International Psoriasis Council

Advancing Knowledge. Improving Care.

Advancing Knowledge. Improving Care.

Commentary: An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis

Lluís Puig, MD, PhD

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

IPC Board Member

Bio

PUBLICATIONS

An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis. Bissonnette R, Pinter A, Ferris L, et al. N Engl J Med. 2024 Feb 8;390(6):510-521. doi: 10.1056/NEJMoa2308713.

Why this article was chosen

The amazing progress in psoriasis treatment since the introduction of biological agents epitomizes the therapeutic achievements of translational medicine. According to a recently published Bayesian network meta-analysis, the short-term (12-16 weeks) psoriasis area and severity index (PASI) 90 response rate estimates for the most recently introduced (and most efficacious) biologics range between 69% and 84%, and complete clearance (PASI100) can be expected to be achieved by 36% to 59% of patients.1  This starkly contrasts with the best performer (and most recently available) of the oral agents, deucravacitinib, for which the corresponding estimated response rates are 29% and 11%, respectively.

There is an unmet need and desire among psoriasis patients for oral agents with improved clinical efficacy and safety profiles comparable to biologics. The publication by Robert Bissonette et al. discloses the results of FRONTIER 1, a phase 2b trial of JNJ-2113, an oral interleukin-(IL)-23–receptor antagonist peptide that represents a potential ground-breaking advance in the oral treatment of moderate to severe plaque psoriasis.2

Commentary

On April 18, 2017, Patent US9624268B2 application (’Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases’) was granted to Protagonist Therapeutics Inc. This patent includes a peptide dimer inhibitor of the IL-23 receptor (preventing binding of IL-23) with several possible variants (intramolecular bonds and linker moieties), the corresponding polynucleotide sequence encoding the peptide monomers, its vector, the pharmaceutical composition comprising an enteric coating, as well as multiple potential therapeutic indications and routes of administration of the peptide.3

On May 30, 2017, Protagonist Therapeutics Inc. entered into a worldwide license and collaboration agreement with Janssen Biotech, Inc. for the co-development and commercialization of PTG-200 for all indications, including inflammatory bowel disease.4 This agreement was built on a prior Series B venture financing that has been ongoing since 2013 and included second-generation compounds such as PN-232 and PN-235 (currently JNJ-2113).

In preclinical trials, JNJ-2113 achieved inhibition of colon inflammation in rat colitis models and inhibited IL-23-induced skin inflammation similar to inhibition observed when using an anti-IL-23 antibody; furthermore, in human pharmacokinetic studies, systemic absorption and pharmacodynamic activity were excellent for an orally administered peptide.5

The FRONTIER 1 Phase 2b trial (NCT05223868) evaluated several dosages of JNJ-2113 in patients with moderate to severe plaque psoriasis. A total of 255 participants were randomized into six treatment groups: placebo (n=43), 25 mg daily (n=43), 25 mg twice daily (BID) (n=41), 50 mg daily (n=43), 100 mg daily (n=43), and 100 mg BID (n=42).2 The total trial duration was 24 weeks, including a four-week screening period, a 16-week treatment period, and a four-week safety follow-up period to be followed by an extension study (FRONTIER 2).

The primary endpoint of the clinical trial was the proportion of patients achieving PASI75 at 16 weeks, and the response rates achieved ranged between 37% and 79% with a well-defined dose-dependent response compared to 9% for placebo. Furthermore, PASI90 responses ranged between 26% and 60%, and the PASI100 response climbed to 40% for the 100 mg BID dose, a previously unattainable goal for oral treatments and many biologics. The safety profile was comparable to that of placebo, with no evidence of a dose-related increase in adverse events.2

Interestingly, the clinical outcomes correlate nicely with serum biomarker levels, such as IL-22 and beta-defensin 2, and JNJ-2113 treatment does not increase serum levels of IL-23 (a potential concern upon blockade of its receptor).6

FRONTIER 2 (NCT05364554) is a Phase 2b multicenter, double-blind, long-term extension of FRONTIER 1 that enrolled 227 participants from FRONTIER 1 who continued with the same dosing regimen; the total duration of the trial was 52 weeks.7 Response rates were maintained from Week 16 to Week 52, with the highest responses observed in the 100 mg BID group (Table 1). Safety in the FRONTIER 2 was consistent with FRONTIER 1. Serious adverse events were uncommon, occurring in 4% of the combined JNJ-2113 patients through Week 52 and seemingly unrelated to study treatment.

