Protagonist Therapeutics' Icotrokinra and PN-881: Transforming Psoriasis Treatment with Breakthrough Data

The psoriasis treatment landscape is on the cusp of a major shift, thanks to Protagonist Therapeutics’ (NASDAQ: PTGX) Phase 3 data for icotrokinra and preclinical findings for PN-881, presented at the 2025 Society for Investigative Dermatology (SID) Annual Meeting. These results underscore the potential of two novel therapies to address critical unmet needs in a $20+ billion market where over 80% of patients remain undertreated.

Icotrokinra: A Breakthrough for High-Impact Psoriasis Sites

The Phase 3 ICONIC-TOTAL trial delivered striking results for icotrokinra, an oral peptide targeting the IL-23 receptor. The drug achieved its primary endpoint with 57% of patients reaching an Investigator’s Global Assessment (IGA) score of 0/1 (clear/almost clear skin) by week 16, compared to 6% on placebo (P < 0.001). Even more compelling:
- Scalp psoriasis: 66% of patients achieved clearance vs. 11% placebo (P < 0.001).
- Genital psoriasis: 77% achieved clearance vs. 21% placebo (P < 0.001).
- Hand/foot psoriasis: 42% achieved clearance vs. 26% placebo.

These outcomes highlight icotrokinra’s ability to treat difficult-to-manage areas where topical creams fail and biologics often fall short. The drug’s oral formulation adds a major advantage over injectable therapies like ustekinumab (Stelara) or deucravacitinib (Crohnjevix), which require subcutaneous or intravenous administration.

Safety data further strengthens its case: adverse events (AEs) occurred in 50% of icotrokinra-treated patients vs. 42% on placebo, with no new safety signals. Serious AEs were rare (0.5% vs. 1.9% placebo), and most side effects were mild, such as injection-site reactions in prior trials.

PN-881: A Next-Gen IL-17 Inhibitor with Game-Changing Potential

While icotrokinra targets IL-23, PN-881 is a first-in-class oral peptide that selectively blocks all three dimeric forms of IL-17 (AA, AF, FF). Preclinical data shows:
- 70-fold higher potency vs. secukinumab (Cosentyx), the leading anti-IL-17A antibody.
- Metabolic stability across species, enabling oral delivery—a first for IL-17 inhibitors.
- In a rat model of IL-23-induced inflammation, PN-881 reduced skin thickness in a dose-dependent manner.

The drug’s broad inhibition of IL-17 dimers addresses a critical limitation of existing therapies, which only target single isoforms. Protagonist plans to initiate human trials for PN-881 in Q4 2025, positioning it as a follow-on asset to icotrokinra.

Market Context: A $20+ Billion Opportunity with Massive Unmet Need

Psoriasis affects 125 million people globally, including 25% with moderate-to-severe disease. Current treatments are fragmented:
- Topicals: Limited to small areas or mild cases.
- Biologics: Effective but require injections, with risks of immunosuppression.
- Small molecules: Like deucravacitinib, which carry liver toxicity concerns.

icotrokinra and PN-881 address these gaps:
1. Convenience: Oral administration improves adherence.
2. Mechanism: Targeting IL-23 and IL-17 pathways—key drivers of psoriasis.
3. Efficacy: Site-specific results (e.g., 77% genital clearance) outperform existing options.

Strategic Moves and Investment Implications

Protagonist’s partnership with Johnson & Johnson (JNJ) is pivotal. J&J leads Phase 2+ development and commercialization for icotrokinra, leveraging its dermatology expertise. Meanwhile, PN-881’s fully owned pipeline asset expands Protagonist’s footprint in IL-17-driven diseases.

Risks and Considerations

• Competitor Threats: Biologics like bimekizumab (IL-17A/F antibody) and small molecules like abrocitinib (JAK inhibitor) are already on the market.
• Regulatory Hurdles: While icotrokinra’s Phase 3 data is robust, FDA approval is not guaranteed.
• PN-881’s Unknowns: Preclinical success does not guarantee human trial outcomes.

Conclusion: A New Era for Psoriasis Treatment

Protagonist’s data positions it as a category-defining player in dermatology. With icotrokinra addressing high-impact psoriasis sites and PN-881 targeting the IL-17 pathway, the company is tackling the 80% of patients inadequately treated by current options.

Key takeaways:
- icotrokinra’s 57% IGA response rate and 75% sustained response at week 52 suggest durable efficacy.
- PN-881’s 70-fold potency over secukinumab hints at superior efficacy, while its oral formulation could boost adherence.
- The global psoriasis market is projected to grow to $23 billion by 2027 (Grand View Research), with oral therapies capturing a growing share.

For investors, Protagonist’s pipeline represents a high-risk, high-reward bet on transformative therapies. If approved, icotrokinra alone could generate annual sales exceeding $1 billion, while PN-881 could extend that success into the IL-17 space.

In a crowded dermatology market, Protagonist is not just keeping up—it’s redefining the finish line.