Protagonist Introduces Oral Peptide IL-17 Antagonist PN-881

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Protagonist Therapeutics announced this week that PN-881 has been identified as a development candidate for immune-mediated skin diseases, positioning it as a potential best-in-class oral interleukin-17 (IL-17) antagonist. They stated this innovative therapeutic represents a promising advance in the treatment of dermatologic conditions driven by IL-17 pathways, including psoriasis.¹

“We are extremely pleased to nominate development candidate PN-881, a promising potential best-in-class oral peptide IL-17 antagonist that has demonstrated robust activity against all three therapeutically relevant dimeric forms of the IL-17 ligand in preclinical testing. The potency of PN-881 in our testing is orders of magnitude better than an anti-IL-17 oral small molecule analog, and better than, or on par with, various approved or developmental stage injectable antibody or nanobody therapeutic agents,” said Dinesh V. Patel, PhD, president and CEO of Protagonist, in a press release. “PN-881 is another example of our expertise with discovery and development of oral peptides. Earlier this week, we and our partner announced the successful outcome in two separate Phase 3 psoriasis studies with the oral peptide IL-23 receptor antagonist icotrokinra.”

Mechanism and Preclinical Performance

According to the release, preclinical studies demonstrated PN-881's ability to inhibit all 3 dimeric forms of IL-17 (AA homodimer, FF homodimer, and AF heterodimer) with remarkable potency. Researchers stated comparative studies reveal that PN-881 exhibits approximately 100-fold greater efficacy than secukinumab and achieves potency on par with the most effective injectable IL-17-targeted antibodies and nanobody therapeutics currently approved or in development.

The preclinical profile includes:

• Oral Stability and Potency: Optimized for oral delivery, PN-881 maintains robust bioactivity.
• Tissue Distribution and Pharmacokinetics: Favorable distribution with measurable pharmacologic activity in serum and skin.
• Efficacy in Disease Models: Demonstrated proof-of-concept in rodent models of skin inflammation, showing effective blockade of IL-17 activity following oral administration.

Development Pathway

Protagonist Therapeutics is advancing PN-881 through IND-enabling studies, including short- and long-term toxicology assessments. The company stated phase 1 clinical trials are scheduled to commence in Q4 2025, encompassing single ascending dose and multiple ascending dose studies. They wrote that these trials will provide foundational data for subsequent dose-ranging studies in psoriasis and potential expansion into additional IL-17-mediated conditions such as psoriatic arthritis, hidradenitis suppurativa, and axial spondyloarthropathies.

“IL-17 and IL-23 blockers are collectively expected to lead the dermatology market, with broad opportunity for multiple indications in addition to psoriasis. An IL-17 antagonist peptide like PN-881, with best-in-class potential as an oral targeted therapy, offers an attractive therapeutic option for patients and represents another potential blockbuster drug opportunity for Protagonist,” added Dr. Patel. “We look forward to progressing PN-881 rapidly into a first-in-human Phase 1 study in Q4 2025.” 

Conclusion

The company stated PN-881 represents a novel oral therapy with the potential to redefine IL-17-targeted treatments. If clinical trials confirm its efficacy and safety, it could provide a transformative alternative for managing psoriasis and other IL-17-mediated conditions, further diversifying the therapeutic landscape.

References

1. Protagonist announces nomination of PN-881, a potential best-in-class oral peptide IL-17 antagonist Development Candidate. News Release. Protagonist Therapeutics. Published November 18, 2024. Accessed November 22, 2024. https://www.biospace.com/press-releases/protagonist-announces-nomination-of-pn-881-a-potential-best-in-class-oral-peptide-il-17-antagonist-development-candidate