Ocrelizumab exposure in relapsing-remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension

Abstract

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing-remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.

Keywords: Disease-modifying therapies; Multiple sclerosis; Ocrelizumab; Safety.

Fig. 1

Patient disposition. Treatment assignments refer to cycle 1 dosing only. All patients received ocrelizumab in treatment cycles 2–4. Patients discontinuing the PTP were asked to enter the assessed TFP. AE adverse event, assessed TFP assessed treatment-free period, LTFU lost to follow-up, OLE open-label extension, PTP primary treatment period, wk week. ^cUnder study statistical coding rules, one patient who died on study day 92 from systemic inflammatory response syndrome was classified as having withdrawn from the PTP for an AE from which the patient subsequently died in the assessed TFP

Fig. 2

Median overall CD19 cell and CD19+ CD38lo CD27+ memory B-cell counts during the primary treatment and assessed treatment-free periods, by initial randomization group. From week 24 to week 96 of the PTP, all patients were on ocrelizumab. Almost all post-baseline medians for predose CD19 in the OLE (OCR 600 mg) were < 5 cells/µL and are not shown. Assessed TFP assessed treatment-free period, BL baseline, OCR ocrelizumab, OLE open-label extension, PTP primary treatment period

Fig. 3

Mean (SD) changes from baseline in immunoglobulin (Ig) fractions in the primary treatment and post-treatment follow-up periods, by initial randomization group. Assessed TFP assessed treatment-free period, BL baseline, Ig immunoglobulin, LLN lower limit of normal.

Fig. 4

Cumulative number of new or enlarging T2 lesions by treatment after last ocrelizumab infusion up to and including the OLE baseline. Patients included had a 24-week MRI assessment and received at least three cycles of ocrelizumab during PTP. Participants randomized at baseline to receive ocrelizumab 2000 mg or 600 mg had scans at week 96 (i.e. 24 weeks after the last ocrelizumab treatment) and at week 144; other patients received an MRI at baseline OLE, which was compared with the 24-week MRI. Dots show all assessments performed; lines connect patients with more than one MRI assessment. One patient (randomized to the ocrelizumab 2000 mg group) had 32 new or enlarging T2 lesions and 11 T1 Gd-enhancing lesions 71 weeks after the last ocrelizumab infusion. This patient had three relapses during the assessed TFP (a clinical relapse at 67 weeks, and two protocol-defined relapses at 94 and 126 weeks, respectively, after the last ocrelizumab infusion). One patient (randomized to the ocrelizumab 600 mg group) had one new or enlarging T2 lesion and one T1 Gd-enhancing lesion at 78 weeks since last ocrelizumab infusion. One patient (randomized to the placebo group) had two new or enlarging T2 lesions and one T1 Gd-enhancing lesion at week 171 since last ocrelizumab infusion. Assessed TFP assessed treatment-free period, Gd gadolinium, OLE open-label extension

Fig. 5

Time to onset of 24-week confirmed disability progression (a) the treatment and assessed TFP by randomization to ocrelizumab (600 or 2000 mg) or comparator (IFN β-1a or placebo) until end of assessed TFP. Last ocrelizumab treatment for all patients at week 72; (b) rebaselined to when patients started ocrelizumab (at randomization or at week 24); (c) from start of open-label extension (all patients on ocrelizumab). 24WCDP confirmed disability progression of at least 24 weeks, assessed TFP assessed treatment-free period, IFN interferon, PTP primary treatment period

Fig. 6

Categoric changes in EDSS for all patients by study visit in the PTP, assessed TFP, and OLE periods (rebaselined at start of OLE). PTP and assessed TFP data are relative to study week 0. Participants in the OLE were rebaselined at OLE week 0, with the baseline defined as the last evaluable EDSS assessment before the first OLE infusion. OLE assessments were performed 2 weeks before dosing visits. Changes were classified using CDP criteria of ±  ≥ 1 EDSS point for an EDSS < 5.5, and ±  0.5 points for EDSS ≥ 5.5. Only visits with data for > 50 subjects are shown for the assessed TFP and OLE. Assessed TFP assessed treatment-free period, CDP confirmed disability progression, EDSS Expanded Disability Status Scale, OLE open-label extension, PTP primary treatment period, TFP treatment-free period