Contributions
Abstract: P668
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Variation in T-cell subpopulation levels is multifactorial and was seen in Phase III studies of ocrelizumab (OCR), a humanised, CD20+ B cell-selective monoclonal antibody approved by the FDA for the treatment of relapsing remitting and primary progressive multiple sclerosis.
Objective: To evaluate changes in T-cell levels and correlations with serious infections in OCR Phase III studies.
Methods: OPERA I (NCT01247324) and OPERA II (NCT01412333) data were pooled; patients received OCR 600 mg intravenous infusions every 24 weeks (N=825) or subcutaneous interferon β1a (IFN β1a) 44 µg three times weekly for 96 weeks (N=826). Patients in ORATORIO (NCT01194570) received OCR 600 mg (N=486) or placebo (PBO; N=239) for ≥120 weeks until the planned number of progression events were seen. Percent change in T-cell levels (calculated using adjusted geometric mean ratios), the proportion of patients with a confirmed (verified at 2 study visits) T-cell drop < lower limit of normal (LLN), and correlation between confirmed drops in T-cells and serious infection rates per 100 patient years were assessed.
Results: Compared with baseline, at the end of the controlled treatment periods of the OPERA and ORATORIO studies, the slight decrease seen in T-cell levels with OCR was less than that seen with IFN β1a (CD3+ 4.3 vs 17.3%; CD4+ 0.8 vs 11.8%; CD8+ 8.6 vs 23.9%) while similar changes were seen with OCR and PBO at Week 120 (CD3+ 3.5% decrease vs 3.3% increase; CD4+ 1.0% vs 5.6% increase; CD8+ 12.5% vs 0.7% decrease). The proportions of patients with T-cells < LLN with OCR were lower than with IFN β1a (CD3+ 6.2 vs 15.0%; CD4+ 3.0 vs 7.6%; CD8+ 14.8 vs 24.9%) and higher than with PBO (CD3+ 11.5% vs 9.6%; CD4+ 4.9 vs 4.2%; CD8+ 28.2 vs 17.6%). Serious infection rates were low; during periods of confirmed CD8+ < LLN, rates (95% CI) with OCR and IFN β1a were 3.44 (1.12-8.02) vs 1.29 (0.27-3.76) and with OCR and PBO were 5.08 (2.84-8.37) vs 3.66 (0.75-10.69). Event rates during periods of CD4+ < LLN were too low to make meaningful conclusion.
Conclusions: OCR had a lesser impact on T-cell populations (overall and < LLN) than IFN β1a in the OPERA studies but a slightly greater effect than PBO in ORATORIO. Periods of T-cell populations < LLN are not considered an isolated safety risk with OCR. Nevertheless, it cannot be ruled out that an increase in the risk of serious infection may exist when B cells are depleted and T cells are decreased concomitantly. Further follow-up is required.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Health Interactions, USA, and Articulate Science, UK.
P. Vermersch has received financial grant/research support from Biogen, Genzyme, Bayer, Merck and Serono; and has received consulting fees from Biogen, Genzyme, Bayer, Novartis, Merck Serono, GSK and Almirall.
C. Harp is an employee and shareholder of Genentech, Inc.
A. Herman is an employee of Genentech, Inc. and shareholder in F. Hoffmann-La Roche.
H. Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd.
C. Li is an employee of F. Hoffmann-La Roche Ltd.
B. Shi is an employee of F. Hoffmann-La Roche Ltd.
S. L. Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Annexon, Symbiotix and Bionure. He has also received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.
Abstract: P668
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Variation in T-cell subpopulation levels is multifactorial and was seen in Phase III studies of ocrelizumab (OCR), a humanised, CD20+ B cell-selective monoclonal antibody approved by the FDA for the treatment of relapsing remitting and primary progressive multiple sclerosis.
Objective: To evaluate changes in T-cell levels and correlations with serious infections in OCR Phase III studies.
Methods: OPERA I (NCT01247324) and OPERA II (NCT01412333) data were pooled; patients received OCR 600 mg intravenous infusions every 24 weeks (N=825) or subcutaneous interferon β1a (IFN β1a) 44 µg three times weekly for 96 weeks (N=826). Patients in ORATORIO (NCT01194570) received OCR 600 mg (N=486) or placebo (PBO; N=239) for ≥120 weeks until the planned number of progression events were seen. Percent change in T-cell levels (calculated using adjusted geometric mean ratios), the proportion of patients with a confirmed (verified at 2 study visits) T-cell drop < lower limit of normal (LLN), and correlation between confirmed drops in T-cells and serious infection rates per 100 patient years were assessed.
Results: Compared with baseline, at the end of the controlled treatment periods of the OPERA and ORATORIO studies, the slight decrease seen in T-cell levels with OCR was less than that seen with IFN β1a (CD3+ 4.3 vs 17.3%; CD4+ 0.8 vs 11.8%; CD8+ 8.6 vs 23.9%) while similar changes were seen with OCR and PBO at Week 120 (CD3+ 3.5% decrease vs 3.3% increase; CD4+ 1.0% vs 5.6% increase; CD8+ 12.5% vs 0.7% decrease). The proportions of patients with T-cells < LLN with OCR were lower than with IFN β1a (CD3+ 6.2 vs 15.0%; CD4+ 3.0 vs 7.6%; CD8+ 14.8 vs 24.9%) and higher than with PBO (CD3+ 11.5% vs 9.6%; CD4+ 4.9 vs 4.2%; CD8+ 28.2 vs 17.6%). Serious infection rates were low; during periods of confirmed CD8+ < LLN, rates (95% CI) with OCR and IFN β1a were 3.44 (1.12-8.02) vs 1.29 (0.27-3.76) and with OCR and PBO were 5.08 (2.84-8.37) vs 3.66 (0.75-10.69). Event rates during periods of CD4+ < LLN were too low to make meaningful conclusion.
Conclusions: OCR had a lesser impact on T-cell populations (overall and < LLN) than IFN β1a in the OPERA studies but a slightly greater effect than PBO in ORATORIO. Periods of T-cell populations < LLN are not considered an isolated safety risk with OCR. Nevertheless, it cannot be ruled out that an increase in the risk of serious infection may exist when B cells are depleted and T cells are decreased concomitantly. Further follow-up is required.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Health Interactions, USA, and Articulate Science, UK.
P. Vermersch has received financial grant/research support from Biogen, Genzyme, Bayer, Merck and Serono; and has received consulting fees from Biogen, Genzyme, Bayer, Novartis, Merck Serono, GSK and Almirall.
C. Harp is an employee and shareholder of Genentech, Inc.
A. Herman is an employee of Genentech, Inc. and shareholder in F. Hoffmann-La Roche.
H. Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd.
C. Li is an employee of F. Hoffmann-La Roche Ltd.
B. Shi is an employee of F. Hoffmann-La Roche Ltd.
S. L. Hauser serves on the board of trustees for Neurona and on scientific advisory boards for Annexon, Symbiotix and Bionure. He has also received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations.