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.

Background

Disease activity in multiple sclerosis (MS) is highly variable, and there are limited prospective studies on predictors of disease outcomes.

Objectives

The aim of the study is to identify and assess clinical characteristics in MS that predict disease activity and progression.

Methods

The study population consisted of a prospective cohort of 1,008 patients with relapsing-remitting (RR) onset MS enrolled in the CombiRx trial. Cox regression analysis was used to determine hazard ratio (HR) associations between baseline (BL) demographics (age <38 vs. ≥38, sex, race), clinical history (number of relapses in prior year <3 vs. ≥3, disease duration, Expanded Disability Status Scale (EDSS)), and MRI metrics (presence or absence of gadolinium (Gd) and number of T2 lesions), and treatment (glatiramer acetate (GA), interferon-beta 1a (IFN), or combination therapy); with outcomes of time to first new disease activity over 7-years of follow-up including relapse, MRI activity defined by new combined unique active lesion, and disease worsening as defined by confirmed 6-month increase in EDSS.

Results

1,008 participants were randomized, with 959 eligible for assessment of disease worsening and activity on follow-up MRI. Participants were median 38 (range 18, 61) years of age at baseline, 72.7% female, 88.3% Caucasian, 7.1% black/African American, mean 1.2 years since diagnosis, with median 2 relapses in the prior 12 months and median EDSS 2 (IQR 1, 2.5). Risk of relapse was higher in patients younger than 38 at BL vs. older (HR 1.36, 95% CI: 1.12,1.65) and with BL EDSS ≥3.5 vs. <3.5 (HR 1.66, 95% CI: 1.27, 2.14). Presence of Gd+ lesions at baseline was also associated with increased risk of relapse (HR 1.37, 95%CI: 1.14, 1.66). Risk of new MRI activity was higher in younger participants (HR 1.56, 95%CI: 1.34, 1.86) and those taking either single agent arms compared to the combination (GA: HR 1.48, 95%CI 1.22, 1.80; IFN: HR 1.43, 95%CI 1.18, 1.74). Similarly, higher preexisting lesion burden greater than the median lesion count with ≥71 T2 hyperintense lesions vs. <71 (HR 1.50, 95%CI 1.27, 1.78) and presence of BL Gd+ lesions (HR 1.75, 95%CI: 1.49, 2.06) were also associated with a higher risk of developing new MRI activity. Risk of disease worsening was higher for those with BL EDSS < 2 (HR 2.79, 95%CI 2.14, 3.67). There were no associations between sex and disease duration on clinical or radiological disease activity or worsening.

Conclusions

Both clinical and radiological disease activity are predicted by younger age and presence of Gd+ lesions. Additionally, relapses are also predicted by higher EDSS, and there is some protective evidence of the combination therapy in lowering risk of new MRI activity. Only baseline EDSS level was associated with disease worsening.

Background

Serum neurofilament light-chain (sNfL) is associated with disease activity and tissue damage, predicts long-term outcomes, and is reduced by disease-modifying therapies in RRMS patients.

Objectives

In a post hoc analysis, determine sNfL differences from baseline (BL) to 48 months and associations with long-term clinical outcomes in patients treated with intramuscular (IM) interferon (IFN) beta-1a, glatiramer acetate (GA), or both therapies (IFN+GA).

Methods

CombiRx was a placebo (PLB)-controlled double-blind phase 3 trial in treatment-naive RRMS patients randomized to IM IFN beta-1a 30 µg weekly+PLB, GA 20 mg/mL daily+PLB, or IFN+GA treatment for up to 7 years. Samples for biomarker analysis were collected at BL, 6, 12, 36, and 48 months from volunteers for a substudy offered in most sites. Relapses and Expanded Disability Status Scale (EDSS) scores were collected every 3 months. A Simoa Human Neurology 4-Plex A assay analysed sNfL levels. A linear mixed model compared sNfL values over time adjusted for BL EDSS, age, sex and body mass index (BMI). A Cox regression model with the same covariates analysed BL sNfL as a predictor of relapse.

