Introduction
Ozanimod (OZA) is approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults. In the phase 3 True North (TN; NCT02435992) study, patient (pt) responses to OZA were heterogenous at Week (W) 52. Group-based trajectory modeling (GBTM) can be used to identify patterns of therapeutic responses in patient subpopulations.
Aims & Methods
This TN post hoc analysis employed GBTM to identify patterns of OZA response trajectories during the TN maintenance period (MP) in W10 OZA clinical responders who were rerandomized to continue OZA (OZA/OZA arm; n=230) in MP. Change from baseline (BL; TN W0) in partial Mayo score (PMS) was used as a variable for identifying pt clusters with various OZA response patterns. GBTM, a specialized application of finite mixture models,1 was used to estimate OZA response trajectories. GBTM was determined by maximum likelihood estimation, and the optimal model was selected using the Bayesian information criterion. The last observation carried forward imputation method was used for handling missing data. After modeling, clinical and mucosal outcomes at W52 were compared in the GBTM-identified pt clusters.
Results
Of the 230 pts in the MP OZA/OZA arm, 1 pt did not have postbaseline PMS data available and was excluded from this analysis. Five distinct groups of pt-response patterns to OZA therapy were identified during MP. At W10, a PMS response was observed in all 5 trajectory groups. Over the 42 weeks during MP, trajectory groups diverged into fast sustained improvement (Group 1; n=38 [16.6%, 38/229]); slow sustained improvement (Group 2; n=85 [37.1%, 85/229]); gradual improvement (Group 3; n=60 [26.2%, 60/229]); fast rebound (Group 4; n=25 [10.9%, 25/229]); and slow rebound (Group 5; n=21 [9.2%, 21/229]). Although all pts entering the MP were OZA clinical responders, 20% of pts did not demonstrate sustained improvement from BL in PMS (Groups 4 and 5), but 80% did demonstrate sustained improved from BL in PMS (Groups 1–3). From W10 onward, 26.2%, 37.1%, and 16.6% of pts achieved and maintained PMS reductions of at least 3.98, 5.27, and 6.71 points, respectively. Pts in Groups 4 and 5 had a slightly younger age at diagnosis and a higher W10 Geboes histologic index score than the other trajectory groups; notably, pts in Group 4 had the most corticosteroid use at screening (Table). At W52, more pts in Groups 1–3 combined achieved clinical response (74%) and clinical remission (46%) than those in Groups 4 and 5 combined (7% and 2%, respectively). Furthermore, Groups 1–3 combined had more pts with endoscopic improvement (56%) and mucosal healing (37%) at W52 than Groups 4 and 5 combined (7% and 2%, respectively).
| Pt characteristics at BL (TN W0) or W10 | Group 1: Fast sustained improvement
(n=38, 16.6% [38/229]) | Group 2: Slow sustained improvement
(n=85; 37.1% [85/229]) | Group 3: Gradual improvement
(n=60; 26.2% [60/229]) | Group 4: Fast
rebound
(n=25, 10.9% [25/229]) | Group 5: Slow
rebound
(n=21, 9.2% [21/229]) |
| Sex, male, n (%) | 15 (39.5) | 43 (50.6) | 33 (55.0) | 13 (52.0) | 12 (57.1) |
| Age at UC diagnosis, y, mean (SD) | 34.6 (12.4) | 35.7 (14.1) | 35.3 (13.0) | 29.8 (11.5) | 31.5 (11.0) |
| Corticosteroid use at screening, n (%) | 11 (28.9) | 28 (32.9) | 14 (23.3) | 11 (44.0) | 7 (33.3) |
| Prior use of tumor necrosis factor antagonist, n (%) | 9 (23.7) | 28 (32.9) | 22 (36.7) | 9 (36.0) | 7 (33.3) |
| Complete Mayo score at W10, mean (SD) | 2.8 (1.7) | 3.5 (1.8) | 3.8 (1.9) | 4.8 (2.1) | 3.7 (1.6) |
| PMS at W10, mean (SD) | 1.3 (1.0) | 1.9 (1.2) | 2.1 (1.4) | 3.0 (1.8) | 2.1 (1.2) |
Mucosal endoscopy subscore of 2 (moderate)
at baseline, n (%) | 14 (36.8)
| 39 (45.9)
| 28 (46.7)
| 9 (36.0)
| 8 (37.1)
|
| Mucosal endoscopy subscore of 3 (severe) at baseline, n (%) | 24 (63.2) | 46 (54.1) | 32 (53.3) | 16 (64.0) | 13 (61.9) |
| Geboes continuous index score at W10, mean (SD) | 5.9 (4.3) | 5.8 (4.9) | 7.0 (5.2) | 7.7 (5.1) | 7.6 (4.8) |
Conclusion
Five groups of pt-response trajectories to OZA therapy were identified, with approximately 80% of pts in Groups 1–3 classified as having sustained response to OZA treatment. This analysis indicates that GBTM identifies clinically meaningful pt subgroups by pt-response patterns to OZA treatment. This approach needs to be validated in prospective studies.
