Recombinant Human Hyaluronidase (rHuPH20)

Impact of rHuPH20 on the SC Injection of Larger Fluid Volumes

Pharmacokinetic Bridging Study

When Can a Pharmacokinetic (PK) Bridging Study Be Used?

A PK bridging*¹ approach can be considered when the same active ingredient of a drug product is used across two different routes of administration (SC/IV) and the clinical profile is already established with one of these routes of administration.²

*Bridging study FDA definition: A study performed to provide nonclinical or clinical data that allows extrapolation of the existing data from the drug product produced by the current process to the drug product from the changed process.²

The OCARINA II Study

A Phase III, Non-Inferiority, Randomized, Open-Label, Parallel Group, Multicenter Study to Investigate the Pharmacokinetics, Pharmacodynamics, Safety and Radiological and Clinical Effects of Subcutaneous Ocrelizumab versus Intravenous Ocrelizumab in Patients with Multiple Sclerosis

Methods: Patient Population and Study Objectives^1-3

^aExploratory radiologic objectives included total T1 Gd+ lesions at Weeks 48 and 96, and N/E T2 lesions at Weeks 8, 48 and 96.
^bExploratory clinical objectives included annualized PDR rate by Weeks 24, 48 and 96 in patients with RMS, and change in EDSS from baseline at Weeks 48, 72 and 96.
^cExploratory PD objectives included the proportion of patients achieving CD19+ B-cell level ≤5 cells/μL at Weeks 48 and/or 96.
^dAssessed via the Treatment Administration Satisfaction Questionnaires (TASQ) which is a self-reported patient instrument, designed to assess satisfaction with and impact of 2 different routes of treatment administration (IV and SC).²

Study Design^3,4

^aThe 920 mg OCR SC dose was established as the recommended dose in the OCARINA I study (NCT03972306).
^bThe first dose of OCR IV 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 two arms.
^dCut-off date is when the last patient completes 12 weeks.

Week 12 Pharmacokinetic Analysis^5-8

OCR PK SC vs IV^a

The differences in pharmacokinetic exposures following administration of OCR SC 920 mg or OCR IV 600 mg were not clinically significant during the first 12 weeks.⁵

CCOD: March 10, 2023.
^aTwo patients from the OCR SC/SC arm were excluded from the PK-evaluable analysis set due to an incomplete SC dose and an impossible concentration-time profile. Two patients from the OCR IV/SC arm were excluded from the PK-evaluable analysis set due to a delay in the second IV infusion and a missing second IV infusion.
^bEstimated mean exposure for AUC or C_max; Ocrevus IV 600 mg was administered as two 300 mg IV infusions given 14 days apart.
^cGMR and two-sided 90% CI of SC vs IV between baseline and Week 12.
Non-inferiority would be established if the lower end of the two-sided 90% CI is >0.8; the non-inferiority limit of 0.8 corresponds to a maximal 20% loss in AUC for the SC administration compared with IV, as recommended in the regulatory guidance documents for demonstration of bioequivalence for PK bridging.^6,7
dThe geometric mean ratio (GMR) is calculated from the geometric mean values for each treatment arm. The geometric mean is used because PK parameters have a log-normal distribution rather than a normal distribution.

B-Cell Depletion⁹

CCOD: December 4, 2023. Error bars represent interquartile range. LLOQ = ≤5 cells/μL.

Excerpts From OCREVUS ZUNOVO USPI⁵

The Results of the PK Bridging Study, OCARINA II, was the Basis of the FDA Approval of Ocrevus Zunovo

^aStudy 1 and 2 refer to the (OCR IV) OPERA I and II Phase 3 clinical trials in patients with RMS.
^bStudy 3 refers to the (OCR IV) ORATORIO Phase 3 clinical trial in patients with PPMS.
^cStudy 4 refers to the OCARINA II Phase 3, PK noninferiority study comparing OCR SC 920 mg vs OCR IV 600 mg.

OCARINA II Efficacy Data

Exploratory Endpoints at Week 48¹

CCOD: December 4, 2023.
^aThe lesion rate is the total number of lesions divided by the number of patients with a readable MRI assessment at the visit.
^bNew or enlarging T2 lesion count measurement is performed with respect to the previous scheduled available visit.
^cAt baseline for T1 Gd+ lesions, 78/103 (75.7%) patients had no lesions and 11/103 (10.7%) had ≥4 lesions.
^dAt baseline for T1 Gd+ lesions, 82/104 (78.8%) patients had no lesions and 5/104 (4.8%) had ≥4 lesions.
^eAt Week 48, two patients (1.9%) in each arm had one protocol-defined relapse, and one patient (0.9%) in the OCR SC/SC arm had two protocol-defined relapses; unadjusted relapse rate per year was 0.04 and 0.02 in the SC/SC and IV/SC arms, respectively. The unadjusted annualized relapse rate is the total number of relapses for all patients in the considered group divided by the total follow-up time.
^fPrespecified Secondary Endpoints: T1-Gd+ lesions at Weeks 8 and 24, N/E T2 lesions at Weeks 12 and 24.

