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EFFICACY OF GUSELKUMAB IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE NOT IN CLINICAL RESPONSE AT WEEK 12: RESULTS FROM THE GALAXI 1 STUDY

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EFFICACY OF GUSELKUMAB IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE NOT IN CLINICAL RESPONSE AT WEEK 12: RESULTS FROM THE GALAXI 1 STUDY

Remo Panaccione 1, Anita Afzali 2, Geert R. D'Haens 3, Leonardo Salese 4, Natalie Terry 4, Aparna Sahoo 4, Mary Ellen Frustaci 4, Zijiang Yang 4, Eran Zittan 5,6, Silvio Danese 7, Tadakazu Hisamatsu 8

Affiliations

1 University of Calgary, Calgary, Canada

2 University of Cincinnati, Cincinnati, United States

3 Amsterdam University Medical Centre, Amsterdam, Netherlands

4 Janssen Research & Development, LLC, Spring House, United States

5 Emek Medical Center, Afula, Israel

6 The Rappaport Faculty of Medicine Technion-Israel Institute of Technology, Haifa, Israel

7 IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy

8 Kyorin University, Tokyo, Japan

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Abstract

Introduction

The Phase 2 GALAXI 1 study evaluated the efficacy and safety of guselkumab (GUS), a human selective IL-23p19 subunit antagonist, in patients (pts) with moderate to severe Crohn’s disease (CD). Pts were randomized to GUS, ustekinumab (UST), or placebo (PBO) through Week (Wk) 48 without rerandomization after IV induction. Previously, we reported that pts who were in clinical response after IV induction had higher rates of clinical and endoscopic outcomes at Wk48 than the overall study population.¹ In this post hoc analysis, we report outcomes for pts who did not achieve Wk12 clinical response based on CD activity index (CDAI) after IV induction.

Aims & Methods

Pts were randomized 1:1:1:1:1 to induction with GUS 200, 600, or 1200mg IV, UST ~6mg/kg IV, or PBO IV. At Wk12 (Wk8 for UST), pts were transitioned to maintenance dosing: GUS 200mg IV→100mg subcutaneous (SC) q8w, GUS 600mg IV→200mg SC q4w, GUS 1200mg IV→200mg SC q4w, UST ~6mg/kg IV→90mg SC q8w, PBO nonresponders→UST ~6mg/kg IV→90mg SC q8w, and PBO responders→PBO SC q4w. Clinical response (all time points) was defined as ≥100-point reduction from baseline in CDAI or CDAI <150. Other endpoints included clinical remission (CDAI <150), pt-reported outcome (PRO)-2 remission (unweighted CDAI components of average daily abdominal pain score ≤1 and average daily stool frequency ≤3, and no worsening from baseline), and endoscopic response (≥50% improvement from baseline in simple endoscopic score [SES]-CD or SES-CD ≤2). The study was not powered to evaluate between-group efficacy differences at Wk48; UST was used for reference.

Results

Table. Efficacy Outcomes Among Patients Not in Clinical Response^a at Week 12
Outcome, %^{b, c}	Week	Combined Guselkumab (N=63)	Ustekinumab (N=21)
Clinical response^a	16 / 20 / 24	36.5 / 47.6 / 46.0	42.9 / 52.4 / 52.4
	28 / 32 / 36	47.6 / 54.0 / 50.8	42.9 / 47.6 / 57.1
	40 / 44	54.0 / 52.4	52.4 / 47.6
	48	58.7	47.6
Clinical remission^d	48	41.3	33.3
PRO-2 remission^e	48	42.9	23.8
Endoscopic response^f	48	31.7	23.8
AP=abdominal pain; CD=Crohn’s disease; CDAI=Crohn’s disease activity index; PRO-2=Patient-reported CDAI components of abdominal pain and stool frequency; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF=stool frequency. ^a Clinical response was defined as ≥100-point reduction from baseline in CDAI or CDAI <150. ^b Patients who had a prohibited change in concomitant CD medication, a CD-related surgery, or discontinued study agent due to lack of efficacy, or an adverse event of worsening CD prior to the designated analysis timepoint, were considered not to have achieved the endpoint. ^cPatients who had insufficient data to calculate the outcome measure at the designated analysis timepoint were considered not to have achieved the endpoint. ^d Clinical remission was defined as a CDAI <150. ^e PRO-2 remission was defined as unweighted CDAI component of average daily AP pain score ≤1 and the unweighted CDAI component of average daily SF ≤3, and no worsening of AP or SF from baseline. ^fEndoscopic response was defined as ≥50% improvement from baseline in SES-CD or SES-CD ≤2.

