Introduction

JAK inhibitors have become an efficacious oral treatment option to antibody-based therapies for ulcerative colitis (UC). However, they have received a black box warning by the FDA for causing serious systemic adverse events.
To increase safety, OST-122 is being developed as an orally administered, GI-targeted and non-systemic JAK3/TYK2 inhibitor for the local treatment of UC. In preclinical models and in healthy volunteers, OST-122 has demonstrated excellent safety and tolerability with minimal systemic exposure reducing the risk of causing serious systemic toxicities associated with current JAK inhibitors.
Here, we report the results of a phase 2a study in patients with UC on the safety, tolerability, pharmacokinetics and preliminary efficacy of OST-122.

Aims & Methods

In this randomized, double-blind trial, 37 adult patients with active UC were treated with oral OST-122 400 mg (n=28) or placebo (n=9) for 28 days. Eligibility criteria required a total Mayo Score TMS 5-10, endoscopic Mayo Score EMS ≥2, inadequate/loss of response to conventional therapy (5-ASA, steroids, immunomodulators) or biologics (anti-TNFα, anti-integrin, anti-interleukin 12/23). Stable cotreatment with oral 5’ASAs and corticosteroids was permitted.
To evaluate the safety and tolerability of OST-122, the number and severity of AEs, including changes in vital signs, safety laboratory values and ECGs, were analyzed. Plasma, tissue and stool samples were collected at various time points to examine the gut-restricted pharmacokinetic profile of the compound in UC patients. Preliminary efficacy was assessed through Mayo Clinical Scores including rectal bleeding (RB) and stool frequency (SF) along with clinical response and remission.

Results

During the 6-week observation period, no serious AEs nor treatment-related AEs leading to discontinuation were reported. Most AEs were tabulated as mild, followed by moderate, and the number of subjects reporting AEs were distributed equally in the placebo and OST-122 group (78% vs. 71%). There were no clinically relevant changes in vital signs, laboratory values or ECG parameters which raise any safety concerns.
Pharmacokinetic analysis indicated minimal plasma concentrations (C_max 0.92 ng/mL) and therapeutically relevant levels in colon tissue (15.5 ug/g tissue) confirming a gut-restricted PK profile of OST-122.
Preliminary efficacy data after 28 days of treatment are summarized in the table below:

Outcome	400 mg OST-122 (n=28)	Placebo (n=9)	∆
Rectal Bleeding Improvement of RB score by ≥1	63% (17/27)	33% (3/9)	33%
Stool Frequency Improvement of SF score by ≥1	52% (14/27)	33% (3/9)	19%
PRO-2 score (RB + SF) Improvement of PRO-2 by ≥2	48% (13/27)	11% (1/9)	37%
Clinical Response Decrease of TMS by ≥3 or ≥30 %, plus improvement in RB by ≥1 and an absolute RB of 0 or 1	44% (12/27)	11% (1/9)	33%
Clinical Remission TMS ≤2 and no individual subscore >1, plus RB of 0	22% (6/27)	0% (0/9)	22%

63% of patients taking OST-122 showed an improvement in rectal bleeding and 52% in stool frequency (vs 33% in the placebo group), and 48% had an improvement of ≥2 in PRO-2 (RB+SF, vs 11% Pbo). Clinical response was achieved by 44% (vs 11% Pbo) and 22% reached clinical remission (vs 0% Pbo). In addition, 16% of patients in the OST-122 group achieved both histological response and remission (vs 0% Pbo). A subgroup analysis showed that OST-122 was able to induce clinical response both in bionaïve and bioexperienced patients. Confirmatory studies will be designed to determine dose and statistical significance.

Conclusion

GI-restricted OST-122 was well tolerated during the 4-week treatment. Its excellent safety profile, minimal systemic exposure and promising trends of clinical activity may provide a safer therapeutic option for a broad range of ulcerative colitis patients.

Disclosure

M. Barreiro de Acosta has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte, Vifor Pharma and Oncostellae.
C. Rodríguez has received consultancy and/or speaking honoraria fees from AbbVie, Ferring, Galapagos, Janssen, Pfizer, Lilly and Takeda.
M.D. Martin-Arranz has received fees as a speaker, consultant and advisory member for or has received funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Shire Pharmaceuticals, Tillots Pharma, and Faes Pharma.
L. Torrealba has served as a speaker for Janssen.
E. Iglesias Flores has served as a speaker, consultant and advisory member for or has received research funding from AbbVie, Janssen, Takeda, Gillead, Celgene, Pfizer, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, and Adacyte.
F. Argüelles-Arias has served as a speaker, consultant and advisory member or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma.
Y. Ber-Nieto has served as a speaker from Abbvie and has received education funding from Abbvie and Pfizer.