Ocrelizumab SC Safety Data

OCARINA II: Safety Data^1,2

Patients With ≥1 Event, n (%)

^aPatients who received their first dose of OCR SC were included regardless of which arm they were randomized to.
^bPatients with ≥1 AE, reported terms of AEs are encoded using MedDRA version 26.0.
^cIRs comprise AEs with the MedDRA Preferred Terms injection-related reaction and injection site reaction, which occurred during or within 24 hours after OCR SC administration and which were judged by the investigator to be related to the OCR SC injection.

Safety Data: Injection Site Reactions Summary

USPI: Excerpts From Section 5.1 Injection Reactions¹

OCREVUS ZUNOVO can cause injection reactions, which can be local or systemic. Common symptoms of local injection reactions reported by patients treated with OCREVUS ZUNOVO in multiple sclerosis (MS) clinical trials included erythema, pain, swelling, and pruritus. Common symptoms of systemic injection reactions reported by patients included headache and nausea. In an open-label, active-controlled trial, injection reactions were more frequently reported with the first injection; 49% of patients experienced an injection reaction with the first injection.

Monitor patients during and after injections [see Dosage and Administration (2.4)]. Inform patients that injection reactions can occur during or within 24 hours of the injection.

Reducing the Risk of Injection Reactions and Managing Injection Reactions

Administer oral premedication (e.g., dexamethasone or an equivalent corticosteroid, and an antihistamine) at least 30 minutes prior to each OCREVUS ZUNOVO injection to reduce the risk of injection reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.

Management recommendations for injection reactions depend on the type and severity of the reaction. For life-threatening injection reactions, immediately and permanently stop OCREVUS ZUNOVO and administer appropriate supportive treatment. For less severe injection reactions, the injection should be interrupted immediately, and the patient should receive symptomatic treatment. The injection should be completed at the healthcare provider’s discretion and only after all symptoms have resolved.

Injection Reactions Over 48 Weeks^a,b,c

^aCCOD: December 4, 2023.
^bIRs comprise adverse events with the MedDRA preferred term injection-related reaction and injection site reaction, which occurred during or within 24 hours after OCR SC administration and which were judged by the investigator to be related to the OCR SC injection.
^cStandard-of-care treatment included mostly analgesics (e.g. paracetamol, oral or topical antihistamines) and were used to treat patients with IRs if needed.
¹The median duration of symptoms was 3 days for systemic injection reactions and 3.5 days for local injection reactions.

Deeper Dive - Injection Site Reactions

Severity of Injection Reactions by Dose^1,2

CCOD: December 4, 2023.
^aFor each injection, in patients with multiple occurrences of IR symptoms, the IR event was counted once, using the symptom with the highest grade of severity; grades were based on National Cancer Institute CTCAE v5.0. Dose 1 corresponds to injection 1 for patients randomized to SC arm, dose 2 corresponds to injection 1 for patients randomized to IV arm and to injection 2 for patients randomized to SC arm; subsequent doses correspond to subsequent injections.

Percentage of Patients With LIR and SIR by Injection^1,2

CCOD: December 4, 2023.
^aFor each injection, in patients with multiple occurrences of IR symptoms, the IR event was counted once, using the symptom with the highest grade of severity; grades were based on National Cancer Institute CTCAE v5.0. Dose 1 corresponds to injection 1 for patients randomized to SC arm, dose 2 corresponds to injection 1 for patients randomized to IV arm and to injection 2 for patients randomized to SC arm; subsequent doses correspond to subsequent injections.
^bStandard of care treatments, such as analgesics (e.g., ibuprofen, paracetamol, oxycodone) and oral or topical antihistamines were administered.

Local IR Symptoms During and Post-Injection¹

Timing of Local IR

CCOD: December 4, 2023.
^a10 min refers to IRs occurring during injection and the duration of the SC injection, which is approximately 10 minutes.
^bExcept bruising, which occurred >1 hour after injection.

Systemic IRs During and Post-Injection¹

Timing of Systemic IR

CCOD: December 4, 2023.
^a10 min refers to IRs occurring during injection and the duration of the SC injection, which is approximately 10 minutes.
^bExcept flushing and fatigue which occurred >1 hour after injection.

Key Takeaways

• Ocrelizumab SC contains the same monoclonal antibody as the IV formulation, Ocrevus, and is combined with recombinant human hyaluronidase PH20 which facilitates subcutaneous dosing of larger volumes.^3,4
• A PK-bridging approach can be considered when the same active ingredient of a drug product is used across two different routes of administration (SC/IV) and the clinical profile is already established with one of these routes of administration.^5,7