F. Hoffmann-La Roche Ltd

Author Of 2 Presentations

Clinical Trials Poster Presentation

P0230 - Rationale and design of two Phase IIIb studies of ocrelizumab at higher than the approved dose in patients with RMS and PPMS (ID 971)

Abstract

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.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0392 - Shorter infusion time of ocrelizumab: results from the ENSEMBLE PLUS study in patients with relapsing-remitting multiple sclerosis (ID 900)

Speakers
Presentation Number
P0392
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

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.

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