Results

Samples were collected from 159 IFN, 172 GA, and 344 IFN+GA patients. BL characteristics were generally well balanced, including mean age, sex, mean BMI, mean time since symptom and diagnosis onset, and mean EDSS scores. Significant reductions relative to BL in sNfL levels were seen at 6, 12 and 36 months in the IFN, GA, and IFN+GA treatment groups. BL sNfL ≥16 pg/mL significantly predicted relapse within 90 days (hazard ratio [HR]: 2.25, P=0.0041), 180 days (HR: 1.67, P=0.0130) and 1 year from BL (HR: 1.40, P=0.0435), but not over the entire study duration (HR: 1.08, P=0.5596). In patients with BL sNfL ≥16 pg/mL and ≥1 BL gadolinium-enhancing (Gd+) lesion, a significantly higher percentage (16.8%) relapsed within 90 days than in patients with BL sNfL ≥16 pg/mL and no BL Gd+ lesions (9.2%), or BL sNfL <16 pg/mL with (7.3%) or without BL Gd+ lesions (6.7%) (P=0.0051).

Conclusions

Treatment with IFN, GA, and IFN+GA significantly reduced sNfL levels within 6 months and was maintained over 36 months. Results suggest that BL sNfL levels predict relapses within 1 year, and that the combination of lesion activity and sNfL is a stronger predictor of relapse than either one alone.

This analysis was funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

Background

Evobrutinib (EVO) is a highly selective Bruton’s tyrosine kinase inhibitor (BTKI) with a dual mode of action targeting both B cells and myeloid cells, which are known to play a key role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Clinical efficacy of EVO in relapsing MS was shown in a Phase II randomized controlled trial (RCT; NCT02975349) with a significant reduction of T1 Gd-enhancing lesions compared to placebo at Week 24 (the primary endpoint of the study) and continued efficacy through Week 48.

Objectives

To report the long-term efficacy of EVO measured as the annualized relapse rate [ARR]), cumulative probability of and time to qualified relapse (QR, change in neurological symptoms or expanded disability status scale score increase attributed to MS lasting ≥24 hours preceded by a stable or improving neurological status ≥30 days).

Methods

In the 48-week double-blind period (DBP), patients received EVO 25mg once daily (QD), 75mg QD, 75mg BID or placebo (PBO) for the first 24 weeks; all arms continued with the original treatment assignment until 48 weeks, except PBO patients who were switched to EVO 25mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75mg QD (for a median of ≈48 weeks) before switching to 75mg BID. Long-term efficacy of EVO was assessed at up to 60 weeks of OLE.

Results

Of 213 patients randomized to EVO or PBO, 164 (77%) entered the OLE; of these 148 (90%) completed 108 weeks of treatment. For patients initially receiving PBO or EVO 25mg QD, 75mg QD or 75mg BID in the DBP, ARR (95% CI) was 0.37 (0.21, 0.59), 0.52 (0.33, 0.78), 0.25 (0.12, 0.44) and 0.11 (0.04, 0.25), respectively, at Week 48, and 0.31 (0.21, 0.45), 0.37 (0.25, 0.52), 0.18 (0.10, 0.29) and 0.12 (0.06, 0.22) at Week 108. The cumulative probability of QR in these groups was 0.26 (0.14, 0.38), 0.24 (0.12, 0.36), 0.15 (0.05, 0.25) and 0.08 (0.00, 0.16) at Week 48, and 0.39 (0.25, 0.53), 0.34 (0.20, 0.48), 0.25 (0.12, 0.38) and 0.20 (0.08, 0.31) at Week 96, respectively. The estimated time from randomization by which 20% of patients had a qualified relapse was almost three times longer for patients initiated in the DBP with EVO 75mg BID (827 days [327, not evaluable]) than for patients initiated in the DBP with PBO (281 days [99, 407]) and longer than for patients initiated in the DBP with EVO 25mg QD (166 days [61, 606]) and 75mg QD (530 days [244, 838]). EVO was generally well tolerated, with the safety profile maintained during the 60-week OLE.

