AAD Reading Room | Oral IL-23 inhibitor shows promise for moderate to severe psoriasis in new trial

JNJ-77242113, an investigational IL-23 inhibitor that can be administered orally, showed robust efficacy after 16 weeks in patients with moderate to severe plaque psoriasis.

Researchers randomly assigned psoriasis patients to receive placebo or JNJ-77242113 at doses of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily. day or 100 mg twice daily for 16 weeks. The primary endpoint was a reduction of at least 75% in Psoriasis Area and Severity Index (PASI) score (i.e., PASI 75).

The phase II dose-finding trial, known as FRONTIER 1, was funded by Janssen Research and Development, the drug’s maker, and undertaken by North American and European researchers, including the first author of the article, Robert Bissonnette, MD, President, CEO and Medical Director of Innovaderm. , a dermatological research company based in Montreal, Canada. The report appears in the New England Journal of Medicine. The following excerpts have been edited for length and clarity.

What key knowledge gap was this survey designed to fill?

IL-23 inhibitors have been shown to be effective in the treatment of psoriasis and are associated with a more favorable safety profile than older oral treatments (e.g., cyclosporine, acitretin, methotrexate, and fumarate dimethyl).

One of the main limitations of IL-23 inhibitors is that they require intravenous or subcutaneous administration. Over the past 10 years, two oral therapies – apremilast (Otezla) and deucravacitinib (Sotyktu) – have been approved for the treatment of psoriasis. However, apremilast has shown only modest effectiveness compared to injectable biologics, and long-term safety data for tyrosine kinase 2 inhibitors like deucravacitinib are limited.

There is therefore a need for effective targeted therapies that can be administered orally.

JNJ-77242113 is an oral IL-23 antagonist peptide that selectively and potently blocks proximal IL-23 signaling and the production of downstream cytokines such as IL-17. Here, researchers reported results from FRONTIER 1, a phase II trial of JNJ-77242113 in patients with moderate to severe plaque psoriasis.

What were the main results?

A total of 255 patients were randomized, with a mean PASI score of 19.1 at baseline. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 dosing groups (37%, 51%, 58%, 65%, 79% in the 25 mg once-a-day groups). daily and 25 mg twice daily, 50 mg once daily, 100 mg once daily and 100 mg twice daily, respectively) than among those in the placebo group (9%). The results showed a significant dose-response relationship (P.<0.001).

Additionally, a PASI 90 response occurred in 26%, 27%, 51%, 47%, and 60% of patients in the respective JNJ-77242113 groups compared to 2% of patients in the placebo group.

What were the safety results?

Adverse events were reported in 20 patients (47%), 20 patients (49%), 26 patients (60%), 19 patients (44%), and 26 patients (62%) in the respective JNJ-77242113 groups and in 22 patients (51%) in the placebo group.

The most common adverse events (incidence ≥5% in all trial groups) were COVID-19, nasopharyngitis, upper respiratory tract infection, diarrhea, headache, and cough. The incidence of adverse events was generally similar in the combined JNJ-77242113 and placebo groups. The incidence of diarrhea was 5% in the JNJ-77242113 combination group and 2% in the placebo group; the incidence of diarrhea does not appear to increase with higher doses of JNJ-77242113. Nervous system disorders (undefined) occurred in 5% of patients in the JNJ-77242113 combination group and in 2% of those in the placebo group.

Three serious adverse events (in three patients) were reported, all in the combined JNJ-77242113 group: one case of COVID-19, one infected cyst, and one suicide attempt.

No major adverse cardiovascular events, cancers or deaths were reported during the trial, the researchers noted. However, the researchers noted that larger, longer trials would be needed to assess the occurrence of any uncommon adverse events.

What are the key takeaway messages for dermatologists?

The level of psoriasis reduction observed with higher doses of JNJ-77242113 at week 16 was of a similar magnitude to responses observed with several of the injectable biologics currently approved for psoriasis. The percentage of patients who had a PASI 90 response with JNJ-77242113 100 mg twice daily at week 16 was 60%. In contrast, phase 3 trials of other available oral treatments showed that 27 to 36% of patients had a PASI 90 response after 16 weeks of treatment with deucravacitinib, and 18 to 20% of patients had a response. PASI 90 with apremilast one week later. 16.

However, without comparative trials, no conclusions can be drawn about the comparative effectiveness of JNJ-77242113. Results from the FRONTIER 2 trial, as well as Phase III trials, may clarify the magnitude and durability of the clinical response to JNJ-77242113.