JNJ-77242113, an experimental IL-23 inhibitor that can be administered orally, showed solid efficacy after 16 weeks in patients with moderate-to-severe plaque psoriasis.
Researchers randomly assigned patients with psoriasis 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, or 100 mg twice daily for 16 weeks. The primary end point was a reduction of at least 75% in the 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 manufacturer, and undertaken by North American and European researchers including paper first author Robert Bissonnette, MD, chief executive officer and medical director at Innovaderm, a dermatological research company based in Montreal, Canada. The report appears in the . The following excerpts have been edited for length and clarity.
What key knowledge gap was this investigation designed to address?
IL-23 inhibitors have shown efficacy in treating psoriasis and are associated with a more favorable safety profile than older oral therapies (e.g., cyclosporine, acitretin, methotrexate, and dimethyl fumarate).
One key limitation among IL-23 inhibitors is that they require intravenous or subcutaneous administration. In the past 10 years, two oral therapies -- apremilast (Otezla) and deucravacitinib (Sotyktu) -- were approved for the treatment of psoriasis. However, apremilast has shown only modest efficacy compared with injectable biologics, and long-term safety data for tyrosine kinase 2 inhibitors like deucravacitinib are limited.
Thus, there is a need for efficacious targeted therapies that can be administered orally.
JNJ-77242113 is an oral IL-23 antagonist peptide that selectively and potently blocks IL-23 proximal signaling and the production of downstream cytokines such as IL-17. Here, researchers reported the results of FRONTIER 1, a phase II trial of JNJ-77242113 in patients with moderate-to-severe plaque psoriasis.
What were the key results?
A total of 255 patients underwent randomization, with a mean PASI score at baseline of 19.1. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 dosage groups (37%, 51%, 58%, 65%, 79% in the 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, and 100 mg twice daily groups, respectively) than among those in the placebo group (9%). The finding showed a significant dose-response relationship (P<0.001).
Further, a PASI 90 response occurred in 26%, 27%, 51%, 47%, and 60% of the patients in the respective JNJ-77242113 groups, compared with 2% of patients in the placebo group.
What were the results on safety?
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 of ≥5% in any trial group) 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 combined JNJ-77242113 group and 2% in the placebo group; the incidence of diarrhea did not appear to increase with higher JNJ-77242113 doses. Nervous system disorders (not defined) occurred in 5% of the patients in the combined JNJ-77242113 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: a case of COVID-19, an infected cyst, and a suicide attempt.
No major adverse cardiovascular events, cancers, or deaths were reported during the trial, researchers noted. However, researchers noted that larger and longer trials will be needed to assess the occurrence of any infrequent adverse events.
What are the key take-home messages for dermatologists?
The level of reduction of psoriasis that was observed with higher doses of JNJ-77242113 at week 16 was similar in magnitude to the responses seen with several of the injectable biologics that are 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 PASI 90 response with apremilast at week 16.
However, without head-to-head trials, no conclusions can be drawn about the comparative efficacy of JNJ-77242113. Results from the trial, as well as from phase III trials, can clarify the magnitude and durability of the clinical response to JNJ-77242113.
Addendum: Shortly after publication of this phase II study in the , phase IIb data were presented at the 2024 annual AAD meeting in March. Key takeaways are detailed .
The trial was supported by Janssen Research and Development.
The authors reported various relationships with industry.
Primary Source
New England Journal of Medicine
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