Systemic lupus erythematosus (SLE), commonly known as lupus, is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. Patients with SLE often experience alternating periods of disease flare-ups and remission.  The diverse presentations of SLE  range from rash and arthritis through anemia and thrombocytopenia to serositis, nephritis, seizures, and psychosis. It is estimated that approximately 90% of SLE patients are women, with most cases presenting between the ages of 15 to 44. Pregnancy in women with SLE is considered high-risk, with elevated maternal and neonatal morbidity and mortality rates compared to the general population.

In recent years, advances in fine immunophenotyping, genome-wide association studies (GWAS), single-cell sequencing, multiomics analysis, and gene editing have significantly enhanced our understanding of the pathogenesis of SLE. These technological breakthroughs have also driven the development and clinical research of therapies targeting immune cells, costimulatory molecules, cytokines, and signal transduction pathways, including monoclonal antibodies, small-molecule drugs, and chimeric antigen receptor (CAR) T-cell immunotherapy. The approval of treatments such as belimumab and anifrolumab has provided clinicians, researchers, and patients with greater confidence and expanded options for managing moderate to severe SLE, particularly refractory cases.

FDA Approved Targeted Therapies for SLE

Belimumab (Benlysta)

Belimumab (Benlysta), developed by GSK, is the first targeted inhibitor of B-lymphocyte stimulator (BlyS). By binding to BlyS, Belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces their differentiation into plasma cells responsible for producing immunoglobulins, despite not directly binding to B cells.

Belimumab was initially approved by the FDA in March 2011 for the treatment of SLE — marking the first SLE therapy in 5 decades, and belimumab received an expanded approval in December 2020 for lupus nephritis. It is commonly used in combination with other medications such as hydroxychloroquine (Plaquenil) and mycophenolate mofetil (CellCept) to enhance treatment efficacy.

Anifrolumab (Saphnelo)

Saphnelo (anifrolumab) is a fully human monoclonal antibody that binds to subunit 1 of the type I IFN receptor,  effectively blocking the activity of type I IFN. Type I IFNs, such as IFN-alpha, IFN-beta and IFN-kappa, are cytokines involved in regulating the inflammatory pathways implicated in SLE. Increased type I IFN signaling is observed in the majority of adult SLE patients and is associated with greater disease activity and severity.

As a "first-in-class" type I IFN receptor antagonist, Saphnelo represents a significant advancement in SLE treatment. On August 2, 2021, the U.S. FDA approved Saphnelo for the treatment of moderate to severe SLE, marking the first new therapy for the disease in over a decade.

Targeted Therapies for Treating SLE Under Development

Table 1. Partial list of targeted therapies for treating sle under-development

Dapirolizumab pegol

Dapirolizumab pegol is a novel investigational humanized Fc-free polyethylene glycol (PEG)-conjugated antigen-binding (Fab') fragment. It inhibits CD40L signaling which has been shown to reduce B cell activation and autoantibody production, mitigate IFN-I secretion, and attenuate T cell and antigen-presenting cell (APC) activation.

On September 24, 2024, UCB and Biogen jointly announced positive results from the Phase III PHOENYCS GO study, evaluating dapirolizumab pegol for the treatment of SLE.

PHOENYCS GO is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase III trial designed to assess the efficacy and safety of dapirolizumab pegol in combination with standard of care (SOC) therapy compared to placebo plus SOC in patients with moderate to severe SLE. A total of 321 patients participated in the study.

The analysis revealed that dapirolizumab pegol, combined with SOC, met its primary endpoint. At Week 48, patients showed significantly greater improvement in moderate to severe disease activity compared to placebo plus SOC, as measured by the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). BICLA is an established composite endpoint for assessing clinical disease activity through patient history, clinical examination, and laboratory tests.

Additionally, key secondary endpoints assessing disease activity and flares demonstrated clinically meaningful improvements.

The safety profile of dapirolizumab pegol was consistent with previous studies and aligned with the expected safety outcomes for SLE patients undergoing immunomodulatory therapy.

Litifilimab

Litifilimab (BIIB059), developed by Biogen, is a fully humanized IgG1 mAb targeting BDCA2. By inhibiting BDCA2, it reduces the production of inflammatory cytokines, including IFN-I, playing a crucial role in modulating the pathological mechanisms of SLE. Currently the most advanced BDCA2-targeting therapy, Litifilimab has entered Phase III clinical trials for the treatment of both cutaneous lupus erythematosus (CLE) and SLE.

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Figure 1. Mechanism of action of Litifilimab

In a phase 2 trial involving participants with SLE, litifilimab was associated with a greater reduction from baseline in the number of swollen and tender joints than placebo over a period of 24 weeks. Longer and larger trials are required to determine the safety and efficacy of litifilimab for the treatment of SLE. 

Upadacitinib

Upadacitinib is a selective, reversible JAK inhibitor being studied for use in various severe immune-mediated inflammatory diseases. In cell and enzyme activity assays, upadacitinib has shown a particularly strong inhibitory effect on JAK1, compared to JAK2, JAK3, and TYK2. The drug has already been approved for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis in adults.

In 2023, AbbVie announced positive results from a Phase 2 clinical trial of upadacitinib, used either as monotherapy or in combination (elsubrutinib 60 mg and upadacitinib 30 mg), for the treatment of adults with moderately to severely active SLE who continued to receive standard lupus therapies. Based on these results, AbbVie stated that it would advance upadacitinib into Phase 3 clinical trials for SLE treatment.

Cenerimod

Cenerimod is a potential "first-in-class," highly selective S1P1 receptor modulator. This once-daily oral tablet is being developed for the treatment of SLE. In December 2022, Idorsia launched the OPUS program, consisting of two multicenter, randomized, double-blind, placebo-controlled Phase 3 trials, to evaluate the efficacy, safety, and tolerability of cenerimod in adults with moderate to severe SLE, in combination with background therapy. Cenerimod has been granted Fast Track designation by the U.S. FDA for the treatment of SLE.

In the Phase II clinical trial, the highest dose tested was 4 mg, and after six months, the treatment group showed a numerical improvement in the primary endpoint, the mSLEDAI-2K score, compared to placebo. However, except for the 4 mg dose, which showed a p-value of 0.029, no significant differences were observed in other groups. Furthermore, at 52 weeks, no significant differences were found in mSLEDAI-2K and SRI-4 scores across all trial groups.

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References:
[1] Dapirolizumab Pegol Phase 3 Data Presented at the American College of Rheumatology Shows Significant Reduction in Systemic Lupus Erythematosus Disease Activity  https://investors.biogen.com/news-releases/news-release-details/dapirolizumab-pegol-phase-3-data-presented-american-college
[2] Trial of Anti-BDCA2 Antibody Litifilimab for Systemic Lupus Erythematosus https://www.nejm.org/doi/full/10.1056/NEJMoa2118025
[3]Phase 2 Study of Upadacitinib (RINVOQ®) Alone or as a Combination Therapy Meets Primary and Key Secondary Endpoints in Patients with Systemic Lupus Erythematosus https://news.abbvie.com/2023-05-31-Phase-2-Study-of-Upadacitinib-RINVOQ-R-Alone-or-as-a-Combination-Therapy-Meets-Primary-and-Key-Secondary-Endpoints-in-Patients-with-Systemic-Lupus-Erythematosus
[4] Encouraging Phase 2 data on cenerimod – Idorsia's S1P1 receptor modulator currently investigated for SLE – presented at ACR 2019 https://www.idorsia.com/investors/news-and-events/media-releases/media-release-details?id=2201271