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

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.

Background

Ocrelizumab (OCR) is an intravenously administered anti-CD20 antibody approved for relapsing and primary progressive multiple sclerosis (MS). Shortening the infusion duration to 2hrs reduces the total site stay (including mandatory pre-medication/infusion/observation) from 5.5–6hrs, to 4hrs, which may reduce patient and site staff burden.

Objectives

ENSEMBLE PLUS aims to investigate the safety and tolerability of OCR when administered over a shorter infusion time.

Methods

ENSEMBLE PLUS is a randomized, double-blind substudy to the ENSEMBLE study (NCT03085810). In ENSEMBLE, treatment-naïve patients with active, early-stage relapsing-remitting MS (18–55 years; disease duration ≤3 years; EDSS score 0–3.5) receive OCR 600mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR (600mg) administered over the approved infusion time (3.5hrs; conventional duration), was compared with a 2hr infusion (shorter duration); the infusion duration of the initial 2×300mg dose was unaffected. The frequency and severity of infusion-related reactions (IRRs) were assessed during and 24hrs post-infusion. The ENSEMBLE PLUS primary endpoint was the proportion of patients with IRRs at the first Randomized Dose.

Results

In total, 373 and 372 patients were randomized to the conventional and shorter infusion groups, respectively. At the first Randomized Dose, 99 patients (26.5%) in the conventional and 107 (28.8%) in the shorter infusion group had IRRs (difference in proportions, stratified estimates [95% CI]: 2.4% [-3.8, 8.7]); most common symptoms during the infusion were throat irritation, dysphagia and ear pruritus, whilst 24hrs post-infusion were fatigue, headache and nausea. IRRs led to infusion slowing/temporary interruption in 22 patients (5.9%) in the conventional and 39 (10.5%) in the shorter infusion group. The majority of IRRs were mild or moderate. Across all Randomized Doses, four severe (Grade 3) IRRs occurred in total, one in the conventional and three in the shorter infusion group. Overall, >99% of IRRs resolved without sequelae in both groups. No IRRs were serious, life-threatening or fatal; no IRR-related discontinuations occurred. Adverse events (AEs) and serious AEs were consistent with the known OCR safety profile.

Conclusions

Frequency and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shorter ocrelizumab infusions reduce the infusion site stay, thus may reduce patient and staff burden.