At Wk12, 63/185 (34.1%) GUS pts and 21/63 (33.3%) UST did not achieve CDAI clinical response. Among GUS Wk12 nonresponders, 46.0% were in clinical response by Wk24 (Table). Percentages of Wk12 nonresponders who went on to achieve outcomes at Wk48 in the GUS and UST groups, respectively, were as follows: clinical response, 58.7% and 47.6%; clinical remission, 41.3% and 33.3%; PRO-2 remission, 42.9% and 23.8%; and endoscopic response, 31.7% and 23.8% (Table).

Conclusion

Pts not responding to IV induction with GUS may benefit from continued SC dosing. Among pts who did not achieve clinical response at Wk12, continued treatment with GUS SC resulted in nearly half achieving clinical response at Wk24. At Wk48, a majority achieved clinical response, >40% achieved either clinical remission or PRO-2 remission, and >30% achieved endoscopic response.

References

1. Panés J, et al. UEG Journal 2022; 10 (Suppl 8).

Disclosure

RP reports consulting fees, speaker fees, or research support from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
AA reports consulting fees from AbbVie, Takeda, Janssen, Bristol Myers Squibb/Celgene, Pfizer, Eli Lilly, Gilead, DiaSorin, and TLL Pharmaceuticals; reports speaker fees from Abbvie, Takeda, Janssen, Bristol Myers Squibb, and Pfizer; has served on advisory boards for Abbvie, Takeda, Janssen, Bristol Myers Squibb, Pfizer, Eli Lilly, and Gilead; has received research/education support from AbbVie, Janssen, Pfizer, Bristol Myers Squibb, and Takeda; and is the co-founder of IBD Horizons.
GRDH served as advisor for Abbvie, Ablynx, Amakem, Amgen, AM Pharma, Avaxia, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo-Smith Kline, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Prometheus laboratories/Nestle, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor; and has received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor.
LS, NAT, AS, MEF, and ZY are employees of Janssen Research & Development, LLC and own stock/stock options.
EZ reports receiving research support and consulting fees from Janssen, AbbVie, Takeda, Neopharm, Celgene, and Pfizer.
SD reports receiving consulting fees from Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Ferring, Gilead Sciences, Hospira, Inc., Janssen Research & Development, LLC, Johnson & Johnson Health Care Systems, Inc., Pfizer, Sandoz, UCB, and Vifor International Inc.
TH has performed joint research with Alfresa Pharma Co. Ltd., and EA Pharma Co. Ltd.; has received grant support from Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Daiichi-Sankyo, Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., and JIMRO Co. Ltd; has received consulting fees from EA Pharma Co. Ltd., AbbVie GK, Celgene K.K., Janssen Pharmaceutical K.K., Pfizer Inc., and Nichi-Iko Pharmaceutical Co., Ltd; and has received lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Pfizer Inc.

