Author Of 2 Presentations
P0217 - Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1−3 trials (ID 991)
Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in the US and EU for the treatment of relapsing forms of multiple sclerosis (RMS).
To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.
Participants with RMS who completed a phase 1, 2, or 3 ozanimod clinical trial were eligible to enroll in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d (equivalent to ozanimod HCl 1 mg). The primary objective was to evaluate safety in the overall population; treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualized relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/enlarging T2 and gadolinium-enhancing (GdE) MRI brain lesions were reported for the subset of participants who entered the OLE from an active-controlled phase 3 trial.
In total, 2639 participants completed the parent trials; this interim analysis (data cut 20 December 2019) included 2494 participants with mean (range) ozanimod exposure of 35.4 (0.03–50.2) months in the OLE. Adjusted ARR in the OLE was 0.112 (95% confidence interval, 0.093‒0.135). At months 24 and 36, 79% and 75% of participants, respectively, were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 24 months was similar, regardless of parent-trial treatment group (range, 1.57–1.90), as were mean number of GdE lesions at month 24 (range, 0.2 ‒0.4). In the OLE, 2039 participants (81.8%) had any TEAE, 236 (9.5%) had a serious TEAE (SAE), and 56 (2.2%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent-trial treatment group. The most common TEAEs were nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%). TEAEs were generally similar to parent trial observations. There were no serious opportunistic infections. Exposure-adjusted incidence rates of TEAEs and SAEs have decreased over time.
In DAYBREAK, ozanimod was associated with low ARR and low new/enlarging T2 and GdE lesion counts over time. Most participants were relapse free and did not experience disability progression. Ozanimod was generally well tolerated and no new safety concerns emerged with long-term use.
P1010 - Comparison of Models for Disability Accumulation on the Expanded Disability Status Scale in Multiple Sclerosis (ID 1665)
When assessing long-term trends in disability accumulation and economic models to compare treatments in multiple sclerosis (MS), disability accumulation on the Expanded Disability Status Scale (EDSS) is commonly assumed to depend only on the present state of the patient. Such models also often assume that the probability of disability accumulation is constant over the disease course.
The objective of this study was to assess the assumptions of models used to describe disability accumulation within patients with MS.
Patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women’s Hospital (CLIMB) who had ≥6 consecutive clinic visits, which occurred every 6 months, were included in this analysis. This yielded 7257 observations for 1039 patients. To assess whether a previous EDSS score only was sufficient for modeling disability accumulation, we compared 2 models for EDSS transitions with the EDSS scale grouped into 3 score levels (0–1.5, 2–3.5, ≥4) using a likelihood ratio test. The first transition model included only the present EDSS score, and the second model included the present and the previous EDSS scores. In addition, we fit a repeated measures proportional odds model with 1, 2, and 3 previous EDSS scores to assess if additional previous EDSS scores added to the model. To determine if the probability of disability accumulation changed with time, we assessed whether disease duration <15 years or ≥15 years was associated with a change in the transition matrix using a likelihood ratio test. Finally, we fit the repeated measures proportional odds model to assess if disease duration improved the model that included 3 previous EDSS scores.
When the model with only the present EDSS score was compared with the model with 2 previous EDSS scores, the model including the 2 previous EDSS scores led to a better model fit (P<0.001). Further, all previous EDSS scores were associated with subsequent EDSS score in the repeated measures proportional odds model (1 previous EDSS, OR [95% CI]: 4.64 [4.31–4.99]; 2 previous EDSS, OR [95% CI]: 1.77 [1.65–1.90]; 3 previous EDSS, OR [95% CI]: 1.63 [1.53–1.73]). Incorporating disease duration also improved model fit using both approaches (P<0.001 for each method).
Additional EDSS history and disease duration may be important to incorporate into disability accumulation modeling for MS.