Introduction

Treatment-refractory small intestinal enteropathies displaying villous atrophy and severe malabsorption are a rare subgroup of patients that are difficult to treat. This is secondary to their disease being hard to assign to an established disease entity by established histopathological diagnostics. Similarly, the underlying immune pathology leading to chronic small intestinal inflammation and malabsorption is mostly unclear. Recently, the identification of acquired somatic mutations in individual enteropathy patients allowed to not only shed light in the underlying immune defects but also to select targeted treatments based on the identified defects.

Aims & Methods

We aimed for identifying relevant somatic mutations in patients suffering from various malabsorptive small intestinal diseases. We included duodenal mucosal samples (FFPE material) from 10 refractory celiac disease patients (4 RCD type-I, 6 RCD-II patients), 2 patients suffering from duodenal Crohn´s disease, 3 patients with Whipple´s disease (CD and WD as inflammation controls) and 4 patients suffering from Barrett´s esophagus (as a healthy control group). Genomic DNA isolated from FFPE material was processed using the SureSelect XT HS Panel (Agilent) covering a panel of 42 selected genes and sequenced in paired-end mode on an Illumina NextSeq-550 machine at a sequencing depth of 3 to 7 Mio reads per run. Data analysis was performed using the Agilent SureCall software. For the RCD patients, mutation analysis was complemented by identifying aberrant intraepithelial lymphocytes after isolation of small intestinal lymphocytes using flow cytometry after immunostaining.

Results

In the RCDII group, a total of 44 mutations were identified in 15 distinct genes. Of these, 13 mutations were only found within the RCD-II group, more specifically in the following signaling pathways: (i) Jak-Stat-pathway (JAK1, STAT3, STAT5B). (ii) NFKB-pathway (NFKBIA, TNIP2). (iii) gene regulation (BCOR, CREBBP, KMT2D, TET2). Approx 2/3 of all RCD-II patients carried mutations that were not found in any of the other patient groups. Two RCDII patients had a mutation in the JAK1 gene at the same amino-acid position (JAK1(p.Gly1097Asp), JAK1(pGly1097Ser)) within the catalytic protein kinase domain. One of the two patients also had a splice variant within the JAK1 gene. In 2 other RCD-II patients, a mutation in the STAT3 gene was found in the SH2 domain (STAT3(p.Tyr640Phe), STAT3(p.Ser614Arg)). Consequently, mutations in either the JAK1 gene or STAT3 gene were found in 2/3 of the RCDI patients. Other genes carrying mutations included CREBBP (p.Pro1948Leu), BCOR (p.Asn1459Ser), NFKBIA (p.Leu150Phe), TNIP3 (splicing variant), TET2 (pGln626*), TET2 (p.Cys1358Arg), KMT2D (p.Glu1527*) and STAT5B (p.Ser715Phe). On the other hand, a total of 43 mutations occurred in 18 different genes within the RCD-I group. Of these, 14 mutations were detected only in RCD-I. The KMT2D gene carried a mutation in 3/4 of the RCD-I patients at the same AA position (p.Ser1107Arg). Further mutations were found in the genes CREBBP, BCL11A, JAK3, NOTCH2, MAP3K15, STAT3, TET2; NCOR1, BCLL11A, MTOR, SETD2, TDRD6, and DOT1L.

Conclusion

Gene mutations in the JAK-STAT, NFKB and the gene regulation pathway are enriched in the RCD-II group, while distinct KMT2D gene mutations might be enriched in the RCD-I patients. Identifying these mutations within the clinical routine might direct treatment using monoclonal antibodies or small molecules as some of these pathways can be targeted specifically. Importantly, these mutational diagnostic modalities appear to be disease-specific.

References

Ettersperger et al., Immunity 2016, doi: 10.1016/j.immuni.2016.07.018. Cording et al., Gut 2021, doi: 10.1136/gutjnl-2020-322935. Ritter et al., Gut 2018, doi: 10.1136/gutjnl-2016-311816. Branchi et al., Dig Liver Dis 2022, doi: 10.1016/j.dld.2022.06.024.

Disclosure

None.