Conclusions

With EVO 75mg BID, the efficacy (ARR, 0.11) at Week 48 was maintained at 108 weeks. Probability of and time to QR highlighted that, despite switching to EVO 75mg QD/BID in OLE, patients initiated in the DBP on EVO 25mg QD, 75mg QD or PBO did not achieve the same level of efficacy of those initiated in the DBP on 75mg BID. The maximum efficacy observed at the 75mg BID dose correlated with optimal BTK occupancy achieved with BID dosing.

Background

The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week controlled double-blind period (DBP) of the Phase III OPERA I (NCT01247324) and OPERA II (NCT01412333) trials.

Objectives

To assess the efficacy of switching from interferon (IFN) β-1a or maintaining OCR therapy on disease activity and confirmed disability progression (CDP) after 4.5 years of follow-up, in the open-label extension (OLE) of OPERA I and OPERA II.

Methods

In the DBP of OPERA I and OPERA II, patients were randomized to receive OCR or IFN β-1a. Patients completing the DBP either continued OCR (OCR-OCR) or switched from IFN β-1a to OCR (IFN-OCR) when entering the OLE period. Adjusted annualized relapse rate (ARR), time to onset of 48-week CDP (CDP48) and time to 48-week confirmed Expanded Disability Status Scale score ≥6.0 (time to require a walking aid) were analyzed up to Week 336.

Results

Overall, 79.2% of patients who entered the OLE period completed OLE Year 4.5. Adjusted ARR decreased year-on-year from the pre-switch year to OLE Year 4.5 in IFN-OCR switchers (pre-switch, 0.20; OLE Year 4.5, 0.06) and was maintained at low levels in OCR-OCR continuers (pre-switch, 0.12; OLE Year 4.5, 0.04). The rates of CDP48 were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (4.1% vs 8.5%; p<0.001) and at OLE Year 4.5 (16.0% vs 20.3%; p=0.05). The rates of patients requiring a walking aid were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (0.8% vs 3.1%; p=0.001) and at OLE Year 4.5 (5.1% vs 8.3%; p=0.024). Over the DBP and OLE periods, the risk of CDP48 was 28% lower (HR [95%CI]: 0.72 [0.56–0.93]; p=0.01) and the risk of requiring a walking aid was 46% lower (HR [95%CI]: 0.54 [0.35–0.83];p=0.004) in OCR-OCR continuers vs IFN-OCR switchers. The safety profile in the OLE was generally consistent with the DBP.

Conclusions

Switching from IFN β-1a to ocrelizumab at the start of the OLE period was associated with a rapid and robust reduction in ARR that was maintained through the 4.5-year follow-up of the OLE period. Compared with patients switching to ocrelizumab at the OLE, patients initiating ocrelizumab 2 years earlier accrued significant benefits on CDP48 and time to require a walking aid that were maintained vs the switch group through the 4.5 years of the OLE period.

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

Background

In a Phase II randomized study (NCT02975349) in patients with relapsing MS, evobrutinib (EVO) 75 mg twice-daily (BID) reduced total T1 Gd+ lesions (primary endpoint) and annualized relapse rate (ARR) over 24 weeks versus placebo, with efficacy maintained through Week 108. EVO was generally well tolerated.

Objectives

To describe the safety profile of EVO in the long-term treatment of MS by reporting detailed safety data from the study’s open-label extension (OLE) over 60 weeks.

Methods

In the 48-week double-blind period (DBP), patients received EVO 25 mg once-daily (QD) or 75 mg QD, 75 mg BID, or placebo for the first 24 weeks. All arms continued with the original treatment assignment until 48 weeks, except placebo patients who were switched to EVO 25 mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75 mg QD (for a median of ~48 weeks) before switching to 75 mg BID. Safety was assessed throughout the OLE by the nature, severity, and occurrence of treatment emergent adverse events (TEAEs) by NCI-CTCAE v4.03 criteria, as well as vital signs, ECGs, and clinical laboratory safety parameters.

