JNJ-2113: An Investigational Oral Therapy Targeting IL-23 in Plaque Psoriasis

Disclaimer: All articles and product details provided on this website are intended for educational and informational purposes only. The products listed here are for in-vitro research only. In-vitro studies are conducted outside of living organisms. These products are not intended as medicines or drugs and have not been approved by the FDA to prevent, treat, or cure any medical condition, ailment, or disease. The direct or indirect administration of these substances to humans or animals is unequivocally prohibited under applicable law.

Overview of JNJ-2113

JNJ-2113 (JNJ-77242113) represents the first oral small molecule specifically developed to inhibit the interleukin-23 (IL-23) receptor. IL-23 is a cytokine central to immune-mediated inflammatory processes, particularly in the pathogenesis of moderate-to-severe plaque psoriasis. By selectively blocking IL-23 receptor activity, JNJ-2113 reduces downstream inflammatory signaling, potentially offering a new therapeutic option distinct from currently available injectable biologics.

The introduction of an oral, targeted agent is clinically significant, as it may provide an alternative for patients who prefer oral administration while maintaining efficacy and safety in long-term disease management.

Psoriasis: Disease Background

Psoriasis is a chronic immune-mediated condition affecting over 8 million individuals in the United States. It is characterized by an accelerated turnover of epidermal keratinocytes driven by dysregulated immune pathways. The most prevalent form, plaque psoriasis, presents with erythematous, raised, scaly plaques often associated with pruritus and discomfort.

Other forms include guttate, pustular, inverse, and erythrodermic psoriasis, each with distinct clinical features. Although no curative therapy exists, available treatments—ranging from topical agents and phototherapy to systemic and biologic therapies—aim to reduce inflammation, normalize epidermal turnover, and achieve sustained remission.

Mechanism of Action of JNJ-2113

The therapeutic effect of JNJ-2113 is mediated through specific antagonism of the IL-23 receptor:

1. Role of IL-23: IL-23 promotes the survival and expansion of Th17 cells, which in turn produce pro-inflammatory cytokines including interleukin-17 (IL-17). These mediators drive keratinocyte proliferation, immune cell recruitment, and the development of psoriatic lesions.
2. Target Engagement: JNJ-2113 binds directly to the IL-23 receptor expressed on T cells and other immune cells, thereby preventing IL-23 from activating downstream signaling pathways.
3. Downstream Effects: By blocking IL-23–mediated signaling, JNJ-2113 reduces Th17 activation and subsequent IL-17 production. This leads to decreased skin inflammation, normalization of keratinocyte turnover, and improvement of clinical symptoms in moderate-to-severe plaque psoriasis.

This precise targeting of the IL-23 pathway distinguishes JNJ-2113 from traditional immunosuppressive therapies that broadly modulate immune activity.

Clinical Data: FRONTIER Studies

FRONTIER 1 (Phase 2b)

The initial randomized, placebo-controlled, dose-ranging trial evaluated the efficacy of JNJ-2113 in adults with moderate-to-severe plaque psoriasis. Results demonstrated dose-dependent improvements in Psoriasis Area and Severity Index (PASI) and Investigator’s Global Assessment (IGA) responses.

FRONTIER 2 (Long-Term Extension)

The extension study followed patients from FRONTIER 1 for an additional year. Key findings included:

• Sustained Efficacy: Across all five dosing regimens, skin clearance rates observed at Week 16 were maintained through Week 52.
• Optimal Dosing: The 100 mg twice-daily regimen achieved the highest clearance, with PASI 75 responses in 78.6% at Week 16 and 76.2% at Week 52.
• Safety Profile: Adverse events occurred in 58.6% of patients, most commonly nasopharyngitis, upper respiratory infections, and COVID-19. Serious adverse events were rare (4%) and none were considered treatment-related.

Dr. Laura Ferris, University of Pittsburgh, emphasized that both efficacy and safety outcomes remained consistent through one year, underscoring JNJ-2113’s potential as a convenient long-term oral option.

Ongoing and Future Research

JNJ-2113 is advancing into pivotal late-stage trials:

• ICONIC Program (Phase 3):
  • ICONIC-LEADe and ICONIC-TOTAL: Designed to confirm long-term efficacy and safety in moderate-to-severe plaque psoriasis.
  • ICONIC-ADVANCE 1 and 2: Comparative studies against placebo and deucravacitinib.
• Ulcerative Colitis (ANTHEM-UC, Phase 2b): Evaluating JNJ-2113 in immune-mediated gastrointestinal disease, broadening its therapeutic potential beyond dermatology.

According to Lloyd Miller, M.D., Ph.D., Vice President at Johnson & Johnson, the program reflects a broader strategy to innovate within immunodermatology and other IL-23–driven conditions.

Clinical Implications

The development of JNJ-2113 introduces the possibility of a first-in-class oral IL-23 receptor antagonist for psoriasis. If validated in Phase 3 studies, this therapy could fill a critical gap for patients requiring effective, durable treatment without injections. Its mechanism of selective IL-23 blockade aligns with evolving strategies to target specific immune pathways while minimizing systemic immunosuppression.

REFERENCES

Bissonnette, R., et al. An Oral Interleukin-23–Receptor Antagonist for Plaque Psoriasis. New England Journal of Medicine. 390(6), 510–521. 2024. https://doi.org/10.1056/nejmoa2308713