Introduction

Fistulizing perianal Crohn’s disease (CD) remains a significant therapeutic challenge, with limited randomized controlled trials to date, restricted so far to infliximab and, more recently, filgotinib. The USTAP (NCT04496063) trial aimed to evaluate the efficacy and safety of UST in patients with actively draining perianal fistulas through a multicenter randomized controlled design.

Aims & Methods

This double-blind, placebo-controlled, multicenter trial enrolled adult patients with active draining fistulizing perianal CD. Between April 2020 and June 2024, eligible patients with persistent fistula drainage were randomized 1:1, after seton placement when necessary, to receive either UST (6 mg/kg IV at baseline followed by 90 mg SC at week 8, then every 8 weeks) or placebo. Steroids were allowed at baseline with a standardized steroid taper. Seton removal was planned at week 6. The primary endpoint was combined clinical remission (absence of drainage from all external fistula openings) and radiological remission (defined as the absence of abscesses >2 cm confirmed by blinded central pelvic MRI) at week 12. Secondary endpoints included clinical remission, radiological remission, changes in disease activity (CDAI, PDAI), IBD-DI, and safety. Endpoints were independently reviewed by a blinded adjudication committee. Randomization was stratified by prior anti-TNF exposure and study center. The intended sample size was 73 patients per group to detect a 20% difference in remission rates (power 80%, alpha 5%). Due to slow recruitment, the study was discontinued in June 2024 after randomizing 32 patients, without unblinding the study data. Patients were subsequently followed until week 48.

Results

Thirty-three patients consented to participate with 32 patients (women: 41%; median age: 42) ultimately randomized (UST: 16; placebo: 16) across 10 French centers. Seventy percent had prior anti-TNF exposure (50% in UST arm, 50% in placebo arm), and 23% had previously failed two or more anti-TNF therapies. At baseline, 84% had one draining fistula, 16% had two, and 25% had associated abscesses. At week 12, combined remission was achieved in 62% in the UST group versus 25% in the placebo group (Table). Clinical remission was observed in 69% in the UST group vs. 31% in the placebo group, while radiological remission rates were 87.5% in the UST group and 75% in the placebo group. In the UST arm, mean change in CDAI, PDAI and IBD-DI from baseline to week 12 was -56.3, -2.2 and -4.9, (vs. -9.8, -1.6 and +4.9, in the placebo arm, respectively). Adverse events (AE) and serious adverse events (SAE) were similar in both treatment groups: 23 AE (62%) occurred in the placebo group, and 14 AE (38%) in the UST group. Six SAEs were reported overall, including two gastrointestinal events, one renal disorder, and one anal abscess. Two patients in the placebo group discontinued study by week 6 due to SAEs (an anal abscess and a peri-ileal abscess).

Endpoints	Overall (N=32)	Placebo (N=16)*	Ustekinumab (N=16)	OR (IC 95%)
Primary endpoints, n (%)
Combined Remission	14 (44%)	4 (25%)	10 (62%)	5.1 [1.07-24.4]
Secondary endpoints, n (%)
Clinical Remission (100% of the fistulas tracts showing no drainage)	16 (50%)	5 (31%)	11 (69%)	0.27 [0.06-1.17]
Radiological Remission (absence of collections >2 cm confirmed by masked central MRI)	26 (81.2%)	12 (75%)	14 (87.5%)	2.7 [0.34-21.1]
Absence of abscess at pelvic MRI	22 (69%)	11 (69%)	11 (68%)	1.51 [0.3-7.46]

*Two patients discontinued study by week 6 in the placebo group

Conclusion

In this trial, where the majority of patients had prior anti-TNF exposure, the observed short-term clinical benefit of UST supports its use in fistulizing perianal CD.

