Introduction

Specific antagonism of α4β7 by the monoclonal antibody vedolizumab is a proven mechanism for IBD treatment¹. MORF-057 is an orally dosed small molecule designed to selectively inhibit the α4β7 integrin, avoiding the need for parenteral administration. This Phase 2a open label study aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of MORF-057 dosed 100 mg twice daily (BID) for induction treatment in adults with moderately to severely active ulcerative colitis (UC).

Aims & Methods

Key eligibility criteria included a modified Mayo Score of 5-9, a centrally read endoscopy sub-score of ≥2, a Robarts Histology Index (RHI) score of ≥ 10 and a history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (approved biologics, JAK inhibitors, and S1P modulators). Patients received 100 mg orally BID of MORF-057 during the induction period of 12 weeks. Saturation of α₄β₇ in peripheral blood was evaluated using a validated FACS analysis. The primary efficacy endpoint was mean change from baseline to Week 12 in the RHI Score.

Results

Of the 35 patients in the Full Analysis Set (FAS), 31/35 (89%) completed the 12-week induction Period. The mean baseline modified Mayo score was 6.7 (SD=1.07) and the mean RHI score was 22.7 (SD=7.32) (Table 1).
At Week 12, the primary endpoint of the study was met with a mean reduction in the RHI score of - 6.4 (SD=11.2) (p = 0.0019). For the secondary endpoint of change from baseline in the modified Mayo Clinic score (mMCS), a change of ‑2.3 (SD=2.14) points was observed. 25.7% of patients achieved mMCS clinical remission. The proportion of patients achieving a mMCS clinical response was 45.7% and endoscopic improvement was achieved in 25.7% of patients.
Pharmacokinetic (PK)/pharmacodynamic (PD) evaluations confirmed results seen in the healthy volunteer studies^2,3, with trough drug concentrations sufficient to lead to a median α₄β₇ receptor occupancy (RO) of >99%. The RO saturation was achieved early and sustained at week 12 that was accompanied by selective increases in circulating ITGb7⁺ lymphocyte subsets without a corresponding rise in the total lymphocyte counts.
.The rates of treatment-emergent adverse events (TEAEs) were low. Common (>5%) TEAEs were exacerbation of UC in 4 patients (11.4%) and anemia in 3 (8.6%) patients. Overall, there were no safety signals identified.

Table 1. Demographic and Disease Characteristics at Baseline

Conclusion

MORF-057 demonstrated desired PK and PD profile. Consistent changes in key efficacy outcomes including statistically significant outcome in the primary endpoint observed. MORF-057 was well tolerated. An ongoing Phase 2b randomized, double blind, placebo-controlled trial is being conducted to further confirm these findings and find optimal dosages for further development.

References

1. Entyvio® (vedolizumab) prescribing information. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125476Orig1s046lbl.pdf)
2. Ray A et al. MORF-057, An oral selective α4β7 integrin inhibitor for inflammatory bowel disease, leads to specific target engagement in a single and multiple ascending dose study in healthy subjects. ECCO. 2021; ePoster 306
3. Hussain, A., et al. Increase in Circulating T and B Lymphocyte Subsets After Treatment with the Potent, Selective, Oral Small Molecule α4β7 Inhibitor MORF-057 In Healthy Subjects. UEG Week, 2022; Poster number P0417

Disclosure

Current employee and stockholder

Introduction

Butyrate has shown anti-inflammatory effects and plays an important role in maintaining gut homeostasis, providing symptomatic relief when orally supplemented in patients suffering from various colonic diseases. In a previous pilot study, we demonstrated an important biologic effect of microencapsulated sodium butyrate (BLM) in patients with IBD(1).

Aims & Methods

In this randomised, double-blind, placebo-controlled study, 140 IBD patients in remission or with mild disease (n=60 Crohn's disease, CD and n=80 Ulcerative Colitis, UC) were randomized to oral administration of BLM/placebo for 3 months, in addition to conventional therapy. As primary aim we investigated the changes in microbiome composition induced by BLM treatment. Fecal microbiota from stool samples was assessed by 16S sequencing. Clinical disease activity assessed by using Harvey Bradshaw Index (HBI) for CD and partial-Mayo Score (pMS) for UC, quality of life assessed by using Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32) and adherence-dietary-raccomandation were evaluated before and after treatment (T0=0 day and T1=90 days).

