In Wake of Lupus Trial Failure, New Research Attacks From Many Angles

‘Lupus is being attacked in a very eclectic manner. It’s just fascinating to me how many different approaches are being taken to attack this condition.’ —Richard Furie, MD

Current Research

In phase 2 studies, researchers are investigating BIIB059, a monoclonal antibody targeting the plasmacytoid dendritic cell BDCA2. Dr. Furie, who is working on this trial, said the antibody’s tail end also binds to the Fc receptor, blocking immune complexes from binding to it, which could heighten its effects.³ “This has a dual mechanism of action,” he said.

Research into obinutuzumab, an antibody approved for chronic lymphocytic leukemia, is also now underway for lupus nephritis.⁴

In the BELIEVE trial, researchers are attempting to re-employ rituximab, which previously failed in lupus trials. The treatment showed favorable signals that killing off CD20-positive B cells may be an effective approach to treating lupus. Researchers are now assessing rituximab preceded by belimumab, an approach that may enhance rituximab’s effects, Dr. Furie notes.⁵

“Belimumab actually mobilizes B memory cells and may allow more B cells to be killed off by rituximab,” he said.

The scientific rationale for the reverse sequence—rituximab preceded by belimumab—stems from the SYNBIOSE and CALIBRATE studies. The concept is to reduce the elevation of circulating levels of BLyS, the B lymphocyte stimulator. This happens after B cell depletion and is responsible for the re-emergence of autoimmunity.

Studies are also underway for a selective inhibitor of the immunoproteasome called KZR616, in both extra-renal disease and lupus nephritis, as well as for an antibody to CD38.

“It’s just been a real tough nut to crack, but I am optimistic about the future,” he said. “We will have more medicines. It’s just a matter of time.” 

Thomas R. Collins is a freelance writer living in South Florida.

References

1. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386.
2. AstraZeneca. News release: Update on TULIP 1 phase 3 trial for anifrolumab in systemic lupus erythematosus. 31 August 2018.
3. Furie R, Werth VP, Merola JF, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Invest. 2019 Mar 1;129(3):1359–1371.
4. Reddy V, Klein C, Isenberg DA, et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology (Oxford). 2017 Jul 1;56(7):1227–1237.
5. Teng YKO, Bruce IN, Diamond B, et al. Phase 3, multicenter, randomized, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. BMJ Open. 2019 Mar 20;9(3):e025687.