Event

UEG Week Copenhagen 2023

Topics

Endoscopy Histopathology IBD

Submission format

Abstract

Session

The new kids on the block for IBD: Part 1

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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EFFICACY OF GUSELKUMAB IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE NOT IN CLINICAL RESPONSE AT WEEK 12: RESULTS FROM THE GALAXI 1 STUDY

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UEG Presentation

SIMBA CAPSULE CAPTURES SMALL INTESTINAL LUMINAL CONTENT FOR METAGENOMICS ANALYSIS AND MAPS SPATIAL DIFFERENCES ALONG THE GI TRACT AS VALIDATED BY MATCHED SALIVA, DUODENAL ENDOSCOPY AND FECES

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SIMBA CAPSULE CAPTURES SMALL INTESTINAL LUMINAL CONTENT FOR METAGENOMICS ANALYSIS AND MAPS SPATIAL DIFFERENCES ALONG THE GI TRACT AS VALIDATED BY MATCHED SALIVA, DUODENAL ENDOSCOPY AND FECES

Gang Wang 1, Cedoljub Bundalovic-Torma 1, Sabina Bruehlmann 1, Yasmin Nasser 2, Matthew Woo 3, Christopher N. Andrews 2

Affiliations

1 Nimble Science, Calgary, Canada

2 University of Calgary, Calgary, Canada

3 University Of Calgary, Calgary, Canada

Summary

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Summary is not available for this content yet.

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Thanks for your feedback.

This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

The small intestine (SI) microbiome plays a crucial role in nutrient absorption and emerging evidence indicates that fecal microbiome is insufficient to represent SI microbiome. Ingestible sampling capsule technologies are emerging. However, potential contamination becomes a major limitation of these devices [1].

Aims & Methods

We previously reported the Small Intestinal MicroBiome Aspiration (SIMBA) capsules as effective means for sampling, sealing and preserving SI luminal contents for 16s rRNA sequencing analysis [2,3]. A subset of the DNA samples, including SI samples collected by SIMBA capsules (CAP) and the matched saliva (SAL), fecal (FEC) and duodenal endoscopic aspirate (ASP) and brush (BRU) samples, from 16 participants recruited for an observational clinical validation study [3] were sent for shotgun metagenomic sequencing. The aims are: 1) to compare the sampling performance of the capsule (CAP) compared to endoscopic aspirates (ASP) and 850 small intestine, large intestine and fecal samples from the Clinical Microbiomics data warehouse (PRJEB28097), and 2) to characterize samples from the 4 different sampling sites in terms of species composition and functional potential.

Results

4/80 samples (1/16 SAL, 2/16 ASP, 0/16 BRU, 1/16 CAP and 0/16 FEC) failed library preparation and 76 samples were shotgun sequenced (average of 38.5 M read pairs / sample). Quality assessment showed that despite the low raw DNA yield of CAP samples, they retained a minimal level of host contamination, in comparison to ASP and BRU (mean 5.27 % vs. 93.09 - 96.44% of average total reads per sample). 3/14 ASP and all BRU samples have too few reads per sample mapping to genes, failed the rarefaction procedure and were excluded from analysis.

Site	Total (read pairs)	Host %	High Quality Non-Human (HQNH, %)	HQNH	Mapped to Gene Catalog
SAL	37.59 M	70.30	26.07	9.58 M	7.22 M
BRU	34.80 M	96.44	0.13	0.04 M	0.03 M
ASP	39.81 M	93.09	5.43	1.98 M	1.48 M
CAP	36.53 M	5.27	88.01	32.06 M	24.98 M
FEC	43.74 M	2.71	85.26	37.35 M	29.54 M

CAP samples shared majority of the species with ASP samples and a big fraction of CAP species detected in the terminal ileum samples. ASP and CAP sample composition was more similar to duodenum, jejunum and saliva and very different from large intestine and stool samples. Functional genomics further revealed GI regional-specific differences: In both ASP and CAP samples we detect a number of Gut Metabolic Modules for carbohydrate digestion and short-chain fatty acids. However, probiotic species, and species and genes involved in the bile acid metabolism were mainly prevalent in CAP and FEC samples and could not be detected in ASP samples.

Conclusion

CAP and ASP microbiome are compositionally similar despite of the high level of host contamination of ASP samples. CAP appears to be of better quality to reveal GI regional-specific functional potentials than ASP. This analysis demonstrates the great potential for the SIMBA capsule for unveiling the SI microbiome.