Table 1. PASI90 and PASI100 response rates corresponding to the most efficacious biologic and oral therapeutic agents for moderate to severe psoriasis at 16 weeks (short term) or 52 weeks (long term), corresponding to network meta-analysis estimates1 or actual clinical trial (FRONTIER 1 and 2) results.2

Table 1. PASI90 and PASI100 response rates corresponding to the most efficacious biologic and oral therapeutic agents for moderate to severe psoriasis at 16 weeks (short term) or 52 weeks (long term), corresponding to network meta-analysis estimates1 or actual clinical trial (FRONTIER 1 and 2) results.2

The pivotal Phase 3 ICONIC clinical development program in psoriasis is underway: ICONIC-LEAD (NCT06095115) will evaluate the safety and efficacy of JNJ-2113 compared with placebo in adolescent and adult patients with moderate to severe plaque psoriasis, with PASI90 and the Investigator’s Global Assessment (IGA) score of 0 or 1 with at least a 2-grade improvement as co-primary endpoints. ICONIC-TOTAL (NCT06095102) will include participants with at least moderate severity affecting special areas (e.g., scalp, genital, and/or palmoplantar psoriasis) with overall IGA score of 0 or 1 with at least a 2-grade improvement as the primary endpoint.

Janssen has also initiated the Phase 2b ANTHEM-UC study (NCT06049017) to evaluate the safety and effectiveness of JNJ-2113 compared with placebo in participants with moderately to severely active ulcerative colitis.

Bioengineering advances have allowed marked improvements in the bioavailability of orally administered peptides. The tolerability of JNJ-2113 seems excellent, though 1) it needs to be taken on an empty stomach, 2) once-daily dosing would be preferred compared to BID, and 3) dose adjustments might be required for patients with higher weight to achieve the maximum therapeutic benefit.

The durability of the effect upon discontinuation of JNJ-2113 (the possibility of disease modification) remains to be assessed. On the other hand, the convenience of long intervals between injections and adherence issues might make subcutaneously administered biologics preferable for many psoriasis patients. If confirmed by the results of ongoing pivotal trials, JNJ-2113 might be the first of a new class of agents with ground-breaking efficacy and safety that may pioneer a new era for the oral treatment of psoriasis and other inflammatory diseases.

References

  1. Short-, Mid-, and Long-Term Efficacy of Deucravacitinib Versus Biologics and Nonbiologics for Plaque Psoriasis: A Network Meta-Analysis. Armstrong AW, Warren RB, Zhong Y, et al. Dermatol Ther (Heidelb). 2023 Nov;13(11):2839-2857. doi: 10.1007/s13555-023-01034-7.
  2. An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis. Bissonnette R, Pinter A, Ferris L, et al. N Engl J Med. 2024 Feb 8;390(6):510-521. doi: 10.1056/NEJMoa2308713.
  3. Oral Peptide Inhibitors of Interleukin-23 Receptor and Their Use to Treat Inflammatory Bowel Diseases 2017. Gregory Thomas Bourne AB, Xiaoli Cheng, et al., inventor; Protagonist Therapeutics Inc, assignee.
  4. Janssen Enters into Worldwide Exclusive License and Collaboration Agreement with Protagonist Therapeutics, Inc. for the Oral Interlukin-23 Receptor Antagonist Drug Candidate for The Treatment of Inflammatory Bowel Disease. Johnson J. 2017 [Available from: https://www.jnj.com/media-center/press-releases/janssen-enters-into-worldwide-exclusive-license-and-collaboration-agreement-with-protagonist-therapeutics-inc-for-the-oral-interlukin-23-receptor-antagonist-drug-candidate-for-the-treatment-of-inflammatory-bowel-disease.
  5. First-in-class Oral Peptide Systemically Targeting the IL-23 Pathway. Fourie A, Cheng X, Chang L, et al. Poster Presented at the ISID Meeting, May 10-13, 2023; Tokyo, Japan.
  6. JNJ-77242113 Treatment Induces a Strong Systemic Pharmacodynamic Response Versus Placebo in Serum Samples of Patients with Plaque Psoriasis: Results from the Phase 2, FRONTIER 1 Study. Pinter A, Eyerich K, Paller A, et al. Oral presentation (FC08) at the European Academy of Dermatology and Venereology (EADV) Congress, October 11-14, 2023; Berlin, Germany.
  7. A Phase 2b, Long-term Extension, Dose-ranging Study of Oral JNJ-77242113 for the Treatment of Moderate-to-Severe Plaque Psoriasis: FRONTIER 2. Ferris L, et al. Oral presentation (Abstract #S026) at the American Academy of Dermatology (AAD) 2024 Annual Meeting. March 2024.

One thought on “Commentary: An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis

  1. Abu Chowdhury says:

    Excellent, time demand

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