More Results for Ozanimod: DAYBREAK Data, Cognition and Gray Matter, Biomarker for Relapsing MS

Results for ozanimod, which is under review by FDA and European regulators for treatment of relapsing multiple sclerosis (MS), were presented in poster sessions September 12, 2019, at ECTRIMS 2019, the 35th Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis, taking place in Stockholm, Sweden.

Continuing or Switching to Ozanimod Linked to Low Relapse Rates

Data presented included results from DAYBREAK, an open-label extension study,¹ as well as post-hoc analyses derived from a pair of phase 3 randomized clinical trials, SUNBEAM and RADIANCE. Celgene sponsored both trials to evaluate the oral immunomodulatory therapy, a sphingosine 1-phosphate (S1P) receptor modulator that selectively binds with S1P subtypes 1 (S1P₁) and 5 (S1P₅). This process keeps immune cells from entering the brain, thus blocking the inflammatory process that triggers MS symptoms.

DAYBREAK followed patients who took wither ozanimod or interferon β-1a in earlier phases of the clinical trial program. The results reported at ECTRIMS covered 2494 of the total 2639 patients who have continued in this open-label extension study, and covered data through June 30, 2018. Patients have taken part for a mean period of 19.0 months. In the phase 3 parent trials, which lasted 12 to 24 months, the annualized relapse rate (ARR) was 0.153 (95% CI, 0.125-0.187) for ozanimod HCI 1 mg and 0.246 for the comparator drug, interferon β-1a (Avonex). Results for DAYBREAK were as follows:

• Among patients who received ozanimod HCI 1 mg in any parent trial—and took the study drug for an additional mean time of 19.2 months—the mean ARR was reduced to 0.126 (0.099-0.161).
• Among patients who took interferon β-1a in parent trials, mean ARR was reduced 0.123 (0.095-0.158) after switching to ozanimod HCI 1 mg and taking the drug for a mean period of 18.3 months.
• Thus far, 1704 participants (68.3%) have had a treatment-emergent adverse event (TEAE), while 144 (5.8%) had a serious TEAE. The most common event was nasopharyngitis (11.7%).

Measures From SUNBEAM Show Ozanimod Preserves Brain Function

Authors led by Sven Schippling, MD, deputy head of the Department of Neuroimmunology and Clinical Multiple Sclerosis Research, University Hospital Zürich, Switzerland, examined data from the phase 3 SUNBEAM trial for a post-hoc analysis of how the oral sphingosine-1 phosphate receptor agonist ozanimod significantly reduced measurable MS disease activity as well the rate of brain volume loss.² In SUNBEAM, patients took ozanimod HCI in either 0.5 mg or 1 mg doses once daily or 30 µg of interferon β-1a once weekly for at least 12 months. Central processing speed (CPS), as measured by the Symbol Digit Modality Test (SDMT), was assessed at baseline. Patients also received magnetic resonance imaging (MRI). Results showed the following:

• SDMT scores were available for 853 participants at month 12. Of these, 35.6% treated with ozanimod and 27.9% treated with interferon had improved SDMT scores.
• Of the group, 22.0% treated with ozanimod and 28.2% treated with interferon had worsened SDMT scores.

Among the 853, there 676 patients who had paired baseline data with cortical gray matter (CGM) and 660 who had paired baseline data with thalamic volume (TV). At month 12, the improved and worsened SDMT groups had similar baseline, CGM, and TV in both ozanimod and interferon. There was less loss of TV among those taking ozanimod, and authors found that CGM loss was “more pronounced” among those taking interferon:

• For those who took interferon, the SDMT improved group showed -1.35% median percentage change (MPC), while the worsened group saw -1.88% MPC at month 12.
• For those who took ozanimod, the SDMT improved group showed -0.82 MPC and -0.91 for the SDMT worsened groups.
• Changes in CGM and SDMT tracked similarly. Among those taking interferon, -1.17% MPC for the improved group and -0.96% MPC for the worsened group; among those taking ozanimod, -0.12% for the improved group and -0.18% for the worsened group.

Neurofilament Light Chain Level as a Biomarker in Relapsing MS

Another post-hoc exploratory analysis explored whether neurofilament light chain (NfL) levels are a reliable market of response to treatment in relapsing MS when data are pooled. The analysis, led by Sarah Harris, PhD, of Celgene, included phase 2 data from RADIANCE and phase 3 data from RADIANCE and SUNBEAM.³

As discussed in an April paper in Frontiers in Neurology, there is a great need for biomarkers for use in treating MS patients, and the discovery of NfL more than 20 years ago in the cerebral spinal fluid has generated significant study.⁴ Authors Varhaug et al, describe neurofilaments as “neuron-specific components that can be assayed in different body compartments,” and that given the findings of recent years, “there is now little doubt that NfL should have a role in the follow-up of MS patients.” On the first day of ECTRIMS, a session examined the use of serum NfL as both a predictive and a diagnostic marker in MS; Mattia Rosso, MD, a postdoctoral investigator in neurology from Brigham & Women's Hospital, Boston, presented data derived from the CLIMB study pn the "temporal dynamics" of sNfL, and showed that levels peaked during the 3 months surrounding new disease activity.⁵

For the post-hoc analysis that Harris et al presented at ECTRIMS, NfL was measured at baseline for 2584 patients and consistent across the 3 trials. Pooled median NfL was 13.88 pg/mL (phase 2 RADIANCE, 12.10; phase 3 RADIANCE 13.35; SUNBEAM, 14.70). Across the 3 studies and the pooled study population, NfL level was higher in patients with more gadolinium-enhancing lesions, based on MRI data. NfL increased with lesion count, the authors said, “supporting NfL as a consistent biomarker of radiologic disease activity.” At the same time, NfL decreased after treatment, both in the individual studies and in the pooled results. Data showed the median change from baseline in NfL was -23.47% in patients receiving ozanimod HCI 0.5 mg and -25.83% in patients receiving ozanimod HCI 1 mg, compared with no change in the placebo group.³

References

1. Steinman L, Comi G, Bar-Or A, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: results from the DAYBREAK open-label extension study. Presented at 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Stockholm, Sweden; September 11-13, 2019. Abstract P1031.
2. Schippling S, DeLuca J, Silva D, et al. Effect of ozanimod on the relationship between changes in cognition and grey matter volume in RMS; a post hoc exploratory analysis of the phase 3 SUNBEAM trial. Presented at 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Stockholm, Sweden; September 11-13, 2019. Abstract P980.
3. Harris S, Comi G, Cree BAC, et al. Effect of neurofilament light chain level in relapsing multiple sclerosis: pooled results from phase 2 and phase 3 trials. Presented at 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Stockholm, Sweden; September 11-13, 2019. Abstract P1047.
4. Varhaug KN, Torkildsen O, Myhr KM, Vedeler CA. Neurofilament light chain as a biomarker in multiple sclerosis. Front Neurol. 2019;10:338. doi: 10.3389/fneur.2019.00338.
5. Rosso M, Gonzalez C, Healy B, et al. Serum neurofilament light chain levels are increased within three months of new gadolinium enhancing lesions in multiple sclerosis. Presented at 2019 Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Stockholm, Sweden; September 11-13, 2019. Abstract 22.