Results

Of 213 patients who received EVO during the double-blind period, 164 (77%) entered the OLE (safety analysis population) and 148 (90%) completed 60 weeks of treatment. Overall, 107 (65.2%) patients had a treatment emergent adverse event (TEAE), the majority of which were mild (47.6%) or moderate (36.0%), and none led to death. TEAEs were balanced across previous DBP treatment groups; the most frequent TEAEs over the OLE period, including the dose-switch, were nasopharyngitis (7.9%, Grade 2 or less), increased lipase (7.9%, Grade 3 or less), upper respiratory tract infection (6.1%, Grade 2 or less), and urinary tract infection (4.9%, Grade 2 or less); analysis of TEAEs by exposure-adjusted incidence rate showed no evidence of an increase after patients switched to 75 mg BID. Thirteen patients (7.9%) reported a serious TEAE, most frequently related to infections (6 patients, not treatment-related). Five patients (3.0%) had a TEAE during the OLE that led to treatment withdrawal, of which 3 were considered related to treatment (nausea, increased lipase, and increased lipase and amylase). The incidence of overall infections in the OLE was similar to that observed in the DBP. Transient elevated liver aminotransferases reported in the 48-week DBP were not observed in the OLE after prolonged treatment or after the switch to 75 mg BID. No adverse ECG findings were noted across all evobrutinib groups. There was also no apparent effect of EVO dose received in the DBP on safety parameters in the OLE.

Conclusions

In a 60 week OLE period of a Phase II study, the safety of EVO was similar to that seen in the DBP. Overall, long-term EVO treatment was generally well tolerated in patients with relapsing MS.

Background

The efficacy and safety of ocrelizumab (OCR) in primary progressive multiple sclerosis were demonstrated vs placebo (PBO) in the Phase III ORATORIO study (NCT01194570).

Objectives

To assess the efficacy of switching to or maintaining OCR therapy on 48-week confirmed disability progression (CDP), in the open-label extension (OLE) of ORATORIO, over 7 years (360 weeks).

Methods

In the double-blind period (DBP), patients were randomized to OCR or PBO and followed for ≥120 weeks until a prespecified number of CDP events occurred. At DBP completion, patients remained on blinded treatment until the trial outcome was determined (extended controlled period; ECP). At OLE start, patients continued OCR (OCR-OCR) or switched from PBO to OCR (PBO-OCR). Time to 48-week CDP-EDSS (Expanded Disability Status Scale [EDSS] score increase from baseline [BL] of ≥1 point if BL EDSS ≤5.5 or ≥0.5 points if BL EDSS >5.5), time to 48-week CDP on the 9-Hole Peg Test (CDP-9HPT; ≥20% increase from BL in timed 9HPT) and time to 48-week confirmed EDSS≥7 (wheelchair requirement) are presented up to Week 360.

Results

Overall, 72% of patients entered the OLE. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 48-week CDP-EDSS in the PBO-OCR and OCR-OCR groups was 44.4% vs 30.5% (Δ=13.9%; p<0.001), respectively; at Week 360 the corresponding proportions were 65.7% vs 54.2% (Δ=11.6%; p=0.006). At Week 168, the proportion of patients with 48-week CDP-9HPT in the PBO-OCR and OCR-OCR groups was 27.9% vs 15.8% (Δ=12.1%; p<0.001); at Week 360 the corresponding proportions were 41.6% vs 31.1% (Δ=10.6%; p=0.014), respectively. At Week 168 the proportion of patients with 48-week confirmed EDSS≥7 in the PBO-OCR and OCR-OCR groups was 9.1% vs 4.8% (Δ=4.3%; p=0.054), respectively; at Week 360 the proportions were 21.7% vs 12.3% (Δ=9.4%; p=0.009). During the DBP+ECP+OLE, compared with the PBO-OCR group, continuous OCR treatment reduced the risk of CDP-EDSS by 31% (HR [95% CI]: 0.69 [0.56–0.86]; p<0.001), CDP-9HPT by 34% (HR [95% CI]: 0.66 [0.50–0.87]; p=0.003) and 48-week confirmed EDSS≥7 by 44% (HR [95% CI]: 0.56 [0.37–0.85]; p=0.006). Timed 25-Foot Walk, composite CDP and 24-week CDP will also be presented. The OLE safety profile was consistent with the DBP.

