The study began in 2020 and also captured data on COVID-19 infections, and found that most were mild and resembled the profile of COVID-19 infections in the broader MS population.
Ozanimod is approved for the treatment of relapsing MS (RMS) and moderately to severe ulcerative colitis.
Dr. Bruce Cree
The DAYBREAK trial revealed a safety profile that broadly matched what was seen in the pivotal studies, with the exception that one case of progressive multifocal leukoencephalopathy (PML) emerged in the study population.
“So now we do know that ozanimod can cause PML, just as fingolimod can cause PML. I think some of us were hoping that perhaps the extent of immune suppression was going to be somewhat different in ozanimod and that PML might not occur. It’s a rare complication, but one that we now know can occur with this drug,” Bruce Cree, MD, PhD, said in an interview.
Ozanimod is a more selective drug than fingolimod. It affects only cell surface expression of the S1P1 and S1P5 receptors, and not other known S1P receptors. Ozanimod does not require first-dose observation and cardiac monitoring in most patients, and it can be taken at home.
“The two products have not been compared head-to-head. This is all comparison of data from different studies, and one has to take those considerations in mind as important caveats. But generally speaking, the safety profile and tolerability profile of ozanimod seems to be a little bit better, in my opinion, compared to that of fingolimod,” said Dr. Cree, who presented the results of the study at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is professor of neurology at the University of California, San Francisco.
Stable efficacy and no worsening of COVID-19 outcomes
Among 2,181 participants in DAYBREAK who were at risk of COVID-19, 8.7% had confirmed or suspected cases of COVID-19 during the study period. All were unvaccinated. Fourteen cases were considered serious, and there were two COVID-19–related deaths, and a third death caused by a pulmonary abscess related to an earlier COVID-19 infection. “When you look at this data and compare it to other datasets, this is not too dissimilar from rates of mortality that we would expect or serious infection that we see in other MS cohorts. So there doesn’t seem to be a striking worsening of COVID outcomes with ozanimod,” said Dr. Cree.
The benefit of the drug appeared to remain stable over multiple years. The annualized relapse rate was low and the relapse rate appeared to decline further over time. “It’s not an absolutely flat line, there is some curvature to it. So that that’s good news as well. And then the objective observation of lesion formation also is attenuated over time. We see a therapeutic effect on new radiographic lesions as well, and very low rates of disability worsening in ozanimod patients,” said Dr. Cree.
Overall, the study included 2,494 patients who entered the open-label extension study of the phase 1-3 trials. The study began in November 2019, and the current data extend through May 10, 2021. A total of 736 patients started out with interferon beta-1a and later switched to 0.92 mg ozanimod, 877 patients started at 0.46 mg ozanimod and switched to 0.92 mg ozanimod, and 881 were on a continuous dose of 0.92 mg ozanimod.
Three-quarters of the patients were relapse free at 36 months, 71% at 48 months. Among those who were on 0.92 mg ozanimod continuously, 64% were relapse-free through 60 months of treatment.
Among the cohort, 7.6% experienced severe treatment-emergent adverse events (TEAEs), 11.9% experienced serious TEAEs, and 3.0% discontinued ozanimod because of TEAEs. Common TEAEs included nasopharyngitis (59.3%), headache (46.1%), upper respiratory tract infection (31.5%), lymphopenia (29.4%), decreased absolute lymphocyte count (ALC, 24.5%), back pain (22.7%), and hypertension (20.7%).
Furthermore, 1.4% of patients developed treatment-emergent malignancies, 0.4% developed macular edema, 2.8% had cardiac TEAEs, and 9.8% had ALC levels below 0.2 x 109/L.
Encouraging data
The COVID-19 data were encouraging, according to Patricia Coyle, MD, who was asked to comment on the study. “190 individuals out of 2,181 seems quite reasonable, and they had three deaths. It certainly didn’t look like any excessive numbers of COVID, or excessive numbers of deaths,” said Dr. Coyle, professor of neurology and director of Stony Brook (N.Y.) MS Comprehensive Care Center.
She noted that other database studies have shown an association between increased risk and anti-CD20 agents, but they haven’t really seen that with the other disease-modifying therapies. “I think this is some long-term data that says that ozanimod appears to be well tolerated without having any surprising late toxicity,” said Dr. Coyle.
The study was funded by Celgene International II. Dr. Cree has consulted for Alexion, Atara, Autobahn, Avotres, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini, and received grant support from Genentech. Dr. Coyle has consulted or received speaker fees from Accordant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alkermes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.