Introduction
Clinical remission of symptoms and endoscopic disease activity were the primary endpoints of two phase-3 studies (LUCENT-1 and -2; NCT03518086 and NCT03524092) in patients with moderately-to-severely active ulcerative colitis (UC) treated with the anti-IL23p19 monoclonal antibody, mirikizumab (miri)(1). This outcome was reached in 24.2% and 49.9% of miri-treated patients at week (W) 12 and 52, respectively.
In clinical practice, access to endoscopic evaluation can be limited. Measurement of faecal calprotectin (FCP) can be a surrogate biomarker for endoscopic disease activity and therapy response in patients with UC(2). Combined symptom and FCP remission may serve as a surrogate for clinical and endoscopic remission in real-world clinical practice.
Aims & Methods
This post-hoc analysis evaluates the proportion of patients in LUCENT-1/-2 who achieved combined symptom and biomarker remission.
Patients in LUCENT-1 (N=1162) were randomised to receive either 300mg miri (n=868) or placebo (PBO; n=294) intravenously (IV) every 4W (Q4W) for 12W. In LUCENT-2, patients from LUCENT-1 with no clinical response to miri at W12 (N=272) received an extended induction therapy of 300mg miri IV Q4W for 12W (W24 of continuous treatment), while miri-responders (N=544) were randomised to either subcutaneous (SC) 200mg miri (n=365) or PBO (n=179), Q4W for 40W (W52 of continuous treatment).
At W4, W12, W24, and W52, patient symptoms and FCP levels were reported as combined endpoints of symptomatic response or remission (defined in Table 1), with FCP remission (FCP ≤250µg/g). The Cochran-Mantel-Haenszel test compared the treatment groups a) miri and PBO at W4 and W12 from LUCENT-1, and b) miri and PBO at W52 from LUCENT-1 miri-responders. The risk difference and its associated confidence intervals and p-values were reported in Table 1. Non-responder imputation was used for binary variables, while modified baseline observation carried forward was used for continuous variables.
Results
At W4 and W12, 14.2% and 33.2% of the miri group compared to 8.5% and 18.7% of PBO (p=0.0113 and <0.0001, respectively) achieved the combined symptomatic response and biomarker remission endpoint, while 7.3% and 23.7% of the miri group compared to 3.7% and 11.2% of PBO (p=0.0282 and <0.0001, respectively) achieved the combined remission endpoints. At W52, 54.3% of the miri group compared to 27.4% of PBO (p=<0.0001) achieved the combined symptomatic response and biomarker remission endpoint, while 48.5% of the miri group compared to 21.8% of PBO (p=<0.0001) achieved the combined remission endpoints. At W12 and W24, 2.9% and 23.5% of the extended induction group achieved combined symptomatic response and biomarker remission endpoints, respectively, while 1.1% and 13.2% achieved the combined remission endpoints.
| Week | Dose | Symptomatic responsea and FCP ≤250 µg/g, n (%)
| Common risk difference (CI)b
| P-Value
| Symptomatic remissionc and FCP ≤250 µg/g, n (%)
| Common risk difference (CI)b
| P-Value
|
| Week 4 | Miri, N=868
| 123 (14.2)
| 5.7 (1.7, 9.6) | 0.0113 | 63 (7.3)
| 3.7 (0.9, 6.4)
| 0.0282
|
PBO, N =294
| 25 (8.5)
| 11 (3.7)
|
| Week 12 | Miri, N=868
| 288 (33.2) | 14.8 (9.4, 20.2) | <0.0001 | 206 (23.7)
| 12.7 (8.1, 17.3)
| <0.0001
|
PBO, N =294
| 55 (18.7) | 33 (11.2)
|
| Week 52 | Miri, N=365
| 198 (54.3) | 25.4 (17.3, 33.6) | <0.0001 | 177 (48.5)
| 25.0 (17.3, 32.6)
| <0.0001
|
PBO, N=179
| 49 (27.4) | 39 (21.8)
|
Table 1: Proportion of patients with Ulcerative Colitis who achieved combined symptomatic and biomarker endpoints in LUCENT-1/-2 studies
aDefined as ≥30% decrease from baseline of the sum of stool frequency (SF) and rectal bleeding (RB) subscores
bCommon risk difference is the percentage difference between miri and PBO adjusted for the baseline factors a) prior biologic or tofacitinib failure (yes/no), b) baseline corticosteroid use (yes/no), c) baseline disease activity (Modified mayo score: [1-6] or [7-9]), and d) region (North America/Europe/Other).
cDefined as SF = 0, or SF = 1 with ≥1 point decrease from baseline and RB = 0
|
Conclusion
In moderate-severe UC, patients treated with miri demonstrated improved efficacy compared to PBO in combined symptomatic and biomarker response and remission endpoints. Additionally, the data from this post-hoc analysis is consistent with the clinical remission data from LUCENT studies, indicating that this is a suitable endpoint measure in real-world practice.