Conclusions

After 7 years, 48-week CDP outcomes favoured those on earlier and continuous OCR treatment. Patients initiating OCR 3–5 years earlier had a significantly reduced risk of requiring a wheelchair vs those switching from PBO.

Background

Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of ocrelizumab in patients with multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterized in Phase II (NCT00676715) and Phase III (NCT01247324; NCT01412333; NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To report longer-term safety evaluations from ocrelizumab clinical trials and open-label extension (OLE) periods up to January 2020 and selected post-marketing data.

Methods

Safety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III trials and associated OLEs plus ongoing Phase IIIb trials in MS (VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO and CONSONANCE). The number of post-marketing ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented.

Results

In clinical trials, 5,680 patients with MS received ocrelizumab (18,218 PY of exposure) as of January 2020. Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 248 (246–251); infections, 76.2 (74.9–77.4); serious AEs, 7.34 (6.96–7.75); serious infections, 2.01 (1.81–2.23); malignancies, 0.46 (0.37–0.57); and AEs leading to discontinuation, 1.06 (0.92–1.22). As of April 2020, over 158,000 patients with MS have initiated ocrelizumab globally in the post-marketing setting. Data remain generally consistent with those observed in clinical trials.

Conclusions

Reported rates of AEs in the ocrelizumab all-exposure clinical trial population and post-marketing settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Rates of serious infections and malignancies remain within the range reported for patients with MS in real-world registries. In patients with RMS and PPMS, ocrelizumab demonstrates a consistent and favorable safety profile, and these longer-term data are in accordance with the safety outcomes initially observed during the controlled treatment periods. Regular reporting of longer-term safety data will continue.

Background

Depression and anxiety have increased prevalence in multiple sclerosis (MS). There are limited studies on associations of depression and anxiety with MS disease characteristics.

Objectives

The aim of the study is to identify and quantify associations of depression and anxiety with MS disease activity and disability.

Methods

The study population included a prospective cohort of 1008 treatment-naïve participants with relapsing-remitting (RR) MS enrolled in the CombiRx trial. Entrance criteria included at least 2 relapses in the prior 2 years. Covariate adjusted linear regression analyses were conducted to determine associations and adjusted R-squared (R2) between baseline scores on three components of the Multiple Sclerosis Quality of Life Index (MSQLI): the Mental Health Inventory (MHI), Depression Subscale (MHD), and Anxiety Subscale (MHA), where lower scores indicated more severe symptoms on each component of the MSQLI subscale; with outcomes of baseline MS disease characteristics including Expanded Disability Status Scale (EDSS) and total MRI lesion volume (T1+T2). Kruskal-Wallace comparison was used to assess prior relapse frequency (0, 1-2, and 3 or more in prior 12 months) and median MSQLI measures.

Results

Lower EDSS scores were associated with higher MHI scores (β = -0.31, R² = 0.1274, p <0.0001), higher MHA scores (β = -0.21, R² = 0.1060, p <0.0001), and higher MHD (β = -0.22, R² = 0.1096, p <0.0001), when adjusted for age and sex at baseline. Baseline MHA score was modestly associated with relapse frequency (p =0.043), with a median rank MHA score of 5 for 0 relapses, 4.6 for 1-2 relapses, and 4.6 for ≥3 relapses. Components of the MSQLI were not associated with MRI lesion volume.

Conclusions

Depression and anxiety in MS are associated with increased baseline EDSS disability. Of the three measures, only anxiety was associated with higher baseline relapse frequency. A follow-up analysis is planned to examine associations of depression and anxiety on longitudinal MS disease outcomes in the trial cohort.

