Phase 3 DAYBREAK Trial Highlights Long-Term Efficacy of Ozanimod for Relapsing Multiple Sclerosis

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Long-term data from the phase 3 DAYBREAK trial affirmed sustained efficacy of ozanimod for relapsing forms of multiple sclerosis, with a high amount of patients who were relapse-free at 6 years.

Jonathan Sadeh, MD, MSc, senior vice president and head of global program leaders, Immunology, Cardiovascular and Neuroscience Development at Bristol Myers Squibb

Jonathan Sadeh, MD, MSc

Credit: Bristol Myers Squibb

New long-term data from the phase 3 open-label extension DAYBREAK trial (NCT02576717) presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, in West Palm Beach, Florida, showed sustained efficacy for measures of disease activity and progression with ozanimod (Zeposia; BMS), an FDA approved disease-modifying therapy for patients with relapsing forms of multiple sclerosis (RMS).1,2

In this analysis of 2494 patients with RMS, the mean exposure of ozanimod 0.92mg/d was 60.9 months (range, 0.03-81.5; patient-years total, 12,664.7). After 72 months of treatment, the adjusted annualized relapse rate (ARR) was 0.098 (95% CI, 0.082‒0.117) and 67% of patients were relapse-free. In addition, investigators observed that 3- and 6-month confirmed disability progression occurred in 17.2% and 15.2% of patients, respectively. Notably, adjusted mean number of new/enlarging T2 lesions per scan (range, 0.789-0.932) and adjusted mean number of gadolinium-enhancing (GdE) lesions (0.062-0.077) were similar at 60 months.

Top Clinical Takeaways

  • Ozanimod, an FDA-approved oral modulator, showed sustained efficacy for relapsing forms of multiple sclerosis over a mean exposure of 60.9 months.
  • DAYBREAK trial data indicated that 67% of patients remained relapse-free after 6 years of ozanimod treatment.
  • The safety profile of ozanimod in the trial remained consistent with prior reports, with common adverse events including nasopharyngitis, headache, and upper respiratory tract infection.

"While no cure exists for MS, effective strategies and treatments can help slow disease progression, alleviate symptoms, and ultimately improve outcomes. The results from the DAYBREAK long-term extension study confirmed ozanimod’s durable efficacy and well-established safety profile. With nearly 10 years of clinical experience, these findings validate the role ozanimod plays in disease management and provides an important option for clinicians and patients,” Jonathan Sadeh, MD, MSc, senior vice president and head of global program leaders, Immunology, Cardiovascular and Neuroscience Development at Bristol Myers Squibb, told NeurologyLive®.

READ MORE: Published Phase 2 Findings Highlight CD40L Inhibitor Frexalimab as Potential Treatment for Multiple Sclerosis

Participants with RMS who completed assessment of ozanimod in the phase 1-3 parent trials (n = 2639) were eligible for DAYBREAK. In the study, the primary objective assessment of safety and investigators monitored treatment-emergent adverse events (TEAEs) among the treated patients. In addition, ARR was calculated though negative binomial regression pooled for all parent trial treatment groups. For the current analysis, new/enlarging T2- and GdE lesions were reported in patients who entered DAYBREAK from active-controlled phase 3 trials.

"The DAYBREAK data demonstrated that two-thirds of patients with relapsing forms of MS receiving ozanimod were relapse-free at 6 years and no new safety signals emerged in this long-term study. These findings are very promising and strengthen our confidence in the role of Zeposia as an effective treatment option with a well understood safety profile for the long-term management of patients with MS," Sadeh told.

Authors noted that the safety profile of ozanimod in the current analysis showed consistency findings observed from prior reports. In DAYBREAK, 2219 (89.0%) patients reported having any TEAE, 381 (15.3%) reported a serious TEAE (SAE), and 98 (3.9%) discontinued the treatment because of a TEAE. These rates of TEAEs and SAEs are similar to those reported by the parent trial treatment. The most common of the TEAEs among the participants were nasopharyngitis (21.3%), headache (17.1%), COVID-19 infection (16.5%), and upper respiratory tract infection (12.4%), which were also similar to those in the parent trials except for COVID-19.

