Novel Biologic Targets Lupus
GLASGOW -- Just a year after the appearance of belimumab, the first new treatment for lupus in 50 years, the anti-CD22 monoclonal antibody epratuzumab is emerging as another potential therapy, a researcher reported here.
Among patients with moderate-to-severe systemic lupus erythematosus, those who received a cumulative dose of 2,400 mg of intravenous epratuzumab had response rates at 12 weeks of 43.2%, compared with a rate of 21.1% among those given placebo (P=0.02), according to Caroline Gordon, MD, of the University of Birmingham in England, and colleagues.
Epratuzumab differs from rituximab in that it depletes only about 30% of B cells, she explained at the annual meeting of the British Society for Rheumatology.
This partial depletion causes phosphorylation and internalization of CD22, a protein on the surface of B cells, resulting in various downstream signaling events such as alterations of adhesion molecule expression and modulation of B-cell function.
Initial studies suggested potential benefits including reductions in disease activity and improved quality of life, so Gordon and colleagues undertook a detailed dose-ranging study that compared results with placebo, 200 mg, 800 mg, 2,400 mg, and 3,600 mg of epratuzumab given as four weekly infusions.
Patients all had at least one body system (mucocutaneous, musculoskeletal, or cardiorespiratory) with severe involvement as measured on the British Isles Lupus Assessment Group (BILAG) index, or moderate involvement in two systems.
In addition, they were anti-nuclear antibody-positive, and had scores of 6 or higher on another disease activity index, the SLEDAI.
The study included 227 patients whose mean age was 40. Almost all were white women, whose mean total BILAG score was 15 and mean SLEDAI score also was 15.
At baseline, 45% were on immunosuppressive drugs such as methotrexate, azathioprine, or mycophenolate, and 47% were also on anti-malarials.
Mean corticosteroid dosage at baseline was 14 mg per day.
The study used a novel composite endpoint, the BICLA, which required that patients meet several criteria at week 12 to be considered a responder:
All body systems measured as having severe involvement at baseline improving to being measured with moderate, mild, or no disease; and all systems measured at baseline as having moderate involvement improving to mild or no disease
- No increase in total SLEDAI score
- No deterioration in physician's global assessment
- No need for increased immunosuppressive or corticosteroid treatment
The odds ratio for being a responder among patients receiving 2,400 mg, given as four weekly infusions of 600 mg, was 3.2, Gordon reported.
A subset of patients were known as enhanced responders, in that all body systems with moderate or severe baseline involvement had reached mild or no disease activity at week 12. A total of 37.9% of those receiving 600 mg weekly achieved that level of response, compared with 13.2% of those on placebo.
Those receiving a cumulative dose of 2,400 mg, but in doses of 1,200 mg every other week rather than 600 mg weekly, also had high rates of enhanced response, at 35.3%.
Three-quarters of patients had at least one adverse event, which most often was a minor infection or headache. Fewer than 10% of patients in all dosage groups experienced serious adverse events.
"A cumulative dose of 2,400 mg was associated with clinically meaningful and statistically significant improvements in disease activity among patients with moderate-to-severe lupus," Gordon concluded.
A larger, phase III study is now under way that will assess four doses of 600 mg weekly every 3 months for up to a year.
That trial also will use the BICLA endpoint, which Gordon believes is more discriminatory than other endpoints used in lupus trials.
The study was sponsored by UCB. Gordon disclosed receiving fees from UCB, Roche, Genentech, and Aspreva. Several co-authors also received fees from UCB, and two were employees of UCB.
Primary source: British Society for Rheumatology