Disclosure

This work was supported by a grant from Johnson & Johnson
Pauline Wils : Johnson & johnson, Takeda, Amgen, Abbvie, Celltrion, Ferring
S Nancey: Abbvie, Johnson and Johnson, Fresenius Kabi, Biogen, Takeda, Medac, Celltrion, MSD, Pfizer, Sandoz, Lilly,Ferring, Amgen
E. Messmer: No conflict of interest for this study
A Bourreille: Johnson and Johnson
A Buisson: Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pileje, Pfizer, Roche, Sandoz, Takeda et Tillotts. Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda
L Caillo: No conflict of interest for this study
L Vuitton: abbvie amgen J&J Pfizer Takeda Lilly MSD Mayoli Ferring Dr Falk Alpha Sigma
R Altwegg: Abbvie, Johnson ans Johnson, Takeda, Pfizer, Lilly, Alphasigma, Celltrion, Amgen, Biogen, Sandoz, Ferring
X Hébuterne reports clinical research funding from Abbvie, Abivax, Amgen, Celltrion, Lilly, Fresenius-Kabi, J&J, InDex Pharmaceuticals, Pfizer, Prometheus, MSD, Roche, Takeda, serving on advisory boards for Abbvie, Biogen, Celltrion, Lilly, J&J, and participating in lectures and educational activities for Abbvie, Amgen, Celltrion, Lilly, Fresenius-Kabi, Galapagos, J&J, MSD, Nestlé Health Sciences, Nutricia, Pfizer, Tillots, Takeda.
O Ernst: No conflict of interest for this study
P Meunier: No conflict of interest for this study
V Laurent: No conflict of interest for this study
D Laharie: received board and lecture fees from: Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Fresenius-Kabi, Janssen, Lilly, MSD, Pfizer, Roche, Sandoz, Takeda
E Vicaut: No conflict of interest for this study
L Peyrin-Biroulet: Consulting : Abbvie, Abivax, Adacyte, Alimentiv, 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, 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 ; lecture : Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots, Viatris

Introduction

Obefazimod (Obe), an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 was studied in patients (pts) with moderately to severely active ulcerative colitis (UC) in Phase 2 studies [1-3]. Here we present efficacy endpoints at week 8 for pts with and without prior inadequate response to advanced therapies (AT-IR-Yes, AT-IR-No) from ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216] Phase 3 trials.

Aims & Methods

The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (modified Mayo score, MMS≥ 5, with rectal bleeding sub-score (RBS) ≥ 1 and centrally read endoscopic score >2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (no upper limit), including corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors (JAKi). Pts were randomized 2:1:1 to Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) for 8 weeks. Clinical remission per MMS and other efficacy measures (clinical response, endoscopic improvement, symptomatic remission, histo-endoscopic mucosal improvement) were analysed among AT-IR-Yes and AT-IR-No pts; all p-values are nominal.

Results

Among pts who participated in ABTECT-1, ABTECT-2, and the pooled analysis, 45.3% (288/636), 49.4% (314/636), and 47.3% (602/1272) were AT-IR-Yes, respectively; 54.7% (348/636), 50.6% (322/636), 52.7% (670/1272) were AT-IR-No. In ABTECT-1, ABTECT-2, and pooled, a higher proportion of the AT-IR-Yes subgroup receiving Obe-50 achieved all efficacy measures relative to PBO including clinical remission (Obe-50-PBO difference: ABTECT-1 12.7%, p=0.0039; ABTECT-2 7.6%, p=0.0652, pooled 10.1%, p=0.0009). In the AT-IR-Yes subgroup, the difference from PBO across all efficacy measures was lower for pts receiving Obe-25 relative to Obe-50 (Table). In the AT-IR-No subgroup, larger proportions achieved all efficacy measures relative to PBO including clinical remission (Obe-50-PBO difference: ABTECT-1 25.0%, p<0.0001; ABTECT-2 19.4%, p=0.0004; pooled 22.4%, p<0.0001). In the AT-IR-No subgroup, Obe-50 and Obe-25 performed similarly in the pooled analysis across efficacy measures. In the subset of pts who failed JAKi, higher proportion of pts receiving Obe-50 or Obe-25 achieved clinical response vs. PBO. The difference from PBO in clinical response for Obe-25 and Obe-50 was similar across lines of treatment, from AT-IR-No through 4+ AT-IRs (Table). Obe was well tolerated with a safety profile similar to previous studies.

