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

Limited evidence-based data exist on potential risks of COVID-19 infection in persons with multiple sclerosis (pwMS) receiving immunotherapy. More than 160,000 pwMS have been treated with ocrelizumab (OCR), in clinical trial and real-world settings; data continue to show a consistent and favorable benefit/risk profile.

Objectives

To present a summary of postmarketing pharmacovigilance data (as of May 31, 2020) from pwMS treated with OCR, who have either confirmed or suspected COVID-19.

Methods

Pharmacovigilance-reported adverse event (AE) COVID-19 cases, identified in a search of the Roche Global Safety Database using MedDRA preferred terms and string searches, were defined as valid when at least an identifiable reporter, a single identifiable patient, a medicinal product and a suspected AE were provided. Cases were designated as serious if described by the reporter as serious according to their judgment or if adjudicated as serious by the company when regulatory definitions were met. Patient characteristics and details of OCR treatment were usually provided. All cases were conservatively considered as having confirmed COVID-19. Outcome was classified as recovered, recovering, not recovered, fatal, or not reported.

Results

Of 201 cases, 61% (n=122/201) were reported as non-serious, and 39% (n=79/201) were reported as serious, mostly due to hospitalization (n=51/79). Where known, reasons for hospitalization included, among others, treatment of pneumonia and treatment in ICU. Serious cases were reported as recovered/recovering in 32% (n=25/79) of patients, whilst the outcome was not reported in 33% (n=26/79) of serious cases. A fatal outcome was reported in 5.5% (n=11/201) of patients; risk factors included hypertension, diabetes mellitus, respiratory disease, and malignancy. Updated assessment of the pharmacovigilance cases will be presented.

Conclusions

Taking into account the known limitations of postmarketing safety data, this analysis appears to be in line with published larger case series of non-MS and MS COVID-19 patients. Risk factors in fatal cases were similar to known risk factors reported in the general population.

Background

Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS). Thalamic atrophy occurs early and may be a sensitive marker of overall brain damage. Ocrelizumab (OCR) reduced brain atrophy and NfL in patients with relapsing MS (RMS) and those with primary progressive MS (PPMS).

Objectives

To examine the independent impact of OCR and baseline (BL) NfL on thalamic volume (TV) and clinical progression in patients with PPMS and RMS, including those with RMS without acute BL activity (i.e. no gadolinium–enhancing [Gd+] lesions or relapse in the last 3 months).

Methods

Patients were from OPERA I/II (RMS, n=1,421) and ORATORIO (PPMS, n=596). Thalamic atrophy was calculated as annualized percentage TV change (PTVC) from Wk 24 to the end of controlled treatment (ORATORIO, Wk 120; OPERA I/II, Wk 96). OCR treatment (vs IFNβ-1a [RMS] or placebo [PPMS]) and log-transformed BL NfL were examined for associations with PTVC (linear regression) and 24-week confirmed disability progression (Cox regression) adjusting for BL demographic and disease characteristics.

Results

In patients with PPMS and RMS, OCR treatment (PTVC: +0.47% and +0.33%, respectively) and lower BL NfL (+0.20% and +0.33% per 2-fold lower NfL) independently associated with a smaller TV reduction (all p<0.005). Adjusting for BL NfL level, Gd+ lesion count, T2 lesion volume and BL disability, OCR still reduced disability progression on Expanded Disability Status Scale (EDSS) (PPMS, hazard ratio [HR]=0.73; RMS, HR=0.65; both p<0.05]), 9-Hole Peg Test (9HPT) (PPMS, HR=0.53, p=0.002; RMS, HR=0.52, p=0.059), Timed 25-Foot Walk (T25FW) (PPMS, HR=0.79, p=0.063), Symbol Digit Modalities Test (RMS, HR=0.54, p=0.002) and time to EDSS 6 (RMS, HR=0.42, p=0.009). In patients with PPMS, higher BL NfL was associated with worsening on 9HPT (HR=1.34 per 2-fold higher NfL), T25FW (HR=1.19) and time to EDSS 7 (HR=1.78) (all p<0.05). In patients with RMS without acute BL activity, higher BL NfL was associated with EDSS worsening (HR=1.49), progression independent of relapse activity (PIRA) (HR=1.61), 9HPT (HR=2.1) and time to EDSS 6 (HR=2.24) (all p<0.05).

Conclusions

Ocrelizumab treatment remained associated with reduced thalamic atrophy and clinical progression after adjusting for baseline NfL and other factors. Higher BL NfL was associated with increased rates of thalamic atrophy and clinical progression in patients with PPMS and those with RMS without acute disease activity.

Background

Blood neurofilament light chain (NfL) is a biomarker of neuroaxonal injury associated with acute disease activity and may be prognostic for disability progression in patients with multiple sclerosis (MS). Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody indicated for relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To assess the impact of OCR on blood NfL distribution in patients with RMS from the OPERA I and II trials and those with PPMS from ORATORIO.

