Subcutaneous ocrelizumab in multiple sclerosis: Results of the Phase 1b OCARINA I study

Abstract

Objective: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825).

Methods: Patients with relapsing or primary progressive multiple sclerosis (aged 18-65 years; Expanded Disability Status Scale score 0.0-6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 mg. Following dose escalation, new patients in Group A were randomized (1:1) to receive a single 600 mg intravenous ocrelizumab dose or the candidate subcutaneous dose, which was predicted to result in similar exposure as the 600 mg intravenous dose while being safe and well tolerated. The area under the concentration-time curve for both formulations was used to select the subcutaneous ocrelizumab dose. Patients in all cohorts could enter a dose-continuation phase.

Results: Eighty-eight and 47 patients were enrolled into Group A and B, respectively; most patients were female (72.7%/63.0%), and mean age at baseline was 45.7 and 39.7 years, respectively. Subcutaneous ocrelizumab was well tolerated across all doses tested. The 920 mg subcutaneous ocrelizumab dose was selected for the OCARINA II study based on pharmacokinetic and safety data.

Interpretation: Subcutaneous ocrelizumab may provide patients with multiple sclerosis with an additional treatment option.

Figure 1

OCARINA I study design. AE, adverse event; AUC, area under the curve; IV, intravenous; OCR, ocrelizumab; PK, pharmacokinetics; SC, subcutaneous; SMC, safety monitoring committee. ^aPatients in Group A were treated with OCR IV for at least 1 year prior to screening (two doses of OCR 600 mg separated by 24 weeks). ^bIn addition to the close safety observation at site, patients continued to be observed for safety throughout the study and could report AEs at any time, as well as have periodic laboratory analyses performed. On the basis of emerging safety and tolerability data, a mandatory overnight stay for patients receiving their first injection of OCR SC was made optional, via a protocol amendment, for patients in cohorts still open for enrollment (Cohorts A5 and B4, as well as patients in Cohort AA after receiving their initial OCR SC injection in the dose‐continuation phase). The overnight stay was shortened to a minimum of 6 h post‐injection for the first injection. ^cPatients were initially randomized to Cohort A5 to receive 1200 mg SC. An analysis of preliminary PK data from patients with at least 12 weeks of observation time indicated that a 920 mg OCR SC dose was more likely to meet the criteria for equivalent exposure to 600 mg OCR IV, based on the estimated bioavailability. To confirm this assumption, the SMC recommended changing the dose from 1200 mg SC to 920 mg SC; consequently, all newly randomized patients in Cohort A5 were treated with 920 mg OCR SC. Thus, some patients received 1200 and 920 mg, while others received 920 mg only. ^dAfter a protocol amendment, the time period was changed to “up to the end of 2024.”

Figure 2

Patient disposition. AE, adverse event; OCR, ocrelizumab; PwMS, patients with multiple sclerosis; SC, subcutaneous. Data cutoff: November 15, 2023. ^aOf patients reaching the dose‐continuation phase, six patients started on a dose of 920 mg OCR, with the remaining starting on 1200 mg OCR. All patients received 920 mg OCR SC for all subsequent doses. ^bOne patient was enrolled in error in Cohort B4 and was withdrawn from the study prior to receiving study treatment. ^cOne patient in Group A and one in Group B entered the dose‐continuation phase but did not receive study drug during this phase.

Figure 3

Local IRs by visit in patients who received ≥1 dose of 1200 or 920 mg OCR SC. Data cutoff: November 15, 2023. Percentages for overall total patients with ≥1 IR are based on n numbers (n = 125 for 1200 mg; n = 118 for 920 mg). For total patients with ≥1 IR, percentages are based on the numbers of patients that received the injection. IR, injection reaction; OCR, ocrelizumab; SC, subcutaneous.

Figure 4

Percentage of patients with ≤5 cells/μL of CD19⁺ B‐cell absolute counts. Data cutoff: November 15, 2023. The analysis shows data for all patients who received at least one dose of 1200 or 920 mg OCR SC. The x‐axis shows OCR SC injection visits, which occur every 24 weeks; thus, Visit 1 refers to the first planned injection of 1200 or 920 mg OCR SC. Visits 2–8 are all subsequent injections of 1200 or 920 mg OCR SC. The n numbers refer to the numbers of patients with assessment results at each visit. B cells were measured prior to each injection. Patients in Group A were previously treated with OCR IV for at least 1 year; therefore, a high proportion of these patients had already achieved B‐cell levels ≤5 cells/μL at Visit 1. Patients in Group B were treatment naïve; note that patients in Cohorts B1–B3 received 600 mg OCR IV as two 300 mg infusions at Weeks 12 and 14, prior to Visit 1 in the graph. Five patients from Cohorts B1–B3 accounted for the 11.1% of patients who had reached B‐cell depletion at Visit 1. The percentages of patients were calculated using the numbers of patients with B‐cell levels ≤5 cells/μL divided by the total number of patients in Group A and Group B. Only the last assessment within an injection visit for a patient and test contributes to the summary. IV, intravenous; OCR, ocrelizumab; SC, subcutaneous.