Results

Demographics and clinical characteristics were similar between the two populations. Moreover, they adhere to the recommendations of World Cancer Research Fund/American Institute for Cancer Research(WCRF-AIRC) regarding good and healthy nutrition(Table.1). After treatment of CD patients, the HBI score, dichotomized into remission and active disease, showed a significant improvement for those treated with BLM as compared to placebo (McNemar’s p=0.013 vs p>0.9). IBDQ-32 significantly improved in CD and UC, more markedly in the treatment group (CD: treat. 170/184 vs Pb. 188/196_95% CI 4.1,21 vs1.1,9.8;; UC: treat.185/195 vs Pb.188/188_95% CI 4.5,19 vs 2.8,7). The microbiota sequencing highlighted two different enterotype in CD population: the first one was characterized by Bacteroidota prevalence (with a genus prevalence of Fecalibacterium, Alistipes, and Roseburia). The second enterotype was characterized by Firmicutes prevalence (with a genus prevalence of Escherichia-Shigella and Lachnoclostridium). BLM had a more pronounced effect on the Bacteroidota enterotype where the taxa associated with intestinal comfort, SCFA production, and anti-obesity increased after treatment, while the taxa associated with CRC and intestinal inflammation, decreased. Finally, a significant separation was observed in samples from patients who have undergone minor surgery (ileo-colon), compared to non-surgery patients. The variable “surgery” seems to be associated with the Bacteroidota enterotype.

Conclusion

Sodium butyrate supplementation significantly improved clinical outcomes and quality of life in patients with CD. The subpopulation of patients undergoing ileo-colonic resection was microbiologically diversified compared to the non-surgery population. These results indicate that butyrate therapy may be more appropriate for the treatment of CD subjects with colonic preservation.

References

1. Facchin S, Vitulo N, Calgaro M, et al.. Microbiota changes induced by microencapsulated sodium butyrate in patients with inflammatory bowel disease. Neurogastroenterol Motil. 2020 Oct;32(10):e13914. doi: 10.1111/nmo.13914. Epub 2020 May 31. PMID: 32476236; PMCID: PMC7583468.

Disclosure

Sonia Facchin has received lecture or consultancy fees from SILA and Unifarco ; Edoardo Savarino has received lecture or consultancy fees from Abbvie, Amgen, Bristol-Myers Squibb, Fresenius Kabi, Grifols, Janssen, Johnson&Johnson, Innovamedica, Merck & Co, Novartis, Sandoz, Shire, SILA, Sofar, Takeda, Unifarco.

Introduction

OZA is a sphingosine 1-phosphate receptor modulator approved for the treatment of moderately to severely active UC. In the phase 3 TN study, OZA was efficacious for up to 52 wk with a favorable safety profile. IL-17A, a proinflammatory cytokine, sustains the release of other inflammatory mediators and is associated with inflammatory bowel disease.

Aims & Methods

This analysis assessed the effect of OZA on IL-17A levels and the association of IL-17A levels with OZA efficacy during TN. During the 10-wk induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or placebo (PBO) and pts in Cohort 2 received open-label OZA 0.92 mg. Pts with clinical response to OZA at Week (W) 10 were rerandomized to OZA or PBO for maintenance through W52. IL-17A levels were assessed at baseline, W10, and W52. Disease activity scores (rectal bleeding and stool frequency subscores, Physician’s Global Assessment subscore, endoscopy subscore, and partial and total Mayo scores) were assessed at baseline and W10. Efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10 and W52. Associations of IL-17A levels with disease activity and efficacy endpoints were assessed using Spearman’s correlation and logistic regression, respectively.

