How Protagonist Therapeutics is building a multi‑indication macrocyclic peptide portfolio with icotrokinra and beyond

Protagonist Therapeutics, Inc. (NASDAQ: PTGX), a clinical-stage American biotech company, is aiming to redefine oral biologic delivery through its macrocyclic peptide platform. The company’s lead candidate, icotrokinra, is progressing through Phase 3 trials in plaque psoriasis and ulcerative colitis, supported by strategic alliances with Johnson & Johnson and Takeda. As regulatory filings near and clinical momentum builds, institutional investors are assessing whether Protagonist Therapeutics could emerge as a new pillar in oral immunology and hematology treatment.

What makes icotrokinra a potential blockbuster in oral IL-23-targeted therapies for psoriasis and colitis?

Icotrokinra, a macrocyclic peptide under development by Protagonist Therapeutics, Inc. (NASDAQ: PTGX), is emerging as one of the most clinically advanced and commercially promising oral biologic candidates in the immunology space. The molecule functions as a selective interleukin-23 receptor (IL-23R) antagonist and is designed to offer injectable-level efficacy in inflammatory conditions—without the need for intravenous or subcutaneous delivery. This novel mode of action positions icotrokinra as a potential first-in-class oral IL-23 pathway inhibitor for chronic autoimmune diseases like psoriasis and ulcerative colitis.

In the ICONIC-LEAD Phase 3 trial for moderate-to-severe plaque psoriasis, icotrokinra demonstrated statistically significant and clinically meaningful outcomes. Approximately 74 percent of patients achieved an Investigator Global Assessment (IGA) score of 0/1, representing clear or nearly clear skin, by week 24. This level of response mirrors that of market-leading injectable biologics but comes with the added convenience of oral dosing. The ICONIC-TOTAL study, which included difficult-to-treat anatomical sites, showed similarly compelling results—66 percent of participants achieved complete scalp clearance, and 77 percent reported genital skin clearance at week 16. These findings are particularly notable given that these areas are often resistant to traditional systemic or topical therapies.

In a dedicated adolescent subgroup analysis, icotrokinra produced even more impressive outcomes. By week 24, 84 percent of adolescent patients reached an IGA 0/1, and 88 percent achieved a 90 percent improvement in their Psoriasis Area and Severity Index (PASI-90). These results underscore the drug’s consistency across age groups and its potential to address the unmet needs of younger patients, who often face adherence challenges and stigma associated with injectable treatments.

On the gastrointestinal front, Protagonist Therapeutics is evaluating icotrokinra in ulcerative colitis through the ANTHEM-UC Phase 2b study. The trial reported a 63.5 percent clinical response rate and a 30.2 percent clinical remission rate by week 12, with durable efficacy extending into week 28. Importantly, the safety profile remained benign throughout the study period, with no significant increase in adverse events compared to placebo. This suggests that icotrokinra could offer long-term disease control without the immunosuppression risks often associated with other biologic or JAK inhibitor therapies.

The drug’s pharmacological profile also addresses a longstanding challenge in immunology drug development: maintaining efficacy without compromising convenience or safety. Icotrokinra is orally bioavailable, supports once-daily dosing, and exhibits a high degree of receptor selectivity. These characteristics not only streamline patient adherence but also make the molecule a viable candidate for first-line therapy—especially in markets where injection fatigue and cost sensitivity remain barriers to biologic adoption.

Market analysts have noted that icotrokinra’s dual-indication potential increases its total addressable market substantially. Moderate-to-severe plaque psoriasis affects an estimated 14 million individuals globally, while ulcerative colitis impacts over 5 million patients, with a growing prevalence in North America, Europe, and Asia-Pacific. If approved in both indications, the drug could generate multi-billion-dollar annual sales, especially given the industry’s pivot toward oral alternatives that reduce healthcare administration costs and increase patient compliance.

Moreover, payer sentiment is likely to be favorable, given the molecule’s potential for improved quality-adjusted life years (QALYs) and lower delivery costs compared to infusion-based therapies. Health technology assessment bodies may prioritize icotrokinra for reimbursement pathways that support innovative oral biologics, further accelerating its uptake post-approval.

