Introduction
Long-term data on bowel urgency (BU) in Crohn’s disease (CD) are limited, and the associations with other efficacy outcomes are not well studied.
Aims & Methods
Our aims were to examine the long-term efficacy of mirikizumab (MIRI) on BU remission and the associations between BU remission and clinical remission, endoscopic remission, and patient-reported outcomes (PRO) improvement at week (W) 104 in patients with moderately to severely active CD who were randomized to MIRI in the Phase 3 study VIVID-1 and continued into the long-term extension study VIVID-2. In VIVID-1, the MIRI group received induction with 900 mg intravenously (IV) at W0, W4, and W8, then 300 mg subcutaneously (SC) every 4W. W52 endoscopic responders (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) continued MIRI SC dosing in VIVID-2. Endoscopic non-responders received reinduction with MIRI IV (3x Q4W) at the start of VIVID-2 followed by SC dosing (IV-SC) as described. Patients that had an Urgency Numeric Rating Scale (UNRS) ≥3 (least to worst range 0-10) at baseline were included in these analyses. BU remission was defined as an UNRS score of ≤2. Associations between BU remission with clinical remission by Crohn’s Disease Activity Index (CDAI), endoscopic remission, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (range 0-52, higher is better), and Inflammatory Bowel Disease Questionnaire (IBDQ) remission, were assessed at W104, within the VIVID-1 W52 endoscopic response subgroups as well as the MIRI total group. Discontinuations or missing data were handled using modified non-responder imputation (mNRI) for categorical data. Missing values were imputed by multiple imputation and modified baseline observation carried forward for FACIT-Fatigue change from baseline.
Results
Over 50% of the MIRI total group, 56% of MIRI W52 endoscopic responders, and 43% of the MIRI W52 endoscopic non-responders achieved BU remission at W104. In the MIRI total group, a significantly higher percentage of patients achieved clinical remission, endoscopic remission and IBDQ remission at W104 in the BU remission group compared to those without BU remission. The improvement in fatigue by FACIT-Fatigue score was significantly more in the group with BU remission versus those without BU remission (p<0.0001). In both MIRI W52 endoscopic responders and non-responders, patients who achieved BU remission at W104, compared to those who did not, achieved significantly higher rates of clinical remission, greater improvements in FACIT-Fatigue, and higher rates of quality of life improvement measured by IBDQ remission (Table 1).
Table 1
| Endpoint at W104 | MIRI Total
N=405 | MIRI W52 endoscopic responders
N=236 | MIRI W52 endoscopic non-responders
N=169 |
| With BU Remission (51%) | Without BU Remission
(49%) | p-value | With BU Remission
(56%) | Without BU Remission
(44%) | p-value | With BU Remission
(43%) | Without BU Remission
(57%) | p-value |
| Clinical remission by CDAI, % | 96% | 48% | <0.0001 | 98% | 54% | <0.0001 | 93% | 41% | <0.0001 |
| Endoscopic remission, % | 34% | 21% | 0.018 | 49% | 35% | 0.058 | 10% | 5% | 0.219 |
| FACIT-Fatigue CFBL, mean (SD) | 12.2 (1.0) | 5.9 (0.9) | <0.0001 | 12.3 (1.2) | 6.1 (1.3) | 0.001 | 12.2 (1.5) | 5.7 (1.2) | 0.002 |
| IBDQ remission, % | 87% | 43% | <0.0001 | 89% | 45% | <0.0001 | 82% | 40% | <0.0001 |
Footnote: P-values for all binary outcomes are from CMH test adjusted by biologic-failed status (yes/no), baseline SES-CD total scores (<12, ≥12), either baseline SF ≥7 and/or baseline AP ≥2.5 (yes or unknown/no). P-values for FACIT-Fatigue are from t-test. mNRI was applied to all binary outcomes and BU remission. Multiple Imputation was applied to FACIT-Fatigue after mBOCF was applied. IBDQ remission is based on patients with baseline IBDQ<170. Clinical remission by CDAI is defined as CDAI total score <150. Endoscopic remission is defined as SES-CD ≤4 and ≥2-point reduction from baseline, and no subscore >1.