Results

In all, 645 pts were randomized to OZA (n=429) or PBO (n=216) and 367 pts received open-label OZA; 230 and 227 OZA-treated pts were rerandomized to OZA and PBO, respectively, for maintenance. Pts on OZA demonstrated reductions from baseline in IL-17A at W10, which was significant vs PBO (P<0.001, both cohorts) (Table). IL-17A reductions were significantly greater in pts with vs without clinical response at W10 in all OZA and PBO treatment groups (P<0.01, all groups) (Table). Significantly greater IL-17A reductions occurred with OZA vs PBO at W10 regardless of prior biologic or anti–tumor necrosis factor exposure (P<0.001, all groups). IL-17A reductions were maintained through W52; pts who continued OZA had significantly greater IL-17A reductions at W52 vs pts who switched to PBO (P<0.001) (Table). IL-17A reductions were significantly greater in pts with vs without clinical response at W52 (P<0.001, OZA and PBO groups) (Table). Baseline IL-17A levels were significantly correlated with all baseline disease activity scores (Spearman’s rho 0.1–0.2, P<0.05, all scores), but were not associated with treatment responses at W10. Change in IL-17A from baseline to W10 was significantly correlated with change in all disease activity scores at W10 with OZA and PBO (Spearman’s rho 0.2–0.4, P<0.05, all scores in both groups). Furthermore, greater reductions from baseline to W10 in IL-17A was significantly associated with higher probability of achieving clinical remission, clinical response, endoscopic improvement, and mucosal healing at W52 (P<0.05, all endpoints) in pts on continuous OZA through W52.

Conclusion

OZA led to IL-17A reductions, indicative of decreases in inflammatory responses. Higher baseline IL-17A was associated with higher baseline disease activity, and greater reductions in IL-17A were associated with better short- and long-term disease outcomes. These data support IL-17A as a good disease marker for UC.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA
SH, RM, CW, YH, and AP: employees and/or shareholders of Bristol Myers Squibb.
SV: received research funding from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; received consulting and/or speaking fees from AbbVie, Abivax, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Eli Lilly, Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, IMIDomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand.

Introduction

A high body mass index (BMI) may negatively impact treatment efficacy in patients with ulcerative colitis (UC) treated with advanced therapies, such as biologics,¹ which is relevant due to the prevalence of obesity and UC increasing substantially over the past decades.^2,3 Etrasimod is an oral, once-daily (QD), selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active UC.

Aims & Methods

This post hoc analysis of ELEVATE UC 52 and ELEVATE UC 12 investigated the impact of BMI on the efficacy and safety of etrasimod in patients with UC. ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) were phase 3, randomised, placebo-controlled trials.⁴ ELEVATE UC 52 had a treat-through design consisting of a 12-week (wk) induction and 40-wk maintenance period; ELEVATE UC 12 comprised a 12-wk induction period. Patients who received ≥1 dose of etrasimod 2 mg QD or placebo were stratified by baseline BMI: <25 kg/m², 25–30 kg/m² and >30 kg/m². Efficacy outcomes (aligned to the predefined outcomes for the ELEVATE UC 52 and ELEVATE UC 12 trials) included the primary endpoint (clinical remission) and selected secondary endpoints at Wk 12 (data pooled for both trials) and Wk 52 (ELEVATE UC 52 only). Safety outcomes assessed the proportions of treatment-emergent adverse events (TEAEs).

Results

Of the 787 patients enrolled in the ELEVATE UC clinical programme, 443 (56.3%) had baseline BMI <25 kg/m², 217 (27.6%) had baseline BMI 25–30 kg/m² and 127 (16.1%) had baseline BMI >30 kg/m². In the BMI <25 kg/m² and BMI 25–30 kg/m² subgroups, significantly more patients (p<0.05) receiving etrasimod vs placebo achieved all efficacy endpoints at Wks 12 and 52. In the BMI >30 kg/m² subgroup, significantly more patients receiving etrasimod vs placebo achieved clinical remission at Wk 52 (p<0.0001; Wk 12: p=0.05), endoscopic improvement and clinical response at Wks 12 and 52, and corticosteroid-free clinical remission at Wk 52 (all p<0.05; Table). The proportions of patients with the most common TEAEs were generally consistent between BMI subgroups receiving etrasimod. Incidence of serious AEs was generally similar across BMI subgroups receiving etrasimod (<25 kg/m²: 17/308 [5.5%]; 25–30 kg/m²: 8/137 [5.8%]; >30 kg/m²: 1/82 [1.2%]).

Conclusion

In the ELEVATE UC clinical programme, significant improvements in efficacy were observed for patients receiving etrasimod 2 mg QD vs placebo, regardless of baseline BMI. The safety profile of etrasimod was consistent between BMI subgroups and with the overall ELEVATE UC population.

