Measure From RADIANCE Data Suggests Ozanimod More Effective in Slowing MS Disease Activity

Ozanimod, an oral immunomodulatory drug now under FDA review for the treatment of relapsing multiple sclerosis (MS), appears to be more effective than interferon β-1a (Avonex) at slowing disease activity, based on an established brain measure taken during phase 3 of the RADIANCE trial.

A poster featuring a post-hoc exploratory analysis of measures of thalamic volume (TV) from RADIANCE was presented September 11, 2019, at ECTRIMS 2019,¹ the 35th Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis, taking place in Stockholm, Sweden.

The study authors noted that whole brain volume is a known measure of disease progression in relapsing MS, yet “evidence of the relationship between thalamic volume and disease activity in prospective, multicenter studies is sparse.” TV has been studied for years as a predictor of cognitive speed; a 2001 paper by Van Der Werf, et al, discussed how a decrease in TV “was apparent before the onset of loss of volume of the total brain.”²

Relapsing MS occurs when inflammation damages myelin, a fatty substance that insulates nerve cells, and thus allows interference with nerve impulses, triggering MS symptoms. Ozanimod works by selectively binding 2 receptors—the sphingosine 1-phosphate (S1PR₁) and the S1PR₅ receptors, which keeps immune cells from entering the brain and blocks inflammation of the central nervous system, so this inflammatory process does not occur.

The investigational therapy has been studied in 2 doses, 0.5 mg and 1.0 mg, in a pair of phase 3 trials, SUNBEAM and RADIANCE. The SUNBEAM trial featured 3 study arms: 1 arm each of patients taking the 2 doses of ozanimod and another taking interferon β-1a; full results of the 12-month study, first presented in 2017, were published last week in Lancet Neurology and show that ozanimod was well-tolerated and demonstrated a significantly lower relapse rate than interferon β-1a.³

RADIANCE was a 2-part trial to assess safety and efficacy of ozanimod compared with placebo. In the first part, 258 patients were randomly assigned to take 0.5 mg or 1.0 mg of the study drug or placebo once daily for 24 weeks. Patients taking ozanimod had fewer brain lesions after week 12, as measured by magnetic resonance imaging (MRI), as well as fewer relapses. During the second, open-label phase, 249 patients continued in the trial for 96 weeks. All those given ozanimod in the first phase stayed on their current dose, while those who had taken placebo were randomly assigned to either 0.5 mg or 1.0 mg. Both groups were free of disease activity and brain lesions after 24 months. Patients from the original placebo group had a large drop in relapses once they started taking ozanimod.⁴

RADIANCE offered an opportunity use TV measures taken at baseline to compare the effectiveness of the study drug, ozanimod, against interferon β-1A. Data presented Wednesday found that in patients with relapsing MS, smaller baseline TV is a sign of a higher disease burden and increased disease activity after 2 years, compared with those with higher baseline TV.¹ Specifically, the data presented Wednesday showed:

• Baseline TV data were available for 1310 patients. The mean (SD) TV data in the smallest quartile (Q1) was 12.8 (1.18) cm³ (n=294) and in the largest quartile (Q4) was 17.7 (0.75) cm³ (n=358).
• Patients in Q1 versus Q4 were older (38.1 years vs 33.1 years) and had more time elapsed since the onset of MS symptoms, with the mean (SD) time 10.0 (6.59) versus 3.9 (3.94) years.
• Patients in Q1 versus Q4 had more gadolinium-enhancing (GdE) lesions; 2.2 (3.56) versus 1.2 (2.96), and larger T2 (or bright white) lesion volume, 25.6 (18.01) versus 3.9 (4.22) cm³ at baseline.
• The mean number of relapses within 2 years prior to enrollment was 1.8 in both Q1 and Q4.
• At month 24, the annual relapse rate was higher in Q1 patients than in Q4 in both groups, but ozanimod was associated with a lower mean ARR than interferon β-1a in both Q1 (0.25 vs 0.38) and Q4 (0.10 vs 0.27).

US and European regulators are evaluating data from the multicenter, randomized, double-blind phase 2/3 RADIANCE and the phase 3 SUNBEAM trials, which were submitted in March. FDA accepted Celgene’s application for ozanimod June 6, 2019, and a decision is expected March 25, 2020.

References

1. Jeffery D, Schippling S, Gass A, et al. Ozanimod efficacy in RMS by baseline thalamic volume quartile: a post hoc exploratory analysis of phase 3 RADIANCE. Presented at 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Stockholm, Sweden; September 11-13, 2019. Abstract P615.
2. Van Der Werf YD, Tisserand DJ, Visser PJ, et al. Thalamic volume predicts performance on tests of cognitive speed and decreases in healthy aging. A magnetic imaging-based volumetric analysis. Brain Res Cogn Brain Res. 2001;11(3):377-385.
3. Comi G, Kappos L, Selmaj KW et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicenter, randomized, minimum 12-month, phase 3 trial [published online September 3, 2019]. Lancet Neurol. 2019; doi:https://doi.org/10.1016/S1474.4422(15)30239-X.
4. Cohen JA, Comi G, Arnold DL, et al. Efficacy and safety of ozanimod in multiple sclerosis: dose-blinded extension of a randomized phase II study. Mult Scler. 2019;25(9):1255-1262. doi: 10.1177/1352458518789884.