Introduction

Advanced combination treatment (ACT), defined as the use of two biologics or a biologic and a small molecule drug with distinct mechanisms of action, is increasingly adopted for refractory inflammatory bowel disease (IBD) and overlapping immune-mediated inflammatory diseases (IMIDs). Despite promising clinical results, the immunological consequences of ACT remain poorly characterized. Here, we investigated how two ACT regimens—anti-TNF + anti-integrin and anti-TNF + anti-IL-23—shape the peripheral CD3⁺ T cell landscape at single-cell resolution, with a focus on clonotype architecture, repertoire diversity, and antigen specificity.

Aims & Methods

We aim to characterize the peripheral CD3⁺ T cell transcriptional landscape and clonal architecture in patients with refractory IBD who achieved clinical response following initiation of two different ACT regimens: anti-TNF + anti-integrin α4β7 and anti-TNF + anti-IL-23. Peripheral blood mononuclear cells (PBMCs) were collected from six patients with Crohn’s disease who achieved clinical response to ACT. Four patients received anti-TNF + anti-integrin α4β7, and two received anti-TNF + anti-IL-23. CD3⁺ T cells were isolated and analyzed via single-cell RNA sequencing (scRNA-seq) coupled with paired T cell receptor (TCRα/β) sequencing. Cell state annotations were performed using supervised deconvolution against the scIBD reference atlas, and TCR repertoire metrics (diversity, clonality, evenness) were computed to assess clonal expansion dynamics.

Results

All patients included demonstrated clinical improvement, underscoring the immunological relevance of the findings. Single-cell transcriptomic and TCR repertoire profiling uncovered distinct treatment-specific patterns in peripheral T cell states and clonal architecture. In the anti-TNF + α4β7 group, there was marked enrichment of CD4⁺ tissue central memory T cells (CD4⁺ tissue-Tcm) and CD4⁺ naïve T cells (CD4⁺ Tn), along with greater TCR diversity, reduced clonal dominance, and enhanced repertoire evenness. In contrast, the anti-TNF + IL-23 group exhibited a marked enrichment of CD8⁺ naive T cells (CD8⁺ Tn) and a repertoire characterized by reduced diversity and pronounced oligoclonal expansion.

Conclusion

In difficult-to-treat IBD patients who achieved clinical response to ACT, distinct patterns of immunological remodeling emerged depending on the therapeutic combination. Treatment with anti-TNF + anti-integrin was associated with a diversified, polyclonal T cell repertoire consistent with a systemic rebalancing of the adaptive immune response, whereas anti-TNF + anti-IL-23 drove more focused, oligoclonal expansions indicative of selective immune activation. These divergent signatures underscore mechanistically distinct pathways of immune reprogramming and highlight the potential of T cell–based immuno-profiling to inform the rational selection of biologic combinations. Incorporating single-cell and TCR repertoire analyses into ACT trials may enable a precision medicine framework for optimizing treatment strategies in IBD.

References

Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022 Dec;71(12):2380-2387. doi: 10.1136/gutjnl-2022-327025. Epub 2022 Jun 14. PMID: 35701092.

Disclosure

Virginia Solitano has received speaker fees from Pfizer and consultancy fees from Johnson & Johnson. Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. Silvio Danese has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenixa, UCB Inc, and Vifor; and lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. The other authors have nothing to disclose.

Introduction

Response to hepatitis B vaccine (HBV) is variable in inflammatory bowel disease (IBD) patients with seroconversion rates of 34-89%. Strategies suggested to improve the seroconversion rates are double dose, accelerated schedule, or addition of booster dose with variable results. This study compared the standard (20 µg) dose and double (40 µg) dose of HBV vaccination in IBD patients.

Aims & Methods

Patients of IBD were randomized to 1:1 to receive standard or double dose of HBV at 0, 1 and 6 months. Anti-HBs titers were assessed at 1 month after the third dose. Response was defined as an adequate immune response (AIR, anti-HBs titer >10 mIU/mL) and effective immune response (EIR, anti-HBs titer >100 mIU/mL). Total mayo score and Crohn’s disease activity index (CDAI) was used to identify the active disease. IBD medications with immunosuppressive effects were categorized as immunomodulators, corticosteroids, tofacitinib and biologic group. Multivariable logistic regression analysis was done to identify the predictors of AIR and EIR.

