Can Protagonist’s icotrokinra become the first oral IL-23 therapy to rival biologics in ulcerative colitis?

Protagonist Therapeutics, Inc. (NASDAQ: PTGX) is edging closer to what could be a breakthrough moment in autoimmune medicine. The American biotech firm has reported compelling new results from its Phase 2b ANTHEM-UC study of icotrokinra, a first-in-class oral peptide designed to block the interleukin-23 receptor (IL-23R) in patients with moderately to severely active ulcerative colitis. Presented at United European Gastroenterology (UEG) Week 2025, the data revealed a potent combination of therapeutic efficacy and favorable safety that analysts say could make icotrokinra the first oral IL-23-targeted therapy capable of rivaling today’s injectable biologics in inflammatory bowel disease treatment.

At Week 12 of the study, all three once-daily doses of icotrokinra achieved clinical response, with the highest 400 mg arm showing the most pronounced effect. A total of 63.5 percent of patients in the 400 mg group achieved clinical response, compared to just 27 percent on placebo. Clinical remission rates reached 30.2 percent in the same group versus 11.1 percent for placebo. These outcomes met the study’s primary and key secondary endpoints, validating the molecule’s potential to deliver meaningful efficacy with once-daily oral administration.

Across safety assessments, the drug performed comparably to placebo, with similar rates of adverse and serious adverse events reported through Week 12. These findings strengthen confidence in icotrokinra’s risk-benefit balance ahead of registrational development.

The American biotechnology company said it expects to begin patient enrollment for a Phase 3 ulcerative colitis trial in Q4 2025, while a Phase 2b/3 Crohn’s disease program will also move forward under the same development umbrella. The announcement follows a period of rapid progress for Protagonist, which has already submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration for icotrokinra in moderate-to-severe plaque psoriasis and advanced its ICONIC-PSA 1 and 2 programs in psoriatic arthritis.

What did the ANTHEM-UC trial reveal about icotrokinra’s clinical impact and safety profile?

The ANTHEM-UC Phase 2b study (NCT06049017) was a randomized, placebo-controlled, dose-ranging trial evaluating icotrokinra at 100 mg, 200 mg, and 400 mg once daily in patients with moderately to severely active ulcerative colitis. Participants included adults who had previously failed or were intolerant to conventional therapies, biologics, or Janus kinase (JAK) inhibitors.

The trial’s primary endpoint was clinical response at Week 12, defined as a reduction in the modified Mayo score by at least 30 percent and two points, combined with improvement in rectal bleeding. Secondary endpoints included clinical remission, symptomatic remission, and endoscopic improvement.

Patients on icotrokinra demonstrated marked improvement across all endpoints, with the strongest results observed in the 400 mg dose group. Clinical response was achieved by nearly two-thirds of patients at that level, and symptomatic remission was evident as early as Week 4. Importantly, no dose-limiting toxicities emerged, and adverse-event rates remained similar to those seen in the placebo group. This balance of efficacy and tolerability reinforces icotrokinra’s differentiated positioning as an oral IL-23R blocker in a therapeutic category still dominated by injectables.

These outcomes are consistent with prior results from icotrokinra’s ICONIC program in plaque psoriasis, which showed rapid, durable skin clearance and an encouraging safety profile. The convergence of data across indications is beginning to define icotrokinra as a modular, multi-disease candidate with potential across the IL-23 pathway.

How does icotrokinra’s mechanism distinguish it from current biologic therapies in ulcerative colitis?

Icotrokinra represents the first oral peptide designed to selectively block the IL-23 receptor, preventing downstream inflammatory signaling associated with chronic autoimmune diseases. Current IL-23 inhibitors such as ustekinumab and risankizumab are injectable monoclonal antibodies, which can present barriers related to cost, adherence, and convenience.

Protagonist’s oral formulation could deliver comparable biological activity through a peptide small enough for systemic delivery yet selective enough to avoid broad immune suppression. The IL-23R blockade interrupts a key cytokine axis implicated in the activation of T-helper 17 cells, which are believed to sustain the mucosal inflammation characteristic of ulcerative colitis.

If validated in Phase 3, icotrokinra could therefore mark the first truly oral, once-daily therapy targeting this pathway. Analysts have suggested that a successful approval could transform treatment algorithms for inflammatory bowel disease by offering an option that merges biologic-level efficacy with oral convenience.

What is the market and investor reaction to Protagonist Therapeutics’ progress?