Bruce Cree, MD, PhD, MAS, professor of clinical neurology at University of California San Francisco (UCSF) Weill Institute for Neurosciences and clinical research director, UCSF MS Center

Bruce Cree, MD, PhD, MAS

Credit: UCSF Health

“These DAYBREAK data continue to validate the role of ozanimod in the long-term management of relapsing forms of MS, with two-thirds of patients relapse-free at 6 years of treatment,” senior author Bruce Cree, MD, PhD, MAS, professor of clinical neurology at University of California San Francisco (UCSF) Weill Institute for Neurosciences and clinical research director, UCSF MS Center, said in a statement.1 “These findings add to our confidence in ozanimodas an important treatment option for people living with the disease, highlighting its efficacy and safety over time.”

In a separate analysis presented at ACTRIMS 2024 on the risk of rebound after ozanimod discontinuation in the DAYBREAK trial, findings showed that posttreatment relapses occurred predominantly 2-3 months (median, 61 days) following ozanimod discontinuation, particularly in untreated patients.3 Despite some of the findings, authors noted that most patients did not have MS relapses in the 90 days after permanent ozanimod discontinuation, and revealed no evidence of rebound characterized by severe exacerbation of disease or severe persistent increase in disability in those who did relapse. These findings suggest clinicians should communicate to their patients about considering when to discontinue ozanimod, for example, family planning or other reasons.

"This analysis of DAYBREAK was conducted to better understand the impact of treatment discontinuation, which can occur for family planning or other reasons. These findings should be taken into consideration by patients and their physicians when considering a pause or discontinuation of ozanimod treatment," Sadeh added. "This DAYBREAK analysis showed nearly 97% of patients were relapse-free at 90 days after stopping treatment with ozanimod . For the patients that did relapse, there was no evidence of rebound effect, defined as severe worsening of disease or severe persistent increase in disability. These findings add to our confidence in ozanimod ’s safety and efficacy profile and how effective it can be in the long-term management of patients with MS, even in the setting of drug discontinuation."

In DAYBREAK, 544 patients (21.8%) discontinued the study early and 1950 (78.2%) discontinued the treatment at the end of the trial. For several reasons, not all of the participants completed posttreatment follow-up but 52.8% were followed for more than 28 days. Of the 55 patients who relapsed after permanently discontinuing ozanimod, 54 did not take a MS disease-modifying therapy at the time of relapse and 1 patient relapsed 13 days after starting fingolimod. Time to relapse onset following ozanimod discontinuation ranged from between 3 days and 141 days (median, 61 days), and 87.3% of relapses occurred between 29 days and 90 days. Authors noted that relapse duration ranged from between 4 days and 74 days (median, 22 days).

In this additional analysis, protocol-defined safety follow-up after ozanimod discontinuation initially was 28 days but was increased to 75 days in 2018 and 90 days in 2019. Investigators analyzed confirmed MS relapses after permanent ozanimod discontinuation for severity and disability. Of note, the patient who demonstrated a 3-point increase in Expanded Disability Status Scale (EDSS) score had a moderate relapse and complete recovery in 23 days. Investigators noted that 1 patient with confirmed relapse did not have a protocol-required EDSS score recorded. Among the 55 patients who relapsed, 42 fully recovered (76.4%), 11 partially recovered (20.0%), and 2 did not recover. Most relapses were reported as mild (n = 20) or moderate (n = 34); 1 was reported as severe. Authors observed an association between posttreatment relapse and severe sustained increase in disability.

"We continue to research ozanimod and are conducting trials to evaluate its effect on the maintenance or improvement on cognition and brain volume, and its role in supporting patients with early MS. We are also studying ozanimod’s efficacy in delaying progression and addressing its underlying drivers such as progression independent of relapse activity (PIRA) and relapse-associated worsening," Sadeh said. "We are also in the early stages of evaluating new mechanisms and targets that may have the potential to address the needs of more patients with MS. BMS has a growing neuroscience portfolio addressing multiple important neurological conditions, including neuroinflammatory diseases like MS and we look forward to sharing more data in the future."

Click here for more coverage of ACTRIMS 2024.

REFERENCES
1. Bristol Myers Squibb Announces New Data from Long-Term DAYBREAK Study Reinforcing Efficacy and Safety of Zeposia (ozanimod) in Patients with Relapsing Forms of Multiple Sclerosis. News Release. Bristol Myers Squibb. Published February 29, 2024. Accessed February 29, 2024.
2. Selmaj KW, Steinman L, Comi G, et al. Long-term Safety and Efficacy of Ozanimod in Relapsing Multiple Sclerosis: Final Analysis of the DAYBREAK Open-label Extension Study. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. P090.
3. Gold R, Selmaj KW, Berkovich R, et al. Absence of Rebound Effect Following Ozanimod Discontinuation Among Participants in the DAYBREAK Open-Label Extension Study. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. P097.
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