Results

Eighty-eight patients of IBD were randomized to receive standard (45, 51.1%) or double (43, 48.9%) dose of HBV. 79 of 88 patients had ulcerative colitis (UC) and 9 had Crohn’s disease (CD). 49 (55.7%) patients had active disease while 39 (44.3%) were in remission. At the end of the study, total 63 (71.61%) patients achieved AIR and 51 (60%) achieved EIR. AIR (88.4 % vs. 55.6 %, p 0.001) and EIR (69.8% vs. 46.7%, p = 0.028) rates were significantly higher with double dose compared to standard dose of HBV. Patients with active IBD had higher AIR (87.5% vs. 44%, p = 0.001) and EIR (70.8% vs. 32%, p = 0.007) rates with double dose of HBV. Patients with IBD in remission also had higher AIR (89.5% vs. 70%) and EIR (78.4% vs. 65%) rates with double dose of HBV, though statistically non-significant.
Multivariable analysis identified the use of double dose of HBV {odds ratio (OR) 10.865, 95% confidence interval (CI): 2.418-48.817} and biologic (OR 0.022, 95% CI: 0.001-0.421) as predictors to achieve AIR. Similarly, double dose of HBV (OR 3.0, 95% CI: 1.087-8.280) and use of biologic (OR 0.074, 95% CI: 0.006-0.931) also predicted the EIR.

Conclusion

Double dose of HBV vaccine demonstrated a superiority over standard dose of vaccine for achieving both AIR and EIR. Use of biologic impaired the response. Double dose of HBV should be used in IBD patients to improve the seroconversion rates.

Disclosure

No conflict of Interest

Introduction

Upadacitinib 15 mg once daily (UPA15) and 30 mg once daily (UPA30) have demonstrated efficacy vs placebo across clinical, endoscopic, and histologic endpoints after 52 weeks of maintenance therapy in the U-ACHIEVE Maintenance study.^1,2

Aims & Methods

This interim analysis presents efficacy and safety data from patients receiving continuous therapy with UPA15 or UPA30 for 1 year in the maintenance study, and an additional 48 weeks (approximately 2 years in total) in the ongoing, 288-week, long-term extension (LTE) study U-ACTIVATE. Patients who underwent dose escalation or de-escalation at Week 48 of the LTE study were excluded from this analysis. Efficacy and safety endpoints were analyzed at Week 48 of the LTE study. Overall safety data and treatment-emergent adverse events (TEAEs) of special interest are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]) of TEAEs, except for some TEAEs that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs).

Results

The proportions of patients achieving efficacy endpoints, including clinical remission per Adapted Mayo score, endoscopic remission, and endoscopic improvement, were similar for UPA15 vs UPA30, while maintenance of endoscopic remission was achieved by a greater proportion with UPA30 vs UPA15 (Table). For safety, 238 (UPA15, n=101; UPA30, n=137) patients, who achieved 426.5 (UPA15, 186.0; UPA30, 240.5) PYs of exposure, were analyzed. Across treatment groups, EAERs of serious TEAEs and TEAEs leading to treatment discontinuation were similar (Table). No TEAEs leading to death occurred in either group. The EAERs for TEAEs of special interest were generally lower with UPA15 vs UPA30, including for serious infections (1.6 vs 4.6, respectively), herpes zoster (3.8 vs 5.8), neutropenia (1.6 vs 4.2), and creatine phosphokinase elevation (2.7 vs 6.2), although the EAER for hepatic disorder was higher with UPA15 vs UPA30 (8.6 vs 4.2, respectively). No adjudicated major adverse cardiovascular events occurred on either dose; no adjudicated venous thromboembolic events occurred on UPA15 and one event occurred on UPA30 (EAIR: 0.4). One event of malignancy excluding non-melanoma skin cancer occurred in both UPA15 (papillary thyroid carcinoma; EAIR: 0.5) and UPA30 (squamous cell carcinoma of uterine cervix; EAIR: 0.4).