References

1. Kurnool S et al. Aliment Pharmacol Ther 2018; 47: 1472–1479.
2. Molodecky NA et al. Gastroenterology 2012; 142: 46-54 e42; quiz e30.
3. Ng M et al. Lancet 2014; 384: 766–781.
4. Sandborn WJ et al. J Crohns Colitis 2023; 17: 338–351.

Disclosure

AJY has received consultancy fees from AbbVie, Pfizer Inc, Arena, Takeda and Bristol Myers Squibb; and lecture/speaker fees from Bristol Myers Squibb. MDL is a consultant for AbbVie, Janssen, Pfizer Inc, Takeda, Bristol Myers Squibb, Target PharmaSolutions, Prometheus, Lilly, Salix, Valeant, Genentech, Roche, Calibr and Theravance; and has received research support from Pfizer Inc and Takeda. JT has received advisory board fees from AbbVie, Arena, Bristol Myers Squibb, Galapagos, Janssen and Pfizer Inc; research grants from AbbVie and Janssen; and speaker fees from AbbVie, Galapagos, Janssen and Pfizer Inc. NN is a consultant and advisory board member for AbbVie, Bristol Myers Squibb, Janssen, Lilly and Pfizer Inc; and has received research support from Ferring, Janssen, Pfizer Inc and Seres. RKC has received consultancy and advisory board fees from AbbVie, Adiso, Bristol Myers Squibb, CorEvitas, Fresenius Kabi, Fzata, IBD Education Group, Janssen, Magellan Health, Option Care, Pfizer Inc, Sandoz, Samsung Bioepis, Sebela and Takeda; and research grant/support from Janssen. AMA is an employee and shareholder of Pfizer Inc. DB and WN are employees of Pfizer Inc. CMC and JW are employees and shareholders of Pfizer Inc. GP is an employee of Pfizer Healthcare India Private Ltd. MG is an employee and shareholder of Pfizer AG. RP is a consultant for Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx and UCB; has received speaker fees for AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Lilly, Merck, Organon, Pfizer, Roche, Sandoz, Shire and Takeda; is an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda and Ventyx; and has received research support from AbbVie, Janssen, Takeda and Pfizer.

Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that was efficacious in double-blind, placebo-controlled, treat-through trials in participants (pts) with moderately to severely active Crohn’s disease (CD) using IV induction and SC maintenance (GALAXI 2 & 3) or SC induction and maintenance (GRAVITI). Assessment of histologic disease activity is becoming increasingly important as a measure of treatment efficacy. Here we report histologic outcomes at Weeks (W) 12 & 48 from GRAVITI.

Aims & Methods

Pts were randomized 1:1:1 to GUS 400 mg SC every 4 weeks (q4w)→200 mg SC q4w, GUS 400 mg SC q4w→100 mg SC every 8 weeks (q8w), or placebo (PBO). Biopsies were obtained from the most affected area (or if no disease activity present, from normal-appearing mucosa) in 5 segments: terminal ileum, ascending colon, transverse colon, descending colon, and rectum. Histologic response, histologic remission, and the composite endpoints of histo-endoscopic response and histo-endoscopic remission were evaluated using Robarts Histopathology Index (RHI), Global Histologic Activity Score (GHAS), and Geboes scoring. Histologic response was assessed in pts with baseline histologic disease; histologic remission, histo-endoscopic response, and histo-endoscopic remission were assessed in the full analysis set (see definitions in table legend). Pts who met rescue criteria at W16 were considered non-responders at W48. Histologic endpoints in GRAVITI were exploratory and not controlled for multiple comparisons; p-values are nominal.

Results

Of the 347 pts in the full analysis set, 273 (78.7%) had baseline histologic disease per RHI score. SC induction with GUS (400 mg SC at W0, W4, & W8) resulted in greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to placebo at W12 (Table). At W48, greater proportions of pts receiving GUS 100 mg SC q8w or GUS 200 mg SC q4w maintenance also achieved histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission compared to PBO. Comparable outcomes were observed using GHAS or Geboes scoring criteria.