Background

Magnetic resonance imaging (MRI)-based measures have been established as robust, non-invasive, in vivo biomarkers of disease. Although the relationship between quantitative regional MRI volume measures and selected aspects of clinical disability in MS has been described, characterization of specific trends by race/ethnicity is lacking.

Objectives

To characterize racial disparities in disability-specific patterns of MRI-based volumetric measures between Hispanic and non-Hispanic Caucasian individuals with MS and explore the relevance of regional brain volumetric measures as predictors of clinical disability progression.

Methods

MRI from 94 Hispanic and 94 Caucasian MS patients was analyzed using automatic and manual brain segmentation techniques. Scans were done between January 2010 and December 2019 on a single 3.0-Tesla scanner using a standardized imaging protocol. Whole brain, cortex, white matter, basal ganglia, thalamus, corpus callosum, lateral ventricular, and T2 lesion volumes were measured and compared with the extent of neurological impairment as measured by Expanded Disability Status Scale (EDSS) scores at baseline and in subsequent follow-up visits. Cox proportional hazard regression models determined the predictive value of baseline MRI metrics for sustained EDSS progression in a time-to-event analysis.

Results

At baseline, Hispanic patients had a higher median EDSS score (median [IQR], 2.0; [1.0–3.5]) compared to Caucasians (median [IQR], 1.0 [0.0–2.0]). In addition, Hispanics were found to develop more rapid accumulation of clinical disability and an increased risk of requiring assistance to ambulate (hazard ratio (HR), 9.7; 95% confidence interval (CI), 2.8–32.5). T2 lesion volume was associated with EDSS in Hispanics (r_s = .38, p < .001), and white matter volume was moderately correlated with disability in Caucasians only (r_s = -.41, p < .001). The association between normalized thalamic volume and EDSS scores was moderate in both (r_s = -.42, P < .001 in Hispanics and r_s = -.32, P = .002 in Caucasians). Baseline thalamic volume was the best predictor of sustained disability worsening in both. Patients with thalamic volumes below the mean had a higher risk for progression, with greater risk in Hispanics (HR, 7.9; 95% CI, 3.5–17.9) compared to Caucasians (HR, 3.0; 95% CI, 1.5–6.4).

Conclusions

Quantitative MRI assessment of brain and lesion volume is a useful tool to explore the influence of race on clinical disease expression in multiple sclerosis. Racial disparities in baseline volumetric MRI correlates of clinical disability suggest a burgeoning trend of possibly differentially regulated pathophysiologic processes through which race-dependent disparities may manifest. The confounding impact of race and ethnicity on brain volumetric measures may affect the interpretation of outcome measures in clinical MS studies and should be controlled in randomized clinical trials.

Background

Nabiximols, a cannabinoid oromucosal spray, improved spasticity vs placebo in multiple sclerosis patients in a phase 3 trial (NCT00681538). Initial responders with ≥20% decrease in average daily numeric rating scale [NRS] spasticity score in Phase A single-blind lead-in period with nabiximols were randomized to nabiximols or placebo in Phase B double-blind period. Efficacy was evaluated relative to Phase B randomization baseline and not Phase A screening baseline (Novotna et al. Eur J Neurol 2011;18:1122–31).

Objectives

This post hoc analysis assessed the safety profile of nabiximols in responders vs nonresponders during Phase A (4 weeks) and efficacy outcomes for nabiximols vs placebo during Phase B (12 weeks) relative to Phase A baseline.

Methods

Incidence of AEs was assessed during Phase A and B. Percent change in NRS spasticity score and daily spasm frequency and the proportion of caregivers reporting an improvement in patients’ functional abilities on a Caregiver Global Impression of Change (CGIC) scale were assessed at the end of Phase B relative to Phase A baseline.