References
1. D'Haens G, Dubinsky M, Kobayashi T, Irving PM, Howaldt S, Pokrotnieks J, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023;388(26):2444-55.
2. Bressler B, Panaccione R, Fedorak RN, Seidman EG. Clinicians' guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease. Can J Gastroenterol Hepatol. 2015;29(7):369-72.
Disclosure
MCF reports payment or honorarium for speaker events: Eli Lilly and Company, Pfzier, AbbVie, Alfa-Sigma, Johnson & Johnson, and Takeda; meeting/travel support: AbbVie, Takeda, and Johnson & Johnson. JG reports grants/contracts: MSD, Janssen, Takeda, Kern Pharma, Sandoz, AbbVie, and GE Healthcare consulting fees: AbbVie, MSD, Jassen, Takeda, Roche, Eli Lilly and Company, Celltrion, Pfizer, Galapagos, GoodGut, and GE Healthcare; payment or honorarium for speaker events: AbbVie, MSD, Janssen, Kern Pharma, Bülhmann, GoodGut, GE Healthcare, Takeda, Eli Lilly and Company, Pfizer, and Galapagos; meeting/travel support: AbbVie, MSD, Janssen, Jern Pahrma, Bülhmann, GE Healthcare, Eli Lilly and Company, and Pfizer. EDM reports grants/contracts: Adacyte Therapeutic; consulting fees: Roche; payment or honorarium for speaker events: Eli Lilly and Company and Adacyte; travel/meeting support Adacyte, Pfizer, Kern Pharma, and AbbVie. CWL reports consulting fees: AbbVie, Janssen, Takeda, Pfizer, Galapagos, GSK, Gilead, Vifor Pharma, Ferring, Dr Falk Pharma, BMS, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novartis, Sandoz, Celltrion, Cellgene, Amgen, Samsung Bioepis, Fresenius Kabi, Tillotts, Kuma Health, and Trellus Health and Iterative Health; payment or honorarium for speaker events: AbbVie, Janssen, Takeda, Pfizer, Galapagos, GSK, Gilead, Vifor Pharma, Ferring, Dr Falk Pharma, BMS, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novartis, Sandoz, Celltrion, Cellgene, Amgen, Samsung Bioepis, Fresenius Kabi, Tillotts, Kuma Health, and Trellus Health and Iterative Health. GS reports consulting fees: AbbVie, Takeda, Johnson & Johnson, Eli Lilly and Company, BMS, Pfizer, and Celltrion; payment or honorarium for speaker events: AbbVie, Takeda, Johnson & Johnson, Eli Lilly and Company, BMS, Pfizer, and Celltrion; participation on data safety monitoring or advisory board: AbbVie, Takeda, Eli Lilly and Company, BMS, and Pfizer; leadership or fiduciary role in committees: ACG training committee, ACG FDA committee, AGA Government Affairs committee, and Crohn’s and Colitis Foundation National Scientific Advisory Committee. ES reports consulting fees: Janssen-Cilag of Johnson & Johnson, Pharmacosmos, Takeda Pharma, AbbVie Deutschland, Pfizer, Tillotts Pharma, AstraZeneca, Galapagos Biopharma, Eli Lilly and Company, Celltrion, DGVS, Dr. Falk Pharma, BMS, Kompetenznetz Darmerkrankungen, and STADA; payment or honorarium for speaker events: Janssen-Cilag of Johnson & Johnson, Pharmacosmos, Takeda, AbbVie Deutschland, Pfizer, Tillotts Pharma, AstraZeneca, Galapagos Biopharma, Eli Lilly and Company, Celltrion, DGVS, Dr. Falk Pharma, BMS, Kompetenznetz Darmerkrankungen, and STADA. DPH reports grants/contracts: Johnson & Johnson and Pfizer; consulting fees: Eli Lilly and Company, AbbVie, Abivax, BMS, Johnson & Johnson, Prometheus, Sanofi, Pfizer, CorEvitas, Fresenius Kabi, Biocon, and Takeda. HG, IR, and ED are employees and minor shareholders in Eli Lilly and Company. AK is an employee of HaaPACS GmBH and a contractor for Eli Lilly and Company.