New treatments of systemic lupus erythematosus

B lymphocyte-activating factor (BAFF)

BAFF, also known as B lymphocyte stimulator (BLyS) is a TNF family cytokine that is expressed on monocytes and dendritic cells. Cleaved BAFF circulates in the serum and is elevated in SLE patients. BAFF interacts with its receptors BAFF-R (BR3), TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), and BCMA (B-cell maturation antigen). BAFF-R is the primary receptor that binds to BAFF, and is almost exclusively expressed on B cells. BAFF: BAFF-R binding activates NF-kB and provides a survival signal that promotes B cell proliferation and maturation especially in the early (transitional) stage of B cell development.

Belimumab, the first medication to be approved for SLE in over five decades, is a fully human monoclonal antibody that inhibits BAFF. Belimumab was shown in two pivotal randomized controlled trials to be significantly better than placebo in patients with active SLE—58% of subjects receiving 10 mg/kg belimumab monthly infusions reached SRI-4 without deterioration of BILAG or PGA versus 44% in the placebo group (BLISS-52 trial). In the BLISS-76 trial the SRI in the belimumab group was 43.2% versus 33.5% in the placebo group. Belimumab also reduced the rate of severe flares. Patients enrolled in both studies had at least moderately active disease, were positive for ANA and/or dsDNA antibodies; patients with active central nervous system and renal disease were excluded. Post marketing analysis confirms that belimumab is safe with no significant increase in the rate of serious infections and malignancies.

Tabalumab, a subcutaneous-administered monoclonal antibody that bound both soluble and membrane-bound BAFF was also evaluated in 2 large randomized clinical trials. Tabalumab did result in a decrease in dsDNA antibody levels and increase in complement. In one of the two trials, the primary end point SRI-5 (SRI responders who had a decrease in the SLEDAI by at least 5 points instead of the classic SRI of 4-point decrease) was reached by 38.4% of subjects on biweekly subcutaneous injections of 120mg of tabalumab versus 27.7% of patients on placebo (p = 0.002). The other trial showed similar trends but the differences among the groups did not reach statistical significance. Other key metrics such as corticosteroid sparring and time to severe flare did not significantly differ among the groups. Consistent with the data from belimumab, tabalumab was shown to be safe without significant increase in the rate of infections and other serious adverse events.

Blisibimod is a fusion molecule that is composed of the Fc portion of IgG1 and four BAFF binding domains. A phase III trial (CHABLISSC1) evaluated the effect of blisibimod in patients with active SLE (SELENA-SLEDAI ≥10). Although the medication was well tolerated, the trial failed to reach its main outcome (SRI-6), with the delta between medication and placebo treated patients being only 4.6% (46.9% vs 42.3%). Corticosteroid dosing was somewhat higher in the placebo arm, potentially confounding the result. Blisibimod did have a steroid-sparing effect, and improved immunologic parameters including autoantibody levels, proteinuria, and complement.

Atacicept, a fusion molecule of the extracellular portion of the BAFF receptor TACI and the Fc portion of human IgG, was also assessed in patients with SLE and lupus nephritis. Atacicept binds BAFF and also a related molecule APRIL (a proliferation inducing ligand). The nephritis trial was prematurely terminated due to serious infections and significant decrease of immunoglobulin levels. A trial assessing atacicept efficacy in preventing flares, failed to show a difference between the group on 75 mg sc twice weekly, and placebo. The group on higher dose (150 mg sc twice weekly) had a statistically significant decrease in the risk of flare and increase in time to first flare compared to placebo. The high dose group was prematurely terminated because of two deaths. Similar to the nephritis trial, total immunoglobulin levels were decreased in the atacicept groups compared to placebo. Complement levels did increase and dsDNA decreased in the atacicept group consistent with its proposed mode of action. Given its side-effect profile, the future of atacicept in the treatment of SLE is unclear and careful considerations, such as use of concomitant immune-suppressive medications, have to be made before further trials are designed.

Finally, briobacept, a fusion molecule of the BAFF-R (BR3) and IgG1 has shown efficacy in preclinical models of lupus.

An interesting approach that is pursued currently is the combination of BAFF inhibition using belimumab following or preceding B cell depletion using the anti-CD20 molecule rituximab (see later). In an open label study of 16 patients with refractory SLE, 11 patients achieved renal remission. The combination did result in the expected immunologic effect of reduced autoantibody titers but also importantly the often observed increase in BLyS concentration following anti-CD20 treatment was not observed. Other small case series showed similar results in patients with refractory disease. Following these open label trials, a phase III trial (BLISS-BELIEVE) will compare belimumab/rituximab combination to belimumab combined with standard of care and belimumab combined with placebo. The primary outcome is complete remission at 52 weeks, as defined by SLEDAI < = 2, prednisone dose < = 5mg/day and no immune-suppressive medications. This ambitious clinical trial is currently underway.

Taken together, blockade of BAFF with various molecules results consistently in improvement of immunological parameters (dsDNA antibodies, complement levels) in patients who are immunologically and clinically active at baseline. The effect on clinical activity is modest for belimumab and marginal for tabalumab and blisibimod. The usefulness of BAFF inhibition in renal and CNS lupus, arguably the most severe manifestations of the disease is unknown to date. In terms of side-effects, BAFF, but not the combined BAFF/APRIL inhibition, with the aforementioned biologics seems to be generally safe without significant increase in serious infections or malignancies.

