Introduction
Ozanimod (OZA) is an oral selective sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator approved for the treatment of moderately to severely active ulcerative colitis (UC) or relapsing multiple sclerosis. Consistent with the mechanism of action (MOA) of S1P receptor modulators, OZA causes lymphocyte retention in lymphoid organs. S1P receptor modulators also bind to specific receptors in cardiac myocytes, but the associated risk of bradycardia may be mitigated with gradual dose escalation. Evidence from the phase 3 True North study (NCT02435992) suggests that absolute lymphocyte count (ALC) is a pharmacodynamic biomarker but is not predictive or prognostic for clinical response in OZA-treated patients with moderately to severely active UC.
Aims & Methods
We analyzed changes in ALC and heart rate (HR) over 65 d of OZA treatment at the therapeutic dose (0.92 mg) and a supratherapeutic dose (1.84 mg). A phase 1, double-blind, placebo (PBO)-controlled study (NCT04978298) evaluated the pressor effect of oral tyramine in healthy adults receiving OZA. The study included 3 periods; this analysis focuses on Period 2, during which participants (ppts) were randomized to OZA (therapeutic dose group: 7-d dose escalation to 0.92 mg once daily [QD]; supratherapeutic dose group: 10-d dose escalation to 1.84 mg QD) or matched PBO for 65 d (Day 8–72). Safety endpoints included adverse events (AEs), clinically significant changes in laboratory tests and electrocardiograms, and vital signs.
Results
This study included 27 ppts in the OZA 0.92 mg group (mean [SD] age 36.4 [8.9] y, males 55.6%), 26 ppts in the OZA 1.84 mg group (36.3 [8.4] y, 53.8%), and 25 ppts in the PBO group (40.3 [9.1] y, 52.0%). Mean group level decreases from baseline (BL) in ALC ranged from 0.32×109/L to 1.18×109/L in the OZA 0.92 mg group and 0.12×109/L to 1.37×109/L in the OZA 1.84 mg group. ALC decreases were similar in OZA groups. Decreases began to plateau after ~14 d of OZA dosing, with mean group level decreases from BL of 0.82×109/L in the OZA 0.92 mg group and 1.09×109/L in the OZA 1.84 mg group at Day 21. Two ppts discontinued due to treatment-related lymphopenia: 1 event (3.7%) in the OZA 0.92 mg group was moderate in intensity (0.07−1.02×109/L, Period 2); 1 event (3.8%) in the OZA 1.84 mg group was considered mild (0.10−0.88×109/L, Periods 2 and 3; reported and discontinued in Period 3). Neither ppt had a reported infection or associated AE. Both events of lymphopenia resolved by end of study. ALC reductions in other ppts were not considered clinically significant. HR was slightly lower with OZA 1.84 mg on Days 8–15 and normalized thereafter, but overall, no clinically meaningful trends in mean HR or change from daily BL occurred across groups (Table).
| Table. Mean predose and 6-h postdose HR and mean change in HR | PBO | OZA 0.92 mg | OZA 1.84 mg |
Mean
(min, max) predose
(BL) HR
(bpm) | Mean
(min, max)
6-h
postdose
HR (bpm) | Mean
(min, max) change in
HRa (bpm) | Mean
(min, max) predose
(BL) HR
(bpm) | Mean
(min, max)
6-h
postdose
HR (bpm) | Mean
(min, max) change in HRa (bpm) | Mean
(min, max) predose (BL) HR (bpm) | Mean
(min, max)
6-h
postdose
HR (bpm) | Mean
(min, max)
change in HRa (bpm) |
| Day 8 | 63.2
(46, 80) | 69.2
(54, 82) | 5.9
(−11, 28) | 59.8
(50, 80) | 62.5
(51, 83) | 2.7
(−8, 23) | 62.2
(42, 86) | 64.1
(51, 78) | 1.9
(−15, 18) |
| Day 12 | 63.6
(44, 81) | 70.4
(56, 94) | 6.9
(−3, 16) | 56.4
(48, 78) | 60.7
(48, 82) | 4.3
(−5, 14) | 58.3
(39, 75) | 61.0
(43, 79) | 2.7
(−11, 16) |
| Day 15 | 63.8
(48, 80) | 69.1
(54, 104) | 5.3
(−6, 24) | 57.2
(43, 80) | 60.9
(45, 71) | 3.7
(−12, 17) | 58.1
(38, 73) | 58.8
(42, 70) | 0.7
(−11, 12) |
| Day 18 | 60.7
(41, 81) | 68.8
(54, 80) | 8.2
(−6, 30) | 55.9
(44, 70) | 59.7
(43, 79) | 3.8
(−9, 14) | 57.5
(43, 73) | 60.8
(44, 73) | 3.3
(−4, 20) |
| Day 21 | 62.6
(44, 80) | 66.5
(48, 82) | 3.9
(−7, 17) | 58.7
(47, 75) | 63.6
(53, 78) | 4.9
(−13, 17) | 59.5
(42, 79) | 64.7
(50, 84) | 5.2
(−7, 24) |
| Day 42 | 61.9
(45, 72) | 68.1
(52, 82) | 6.2
(−7, 16) | 58.4
(49, 79) | 63.0
(51, 77) | 4.5
(−12, 14) | 59.7
(46, 72) | 66.6
(45, 87) | 6.9
(−7, 25) |
| Day 72 | 58.4
(41, 75) | 65.5
(50, 78) | 7.1
(−6, 20) | 58.1
(47, 73) | 64.7
(53, 80) | 6.6
(−2, 15) | 59.4
(41, 80) | 66.4
(46, 84) | 7.0
(−4, 17) |
| aCalculated as the mean change in HR from predose (BL) to 6-h postdose for each day. |
Conclusion
In healthy ppts who received OZA at the therapeutic or supratherapeutic dose, ALC decreased as expected given the therapeutic MOA. No clinically significant changes from BL were noted. The ALC decrease was similar across OZA groups and was not dose dependent. No new cardiac safety signals were observed.
Disclosure
Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, and Alexandra Stafford, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.
PZ, MA, SW, KY, MS, MT, BM, GL, and DT: employees and/or shareholders of Bristol Myers Squibb.
DR: 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, Syneos, Takeda, Target RWE, and Trellus Health.
BES: received consulting fees from AbbVie, Alimentiv, Amgen, Arena, Artugen, AstraZeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, and Ventyx Biosciences; received consulting and speaking fees from Abivax; received consulting and speaking fees and other support from Eli Lilly; received research grants, consulting and speaking fees, and other support from Bristol Myers Squibb, Janssen, Pfizer, and Takeda; received research grants and consulting fees from Theravance Biopharma; received stock options from Ventyx Biosciences.