Table: Efficacy of obefazimod at week 8 in pts with and without prior inadequate response* to AT– ABTECT-1, ABTECT-2 and pooled studies

ABTECT-1 a AT-IR-Yes

ABTECT-1 a AT-IR-No

ABTECT-2 a AT-IR-Yes

ABTECT-2 a AT-IR-No

Pooled ABTECT trials a AT-IR-Yes

Pooled ABTECT trials a AT-IR-No

Efficacy Endpoints at week 8, % (n)

PBO (N=69)

Obe-25 (N=70)

Obe-50 (N=149)

PBO (N=89)

Obe-25 (N=90)

Obe-50 (N=169)

PBO (N=79)

Obe-25 (N=76)

Obe-50 (N=159)

PBO (N=80)

Obe-25 (N=83)

Obe-50 (N=159)

PBO (N=148)

Obe-25 (N=146)

Obe-50 (N=308)

PBO (N=169)

Obe-25 (N=173)

Obe-50 (N=328)

Clinical remission Placebo adjusted Δ% p-value

1.4 (1)

8.6 (6) 7.1 p=0.0556

14.1 (21) 12.7 p=0.0039

3.4 (3)

35.6 (32) 32.4 p<0.0001

28.4 (48) 25.0 p<0.0001

5.1 (4)

5.3 (4) 0.7 p=0.8529

12.6 (20) 7.6 p=0.0652

7.5 (6)

16.9 (14) 9.5 p=0.0659

27.0 (43) 19.4 p=0.0004

3.4 (5)

6.8 (10) 3.5 p=0.1728

13.3 (41) 10.1 p=0.0009

5.3 (9)

26.6 (46) 21.3 p<0.0001

27.7 (91) 22.4 p<0.0001

Endoscopic improvement Placebo adjusted Δ% p-value

4.3 (3)

14.3 (10) 9.9 p=0.0457

22.1 (33) 17.8 p=0.0011

6.7 (6)

55.6 (50) 48.9 p<0.0001

43.2 (73) 36.4 p<0.0001

8.9 (7)

11.8 (9) 3.5 p=0.4675

26.4 (42) 17.7 p=0.0015

11.3 (9)

31.3 (26) 20.3 p=0.0016

44.7 (71) 33.1 p<0.0001

6.8 (10)

13.0 (19) 6.4 p=0.0687

24.4 (75) 17.8 p<0.0001

8.9 (15)

43.9 (76) 34.9 p<0.0001

43.9 (144) 34.9 p<0.0001

Symptomatic remission Placebo adjusted Δ% p-value

10.1 (7)

27.1 (19) 17.0 p=0.0108

34.9 (52) 25.0 p=0.0001

23.6(21)

54.4 (49) 31.0 p<0.0001

46.7 (79) 23.2 p=0.0003

15.2 (12)

26.3 (20) 11.3 p=0.0841

37.1 (59) 21.7 p=0.0006

28.8 (23)

39.8 (33) 11.0 p=0.1430

43.4 (69) 14.2 p=0.0329

12.8 (19)

26.7 (39) 13.8 p=0.0031

36.0 (111) 23.4 p<0.0001

26.0 (44)

47.4 (82) 21.3 p<0.0001

45.1 (148) 19.2 p<0.0001

HEMI Placebo adjusted Δ% p-value

1.4 (1)

5.7 (4) 4.3 p=0.1803

12.8 (19) 11.3 p=0.0073

4.5 (4)

37.8 (34) 33.4 p<0.0001

32.0 (54) 27.5 p<0.0001

6.3 (5)

7.9 (6) 1.8 p=0.6596

17.0 (27) 11.0 p=0.0197

8.8 (7)

18.1 (15) 9.3 p=0.0805

30.8 (49) 21.8 p=0.0002

4.1 (6)

6.8 (10) 2.9 p=0.2785

14.9 (46) 11.1 p=0.0005

6.5 (11)

28.3 (49) 21.7 p<0.0001

31.4 (103) 24.7 p<0.0001

Clinical response Placebo adjusted Δ% p-value

21.7(15)

52.9 (37) 31.2 p=0.0002

54.4 (81) 32.5 p<0.0001

33.7(30)

75.6 (68) 41.8 p<0.0001

66.9 (113) 33.2 p<0.0001

20.3 (16)

40.8 (31) 21.0 p=0.0043

57.2 (91) 36.8 p<0.0001

46.3 (37)

65.1 (54) 18.8 p=0.0165

69.2 (110) 22.2 p=0.0008

20.9 (31)

