Ocrelizumab Looks Safe, Effective in Phase I/II

BOSTON — A single course of the humanized anti-CD20 antibody ocrelizumab was safe and effective for rheumatoid arthritis in a phase I/II trial, Dr. Mark Genovese reported at the annual meeting of the American College of Rheumatology.

Ocrelizumab is similar to the chimeric anti-CD20 antibody rituximab in its ability to deplete B cells, but this second-generation antibody differs in its Fc region by two amino acid sequences, resulting in slightly increased antibody-dependent cytotoxicity and slightly decreased complement-dependent toxicity, Dr. Genovese said.

The trial included 237 rheumatoid arthritis (RA) patients who had an inadequate response to methotrexate and received a single course of ocrelizumab in doses of 10 mg, 50 mg, 200 mg, 500 mg, or 1000 mg or placebo, given by intravenous infusion on days 1 and 15. There was no treatment with corticosteroids before the infusions, and patients remained on a stable 10- to 25-mg/week dose of methotrexate through 72 weeks.

Clinical assessments were done every 4 weeks until week 24, at which time efficacy was evaluated, and every 12 weeks thereafter.

Most patients were women in their 50s, all were rheumatoid factor positive, and their mean disease duration exceeded 10 years. At baseline, patients had moderate to severe RA and had failed on average at least two disease modifying drugs. Slightly fewer than half had tried and failed with a tumor necrosis factor blocker, said Dr. Genovese, a rheumatologist at Stanford (Calif.) University.

Rapid depletion of B cells was seen in patients in all active treatment groups after the infusions, followed by a gradual dose-dependent repletion. Higher doses demonstrated the greatest efficacy at week 24, with ACR50 responses seen among 25%, 20%, and 28% of patients in the 200-, 500-, and 1,000-mg groups. Remission was achieved by 10%, 3%, and 8% of patients in these groups, respectively. Among placebo patients, ACR50 responses and remission were achieved by 7% and 2%, respectively.

The higher doses also showed greater reductions in C-reactive protein and low immunogenicity, he said.

The most frequent adverse events were infusion related, including headaches, nausea, chills, pyrexia, and dizziness. These events were similar across the active treatment groups and occurred more frequently than in the placebo group.

Rates of serious adverse events were similar across all groups, with 15 events being seen in the placebo group and 14, 20, 18, 23, and 15 events in the 10-, 50-, 200-, 500-, and 1,000-mg groups, respectively.

There was one metastatic ovarian cancer in the placebo group, two basal cell carcinomas in a single patient at the 10-mg dose, one laryngeal cancer and one breast cancer in the 50-mg group, one B-cell lymphoma in the 200-mg group, and one adenocarcinoma and two basal cell carcinomas in the 500-mg group. No malignancies were seen in the highest dose group.

Administration of ocrelizumab was tied to a slight decrease in immunoglobulin M levels, but this did not appear to have any clinical significance, since there were no infections associated with this decrease, he said.

Dr. Genovese disclosed financial ties to trial funder Genentech Inc. as well as Biogen Idec Inc., and Hoffmann-LaRoche Ltd.

BOSTON — A single course of the humanized anti-CD20 antibody ocrelizumab was safe and effective for rheumatoid arthritis in a phase I/II trial, Dr. Mark Genovese reported at the annual meeting of the American College of Rheumatology.

Ocrelizumab is similar to the chimeric anti-CD20 antibody rituximab in its ability to deplete B cells, but this second-generation antibody differs in its Fc region by two amino acid sequences, resulting in slightly increased antibody-dependent cytotoxicity and slightly decreased complement-dependent toxicity, Dr. Genovese said.

The trial included 237 rheumatoid arthritis (RA) patients who had an inadequate response to methotrexate and received a single course of ocrelizumab in doses of 10 mg, 50 mg, 200 mg, 500 mg, or 1000 mg or placebo, given by intravenous infusion on days 1 and 15. There was no treatment with corticosteroids before the infusions, and patients remained on a stable 10- to 25-mg/week dose of methotrexate through 72 weeks.

Clinical assessments were done every 4 weeks until week 24, at which time efficacy was evaluated, and every 12 weeks thereafter.

Most patients were women in their 50s, all were rheumatoid factor positive, and their mean disease duration exceeded 10 years. At baseline, patients had moderate to severe RA and had failed on average at least two disease modifying drugs. Slightly fewer than half had tried and failed with a tumor necrosis factor blocker, said Dr. Genovese, a rheumatologist at Stanford (Calif.) University.

