clinical topic updates

Systemic Lupus Erythematosus: Treatments in Development

by Bevra H. Hahn, MD

Overview

Recent data with belimumab and voclosporin are of interest in the setting of lupus nephritis, a common complication in patients with systemic lupus erythematosus (SLE). A variety of agents, including entirely novel approaches, are in development and hold promise in SLE, but additional data from phase 3 clinical trials are needed.

Expert Commentary

Bevra H. Hahn, MD

Professor of Medicine, Emeritus
Rheumatologist
UCLA School of Medicine
Los Angeles, CA

“In looking to recently emerging treatments and to those in development, there are a number of good possibilities.”

Bevra H. Hahn, MD

In looking to recently emerging treatments and to those in development, there are a number of good possibilities. If it truly has less renal toxicity than tacrolimus, voclosporin seems to be a very good addition to the treatment armamentarium for lupus nephritis. I will be eager to see whether voclosporin works as well in the community as it did in the phase 3 AURORA trial. A key question will be: How long can patients use voclosporin before they start to experience some of the side effects? If these side effects (eg, rising creatinine and hypertension) are emerging after 6 to 12 months of use, that would be similar to what we have seen with tacrolimus.

In the past, I had not been terribly enthusiastic about prescribing belimumab for my patients with lupus nephritis, but I changed my mind after seeing the most recent data, and I do like using it in those with non-nephritis lupus. It works in at least 50% of my patients who start on it, and many of them stay on it for years. It does not increase the infection risk much over background therapy. Unfortunately, there is no oral form of belimumab; however, with the newer data, I was excited by the kidney protection it afforded. The BLISS-LN trial was run for 2 years, which is very admirable, and, as noted by Furie and colleagues, the risk of a renal-related event during the trial was almost 50% lower among patients who received belimumab than among those who received standard therapy alone.

There are many agents with phase 2 data. I am particularly interested in the studies of obinutuzumab, which, like rituximab, targets CD20. With rituximab, hypogammaglobulinemia and inactivating antibodies can develop. In addition, allergic reactions may develop as you approach, say, 3 to 4 years of treatment. Obinutuzumab is promising in that it is more B-cell depleting and less immunogenic than rituximab. The phase 2 trial looked very promising, so we shall see.

The monoclonal antibody anifrolumab is also of interest, and our group participated in one of the trials. Early data suggest that it may be particularly good for skin manifestations. I have not been too enthusiastic about agents that work on the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway (eg, baricitinib and the Bruton tyrosine kinase inhibitor fenebrutinib) based on what I have seen thus far. The advantage of the JAK/STATs would be the oral route. Now, BIIB059, which is an antibody against the BDCA2 receptor on the dendritic cell, is quite interesting. I think that the data look quite good. That is a whole new approach and should really reduce the type I interferon production by the plasmacytoid dendritic cell.

Finally, telitacicept is another agent to watch, as it interferes with APRIL and BAFF, and that can be considered either positive or negative. In earlier studies with other similar drugs, there was a problem with infections and/or the agents did not work as well as belimumab. However, telitacicept looks quite good, and it is on an accelerated track at the US Food and Drug Administration for approval. I have not seen phase 3 data, and we will have to wait and see whether inhibiting both of these molecules results in increased infection.

References

Anderson E, Furie R. Anifrolumab in systemic lupus erythematosus: current knowledge and future considerations. Immunotherapy. 2020;12(5):275-286. doi:10.2217/imt-2020-0017

Arriens C, Polyakova S, Adzerikho I, Randhawa S, Solomons N. AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis. Ann Rheum Dis. 2020;79:172-173. doi:10.1136/annrheumdis-2020-eular.5010

Felten R, Scher F, Sagez F, Chasset F, Arnaud L. Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date. Drug Des Devel Ther. 2019;13:1535-1543. doi:10.2147/DDDT.S170969

Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117-1128. doi:10.1056/NEJMoa2001180

Furie R, van Vollenhoven R, Kalunian K, et al. Efficacy and safety results from a phase 2, randomized, double-blind trial of BIIB059, an anti-blood dendritic cell antigen 2 antibody, in SLE [abstract 0935]. Abstract presented at: American College of Rheumatology Convergence 2020; November 5-9, 2020.

Furie R, Werth VP, Merola JF, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Invest. 2019;129(3):1359-1371. doi:10.1172/JCI124466

Morand EF, Furie R, Tanaka Y, et al; TULIP-2 Trial Investigators. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020;382(3):211-221. doi:10.1056/NEJMoa1912196

Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial [published correction appears in Lancet. 2018;392(10146):476]. Lancet. 2018;392(10143):222-231. doi:10.1016/S0140-6736(18)31363-1

Wu D, Li J, Xu D, et al. A human recombinant fusion protein targeting B lymphocyte stimulator (BlyS) and a proliferation-inducing ligand (APRIL), telitacicept (RC18), in systemic lupus erythematosus (SLE): results of a phase 2b study [abstract L18]. Abstract presented at: 2019 American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting; November 8-13, 2019.

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