Epratuzumab May Work for SLE Subgroups

Numstocker / shutterstock.com

A recent analysis of the monoclonal antibody epratuzumab finds new evidence for its effectiveness in a subset of systemic lupus erythematosus (SLE) patients who have a concurrent diagnosis of Sjögren’s syndrome, a progressive autoimmune disease that affects exocrine glands and is characterized by dry eyes and mouth.¹ Sjögren’s can be primary, meaning independent of other conditions, or associated with coexisting autoimmune diseases, such as SLE. An estimated 6.5–19% of SLE patients will develop an associated Sjögren’s diagnosis.²

A multinational European and U.S. team, supported by UCB Pharma and led by Jacques-Eric Gottenberg, MD, PhD, professor and hospital practitioner at Strasbourg University Hospital in France, conducted a post-hoc analysis of data from the Epratuzumab versus Placebo in Subjects with Moderate to Severe General Systemic Lupus Erythematosus (EMBODY 1 and 2) study, two matched clinical trials of the efficacy and safety of epratuzumab. The new study compared patients with SLE and Sjögren’s with controls who had SLE but no evidence of Sjögren’s to see if epratuzumab had a different clinical efficacy profile in the two groups.

Epratuzumab is a humanized mono­clonal antibody that targets the B cell-specific protein CD-22, an antigen receptor on the surface of B cells, resulting in selective modulation of their activity. EMBODY 1 and 2 trials were phase 3, randomized, double-blind, placebo-controlled, multicenter studies, with a total of 1,584 enrolled SLE patients.³ After promising results for the drug from the phase 2B EMBLEM trial, which found improvement in disease activity for patients with moderate to severe SLE, it was thought that epratuzumab could diminish SLE-related hyperactivity of B cells without depleting them.⁴ But the EMBODY trials failed to achieve their clinical efficacy endpoints.

For patients with moderate or severe, active SLE, treatment with epratuzumab plus standard therapy failed to result in statistically significant improvements in treatment response rates over the placebo plus standard therapy group at 48 weeks, even though it was well tolerated, had few adverse events and showed a 30–40% reduction in the number of B cells in peripheral blood and a reduction in B cell activity.

The disappointing EMBODY results were announced in 2015 at the ACR/ARHP Annual Meeting and other places.⁵ In response, the Lupus Foundation of America issued a press release emphasizing the disease’s heterogeneity, differences between patients and even in the same patient from day to day, and the resulting difficulty of demonstrating the impact of a drug on SLE in clinical trials. The foundation stated, “Patients cannot afford to wait another half century for a new lupus treatment,” referring to the approval of belimumab in 2011.⁶

Lupus is not believed to arise from a single pathogenesis mechanism, and multiple factors—including high placebo response, presence of the disease in different parts of the body and prescribing excessive corticosteroids or immunosuppressive drugs—may further challenge the clinical trial pathway for SLE.⁷

Significant Improvements

Dr. Gottenberg tells The Rheumatologist that his group analyzed subgroups of SLE patients that could respond to epratuzumab, taking advantage of the variety of research data, including assessment of antibodies, in the EMBODY database. The team identified 113 patients (13% of the EMBODY SLE population) whose medical history included a diagnosis of Sjögren’s and who were positive for the anti-SS-A/Ro extractable nuclear antigen, linked to both SLE and SLE associated with Sjögren’s.

Their analysis found a higher proportion of SLE patients with Sjögren’s who received epratuzumab responded to treatment according to the BILAG-Based Composite Lupus Assessment (BICLA) of disease activity, which draws on the British Isles Lupus Assessment Group disease activity index.⁸ Results also included a 30–40% reduction in the number of B cells in the blood. “For the first time, a significant improvement was observed for a subset of SLE patients treated with epratuzumab,” he says, emphasizing this study was a post-hoc analysis. “This is an interesting result, pointing to a general strategy of treating lupus or Sjögren’s syndrome by targeting B cells,” he says.

“There is a need to confirm the results via randomized controlled trials,” Dr. Gottenberg says. He is unaware of any trials underway to examine the effectiveness of epratuzumab.

A recent summary of seven clinical trials investigating the efficacy and safety of epratuzumab in SLE underscores opportunities for subgroups, such as Sjögren’s patients, as well as the need for further research to explore other potential subgroups that might respond.⁹ Another open trial study of epratuzumab in primary Sjögren’s produced similar effects—including a 30% reduction in B cell count and clinical improvements in disease, although it only involved 16 patients.¹⁰

The data suggest that epratuzumab may have clinical benefits in certain subsets of SLE patients, pointing to the importance of patient stratification for research in this area. “We may find other subgroups of lupus patients where targeting B cells may be useful,” Dr. Gottenberg said. Small and preliminary studies targeting different subgroups could show positive results whereas big lupus trials with mixed patient populations tend to produce negative results and disappointment. There may also be implications for primary Sjögren’s, as well.

The key message for rheumatologists, Dr. Gottenberg says, is that B cells remain a relevant target in autoimmune diseases.

Larry Beresford is a medical journalist in Oakland, Calif.

References

1. Gottenberg JE, Dörner, T, Bootsma H, et al. Efficacy of epratuzumab, an anti-CD22 monoclonal IgG antibody, in systemic lupus erythematosus patients with associated Sjögren’s syndrome: Post hoc analyses from the EMBODY trials. Arthritis Rheumatol. 2018 May;70(5):763–773.
2. Patel R, Shahane A. The epidemiology of Sjögren’s syndrome. Clin Epidemiol. 2014 Jul 30;6:247–255.
3. Clowse ME, Wallace DJ, Furie RA, et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: Results from two phase III, randomized, double-blind, placebo-controlled trials. Arthritis Rheumatol. 2017 Feb;69(2):362–375.
4. Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: Results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis. 2014 Jan;73(1):183–190.
5. Clowse MEB, Wallace DJ, Furie R, et al. Efficacy and safety of epratuzumab in patients with moderate-to-severe systemic lupus erythematosus: Results from two Phase 3 randomized, placebo-controlled trials (abstract 4L). Arthritis Rheumatol. 2015;67(suppl 10).
6. Statement on the results of epratuzumab study for the treatment of lupus. Lupus Foundation of America. 2015 Jul 28.
7. Strand V, Petri M, Kalunian K, et al. Epratuzumab for patients with moderate to severe flaring SLE: Health-related quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study. Rheumatology (Oxford). 2014 Mar;53(3):502–511.
8. Wallace D, Strand V, Furie R, et al. Evaluation of treatment success in systemic lupus erythematosus clinical trials: Development of the British Isles Lupus Assessment Group-based composite lupus assessment endpoint. Arthritis Rheumatol. 2011;63(suppl 10):S894.
9. Geh D, Gordon C. Epratuzumab for the treatment of systemic lupus erythematosus. Expert Rev Clin Immunol. 2018 Apr;14(4):245–258.
10. Steinfeld SD, Tant L, Burmester GR, et al. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren’s syndrome: An open-label phase I/II study. Arthritis Res Ther. 2006;8(4):R129.