46.6 (68) 25.6 p<0.0001

55.8 (172) 34.9 p<0.0001

39.6 (67)

70.5 (122) 30.7 p<0.0001

68.0 (223) 28.2 p<0.0001

NRI is used for subjects with missing outcome at Week 8 and subjects reporting any IE prior to Week 8. % Difference is for Obe minus placebo and is based on estimated common risk difference using the Mantel-Haenszel weights adjusting for the randomization stratification factors: inadequate response to advanced therapies (yes/no), baseline oral corticosteroids usage (yes/no), and region (Japan/rest of world) [ABTECT-2 only]. p-values are two sided. a: all p-values are nominal Clinical remission: stool frequency sub-score (SFS) ≤1, rectal bleeding sub-score (RBS) = 0 and endoscopic sub-score ≤1; Clinical response: decrease from baseline in the MMS ≥ 2 points and ≥30% from baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1; Endoscopic improvement: endoscopic sub-score ≤1; Symptomatic remission: RBS=0, SFS <1; Histo-endoscopic mucosal improvement (HEMI): combination of histologic improvement (Geboes histologic score ≤3.1) and endoscopic improvement (endoscopy sub-score ≤1) *: inadequate response = lack of response, loss of response, or intolerance to advanced therapies. **: N1, N2 = total number of pts in the respective subset ; JAKi: Janus kinase inhibitor

Clinical response, % AT-IR pts w/JAK failure (n/N1**) Placebo adjusted Δ% p-value AT-IR pts w/ 1 AT failure (n/N2**) Placebo adjusted Δ% p-value AT-IR pts w/ 2 AT failures (n/N2**) Placebo adjusted Δ% p-value AT-IR pts w/ 3 AT failures (n/N2**) Placebo adjusted Δ% p-value AT-IR pts w/ 4+ AT failures (n/N2**) Placebo adjusted Δ% p-value

20.0 (7/35) 24.2 (15/62) 20.6 (7/34) 14.3 (4/28) 20.8 (5/24)

47.1 (16/34) 27.0 p=0.0196 53.3 (24/45) 30.5 p=0.0018 48.9 (22/45) 28.6 p=0.0114 42.4 (14/33) 27.3 p=0.0297 34.8 (8/23) 14.4 p=0.2968

54.5 (30/55) 34.4 p=0.0017 50.7 (76/150) 25.3 p=0.0008 67.2 (43/64) 45.5 p<0.0001 61.5 (32/52) 46.3 p<0.0001 50.0 (21/42) 28.7 p=0.0242

Conclusion

Among AT-IR-Yes and AT-IR-No subgroups, improvements in clinical, endoscopic, symptomatic and combined endoscopic-histologic measures were observed in pts treated with Obe at week 8 relative to PBO in ABTECT-1, ABTECT-2, and in the pooled analysis. Improvements vs. PBO in clinical response were observed in a pooled analysis in AT-IR-Yes JAKi-IR pts and across lines of therapy up to 4+ AT-IR.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.
3. Vermeire S, et al. J Crohns Colitis. 2025 ; 19 : jjaf074

Disclosure

Authors reports following potential conflicts of interest:
BES: Abbvie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Kaleido, Kallyope, Lilly, Merck & Co., Microba, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Janssen, Palisade Bio, Pfizer, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Takeda, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Trex Bio, Union Therapeutics, Ventyx Biosciences.
SV: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
LPB: Abbvie, Abivax, Adacyte, Alimentiv, 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, 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.
SD: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
PSD: Abbvie, Abivax, Adiso, Alimentiv, Bristol Meyer Squibb, Celltrion, Genentech, Geneoscopy, Janssen, Pfizer, Takeda.
MD: Abbvie, Abivax, Arena Pharmaceuticals, Astra Zeneca, Boehringer Ingelheim International GmbH, Bristol-Meyer Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech Inc, Gilead, Janssen Pharmaceuticals, Merck, Pfizer Inc, Prometheus Biosciences, Takeda Pharmaceuticals.
HT: Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
BS: AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Pfizer, and Takeda; AlfaSigma, CED Service GmbH, MSD, Ferring, Galapagos, Tr1x bio
TH: 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, Kissei Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax.
XT: Celltrion, AbbVie, Johnson & Johnson, Lilly, Takeda, Alpha Sigma, Dr. Falk, Abivax, Biogen, Fresenius Kabi, MSD, Pfizer, Tillotts, and Thabor Therapeutics.
RA:AbbVie, Abivax, AstraZeneca, Bristol-Myers Squibb, Celltrion Healthcare, Galapagos, Johnson&Johnson, Lilly, MSD, Pfizer, and Takeda Pharma.
US: AbbVie, Abivax, Amgen, Galapagos, Janssen, Eli Lilly, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead Sciences, Pfizer, Roche, Takeda Pharmaceuticals
AA: AbbVie, Abivax, AG Pharma, Alfa Sigma, Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Enthera, Ferring, Galapagos, Gilead, Giuliani, Janssen, Lionhealth, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sanofi, Sandoz, Takeda, Teva Pharmaceuticals, Tillots Pharma
FB: AbbVie, Amgen, Eurogenerics, J&J, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc, Takeda, Celgene, Fresenius Kabi, Sandoz
DTR: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx.