Following the announcement, Protagonist Therapeutics’ stock (NASDAQ: PTGX) attracted increased investor attention. Shares have risen nearly 50 percent year-to-date, with average trading volumes spiking after the presentation of the ANTHEM-UC data. Market analysts described the results as “clinically meaningful and commercially relevant,” highlighting that oral IL-23 inhibition could redefine patient management in autoimmune diseases.

Institutional investors appear to be reassessing the company’s valuation on the back of this pipeline momentum. Although short-term volatility persists, overall sentiment across buy-side desks has turned positive. Several investment research notes released in early October described Protagonist as “a strategic immunology asset” given its late-stage programs and ongoing collaboration with Johnson & Johnson, which holds development rights for icotrokinra under its Janssen Biotech division.

Industry sources have also reported that Johnson & Johnson is exploring an acquisition of Protagonist Therapeutics, potentially consolidating its stake in the IL-23 oral peptide franchise. While neither company has confirmed these discussions, the mere prospect of a deal has added fuel to speculation that large pharmaceutical firms view Protagonist’s discovery platform as a key competitive advantage in peptide-based immunology.

How are analysts and institutional investors evaluating Protagonist Therapeutics’ Phase 3 ulcerative colitis plans and the likelihood of regulatory success?

Analysts generally describe the upcoming Phase 3 program as a major inflection point for Protagonist Therapeutics. The ANTHEM-UC study has provided compelling proof-of-concept, but pivotal confirmation will depend on whether efficacy and safety are sustained over longer durations and across broader patient populations.

The registrational Phase 3 trial will likely compare icotrokinra directly with existing standards of care such as biologic IL-23 or TNF inhibitors. Success in these head-to-head or placebo-controlled arms could validate the drug’s position as a first-line or early-line therapy.

From a regulatory standpoint, the company’s prior NDA filing for icotrokinra in plaque psoriasis may also streamline the path to approval in ulcerative colitis if data remain consistent. Analysts expect the FDA to closely evaluate long-term safety, particularly gastrointestinal and hepatic adverse events, before granting broader indications.

Several buy-side healthcare funds reportedly view Protagonist as one of the few small-cap biotechs capable of graduating into the mid-cap segment through organic data execution rather than external acquisition. However, analysts also emphasize risks common to the sector, including trial delays, high R&D expenditure, and capital-raising pressures in 2026 should timelines extend.

What other programs define Protagonist Therapeutics’ late-stage pipeline?

Beyond icotrokinra, Protagonist Therapeutics is advancing multiple peptide-based assets derived from its proprietary discovery platform. The company’s rusfertide program — a hepcidin mimetic currently in Phase 3 for polycythemia vera — remains on track for an NDA submission by the end of 2025 under a collaboration with Takeda Pharmaceuticals.

It is also conducting early-stage trials for PN-881, an oral IL-17 antagonist being explored for psoriasis and other autoimmune conditions, and PN-477, a triple-agonist peptide targeting obesity and metabolic disorders. Collectively, these assets reflect the company’s strategy of building a diversified peptide-based pipeline addressing validated biological pathways with oral alternatives to injectable biologics.

Chief Executive Officer Dr Dinesh V. Patel has said that the company’s mission is to “deliver well-differentiated oral treatments for patients while advancing scientific and innovation leadership in immunology and inflammation.” The leadership team has consistently reiterated that the convergence of biology, chemistry, and pharmacology in peptide design allows for smaller, safer, and more accessible therapeutics compared to traditional biologics.

What lies ahead for icotrokinra and Protagonist Therapeutics’ valuation story?

If icotrokinra’s efficacy and safety are replicated in Phase 3, Protagonist could find itself at the center of a significant market re-rating. Oral biologic alternatives are highly sought after, and the inflammatory bowel disease therapeutics market is projected to exceed USD 28 billion by 2030. A product that can achieve efficacy similar to biologics while offering oral convenience could capture a meaningful share of that total addressable market.

Short-term milestones to watch include the initiation of patient enrollment for the Phase 3 ulcerative colitis study, the commencement of the Crohn’s disease program, and ongoing regulatory discussions surrounding psoriasis and psoriatic arthritis indications. Analysts expect data readouts and corporate updates over the next 12 months to drive substantial investor interest, with potential partnership or acquisition activity serving as additional catalysts.

Given the strength of the Phase 2b ANTHEM-UC data and the company’s expanding late-stage pipeline, institutional sentiment toward Protagonist Therapeutics (NASDAQ: PTGX) remains cautiously optimistic. While inherent risks persist in every clinical-stage biotechnology investment, the consistent demonstration of efficacy across multiple autoimmune indications places the company among the most closely watched mid-cap names in immunology today.