Conclusion

Compared to PBO, pts with moderately to severely active CD receiving SC induction and maintenance treatment with GUS achieved greater rates of histologic response, histologic remission, histo-endoscopic response, and histo-endoscopic remission through W48. These results support the use of histologic and composite histologic and endoscopic endpoints as a measure of CD activity, and the efficacy of SC guselkumab in CD.

Disclosure

GRD’H: consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Galapagos, GlaxoSmithKline, Gossamerbio, Immunic, Index, Johnson & Johnson, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist Therapeutics Inc.; speaker’s bureau for AbbVie, Bristol Myers Squibb, Galapagos, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, and Seres Health.
ALH: lecturer and/or advisory board member for Bristol Myers Squibb, Celltrion, Falk, AbbVie, Johnson & Johnson, Takeda, Pfizer, Galapagos, MSD, and GSK.
RP: consulting fees from Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, AnaptsyBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Spyre Therapeutics, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, and UCB; speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Johnson & Johnson, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and participation in Advisory Boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
FS: consultant, speaker, or researcher for AbbVie, Amgen, Celltrion, Ferring, Johnson & Johnson, Pfizer, Sandoz, and Takeda.
QC: steering committee adviser for Bristol Myers Squibb and Johnson & Johnson; research grants from Takeda and Johnson & Johnson.
SD: consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB and Vifor; and lecture fees from AbbVie, Amgen, Ferring, Gilead, Johnson & Johnson, Mylan, Pfizer and Takeda
TH: grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, and Kissei Pharmaceutical Co. Ltd.; consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Johnson & Johnson, Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Abivax; lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Johnson & Johnson, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., and Kissei Pharmaceutical Co. Ltd.
BES: consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Johnson & Johnson, Pfizer, and Takeda; and stock/stock options from Ventyx Biopharma.
MO, LS, PB, WvD, NT: employees and shareholders of Johnson & Johnson

Introduction

Crohn’s disease (CD) can lead to inflammation of the intestinal tract and may be complicated by strictures¹. Patients want diet-based approaches to therapy but relatively few prospective diet studies have been conducted with high rates of adherence.

Aims & Methods

We conducted a patient preference study NCT04213729 to test a high fiber(17gm/1000 calories for fiber), low fat(20-25% calories from fat) diet in CD patients. In the current study, we asked whether patients changed their symptoms following the catered diet intervention and whether the CD-related phenotype impacted the response to diet. Patients chose to receive diet counseling alone (group 1), catered food for 8 weeks (group 2), or catered food for a patient and a household member as well as participate in Dyadic Psychosocial Support (DPS)sessions (group 3).DPS sessions incorporated psychoeducational components that combined didactic and behavioral procedures. High fiber catered foods consisted of soluble and insoluble fibers as well as fermentable fibers such as fructans and galactooligosaccharides, etc. Detailed demographic, clinical, anthropomorphic, quality of life, biochemical and food knowledge data were collected at baseline and week 8. A total of 73 patients and 24 household controls were enrolled.

Results

At baseline,60-80%of CD patients were in remission based on PRO2 score (stool frequency≤ 1.5, abdominal pain ≤1)and Harvey Bradshaw index<5. On average, CD patients consumed a diet with less than 9gm/1000 calories of fiber and >40% fat at baseline. All three CD groups were well-matched at baseline with the household controls consuming also less fiber. Patients receiving the catered food had a high rate of adherence to the diet(80%)at week 8; patients receiving diet counseling alone had 5%adherence to a low-fat diet and 10%adherence to a high-fiber diet at week 8. Serum amyloid A(SSA), CRP, and fecal calprotectin were low at baseline and remained low. Catered meals improved values of fecal calprotectin or SAA in the subset of patients that had elevated levels of these biomarkers. Group 3 received DPS sessions for the CD patient and household control and had significantly improved nutrition literacy (score average:70.6,p=0.000636)while groups 1 and 2 averaged 57 and 57.1, respectively. Food-related quality of life(FRQoL 29)scores were significantly improved for those participants that received diet and DPS. FRQoL average increased from 82.1 to 107(p=0.000541).29% had B2 fibro-stenotic disease and received high-fiber catered food. This subset of patients had a decrease in stool frequency and no increase in abdominal pain symptoms. The mean number of bowel movements and pain scores improved or did not change.

