achieved PASI75, including 38.5% achieving PASI90.

In summary, small peptides have shown initial potential for treating psoriasis through inhibition of the IL-23 pathway, while several upcoming inhibitors of the known TYK2 and PDE4 inhibitors are being assessed in several clinical trials with promising results [2].

1. 
   
   1. Ferris LK, et al. Abstract S026, 2024 AAD Annual Meeting, 8–12 March, San Diego, USA.
   2. Armstrong A, et al. Emerging oral therapies. IFPA Conference 2024, 27–29 June. Stockholm, Sweden.
   3. Papp KA, et al. EADV 2023. Abstract 6624, EADV Congress 2023, 11–14 October, Berlin, Germany.
   4. Armstrong A, et al. AAD 2023. Abstract S025, AAD 2023 Annual Meeting, 17–21 March, New Orleans, USA.
   5. Krueger JG, et al. Poster 50378, 2024 AAD Annual Meeting, 8–12 March, San Diego, USA.
   6. Papp KA, et al. LB1, 2024 AAD Annual Meeting, 8–12 March, San Diego, USA.

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Posted on 17 July 202417 July 2024