Systemic lupus erythematosus: Novel therapies and targeted treatments
Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which a convoluted manifold of dysregulated pathways contributes to heterogenous clinical phenotypes. In the past three decades, a broad array of new treatments has been developed to treat autoimmune diseases, including SLE. Here, we review new strategies and agents for the treatment of SLE that have most recently showed promise in clinical trials.
Multitarget combination therapy: Mycophenolate mofetil with tacrolimus
Mycophenolate is an effective and widely-used induction and maintenance therapy for lupus nephritis (LN). Calcineurin inhibitors have also shown efficacy in LN and may be as effective as mycophenolate or cyclophosphamide. The combination of these therapies is currently used in preventing transplant rejection and in refractory LN. In a large randomized clinical trial, 368 Chinese patients with class III/IV/V LN received either a combination of tacrolimus (4 mg/day) and low-dose mycophenolate mofetil (1 g/day) (multitarget), or monthly intravenous cyclophosphamide (0.5–1 g/m2). After 6 months, complete remission was achieved in 45.9% of patients in the multitarget group versus 25.6% in the cyclophosphamide group, and an overall response was achieved in 83.5% of the multitarget group compared with 63% in the cyclophosphamide group. However, more patients withdrew from the multitarget arm, mostly due to pneumonia and zoster reactivation.
Rituximab with belimumab
Two large randomized placebo-controlled trials of rituximab in renal (LUNAR) and non-renal (EXPLORER) lupus failed to meet their primary outcomes. The disappointing results of these trials led to the identification of a surge of B-cell activating factor, and reconstitution of B cells following depletion therapy. This provided the rationale for SynBioSe, a proof-of-concept phase IIA trial of rituximab followed by belimumab in patients with refractory severe LN. A renal response was observed in 11 out of 16 patients, with five patients showing a complete response. Infections were observed in 39% of patients (hospitalization was required in one case) with hypogammaglobulinemia observed in three patients. In the CALIBRATE trial, patients with refractory LN were treated with rituximab, cyclophosphamide, and corticosteroids, followed by either belimumab or placebo. However, this trial did not show a benefit of belimumab, with 24-week renal responses of 24% in the belimumab group versus 23% in the placebo group. A second open-label phase II trial is currently recruiting patients.
New therapeutic agents
Voclosporin is a new potent calcineurin inhibitor with faster elimination and less variability in blood concentration compared with tacrolimus or cyclosporine. In the AURA phase IIb study, 265 patients with active LN were randomized to receive voclosporin or placebo, in addition to mycophenolate and corticosteroids. Both voclosporin doses showed a higher complete remission rate compared with mycophenolate alone at 48 weeks (40% of low-dose patients and 48% of high-dose patients, compared with 24% of the mycophenolate group). Glomerular filtration rate decreased with voclosporin. Serious adverse effects were noted in 25.0–25.9% of patients in the voclosporin arms, and in 15.9% with placebo. There were 13 deaths in the low-dose voclosporin arm, compared with two in the high-dose arm, and one in the placebo arm. According to the investigators, all deaths were unrelated to the study drug. A phase III trial (AURORA) is currently ongoing.
Anifrolumab is a monoclonal antibody blocking the type I interferon (IFN)-α/β/ω receptor. In a phase IIb trial, 305 lupus patients were randomized to receive placebo or one of two dosages of anifrolumab. At 24 weeks, 34% and 29% of patients receiving anifrolumab (300 mg and 1000 mg every 4 weeks, respectively) achieved the primary outcome of SLE responder index 4 (SRI4) response with sustained reduction of oral corticosteroids, compared with only 17.6% in the placebo group, with particularly favorable effect on skin and joints. There was a mild increased risk of viral infections, including influenza and herpes zoster. However, the first phase III trial (TULIP 1) did not reach its primary endpoint of decreasing SRI4. TULIP 2 is currently underway.
The T-helper 17 response is activated in lupus, and can be disrupted by ustekinumab, a monoclonal antibody blocking IL-12 and IL-23 that is currently FDA approved to treat psoriasis, psoriatic arthritis, and inflammatory bowel disease. In a phase II trial, 102 patients with SLE were randomized (3:2) to either ustekinumab or placebo. At 24 weeks, 60% of ustekinumab-treated patients achieved the primary endpoint, SRI4 response, compared with 31% in the standard-of-care group. Subgroup analysis showed significant improvement in skin and joint scores. The risk for infection was similar to the placebo group. A phase 3 trial (LOTUS) is underway.
Baricitinib is a reversible inhibitor of Janus kinase (JAK)1 and JAK2, which is currently FDA approved for the treatment of rheumatoid arthritis. These kinases mediate signaling for type 1 interferons, IFN-γ, IL-6, IL-12, and IL-23 among others. In an international, double-blind, placebo-controlled phase 2 trial, 314 patients with uncontrolled SLE were randomized to receive either baricitinib or placebo. The primary outcome was the proportion of patients achieving resolution of rash or arthritis at 24 weeks, defined by SLEDAI-2K. The primary outcome was achieved in the higher dose baricitinib arm (4 mg daily), but not at 2 mg daily, as compared with placebo (67% and 58% vs 53%, respectively). Differences were noted only in arthritis. The frequency of flares was also lower in the 4 mg group compared with placebo (33% vs 51%). There were more serious infections in the 4 mg arm (6%) compared with the 2 mg (2%) and placebo (1%) arms. There was one deep venous thrombosis (1%) detected in the 4 mg arm. Two phase 3 trials (BRAVE I and BRAVE II) are currently recruiting patients.
Atacicept is a TACI-Ig fusion protein that inhibits B cells by dual inhibition of APRIL and BLyS. In a phase 1b trial, atacicept showed a dose-dependent reduction in circulating B cells and immunoglobulins. In ADDRESS II, a phase 2b trial, 306 patients were randomized to receive weekly subcutaneous atacicept (75 mg or 150 mg) or placebo. Atacicept was associated with a trend toward better SRI4 response at 4 weeks compared with placebo, especially in individuals with high disease activity, serologically active disease, or both. For example, in the serologically active group, 62% of patients treated with atacicept achieved SRI4 at 24 weeks compared with 24% in the placebo arm. Currently, there are no active trials.
These are exciting times for the treatment of lupus, with several positive phase II trials that may readily lead to new available treatments. In addition, many other novel therapies are under development, including anti-Fcγ-receptor-IIb, toll-like receptor inhibitors, other JAK inhibitors, histone deacetylase inhibitors, and others. Furthermore, the enormous research effort in precision medicine, such as in the Accelerating Medicines Partnership, is bound to identify novel pathways and mechanisms underlying SLE and LN, paving the way for innovative approaches tailored to each patient’s needs.