Abbreviations: AP= abdominal pain; BU= bowel urgency; CDAI= Crohn’s disease activity index; CI=confidence interval; CFBL = change from baseline; CMH= Cochran Mantel Haenszel; mBOCF= Modified Baseline Observation Carried Forward; MIRI = mirikizumab; mNRI = modified nonresponder imputation; N = number of patients in the analysis population; FACIT= Functional Assessment of Chronic Illness Therapy; IBDQ = Inflammatory Bowel Disease Questionnaire; SD= standard deviation; SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF= stool frequency; W=week |
Conclusion
Over 50% of patients with CD achieved BU remission at 2 years of treatment with MIRI. These results highlight that the achievement of BU remission corresponded with improvements to outcomes important to patients with CD, underscoring the importance of long-term management of BU in improving overall patient outcomes.
Disclosure
SRV: has received consulting fees, speaker’s honoraria and unrestricted research grants from Abbott, Alfasigma, Amgen, Arenapharm, BMS, Falk Pharma GmbH, Ferring Pharmaceuticals, Gilead, iQuone, Janssen, MSD, Permamed, Pfizer, Sanofi-Aventis, Schwabe Pharma, Takeda, Tillotts, UCB and Vifor
DTR: receives grants or contracts from Takeda, and discloses consultancy fees with AbbVie, Altrubio, Apex, Avalo Therapeutics, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen Pharmaceuticals, Lilly, Pfizer, Samsung Neurologica, and Takeda. He serves on the Board of Directors for Cornerstones Health.
JW, GY, AV, REM, and RRH: Employees and stockholders of Eli Lilly.
GD-H: Has received research grants from: Alimentiv BV, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and Takeda; and consulting fees from: AbbVie, Alimentiv, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, GSK, Merck Sharp & Dohme, Pfizer, Sorriso Pharmaceuticals, Takeda, Tillotts Pharma AG, and Ventyx Biosciences
ST: has received grants from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Norman Collison Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott; and reports other disclosures from: Abacus Pharma, AbbVie, Actial Farmaceutica, ai4gi, Alcimed, Allergan, Amgen, Aptel, Arena Pharmaceuticals, Asahi Kasei Pharma, Aspen Pharmacare, Astellas, AstraZeneca, Atlantic Pharmaceuticals, Barco, Biocare Medical, Biogen, BL Pharma, Boehringer Ingelheim, Bristol Myers Squibb, BUHLMANN Diagnostics, Calcico Therapeutics, Celgene, Cellerix, Cerimon Pharmaceuticals, ChemoCentryx, Chiesi, Cisbio, Comcast, Coronado Biosciences, Cosmo Pharmaceuticals, Dr. Falk Pharma, Ducentis BioTherapeutics, Dynavax Technologies, Elan Pharma, Eli Lilly and Company, Enterome, Equillium, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Genzyme, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Grünenthal, GW Pharmaceuticals, Immunocore, Indigo Biosciences, Janssen, Lexicon Pharmaceuticals, Medarex, MedTrix, Merck, Merrimack Pharmaceuticals, Mestag Therapeutics, Millennium Pharmaceuticals, Neovacs, Novartis, Novo Nordisk, NPS Pharmaceuticals/Nycomed, Ocera Therapeutics, OPTIMA Pharma, Origin Pharma, Otsuka, Palau Pharma, Pentax Medical, Pfizer, PharmaVentures, Phesi, Phillips Pharma Group, Procter & Gamble, Pronota, Proximagen, Resolute Pharma, Robarts Clinical Trials, Sandoz, Santarus, Satisfai Health, Sensyne Health, Shire, Sigmoid Pharma, Sorriso Pharmaceuticals, Souffinez, SynDermix, Synthon, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma AG, Topivert, Trino Therapeutics with Wellcome Trust, TxCell SA, UCB Pharma, Vertex Pharma, VHsquared, Vifor Pharma, Warner Chilcott, and Zeria Pharmaceutical
AW: reports consulting and/or speaking fees from Abbvie, Bristol-Myers Squibb, Ferring, Galapagos, Janssen, Pfizer, and Takeda.
