The Complexity of SLE Drug Research

These clusters shared key characteristics of low inflammation, high B cell and plasma cell pathway signals and signals relating to rapid cell cycle rates. “If you look at people with high inflammation, this drug does not work,” said Dr. Merrill, “But if you look at patients with low inflammation, you get a big difference from the placebo group.”

Moving Forward

Dr. Merrill noted that trials as large as belimumab’s usually aren’t possible, and we need to find ways to design studies that can demonstrate effectiveness with smaller patient numbers. “We are better at clinical data accuracy than we were 10 years ago; we are better at trial design; we know how to get end points that are a little more discriminatory than what we were using in the past, and we’ve been reducing polypharmacy,” she said. “But we also need to reduce immune heterogeneity and select the patients that are most likely to respond to a drug.”

Dr. Merrill concluded that we can carefully construct clinical trials and analyze results to “improve the feasibility of unraveling complex pharmacodynamic interactions at many levels, from the gene to environmentally-induced activation states.”

Dr. Merrill is planning to use these strategies in her upcoming trial of mycophenolate mofetil alone or with voclosporin in patients with lupus, sponsored by the National Institutes of Health. Dr. Merrill and colleagues will also study gene expression patterns at baseline and/or in response to mycophenolate mofetil alone or along with voclosporin, to get a better idea of the immunologic changes involved in treatment response and treatment failure.

Dr. Hickman

Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.

References

1. Guthridge JM, Lu R, Tran LTH, et al. Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study. EClinicalMedicine. 2020 Mar 4;20:100291.
2. Merrill JT, Immermann F, Whitley M, et al. The biomarkers of lupus disease study: A bold approach may mitigate interference of background immunosuppressants in clinical trials. Arthritis Rheumatol. 2017 Jun;69(6):1257–1266.
3. Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221.
4. Merrill JT, June J, Koumpouras F, et al. Top-line results of a phase 2, double-blind, randomized placebo-controlled study of a reversible B cell inhibitor, XmAb5871 in systemic lupus erythematosus (SLE) [abstract]. Arthritis Rheumatol. 2018;70(suppl 9).
5. Merrill JT, Guthridge J, Zack D, et al. Discrimination of systemic lupus (SLE) patients with clinical response to obexelimab (XmAb5871) based on a pattern of immunologic markers [abstract SAT0187]. Ann Rheum Dis. 2020;79(suppl 1).