Introduction
Many ulcerative colitis (UC) patients (pts) are suboptimally controlled on conventional therapies but are hesitant to move to biologics, indicating an unmet need for oral advanced therapies early in the treatment paradigm. Ozanimod (OZA), an oral, selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active UC in adults.
Aims & Methods
This post hoc analysis of the phase 3 True North clinical trial explored the efficacy of OZA in advanced therapy–naive UC pts who had active, symptomatic disease while on conventional therapies. OZA efficacy was assessed at Week (W) 10 in pts who had either moderate (Mayo endoscopy subscore [MES]=2) or severe (MES=3) endoscopic disease activity at baseline. Pts in Cohort 1 (C1) were randomized to OZA 0.92 mg or placebo (PBO) or received open-label OZA in Cohort 2 (C2) through W10. Pts were required to be on oral 5-aminosalicylate and/or corticosteroid for ≥2 wk before screening and continue through induction. Clinical endpoints (clinical remission, clinical response, endoscopic improvement, and mucosal healing) were assessed at W10. Treatment differences for OZA (C1) vs PBO were based on the Cochran-Mantel-Haenszel test, stratified by corticosteroid use at screening. Symptomatic clinical response and symptomatic clinical remission were assessed from W2 to W10.
Results
Of 616 advanced therapy–naive pts at baseline, 296 had moderate (PBO, n=64; OZA [C1], n=138; OZA [C2], n=94) and 320 had severe (PBO, n=73; OZA [C1], n=149; OZA [C2], n=98) endoscopic disease. Baseline pt characteristics were similar between groups, with higher prior immunomodulator use in severe (22%–34%) vs moderate (13%–23%) pts. Significantly higher symptomatic responses with OZA vs PBO were observed by W4 in moderate pts (OZA [C1] vs PBO: 67.4% vs 42.2%; difference: 23.0% [95% CI 8.6–37.3]) and by W5 in severe pts (OZA [C1] vs PBO: 51.0% vs 32.9%; difference: 17.6% [95% CI 4.1–31.2]). Similarly, significantly higher symptomatic remission rates were observed with OZA vs PBO by W5 in moderate pts (OZA [C1] vs PBO: 39.9% vs 18.8%; difference: 19.5% [95% CI 6.9–32.2]) and by W8 in severe pts (OZA [C1] vs PBO: 32.2% vs 16.4%; difference: 15.4% [95% CI 4.0–26.8]). OZA was more effective than PBO in achieving all clinical endpoints at W10 in moderate and severe pts (Table). Treatment differences (OZA [C1] vs PBO) were greater in moderate vs severe pts for clinical remission (22.8% [95% CI 11.7–33.9]; P<0.001 vs 8.0% [95% CI 1.7–14.2]; P=0.04), clinical response (27.2% [13.1–41.3]; P<0.001 vs 21.0% [8.2–33.8]; P=0.003), endoscopic improvement (28.7% [15.7–41.7]; P<0.001 vs 13.4% [5.2–21.7]; P=0.008), and mucosal healing (18.0% [8.1–27.9]; P=0.003 vs 5.4% [0.5–10.2]; P=0.09).
| OZA vs PBO efficacy at W10 in advanced therapy–naive pts by baseline endoscopic disease activity |
| Moderate disease (MES=2) | Severe disease (MES=3) |
C1: PBO
(n=64) | C1: OZA
(n=138) | C2: OZA
(n=94) | C1: PBO
(n=73) | C1: OZA
(n=149) | C2: OZA
(n=98) |
| Clinical remission,a n (%) | 7 (10.9) | 49 (35.5) | 38 (40.4) | 2 (2.7) | 17 (11.4) | 18 (18.4) |
| Clinical response,b n (%) | 20 (31.3) | 83 (60.1) | 64 (68.1) | 18 (24.7) | 69 (46.3) | 54 (55.1) |
| Endoscopic improvement,c n (%) | 13 (20.3) | 68 (49.3) | 48 (51.1) | 4 (5.5) | 29 (19.5) | 23 (23.5) |
| Mucosal healing,d n (%) | 5 (7.8) | 36 (26.1) | 23 (24.5) | 1 (1.4) | 10 (6.7) | 6 (6.1) |
Pts with missing data were considered nonresponders.
aClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from baseline SFS), and MES ≤1 point. bClinical response: decrease from baseline in the 3-component Mayo score (sum of RBS, SFS, and MES) of ≥2 points and ≥35% and a reduction of ≥1 point in RBS or absolute RBS of ≤1 point. cEndoscopic improvement: MES ≤1 point. dMucosal healing: MES ≤1 point and Geboes index score <2.0. |
Conclusion
Pts with inadequate disease control while on conventional therapies were better controlled with OZA treatment than those who continued conventional treatments. Pts with moderate disease achieved greater benefit and responded more rapidly than those with severe disease. OZA is an effective oral advanced therapy option for pts suboptimally controlled on conventional therapies, especially those with moderate disease.
Disclosure
This study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
PI: received lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, Sandoz, Sapphire Medical, Shire, Takeda, Tillotts, and Warner Chilcott; received financial support for research from Celltrion, MSD, Pfizer, and Takeda; received advisory fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Hospira, Janssen, MSD, Pfizer, Pharmacosmos, Prometheus Biosciences, Roche, Samsung Bioepis, Sandoz, Takeda, TopiVert, VH2, Vifor, and Warner Chilcott.
MDL: received research funding from Pfizer and Takeda; consulted for AbbVie, Bristol Myers Squibb, Calibr, Eli Lilly, Genentech, Janssen, Pfizer, Prometheus, Roche, Salix, Takeda, Target RWE, and Theravance.
BS: consulted for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Falk Pharma, Galapagos, Janssen, Lilly, Pfizer, Prometheus, and Takeda; received speaker fees from AbbVie, CED Service GmbH, Falk Pharma, Ferring, Janssen, Novartis, Pfizer, and Takeda.
GD: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cytoki, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; and received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
IB: received consulting fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Shire, and Takeda; received speaker fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Janssen, Mylan, Pfizer, Shire, and Takeda.
AJ, HW, and MTO: employees and/or shareholders of Bristol Myers Squibb.
DCW: received research funding from AbbVie, Bristol Myers Squibb, Genentech, Janssen, Pfizer/Arena, and Takeda; consulted for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda; received speaker fees from AbbVie, Bristol Myers Squibb, Janssen, and Takeda.
DTR: received grant support from Takeda; consulted for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chronicles, ClostraBio, Connect BioPharma, EcoR1, Eli Lilly, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen, Kaleido Biosciences, Pfizer, Prometheus Biosciences, Reistone, Seres Therapeutics, Syneos, Takeda, Target RWE, and Trellus Health.