Overall, icotrokinra’s potent efficacy, clean safety profile, and oral administration create a differentiated product that could disrupt both the psoriasis and inflammatory bowel disease markets. These clinical and pharmacoeconomic advantages have made the asset a focal point among institutional investors, healthcare-focused hedge funds, and long-only biotech portfolios looking to diversify beyond traditional antibody and gene therapy platforms.

How is the Johnson & Johnson collaboration shaping Protagonist’s late-stage development strategy?

Protagonist Therapeutics’ global licensing partnership with Johnson & Johnson’s Janssen Biotech has accelerated the development and de-risking of icotrokinra. Janssen is now funding and leading the pivotal ICONIC Phase 3 program, which includes comparative trials against both placebo and standard-of-care injectables like ustekinumab. In ulcerative colitis, the ANTHEM-UC trial is similarly designed to assess long-term durability of response and mucosal healing.

Financially, the deal includes upfront funding, milestone payments, and royalties on future sales, enabling Protagonist Therapeutics to focus on pipeline diversification while benefiting from Big Pharma infrastructure. If successful, icotrokinra could become the first oral IL-23 pathway inhibitor to receive global approvals, with potential peak annual sales estimated in the multi-billion-dollar range for psoriasis and inflammatory bowel disease combined.

What other clinical-stage macrocyclic peptides are driving platform expansion at Protagonist?

In addition to icotrokinra, Protagonist Therapeutics is advancing rusfertide, an investigational therapy for polycythemia vera that mimics the action of hepcidin, a natural regulator of iron metabolism. The VERIFY Phase 3 trial showed a 77 percent therapeutic response compared to 33 percent in placebo. Rusfertide’s potential to eliminate the need for phlebotomy and manage hematocrit without cytotoxic side effects has garnered attention from hematology specialists and institutional investors alike.

Another candidate, PN-881, is an oral IL-17 antagonist designed to address both dermatologic and gastrointestinal indications. PN-881 is currently in early clinical development and represents the next wave of immune-modulating macrocyclic peptides within the company’s pipeline. Taken together, these programs demonstrate that Protagonist Therapeutics is not a single-asset company but rather a growing oral biologics platform with deep expertise in inflammation and hematologic modulation.

How are institutional investors and analysts positioning around Protagonist Therapeutics?

Protagonist Therapeutics has seen rising institutional accumulation throughout 2024 and into 2025, driven by clinical de-risking and expanding partnerships. According to recent filings, several major healthcare-focused funds increased their holdings in the company, while broader biotech indices began to reflect growing confidence in oral peptide platforms.

Multiple analysts have raised their 12-month price targets for Protagonist Therapeutics into the $70–$80 range, citing the company’s dual late-stage programs and the increasing payer and patient demand for oral alternatives to injectable biologics. Protagonist Therapeutics currently trades in the $50–$55 range, with a “Strong Buy” consensus across tracked financial research platforms. Long-only biotech portfolios are particularly interested in the platform’s modularity and relatively fast development cycles compared to cell and gene therapies.

What are the key commercial challenges and opportunities for oral IL-23 therapy adoption?

While oral convenience is a major advantage, Protagonist Therapeutics will face substantial hurdles in achieving preferred formulary placement. Payers will closely examine head-to-head data against existing therapies such as ustekinumab and deucravacitinib. Guideline inclusion will be essential for broad adoption, especially in chronic diseases like psoriasis and ulcerative colitis, where treatment inertia favors incumbent biologics.

However, the ability to offer comparable efficacy with lower manufacturing and distribution complexity gives oral peptides a cost-effectiveness edge. If pricing aligns with payer expectations and patient adherence improves through oral access, icotrokinra could displace a meaningful share of the current biologics market.

Could Protagonist’s macrocyclic platform expand into new disease areas beyond immunology and hematology?

The macrocyclic peptide modality lends itself to broad pharmacological tuning, enabling Protagonist Therapeutics to pursue novel protein–protein interaction targets beyond immunology. Preclinical programs are being developed in metabolic and oncologic indications, with exploratory data suggesting potential in fibrosis, cardiovascular inflammation, and even checkpoint inhibition.

Analysts expect Protagonist to announce at least one new first-in-class development program by mid-2026. The company’s rapid progression from discovery to pivotal trials across two therapeutic areas suggests a nimble and highly integrated R&D model. Future growth could also include out-licensing macrocyclic scaffolds to partners seeking oral versions of injectable-only drug classes.