Results

Of 572 patients enrolled, 266 were responders at the end of Phase A; 241 of these patients were then randomized to nabiximols (n=124) or placebo (n=117) in Phase B. During Phase A, 40% of responders and 53% of nonresponders had an AE. The AE profile was similar between the 2 groups, except dizziness, which occurred more frequently in nonresponders vs responders (18% vs 10%). During Phase B, 53% of patients on nabiximols reported ≥1 AE vs 49% on placebo; 9 patients on nabiximols discontinued due to an AE vs none on placebo. The subcohort of responder patients from Phase A randomized to continue nabiximols or switch to placebo in Phase B had similar mean percent reductions in NRS spasticity (44% for both) and spasm frequency (47% vs 45%) during Phase A. At the end of Phase B, mean percent decrease from Phase A baseline in spasticity NRS was 46% for nabiximols vs 34% for placebo (P=0.011); mean percent decrease in spasm frequency was 44% for nabiximols vs 24% for placebo (P=0.006). Change of ≥1 point from Phase A baseline on the CGIC scale was reported for 68% of patients on nabiximols vs 43% on placebo during Phase B.

Conclusions

Nabiximols was well tolerated and provided continued benefit to patients who remained on therapy in Phase B, with a variable loss of efficacy in patients who switched from nabiximols in Phase A to placebo in Phase B. Funding: Greenwich Biosciences, Inc.

Background

The efficacy and safety of ocrelizumab (OCR) in primary progressive multiple sclerosis were demonstrated vs placebo (PBO) in the Phase III ORATORIO study (NCT01194570).

Objectives

To assess the efficacy of switching to or maintaining OCR therapy on 48-week confirmed disability progression (CDP), in the open-label extension (OLE) of ORATORIO, over 7 years (360 weeks).

Methods

In the double-blind period (DBP), patients were randomized to OCR or PBO and followed for ≥120 weeks until a prespecified number of CDP events occurred. At DBP completion, patients remained on blinded treatment until the trial outcome was determined (extended controlled period; ECP). At OLE start, patients continued OCR (OCR-OCR) or switched from PBO to OCR (PBO-OCR). Time to 48-week CDP-EDSS (Expanded Disability Status Scale [EDSS] score increase from baseline [BL] of ≥1 point if BL EDSS ≤5.5 or ≥0.5 points if BL EDSS >5.5), time to 48-week CDP on the 9-Hole Peg Test (CDP-9HPT; ≥20% increase from BL in timed 9HPT) and time to 48-week confirmed EDSS≥7 (wheelchair requirement) are presented up to Week 360.

Results

Overall, 72% of patients entered the OLE. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 48-week CDP-EDSS in the PBO-OCR and OCR-OCR groups was 44.4% vs 30.5% (Δ=13.9%; p<0.001), respectively; at Week 360 the corresponding proportions were 65.7% vs 54.2% (Δ=11.6%; p=0.006). At Week 168, the proportion of patients with 48-week CDP-9HPT in the PBO-OCR and OCR-OCR groups was 27.9% vs 15.8% (Δ=12.1%; p<0.001); at Week 360 the corresponding proportions were 41.6% vs 31.1% (Δ=10.6%; p=0.014), respectively. At Week 168 the proportion of patients with 48-week confirmed EDSS≥7 in the PBO-OCR and OCR-OCR groups was 9.1% vs 4.8% (Δ=4.3%; p=0.054), respectively; at Week 360 the proportions were 21.7% vs 12.3% (Δ=9.4%; p=0.009). During the DBP+ECP+OLE, compared with the PBO-OCR group, continuous OCR treatment reduced the risk of CDP-EDSS by 31% (HR [95% CI]: 0.69 [0.56–0.86]; p<0.001), CDP-9HPT by 34% (HR [95% CI]: 0.66 [0.50–0.87]; p=0.003) and 48-week confirmed EDSS≥7 by 44% (HR [95% CI]: 0.56 [0.37–0.85]; p=0.006). Timed 25-Foot Walk, composite CDP and 24-week CDP will also be presented. The OLE safety profile was consistent with the DBP.

Conclusions

After 7 years, 48-week CDP outcomes favoured those on earlier and continuous OCR treatment. Patients initiating OCR 3–5 years earlier had a significantly reduced risk of requiring a wheelchair vs those switching from PBO.