Author Of 1 Presentation
SS02.05 - COVID-19 in persons with multiple sclerosis treated with ocrelizumab: pharmacovigilance update
Limited evidence-based data exist on potential risks of COVID-19 infection in persons with multiple sclerosis (pwMS) receiving immunotherapy. More than 160,000 pwMS have been treated with ocrelizumab (OCR), in clinical trial and real-world settings; data continue to show a consistent and favorable benefit/risk profile.
To present a summary of postmarketing pharmacovigilance data (as of May 31, 2020) from pwMS treated with OCR, who have either confirmed or suspected COVID-19.
Pharmacovigilance-reported adverse event (AE) COVID-19 cases, identified in a search of the Roche Global Safety Database using MedDRA preferred terms and string searches, were defined as valid when at least an identifiable reporter, a single identifiable patient, a medicinal product and a suspected AE were provided. Cases were designated as serious if described by the reporter as serious according to their judgment or if adjudicated as serious by the company when regulatory definitions were met. Patient characteristics and details of OCR treatment were usually provided. All cases were conservatively considered as having confirmed COVID-19. Outcome was classified as recovered, recovering, not recovered, fatal, or not reported.
Of 201 cases, 61% (n=122/201) were reported as non-serious, and 39% (n=79/201) were reported as serious, mostly due to hospitalization (n=51/79). Where known, reasons for hospitalization included, among others, treatment of pneumonia and treatment in ICU. Serious cases were reported as recovered/recovering in 32% (n=25/79) of patients, whilst the outcome was not reported in 33% (n=26/79) of serious cases. A fatal outcome was reported in 5.5% (n=11/201) of patients; risk factors included hypertension, diabetes mellitus, respiratory disease, and malignancy. Updated assessment of the pharmacovigilance cases will be presented.
Taking into account the known limitations of postmarketing safety data, this analysis appears to be in line with published larger case series of non-MS and MS COVID-19 patients. Risk factors in fatal cases were similar to known risk factors reported in the general population.
Author Of 1 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)
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.
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.
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).
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.
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.