References
- Nagin D. Group-based trajectory modeling: an overview. Ann Nutr Metab. 2014;65:205-210.
Disclosure
The study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
SS: received speaker fees from and consulted for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Falk Pharma, Galapagos/Gilead, Genentech/Roche, Hikma, Janssen, MSD, Pfizer, and Takeda.
BGF: consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, Eli Lilly, enGene, Ferring Pharmaceuticals, Genentech/Roche, gIcare, Gilead, Given Imaging, GlaxoSmithKline, Ironwood, Janssen, Johnson & Johnson, Lexicon, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus, Protagonist, Sanofi, and UCB; director for Robarts Clinical Trials.
BES: received speaker fees from and consulted for Abivax, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda; received consulting fees from AbbVie, Adiso Therapeutics, Alimentiv, Amgen, Arena, Artizan Biosciences, Artugen, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celltrion, ClostraBio, Cytoki Pharma, Connect Biopharma, Entera, Evommune, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Therapeutics, Inotrem, Ironwood Pharmaceuticals, Kaleido Biosciences, Kallyope, MiroBio, Morphic Therapeutics, MRM Health, OSE Immunotherapeutics, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma, Surrozen, Synlogic, Target RWE, Teva, Theravance Biopharma, TLL Pharmaceutical, USWM Enterprises, Viela Bio, and VTA Labs; received personal fees and stock options for consulting from Thelium Therapeutics and Ventyx.
FR: consulted or participated in advisory board for 89Bio, AbbVie, Adnovate, Agomab, Allergan, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb, CDISC, Ferring, Galapagos, Galmed Pharmaceuticals, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, InDex Pharmaceuticals, Janssen, Koutif Therapeutics, Mestag Therapeutics, Metacrine, Morphic Therapeutic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, REDX, Roche, Samsung, Surmodics, Surrozen, Takeda, TD Cowen, Techlab, Theravance, Thetis Pharmaceuticals, UCB, and Ysios Capital.
JT: received advisory board or speaker fees from AbbVie, Bristol Myers Squibb, Janssen, and Pfizer; received grant support from AbbVie.
ZL, AJ, HW, and MTO: employees and/or shareholders of Bristol Myers Squibb.
MTA: consulted or participated in advisory board for AbbVie, Amgen, Arena, Bristol Myers Squibb, Celsius Therapeutics, Eli Lilly, Gilead Sciences, Janssen, Microba Life Sciences, Pfizer, Prometheus Biosciences, UCB Biopharma, and WebMD Global; reported teaching, lecturing, or speaking for Alimentiv, Amgen, Janssen, and Takeda.
PD: received research support from Bristol Myers Squibb, Pfizer, and Takeda; consulted for Abivax, Adiso, Bristol Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, and Takeda.
