Safely targeting combination TNF and IL-23 using a gut-restricted and orally delivered therapeutic approach: proof-of-concept for the development of SOR102 in ulcerative colitis

Advanced combination therapy in inflammatory bowel disease (IBD) is increasingly transitioning from an experimental hypothesis to entering into relevant clinical discussions and decision-making (1). This has been driven by the recognition that single pathway inhibition may be insufficient to fully control a disease characterized by complex, redundant, and often overlapping inflammatory pathways. Practically, advanced combination therapy has also been proposed in the management of patients with complex presentations beyond luminal inflammation alone, including patients with extraintestinal manifestations or co-existing immune-mediated inflammatory diseases, uncontrolled with targeting a single mechanism of action (2).

Currently, tumor necrosis factor (TNF)α and interleukin (IL)-23 are among the most validated targets in patients with IBD; their individual blockade has demonstrated clinical and endoscopic benefit, although remission rates have generally plateaued at approximately 30% (3). Targeting the combination of TNFα and IL-23 has been appealing: there is pre-clinical evidence suggesting these are complementary pathways and in a proof-of-concept phase 2 trial (VEGA), the combination of guselkumab (IL23p19 antagonist) and golimumab (TNFα antagonist) resulted in higher rates of clinical efficacy compared to monotherapy with tissue transcriptomic evidence of synergistic changes in gene modulation, particularly in biologic modules associated with epithelial restoration and mucosal healing (4,5). The potential trade-off for improved efficacy is concerns about the long-term safety of combination treatment, along with the practical feasibility of co-administering multiple advanced therapies with different dosing intervals and regimens.

In a recent issue of Lancet Gastroenterology & Hepatology, Jairath et al. report a novel approach that may overcome some of these challenges, using an orally administered, bispecific, gut-restricted antibody construct (6). SOR102, a novel treatment under development by Sorriso Pharmaceuticals, is composed of two single-domain antibodies, engineered to simultaneously target TNFα and IL-23 (7). This allows SOR102 to bind and neutralize TNF and IL-23, either as an intact molecular construct or, perhaps more relevantly, independently when cleaved by trypsin into SOR102-TNF and SOR102-IL-23 monomers. Specifically targeting gut delivery allows for inhibition of the immune response at the level of intestinal tissue but minimizing systemic absorption with the potential implication of improved long-term safety from minimized systemic drug exposure.

To demonstrate this proof-of-concept, Jairath et al. performed a phase 1, randomized, double-blinded, placebo-controlled trial sponsored by Sorriso (6). Figure 1 summarizes the design and key findings of the three-part clinical development program for SOR102: part 1 was a single ascending dose study of healthy participants, part 2 included 10 participants treated with twice-daily SOR102 1,215 mg vs. placebo × 7 days after dose selection and pharmacokinetic (PK) data review, and part 3 included 22 patients with ulcerative colitis (UC) treated with two doses of SOR102 or placebo. The primary endpoint across all three parts of the study was safety and tolerability.

Figure 1 Clinical development program of SOR102. Part 1: single ascending doses or placebo were administered to assess safety, tolerability, and pharmacokinetics. Serum concentrations were below the lower LLOQ. Fecal recovery of SOR102-TNF and SOR102-IL-23 increased dose-dependently. Part 2: SOR102 was evaluated for safety, pharmacokinetics, and immunogenicity. Serum and urine concentrations remained below LLOQ. Fecal SOR102-TNF and SOR102-IL-23 levels were >1,000-fold higher than intact SOR102. ADAs were detected in 25% of treated participants. Part 3: patients received 810 mg once or twice daily. Serum levels remained below LLOQ; urinary SOR102-TNF was detectable in a subset. Fecal SOR102-TNF and SOR102-IL-23 were up to four orders of magnitude higher than intact drug. ADAs developed in 38% of patients, and clinical efficacy was assessed. ADAs, anti-drug antibody; BID, twice daily; IL, interleukin; LLOQ, lower limit of quantitation; PK, pharmacokinetics; QD, once daily; TNF, tumor necrosis factor alpha; UC, ulcerative colitis.

Overall, SOR102 was well tolerated in both healthy participants and patients with UC, with a low incidence of treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. In part 1, TEAEs were reported in 3/24 (13%) participants receiving SOR102 compared with 2/8 (25%) receiving placebo. No TEAEs were observed in part 2. In part 3, at least one TEAE occurred in 7/16 (44%) patients treated with SOR102 and 3/6 (50%) patients receiving placebo. Only 1 severe TEAE was reported, a flare of UC requiring hospitalization, which was not considered related to the study drug. Importantly, no clinically meaningful effects of SOR102 were observed on electrocardiograms, vital signs, physical examination findings, or safety laboratory parameters at any dose or dosing frequency evaluated. This trial also critically demonstrated proof-of-concept for the therapeutic target and delivery mechanism: from a PK perspective, no detectable serum or urine concentrations of SOR102, SOR102-TNF, or SOR102-IL-23 were identified across study parts, suggesting minimal systemic drug exposure. In contrast, fecal concentrations of SOR102-TNF and SOR102-IL-23 could be more than 1,000-fold higher than those of intact SOR102, suggesting that the molecule was effectively cleaved post-oral administration and pharmacodynamically active monomers could be detected throughout the gastrointestinal (GI) tract.

