Author Of 1 Presentation
FC03.05 - Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO
Abstract
Background
In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.
Objectives
To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.
Methods
At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.
Results
In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.
Conclusions
In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.
Presenter Of 1 Presentation
FC03.05 - Reduced thalamic atrophy in patients initiating earlier versus delayed ocrelizumab therapy: results from the OLE of OPERA I/II and ORATORIO
Abstract
Background
In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.
Objectives
To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.
Methods
At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.
Results
In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.
Conclusions
In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.
Author Of 1 Presentation
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)
Abstract
Background
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).
Objectives
To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.
Methods
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.
Results
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.
Conclusions
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.