Methods

Pretreatment and posttreatment NfL levels (measured using the SiMOA assay) with OCR vs interferon β-1a (OPERA I and II; n=1,421) or placebo (ORATORIO; n=596) were compared using geometric mean (GM) and GM ratios (GMR). Patients were stratified by presence/absence of acute disease activity at baseline (BL) (T1 gadolinium [Gd]-enhancing lesions and/or relapse in prior 3 months for RMS; T1 Gd-enhancing lesions for PPMS). Age-adjusted NfL distributions (using a linear model for log-NfL and age derived from a healthy donor [HD] cohort) at BL and after OCR were compared with HD using the Kolmogorov-Smirnov test.

Results

Significant reductions in NfL were observed 3 months after OCR initiation (RMS, GMR=0.80; PPMS, GMR=0.89) and sustained through the end of controlled treatment (RMS [96 weeks], GMR=0.56; PPMS [120 weeks], GMR=0.81; all p<0.0001). Age-adjusted BL serum NfL was elevated in patients with RMS disease activity (GM [95% CI]=12.7 [11.9–13.6] pg/mL) vs those without (5.5 [5.3–5.7] pg/mL) and HD (4.1 [3.9–4.4] pg/mL; all p<0.0001). In OCR-treated patients with RMS, GM [95% CI] serum NfL levels after 96 weeks (with activity at BL, 4.4 [4.2–4.6] pg/mL; without activity at BL, 4.1 [4.0–4.3] pg/mL) were comparable to HD (4.1 [3.9–4.4] pg/mL; all p>0.1). Age-adjusted BL plasma NfL was also elevated in PPMS patients with disease activity (GM [95% CI]=8.7 [7.5–10.1] pg/mL) vs those without (4.9 [4.6–5.2] pg/mL) and HD (3.1 [2.9–3.3] pg/mL; all p<0.0001). In OCR-treated patients with PPMS, GM [95% CI] plasma NfL levels after 120 weeks (with activity at BL, 4.6 [4.1–5.1] pg/mL; without activity at BL, 4.2 [4.0–4.4] pg/mL) were reduced from BL (all p<0.005) but remained elevated vs HD (all p<0.001).

Conclusions

NfL is highly elevated in patients with acute MS disease activity, and more subtle elevations are observed in RMS and PPMS patients without detectable disease activity. Ocrelizumab significantly reduces NfL in RMS and PPMS patients with and without detectable disease activity.

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

Ocrelizumab (OCR) is approved for the treatment of relapsing (RMS) and primary progressive multiple sclerosis (PPMS) at a dose of 600 mg iv twice yearly and showed significant benefit on disability progression (DP). Exposure-response (ER) analyses of the pivotal OCR Phase III studies in patients with RMS or PPMS showed that those with higher exposures (based on individual mean serum concentration [Cmean] exposure quartiles) had a greater benefit on DP vs patients with lower exposure, without an increase in adverse events. While doses of OCR of 1000–2000 mg were studied in a Phase II study, doses >600 mg have not been investigated in Phase III studies in RMS or PPMS patients.

Objectives

To present the OCR higher dose selection rationale and design of two double-blind, parallel-group, randomized Phase IIIb studies (one in RMS and one in PPMS) aiming to explore if a higher dose of OCR will provide even higher benefits vs 600 mg on DP without adversely affecting the established favorable benefit-risk profile.

Methods

The higher dose of OCR in both studies is based on achieving a Cmean of at least that observed in the highest exposure quartile of the Phase III ER analyses while limiting Cmean below that observed with the highest OCR dose of 2000 mg in the Phase II study that had a similar safety profile, except for a slightly higher incidence of infusion-related reactions (pre-medication: methylprednisolone only; no mandatory antihistamine).

Results

Modeling predicts that doses of 1200 mg (patients <75kg) or 1800 mg (patients ≥75kg) twice yearly would fulfill these criteria. Based on data from the pivotal trials, the expected risk reduction vs 600 mg in 12-week composite confirmed DP (cCDP; consisting of time to progression measured by the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test) would be ≥35% in RMS and ≥27% in PPMS. Patients with RMS (EDSS score 0–5.5; N=786) or PPMS (EDSS score ≥3.0–6.5; N=699) will be randomized (2:1) to either the higher dose (above) or OCR 600 mg administered every 24 weeks (first dose divided into 2 infusions separated by 14 days) for ≥120 weeks (minimum 5 doses).

The primary outcome for both trials is risk reduction on cCDP. Immunoglobulin and oligoclonal bands in the CSF will be assessed in a sub-study of up to 288 patients.

Conclusions

These studies will test if higher-dose ocrelizumab provides an even higher benefit on cCDP vs the approved 600 mg dose without adversely affecting the established favorable benefit-risk profile.

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.