References

[1] Yersin S and Vonaesch P. Small intestinal microbiota: from taxonomic composition to metabolism. Trends in Microbiology, 2024, https://doi.org/10.1016/j.tim.2024.02.013
[2] Wang G, Menon S, Wilsack L, Rehak R, Lou L, Turbide C, et al. Spatially and Temporally Precise Microbiome Profiling in the Small Intestine using the SIMBA Capsule with X-ray tracking. MedRxiv 2024:2024.04.02.24305212. https://doi.org/10.1101/2024.04.02.24305212.
[3] Wang G, Bundalovic-Torma C, Menon S, Bruehlmann S, et al. Clinical Sampling of Small Intestine Luminal Content for Microbiome Multi-Omics Analysis: A Performance Analysis of The Small Intestine Microbiome Aspiration (SIMBA) Capsule and Benchmarking Against Endoscopy. MedRxiv 2024:04.07.24305299. https://doi.org/10.1101/2024.04.04.24305299.

Disclosure

G.W, C.BT and S.B are employees of Nimble Science. G.W, C.BT, S.B. and C.N.A. are shareholders and hold stock options of Nimble Science.

Event

UEG Week Vienna 2024

Topics

Gut Microbiota Colorectal

Submission format

Abstract

Session

Microbiome: Bench to the future

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Week 104	Without Histologic or Endoscopic Response	Histologic and Without Endoscopic Response	Endoscopic response Without Histologic	Histologic and Endoscopic Response	P‑value	Without Histologic or Endoscopic Remission	Histologic Without Endoscopic Remission	Endoscopic Without Histologic Remission	Histologic and Endoscopic Remission	P‑value
	Week 12^a					Week 12
CDAI remission	60 (12/20)	57.9 (11/19)	50 (2/4)	61.3 (19/31)	>0.999	Due to the low number of patients with endoscopic or histologic remission at Week 12, no data are shown in this quadrant
PRO remission	55 (11/20)	31.6 (6/19)	50 (2/4)	61.3 (19/31)	0.237
Hospitalizations due to CD^b	0 (0/42)	3.9 (1/26)	0 (0/8)	3.2 (1/31)	0.426
	Week 52^c					Week 52^c
CDAI remission	10.5 (2/19)	60 (6/10)	25.9 (7/27)	56.3 (9/16)	0.006	19.5 (8/41)	72.7 (8/11)	40 (6/15)	40 (2/5)	0.007
PRO remission	10.5 (2/19)	30 (3/10)	11.1 (3/27)	68.8 (11/16)	<0.001	12.2 (5/41)	63.6 (7/11)	33.3 (5/15)	40 (2/5)	0.003
Hospitalizations due to CD^b	3.9 (1/26)	16.7 (2/12)	0 (0/39)	0 (0/24)	0.021	3.9 (2/52)	5 (1/20)	0 (0/24)	0 (0/5)	0.809
Note: Data displayed as % (n/N). For categorical outcomes, p-values are based on Fisher’s exact test. Histologic response was defined as: a) absence of neutrophils in epithelium, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or modified GHAS ≥50% from baseline. Endoscopic response is defined as a 50% reduction from baseline in SES-CD. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Endoscopic remission is defined as SES-CD of <4 ileal-colonic or <2 for isolated ileal disease, and no subscore of >1. CDAI remission is defined as CDAI Total Score <150; PRO remission is defined as (7-day average of SF ≤2.5 and no worse than baseline) + (7-day average of AP≤1 and no worse than baseline). SF captures number of liquid or very soft stools; AP score is classified as 0=none, 1=mild, 2=moderate, 3=severe. Abbreviations: AP= abdominal pain; CDAI= Crohn’s Disease Activity Index; GHAS= Global Histologic Disease Activity Score; PRO= patient-reported outcomes; N=number of patients in the histologic/endoscopic response group; n = number of patients in the specified category; RHI= Robarts Histologic Index; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF= stool frequency. ^a Patients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 12. ^b Defined as serious adverse event due to hospitalization. Week 12 columns depict hospitalizations from Weeks 12-52. Week 52 columns depict hospitalizations from Weeks 52-104. ^c Patients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 52.

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