Rapid depletion of B cells was seen in patients in all active treatment groups after the infusions, followed by a gradual dose-dependent repletion. Higher doses demonstrated the greatest efficacy at week 24, with ACR50 responses seen among 25%, 20%, and 28% of patients in the 200-, 500-, and 1,000-mg groups. Remission was achieved by 10%, 3%, and 8% of patients in these groups, respectively. Among placebo patients, ACR50 responses and remission were achieved by 7% and 2%, respectively.

The higher doses also showed greater reductions in C-reactive protein and low immunogenicity, he said.

The most frequent adverse events were infusion related, including headaches, nausea, chills, pyrexia, and dizziness. These events were similar across the active treatment groups and occurred more frequently than in the placebo group.

Rates of serious adverse events were similar across all groups, with 15 events being seen in the placebo group and 14, 20, 18, 23, and 15 events in the 10-, 50-, 200-, 500-, and 1,000-mg groups, respectively.

There was one metastatic ovarian cancer in the placebo group, two basal cell carcinomas in a single patient at the 10-mg dose, one laryngeal cancer and one breast cancer in the 50-mg group, one B-cell lymphoma in the 200-mg group, and one adenocarcinoma and two basal cell carcinomas in the 500-mg group. No malignancies were seen in the highest dose group.

Administration of ocrelizumab was tied to a slight decrease in immunoglobulin M levels, but this did not appear to have any clinical significance, since there were no infections associated with this decrease, he said.

Dr. Genovese disclosed financial ties to trial funder Genentech Inc. as well as Biogen Idec Inc., and Hoffmann-LaRoche Ltd.

BOSTON — A single course of the humanized anti-CD20 antibody ocrelizumab was safe and effective for rheumatoid arthritis in a phase I/II trial, Dr. Mark Genovese reported at the annual meeting of the American College of Rheumatology.

Ocrelizumab is similar to the chimeric anti-CD20 antibody rituximab in its ability to deplete B cells, but this second-generation antibody differs in its Fc region by two amino acid sequences, resulting in slightly increased antibody-dependent cytotoxicity and slightly decreased complement-dependent toxicity, Dr. Genovese said.

The trial included 237 rheumatoid arthritis (RA) patients who had an inadequate response to methotrexate and received a single course of ocrelizumab in doses of 10 mg, 50 mg, 200 mg, 500 mg, or 1000 mg or placebo, given by intravenous infusion on days 1 and 15. There was no treatment with corticosteroids before the infusions, and patients remained on a stable 10- to 25-mg/week dose of methotrexate through 72 weeks.

Clinical assessments were done every 4 weeks until week 24, at which time efficacy was evaluated, and every 12 weeks thereafter.

Most patients were women in their 50s, all were rheumatoid factor positive, and their mean disease duration exceeded 10 years. At baseline, patients had moderate to severe RA and had failed on average at least two disease modifying drugs. Slightly fewer than half had tried and failed with a tumor necrosis factor blocker, said Dr. Genovese, a rheumatologist at Stanford (Calif.) University.

Rapid depletion of B cells was seen in patients in all active treatment groups after the infusions, followed by a gradual dose-dependent repletion. Higher doses demonstrated the greatest efficacy at week 24, with ACR50 responses seen among 25%, 20%, and 28% of patients in the 200-, 500-, and 1,000-mg groups. Remission was achieved by 10%, 3%, and 8% of patients in these groups, respectively. Among placebo patients, ACR50 responses and remission were achieved by 7% and 2%, respectively.

The higher doses also showed greater reductions in C-reactive protein and low immunogenicity, he said.

The most frequent adverse events were infusion related, including headaches, nausea, chills, pyrexia, and dizziness. These events were similar across the active treatment groups and occurred more frequently than in the placebo group.

Rates of serious adverse events were similar across all groups, with 15 events being seen in the placebo group and 14, 20, 18, 23, and 15 events in the 10-, 50-, 200-, 500-, and 1,000-mg groups, respectively.

There was one metastatic ovarian cancer in the placebo group, two basal cell carcinomas in a single patient at the 10-mg dose, one laryngeal cancer and one breast cancer in the 50-mg group, one B-cell lymphoma in the 200-mg group, and one adenocarcinoma and two basal cell carcinomas in the 500-mg group. No malignancies were seen in the highest dose group.

Administration of ocrelizumab was tied to a slight decrease in immunoglobulin M levels, but this did not appear to have any clinical significance, since there were no infections associated with this decrease, he said.

Dr. Genovese disclosed financial ties to trial funder Genentech Inc. as well as Biogen Idec Inc., and Hoffmann-LaRoche Ltd.