Introduction
SOR102 is a novel, orally delivered, bispecific construct with two humanized single domain antibodies (SDA) targeting TNFα and IL-23p19 bound by a trypsin-labile linker, enabling monomer separation in the small intestine and inhibition of TNFα and IL-23 activity in GI tissue, with minimal systemic exposure. SOR102 SDAs were engineered for stability to intestinal and inflammatory proteases, enabling oral dosing.1 The Phase 1, first-in-human study (NCT06080048) had 3 parts. Parts 1 and 2 enrolled healthy subjects. Part 3 was a Phase 1b randomized, double-blind, placebo-controlled study in patients (pts) with mild to severe ulcerative colitis (UC). Results for Parts 1 and 2, and clinical results (safety, efficacy, immunogenicity) for Part 3 were previously presented.2,3 Here, we present Part 3 biodistribution and tissue pharmacodynamic (PD) results, and their correlation with clinical results.
Aims & Methods
Pts with Mayo endoscopy score ≥2, rectal bleeding score ≥1 and stool frequency score ≥1 were randomized 1:1:1 to receive SOR102 810mg BID, SOR102 810mg QD, or placebo for 6 weeks. Pts underwent a baseline and end of treatment sigmoidoscopy and biopsies. The primary objective was safety and tolerability. Secondary objectives were concentrations of SOR102 and monomers in serum, urine and feces, and anti-drug antibodies. Exploratory efficacy endpoints included change from baseline in Mayo Score (MS), modified Mayo Score (mMS), and UC-100 score, and MS and mMS clinical response and symptomatic remission (SR). Exploratory colonic tissue biodistribution and PD endpoints included measurements of SOR102, cytokine protein levels and gene expression changes. Serum cytokine protein levels were also assessed. Outcomes are reported in pts who completed the study.
Results
22 pts were randomized; 17 pts completed the study (SOR102 BID=5; SOR102 QD=6; placebo=6). Mean age was 50 yrs; 45% were male; median MS was 8 (range 6-11). Most pts were advanced therapy-naïve. One patient (QD arm) had detectable SOR102-IL-23 monomer levels in serum (<135.2 ng/ml). High and consistent micromolar levels of active monomers and low levels of intact SOR102 in feces confirm SOR102 is efficiently cleaved and activity is maintained after oral dosing in UC patients, as demonstrated through TNF/IL-23 binding analysis. Median colonic tissue concentrations of SOR102 monomers were 20-35x higher in the SOR102 BID arm compared to QD. Higher rates of MS and mMS clinical response, and SR, and greater decreases in MS, mMS, and UC-100 score were observed in the SOR102 BID arm compared to placebo. In the SOR102 BID arm there was strong correlation between clinical activity, tissue drug concentrations, and PD outcomes, which included reduced colonic tissue IL-1b, IL-6, TNFα, IFNγ, IL-17A, and IL-10 protein levels and changes in gene expression corresponding to reduced myeloid inflammation and T & B cell responses, with upregulation of cellular repair mechanisms. No notable changes were observed in serum cytokine protein levels. In the QD arm, there was a tendency towards favorable tissue PD responses, suggesting a higher dose or longer duration of treatment are needed for higher clinical responses.
Conclusion
High and sustained levels of active monomers in feces confirmed SOR102 is efficiently cleaved, and activity is maintained after oral dosing in UC patients. Levels of SOR102 monomers in sigmoid colonic tissue increased with oral dose, with minimal systemic exposure. In the BID arm, SOR102 demonstrated strong and consistent activity across multiple clinical and tissue PD endpoints in patients with UC.
References
- Roberts KJ et al. Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease. Sci Rep 2021;11:19422.
- Jairath V et al. First in human study of SOR102, a novel, orally delivered bispecific anti-TNF/anti-IL-23 domain antibody in clinical development for the treatment of inflammatory bowel disease. UEG Journal 2024;12(S8):72-73.
- Jairath V et al. Phase 1b study of SOR102, a novel, orally delivered bispecific anti-TNF/anti-IL-23 domain antibody in patients with mild to severe ulcerative colitis. J Crohns Colitis 2025;19(S1):i62-i63.
Disclosure
VJ reports potential conflicts of interest with AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Gilead, Innomar, JAMP Pharma Group, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, F. Hoffmann La Roche Ltd/Genentech, Roivant, Sandoz, Second Genome, Shire, Sorriso, Synedgen, Takeda, Toronto Dominion Securities, Teva, Topivert, Ventyx, Vividion.
SD reports potential conflicts of interest with AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor.
GDH reports potential conflicts of interest with AbbVie, Agomab, Alimentiv, Arena, AstraZeneca, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Gilead, GlaxoSmithKline, Immunic, Johnson & Johnson, Pfizer, Polpharma, Procise Diagnostics, Prometheus Biosciences, Prometheus Laboratories, Progenity, Protagonist Therapeutics Inc., Seres Health, Spyre, Takeda.
BGF reports potential conflicts of interest with AbbVie, Abivax, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, AnaptysBio, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, BioFactura, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Celltrion, Clarivate, Connect BioPharma, Disc Medicine, Duality, EcoR1 Capital, Eli Lilly, EnGene, Ensho Therapeutics, Equillium, Evida, Enveda, Faes Farma, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gilead, Gossamer Pharma, GSK, Imhotex, ImmiDomics, Immunic Therapeutics, Intercept, Janssen, Japan Tobacco Inc., Klick Health, LifeMine Therapeutics, Mage Biologics, Merck, Mestag, Mirador Therapeutics, MiroBio, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nexys Therapeutics, Nighthawk Therapeutics, Nimbus Therapeutics, Novartis, OncoC4, OrbiMed, Origo BioPharma, Orphagen, Palisade Bio, Pendopharm, Pfizer, Protagonist,32 Bio, REDX, Roivant/Televant, Sanofi, Sobi, Sorriso, Spyre Therapeutics, SRT Therapeutics, Sun Pharma, Surrozen Inc., Synedgen, Takeda, Teva, Triastek, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Zagbio.
LP-B reports potential conflicts of interest with Abbvie, Abivax, Adacyte, Alimentiv, Alfasigma, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia.
BES reports potential conflicts of interest with Abbvie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb Calibr, Celgene, Celltrion, ClostraBio, Eli Lilly & Company, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Merck & Co., Inc., Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Palisade Bio, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Surrozen, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences.
MW is an employee of Inotiv.
ICG is an employee of Tytgat Institute for Liver & Intestinal Research.
BS is an employee of Alimentiv Inc.
KR, AT, SB, PW, CS and JB are employees of Sorriso Pharmaceuticals.