Efficacy endpoints at Week 48 of the LTE study n/N (%) [95% CI]	Upadacitinib 15 mg QD (N=101)	Upadacitinib 30 mg QD (N=137)
Clinical remission per Adapted Mayo scorea	68/87 (78.2) [69.5, 86.8]	92/119 (77.3) [69.8, 84.8]
Clinical remission per Partial Mayo scoreb	85/92 (92.4) [87.0, 97.8]	110/121 (90.9) [85.8, 96.0]
Clinical response per Adapted Mayo scorec	85/87 (97.7) [94.6, 100.0]	114/119 (95.8) [92.2, 99.4]
Endoscopic improvementd	73/89 (82.0) [74.0, 90.0]	102/123 (82.9) [76.3, 89.6]
Endoscopic remissione	49/89 (55.1) [44.7, 65.4]	70/123 (56.9) [48.2, 65.7]
Maintenance of endoscopic remissionf	28/39 (71.8) [57.7, 85.9]	43/53 (81.1) [70.6, 91.7]
EAERs at Week 48 of the LTE study Events (events/100 PYs)	Upadacitinib 15 mg QD (N=101; PYs=186.0)	Upadacitinib 30 mg QD (N=137; PYs=240.5)
Any TEAEs Serious TEAEs TEAEs leading to treatment discontinuation TEAEs leading to death	350 (188.1) 11 (5.9) 6 (3.2) 0	474 (197.1) 21 (8.7) 7 (2.9) 0
As-observed data are presented, with no imputation for missing values; patients who did not have an evaluation at Week 48 were excluded. aAdapted Mayo score ≤2, with stool frequency subscore ≤1 and not greater than baseline, RBS=0, and ES ≤1. bPartial Mayo score ≤2, with no subscore >1. cDecrease in Adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in RBS ≥1 or an absolute RBS ≤1. dES≤1. eES=0. fPatients who achieve endoscopic remission at Week 0 and Week 48 of the LTE study. EAER, exposure-adjusted event rate; ES, endoscopic subscore; LTE, long-term extension; PY, patient-year; QD, once daily; RBS, rectal bleeding subscore; TEAE, treatment-emergent adverse event.

Conclusion

Achievement of clinical and endoscopic endpoints observed with UPA15 and UPA30 after the 52-week maintenance study^1,2 was sustained through Week 48 of the LTE study, demonstrating continued benefit for up to 2 years of maintenance therapy with both doses. The safety profile of UPA at Week 48 of the LTE study was consistent with previous analyses, and no new safety signals were identified.

References

1. Danese S, et al. Lancet 2022;399:2113–28
2. Vermeire S, et al. Presented at UEGW [OP001], 8–11 October 2022

Disclosure

RP has received consulting fees, speaker fees, and research support from Abbott, AbbVie, Alimentiv (formerly Robarts Clinical Trials), Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Élan, Eli Lilly, Ferring, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance, and UCB.
PDRH has received grants from AbbVie, the Crohn’s & Colitis Foundation, the National Institutes of Health, and Takeda; and has served as a consultant for Eli Lilly, the Gastrointestinal Health Foundation, Imedex, Pfizer, Takeda, and Vindico Medical Education.
GL has received research support and/or funding from Celgene, Janssen Orthobiotech, Pfizer, Takeda, and UCB; consulting fees from AbbVie, American Regent, Cellceutix, Celgene, Eli Lilly, Endo Pharmaceuticals, Ferring, Gilead, Janssen Orthobiotech, Merck, Morphic Therapeutics, Pfizer, Prometheus Laboratories, Romark, Salix/Valeant, Shire, Takeda, and UCB; honoraria from the American College of Gastroenterology, American Regent, Merck, Romark, Springer Science and Business Media, and Up-To-Date; and royalties from Professional Communications Inc. and SLACK Inc.
HN has received support from AbbVie, Celgene, Daiichi Sankyo, EA Pharma, Janssen, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; as well as grants for commissioned/joint research from Boehringer Ingelheim, Bristol Myers Squibb, and Hoya Group Pentax Medical.
MK, EC, DI, GL, and JE are full-time employees of AbbVie, and might hold AbbVie stock or stock options.
SCG has served as a consultant for Bristol Myers Squibb and Janssen.
SD has served as a speaker, consultant, and/or advisory board member for AbbVie, Alfa Wassermann, Allergan, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Johnson & Johnson, Merck, MSD, Mundipharma, Pfizer, Sandoz, Takeda, Tigenix, UCB and Vifor.
JFC has received personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring, Genentech, Janssen, Johnson & Johnson, MedImmune, Merck, Pfizer, PPM Services, Protagonist Therapeutics, Second Genome, Seres, Shire, Takeda, and Theradiag; has received grant support from AbbVie, Janssen, Johnson & Johnson, and Takeda; and holds stock options in Genfit and Intestinal Biotech Development.
SS has received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Falk Pharma, Ferring, Galapagos/Gilead, Genentech/Roche, GlaxoSmithKline, I–MAB Biopharma, MSD, Pfizer, Shire, and Takeda.
AbbVie and the authors thank all of the trial investigators and patients who participated in these clinical trials. AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Carl Davies, MSc, of 2 the Nth (Cheshire, UK), and Fraser Harris, MRes, on behalf of 2 the Nth (Cheshire, UK), and was funded by AbbVie.