Immunogenicity represents an important consideration in the development of SOR102. In this early-phase study, anti-drug antibodies (ADAs) were detected in 2/8 (25%) subjects in part 2 and 6/16 (38%) patients in part 3. Notably, some ADA positivity was present at baseline, and most treatment-emergent ADA titers were low. Despite no apparent short-term impact, the relatively high ADA rates warrant further evaluation for potential effects on long-term efficacy, potential neutralization of drug effects, durability of response, and potential for inducing hypersensitivity reactions in later phase trials. Of additional interest, results from part 3 provided preliminary signals of clinical efficacy in patients with active UC, which should be interpreted with caution given the early phase design and small sample size. Although not powered for efficacy in phase 1, rates of clinical response ranged from 29% to 67%, depending on the definition applied, with a trend toward greater response observed with twice-daily administration of SOR102 compared with once-daily dosing. Also, in part 3, patients with UC underwent flexible sigmoidoscopy with colonic tissue sampling. Treatment with SOR102 resulted in up to a 35-fold increase in median concentrations of SOR102-IL-23 and SOR102-TNF detection peptides in colonic tissue compared with placebo. SOR102 administration was associated with reductions in pro-inflammatory cytokines (including IL-1β, IL-6, and TNF) as well as Th1/Th17-associated cytokines (including IFN-γ, IL-17A, and IL-10) within colonic tissue relative to placebo.

In summary, SOR102 demonstrated a favorable safety and tolerability profile across early-phase evaluation, with no signal of systemic toxicity or immunogenicity. The lack of detectable systemic exposure, together with substantial fecal recovery of cytokine-bound fragments and demonstrable modulation of mucosal inflammatory mediators, supports a gut-restricted mechanism with convincing evidence of local tissue engagement. Preliminary clinical signals further suggest that dual neutralization of TNF and IL-23 within the intestinal lumen may translate into biologically meaningful activity, like what has previously been demonstrated with combination monoclonal antibody therapy. From a translational perspective, SOR102 may be particularly suited for patients with severe luminal disease or disease refractory to monotherapy, although its precise role within future treatment algorithms remains to be defined. Moreover, the oral administration of SOR102 introduces a practical advantage that could enhance patient adherence, although twice daily administration is suboptimal for ensuring long-term adherence. Given these considerations, further clinical development of SOR102 is supported.

However, the path forward is not without potential pitfalls. First, although gut restriction may offer potential safety advantages, this is irrelevant without evidence of clinical efficacy. Previous attempts at gut-restricted delivery in patients with UC have been unsuccessful. A notable example is the experience with izencitinib (TD-1473), an oral gut-restricted therapy which did not demonstrate efficacy in moderately-to-severely active UC despite targeting a known, effective mechanism of action (Janus kinase inhibition) (8). Developing gut-restricted treatments has historically been challenging because of physiologic barriers such as the very large surface area of the GI tract with vast differences in pH, epithelial permeability, mucous layers, and inter-individual variability in gut transit, which are exacerbated in the context of intestinal inflammation in IBD. Furthermore, it may be difficult to achieve an adequate therapeutic index with sufficiently high concentrations in inflamed mucosal tissue to treat the disease. Finally, even achieving mucosal tissue engagement may not be sufficient to control the intense systemic inflammatory reaction that is characteristic of patients with IBD. Second, dose selection for future phases may be challenging: in the absence of measurable systemic drug concentrations and quantification of exposure metrics [e.g., maximum concentration (C_max), area under the curve (AUC)], classical PK/PD modelling based on serum drug levels and exposure-response relationships cannot be readily established. Alternative pharmacodynamic surrogates may be needed, although fecal recovery of SOR102-cytokine complexes as an indirect marker of luminal target engagement is likely subject to inter-individual variability. Whether such PK/PD strategies and using fecal biomarkers alone can reliably inform dose selection is unclear. From a regulatory perspective, the development of bispecific antibodies requires robust manufacturing processes, and the relatively high doses required for luminal activity in the case of SOR102 may introduce additional challenges in scalability and product consistency. Finally, the minimal systemic absorption that underpins SOR102 safety may also limit potential benefits in patients with extraintestinal manifestations or comorbid immune-mediated diseases, despite this being a patient population where combination treatment could be beneficial.

The clinical experience with bispecific antibodies in IBD remains limited but is rapidly evolving. Several agents are currently entering the therapeutic landscape, including preclinical data for a TL1A × IL-23 bispecific antibody, an IL23p40 × TL1A bispecific antibody (PF-07261271), and perhaps most notably, lutikizumab, a bispecific antibody targeting both IL-1α and IL-1β, which is being evaluated in both IBD and other immune-mediated diseases such as hidradenitis suppurativa (9,10). To date, no major safety concerns have emerged; however, immunogenicity and the long-term consequences of dual-pathway immunosuppression will require careful evaluation in ongoing and future studies (11). Despite these potential challenges, bispecific antibodies offer the potential ability to simultaneously target multiple mechanisms and enhance biological synergy, making them an attractive therapeutic platform across immune-mediated diseases such as IBD.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0032/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0032/coif). R.P. received grant/research support/speaker honoraria/advisory board fees/consulting fees from Abbott, AbbVie, Abbivax, Alimentiv, Amgen, AnaptysBio, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Inviva, Innomar Strategies, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mirador, Novartis, Oppilan Pharma, Odyssey, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Teva Tillots, Trellus, Union Biopharma, Viatris, and Ventyx. C.M. received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc., Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Mirador Therapeutics, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc, Roche, Sanofi, Takeda, and Tillotts Pharma; speaking fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, and Tillotts Pharma; royalties from Springer Publishing; and research support from AbbVie, Eli Lilly, Ferring, and Pfizer. The other author has no conflicts of interest to declare.

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