Introduction

Obefazimod is an oral small molecule that modulates inflammation by upregulating a specific anti-inflammatory micro-RNA (miR-124). Obefazimod has demonstrated safety and efficacy in patients with moderate-to-severe ulcerative colitis (UC) in the randomized, placebo-controlled, phase 2b induction study (1). This analysis presents data at week 96 after subjects enrolled in the open-label (OL) maintenance study.

Aims & Methods

Patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) during the 16-week induction Phase 2b and, irrespective of their clinical response, could enter the optional OL 96-week maintenance study with obefazimod 50mg od. A total of 217 patients were enrolled into this study from January 13, 2020 onwards. Patients were followed monthly for safety and efficacy. Non-responder imputation (NRI) was used for missing efficacy data.

Results

Of 222 patients who completed the phase 2b induction study, 217 (97.7%) were enrolled in the OL maintenance study. 30/217 (13.8%) subjects dropped out prior to week 48, 6 subjects did not qualify the second year of treatment (non-responders) and 17/181 (9.4%) subjects dropped out between week 48 and week 96. All dropouts were considered as treatment failures for this analysis. 164 subjects completed the second year of treatment. Main efficacy results are presented in the Table below.

Criteria	Definition	All patients (NRI) N=217
Clinical remission	MMS : stool frequency sub-score ≤1, RBS = 0 and endoscopic sub-score ≤1	52.5%
Endoscopic improvement	Endoscopic sub-score ≤1	59.0%
Endoscopic remission	Endoscopic sub-score = 0	35.9%
Clinical response	Decrease from baseline in the MMS ≥ 2 points and ≥30% from baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1	70.5%

MMS: Modified Mayo score ; NRI: Non-responder imputation ; RBS: rectal bleeding sub-score
Among the 168 patients with no clinical remission after week 16 induction, 81 (48.2 %) achieved de novo clinical remission at week 96 of the OL maintenance study. Among the 49 patients with clinical remission after induction, 33 (67.3 %) maintained remission at week 96.
In total, 149 /217 subjects (68.7 %) reported at least one treatment emergent adverse events (TEAE) over 2 years of treatment. TEAEs leading to study discontinuation were reported in 17 subjects (7.8 %) and serious adverse events (SAEs) were reported in 18 subjects (8.3 %). The most frequent TEAEs (≥ 5 %) were COVID-19 (14.3 %), headache (11.5%), ulcerative colitis (7.8 %) and nasopharyngitis (6.9 %). No new safety risks were identified over these 96 weeks.

Conclusion

Results from this 96-week analysis of the OL maintenance Phase 2b study confirmed long-term efficacy of obefazimod 50 mg od, with durable clinical remission, as well as a favorable long-term safety profile.

References

1. Vermeire S, Sands B, Tilg H et al. ABX464 (obefazimod) for moderate-to-severe, active ulcerative Colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension. Lancet Gastroenterol Hepatol 2022, 7 (11): 1024-1035

Disclosure

Bruce E Sands reports consulting fees from Abbvie, Alimentiv , Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Ventyx Biosciences; 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, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; Séverine Vermeire has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.