Conclusion

CD patients even those in remission, have very low consumption of fruits and vegetables. We show that even patients with B2 phenotype CD can tolerate 8 weeks of high fiber, low-fat diet without worsening of symptoms. One time diet counseling was not able to change diet behavior. Catering meals offers an effective way to control dietary intake in CD clinical trials. Psychology interventions for the CD patient and household improved food-related quality of life and nutritional literacy.

References

1. Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ. Crohn's disease complicated by strictures: a systematic review. Gut. 2013 Jul;62(7):1072-84. doi: 10.1136/gutjnl-2012-304353. Epub 2013 Apr 26. PMID: 23626373; PMCID: PMC4884453.

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of digestive tract, and anti-inflammatory drugs, such as vedolizumab, have central role in their treatment. Intravenous form of vedolizumab is approved for induction and maintenance of remission in patients with CD and UC. Recently, subcutaneous form of vedolizumab was approved as a maintenance therapy after the induction with, at least, two intravenous doses.

Aims & Methods

The aim of this study was to show how the switch from intravenous to subcutaneous vedolizumab in a real-life setting in inflammatory bowel disease (IBD) patients on stable maintenance therapy affects vedolizumab serum concentration and clinical outcomes. IBD patients treated with intravenous vedolizumab and planned to switch to subcutaneous vedolizumab at the Department of Gastroenterology and Hepatology in the University Hospital Centre Osijek were included in the study. Patients were in remission at the time of transition (based on clinical symptoms, fecal calprotectin level or endoscopy scores). Data on vedolizumab serum trough concentration and clinical outcomes (remission rate, fecal calprotectin level, clinical scores, hospitalization rate, rate of surgical procedures, change of therapy, and adverse events) were collected prior to and after the switch from intravenous to subcutaneous vedolizumab.

Results

In total, 31 patients, 17 with CD and 14 with UC, were included in final analysis. Median follow up was 12 months (interquartile range, IQR 9-12). Median duration of therapy with intravenous vedolizumab prior to switch was 14 months (IQR 6-32). Mean serum trough concentration of intravenous vedolizumab was significantly lower than mean serum trough concentration of subcutaneous vedolizumab (25.62 mg/L±14.29 vs. 34.93±14.59 mg/L; p=0.002). This rise in vedolizumab serum concentration after the switch to subcutaneous drug, was more evident in CD (Δ11.8 mg/L) than in UC (Δ5.79 mg/L) patients. There was no significant difference between fecal calprotectin level in all patients, as well as fecal calprotectin and Harvey–Bradshaw index in CD patients prior to or after the transition to subcutaneous vedolizumab. In UC patients, fecal calprotectin and Partial Mayo score were significantly higher (p= 0.011 and p=0.018, respectively) after the switch to subcutaneous vedolizumab, although this difference was not clinically significant. There was a significant difference in remission rate before and after the transition to subcutaneous vedolizumab in all patients (100% vs 71%; p=0.004), and in UC patients (100% vs. 57.1%; p=0.031). During the follow up, one (3.2%) CD patient was hospitalized and had a surgical procedure due to IBD. In 7 (22.6%) patients, the therapy was discontinued during the follow-up period with a median of 8 months. In all patients, therapy was discontinued due to loss of response. In total, 27 adverse events were reported by 17 patients, and the most common adverse event was COVID-19. One serious adverse event was reported (a patient was hospitalized for subileus).

Conclusion

Despite the rise in serum vedolizumab trough concentration after the switch from intravenous to subcutaneous vedolizumab, total remission rate was significantly lower in all patients and in the subgroup of UC patients. No new safety signals were observed in patients after the switch to subcutaneous vedolizumab.

Disclosure

Vlasta Oršić Frič has received speaker honoraria from Takeda, Janssen, Merck Sharp & Dohme, Sandoz, Ferring, Oktal Pharma, Abbvie, Viatris-Mylan and has been a member of advisory board for Janssen. Vladimir Borzan has received speaker honoraria from Takeda, Janssen, Sandoz, Merck Sharp & Dohme, Abbvie, Oktal Pharma, Viatris-Mylan, Ferring and has been a member of advisory board for Takeda, Sandoz, Abbvie, Viatris-Mylan, Merck Sharp & Dohme. Other authors declare no conflict of interest.