Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase 3 OCARINA II Study

Abstract

Background and objectives: IV-administered ocrelizumab (OCR) is approved for the treatment of relapsing and primary progressive multiple sclerosis (RMS/PPMS). OCARINA II (NCT05232825) was designed to demonstrate noninferiority in drug exposure of OCR subcutaneous (SC) vs IV administration.

Methods: This phase 3, randomized, open-label study enrolled OCR-naive patients aged 18-65 years with RMS/PPMS and an Expanded Disability Status Scale score of 0-6.5. Patients received OCR IV 600 mg or OCR SC 920 mg (controlled period), followed by OCR SC 920 mg every 24 weeks, up to week 96 (OCR IV/SC and OCR SC/SC). The primary end point was OCR area under the serum concentration-time curve from day 1 to week 12 (AUC_W1‒12); other end points included clinical, biomarker, and pharmacodynamic outcomes and safety data.

Results: Baseline demographics were balanced across OCR IV/SC and OCR SC/SC arms (N = 118/118, 40.0 ± 11.9/39.9 ± 11.4 years, 59.3%/65.3% female, 89.0%/89.0% with RMS). The study demonstrated noninferiority of OCR SC 920 mg to OCR IV 600 mg for the primary end point AUC_W1-12 and also over the dosing interval for AUC_W1‒24 (geometric mean ratios [90% CI] 1.29 [1.23-1.35] and 1.27 [1.21-1.34], respectively). At week 48, 111 of 118 (OCR IV/SC) and 114 of 118 (OCR SC/SC) had received OCR SC. A near-complete suppression of MRI activity was reported in OCR IV/SC and OCR SC/SC: 0 of 113 and 0 of 113 patients had T1 lesions while 1 of 114 and 1 of 113 had 2 and 1 new/enlarging T2 lesions, respectively. Two patients (1.9%) in each arm had 1 relapse, and 1 patient (0.9%; OCR SC/SC) had 2 relapses. In both arms, rapid and sustained B-cell depletion was observed and serum neurofilament light chain reduction was comparable. Patients receiving at least 1 dose of OCR SC 920 mg in the OCR IV/SC and OCR SC/SC arms reported adverse events (AEs): 75.4% and 86.4%, and serious AEs: 5.9% and 2.5%. The most frequently reported AEs were injection reactions (IRs, 51.5%); local and systemic IRs were experienced by 117 of 233 patients (50.2%) and 27 of 233 patients (11.6%), respectively. All IRs were mild/moderate; intensity and duration decreased with subsequent injections.

Discussion: The OCR SC formulation demonstrated noninferiority to OCR IV formulation regarding drug exposure, providing comparable efficacy and safety and an additional treatment option for patients with multiple sclerosis.

Classification of evidence: This study provides Class II evidence that a single SC injection of 920 mg of OCR achieves a noninferior 12-week area under serum concentration-time curve to that of 2 IV infusions of 300-mg OCR administered 2 weeks apart.

Trial registration information: ClinicalTrials.gov Identifier NCT05232825; submitted: January 27, 2022; first patient enrolled: May 3, 2022; available at: clinicaltrials.gov/study/NCT05232825?term=NCT05232825&rank=1.

Figure 1. OCARINA II Study Design

ADA = antidrug antibody; EDSS = Expanded Disability Status Scale; OCR = ocrelizumab; PD = pharmacodynamic; PK = pharmacokinetic; PPMS = primary progressive multiple sclerosis; RMS = relapsing multiple sclerosis; SC = subcutaneous. ^aThe 920 mg OCR SC dose was selected based on the OCARINA I study data (NCT03972306). ^bThe first OCR IV dose was administered as two 300-mg IV infusions given 2 weeks apart. ^cThe screening phase in patients with RMS and PPMS took place before baseline MRI readings, and patients were randomized 1:1 between the 2 arms.

Figure 2. Patient Disposition

OCR = ocrelizumab; SC = subcutaneous; SFU = safety follow-up. ^aOne patient who entered the SFU from the OCR IV/SC arm discontinued the study because of physician decision.

Figure 3. Observed Individual OCR Serum Concentration vs Time Profiles by Treatment (A: Linear Scale; B: Log Scale)

OCR = ocrelizumab; SC = subcutaneous.

Figure 4. (A) Percentage of Patients With ≤5 Cells/µL of CD19+ B-Cell Absolute Counts, (B) MRI Activity Over Time: Gd+ Lesion Rate, and (C) N/E T2w-L Rate

Gd+ = gadolinium-enhancing; N/E = new/enlarging; OCR = ocrelizumab; SC = subcutaneous; T2w-L = T2-weighted lesion. ^aThe n/N values refer to the number of patients with CD19⁺ B-cell count ≤5 cells/μL divided by the number of patients with a valid CD19⁺ B-cell count result at the visit. ^bThe lesion rate is the total number of lesions divided by the number of patients with a readable MRI assessment at the visit. ^cN/E T2 lesion count measurement is performed regarding the previous scheduled available visit. ^dAt baseline for T1 Gd+ lesions, 78 of 103 patients (75.7%) had no lesions and 11 of 103 (10.7%) had ≥4 lesions. ^eAt baseline for T1 Gd+ lesions, 82 of 104 patients (78.8%) had no lesions and 5 of 104 (4.8%) had ≥4 lesions.

Figure 5. Percentage of Patients With Injection Reactions by Injection and Severity: (A) Injection Reactions by Treatment Arm; (B) Local Injection Reactions for the All-Exposure Population; (C) Systemic Injection Reactions for the All-Exposure Population

IR = injection reaction; NCI CTCAE = National Cancer Institute's Common Terminology Criteria for Adverse Events; OCR = ocrelizumab; SC = subcutaneous. The percentage of patients with at least 1 IR for the selected injection is calculated as the number of patients with IRs at this injection (n) divided by the number of patients who received the injection per treatment group (N). The reported most extreme NCI CTCAE grade of IRs is used to display the severity of IRs. If patients experience multiple IRs for 1 injection, the maximum most extreme NCI CTCAE grade is displayed per patient and injection. Injection 1 corresponds to dose 2 for patients randomized to the OCR IV/SC arm and dose 1 for patients randomized to the OCR SC/SC arm. Subsequent injections correspond to subsequent doses.