Interferon-α

Interferon alpha is a cytokine that is primarily produced by cells in response to viral infections. It binds to its receptors (IFNAR) on a variety of cells leading to the activation of the Jak-STAT pathway. SLE peripheral blood mononuclear cells have a distinct transcriptional phenotype, called the interferon signature, thought to be due to exposure to excessive interferon alpha.

The anti-interferon alpha monoclonal antibody, Sifalimumab met its primary endpoint (SRI-4) at 1 year of treatment of patients with non-renal SLE in a phase IIb trial. SRI-4 was 59.8% in the high dose (1200 mg IV monthly infusions) of sifalimumab versus 45.4% in the placebo group. The complement levels and anti-dsDNA levels were not significantly affected by sifalimumab, while herpes zoster was more common in patients treated with sifalimumab (8.4% in the high dose vs. 0.9% in the placebo). The modest effect size led to termination of further development of this molecule.

Rontalizumab, another anti-IFN alpha antibody did not differ from placebo in a phase II trial. Unexpectedly, only patients with low interferon signature gene expression benefited, with reduction in disease activity, steroid burden, and flare rates, as compared to placebo.

The most promising interferon blocking agent to date was Anifrolumab. This anti-interferon receptor 1 (IFNAR1) antibody blocks both IFN-α and IFN-β from binding to the receptor. Given interesting results in an open label trial with sustained almost universal suppression of the interferon signature gene expression, more so than sifalimumab, it was suggested that inhibiting the receptor rather than the offending cytokine(s) may be a better strategy. In a phase IIb study anifrolumab at two doses (300 and 1000 mg IV every 4 weeks) was compared to placebo in its effectiveness to reduce lupus disease activity in patients with moderate to severe SLE. Three quarters of the patients had the IFN signature at baseline. As primary endpoint the investigators chose SRI-4 with reduction of corticosteroid dose to below 10 mg/day of prednisone equivalent. There was statistically significant difference in the response rate at 24 weeks between anifrolumab and placebo but no apparent dose effect—34.3% in the 300 mg group versus 28.8% in the 1000 mg versus 17.6% in the placebo group. The difference was more pronounced in the IFN signature high group primarily due to differences in the placebo response between the IFN signature high and low groups. Two phase III trials were conducted. To date, TULIP I, one of the two phase III trials, was reported as negative.

Interferon-α inhibition showed some early promising, yet not impressive results. The report of the negative phase III trial has dampened the interest in blocking this cytokine. Post-hoc analysis of these studies may help us better understand the role of IFN blockade in SLE.

Interferon-γ

Interferon-γ, a Th1 signature cytokine, is a major proinflammatory cytokine that plays a pivotal role in the development of nephritis in the preclinical lupus model MRL- lpr. AMG 811, a human IgG1 anti-interferon γ monoclonal antibody was evaluated in two phase I trials in subjects with discoid lupus (16 individuals), and mild systemic lupus (26 individuals received one dose and 28 multiple doses). The medication was given subcutaneously or intravenously. There was a reduction in the expression of interferon-γ associated genes, and a decrease in the serum levels of CXCL10, a marker of future lupus flares. None of the two studies showed any clinical effect and no significant increase over placebo in the rate of adverse events were observed either. A larger trial is needed to evaluate whether positive biologic outcomes can translate into clinical effectiveness.

Interleukin-23/Interleukin-17

It has become apparent that the manifestations of several autoimmune diseases depend not only on the activation of Th1 T cells but also Th17 cells. Th17 cells produce among other cytokines, the signature cytokine IL-17A. The relative contribution of these two T cell subtypes in different diseases is a subject of intense investigation. In the case of SLE, IL-17 expressing cells are present in the spleen and kidneys of murine models of the disease and patients with nephritis. Moreover, inhibition of the pro-inflammatory cytokine IL-23 that stabilizes Th17 phenotype, leads to amelioration of murine lupus nephritis. Contrary to the apparent effectiveness of IL-23 inhibition, IL-17 inhibition in murine models of lupus had no effect, bringing into question whether other IL-23 regulated cytokines, such IL-17F or IL-21 may be playing a role in lupus pathophysiology. Nevertheless, this pathway shows a lot of promise as a treatment target for a variety of autoimmune diseases.

Ustekinumab is a monoclonal antibody that inhibits both Th1 and Th17 cell differentiation by blocking IL-12 and IL-23 by binding to their common subunit p40. It is effective in the treatment of psoriasis, psoriatic arthritis, and inflammatory bowel disease and is administered subcutaneously every 8–12 weeks after initial loading. Given preclinical data, strong theoretical rationale and acceptable side-effect profile, ustekinumab was evaluated in a phase II trial in patients with SLE. 102 active SLE patients already receiving with active disease despite ongoing standard of care were enrolled. Ustekinumab was administered after intravenous loading every eight weeks subcutaneously and SRI-4 response index at 24 weeks was the chosen endpoint. Ustekinumab was superior to placebo at week 24 (SRI-4: 60% vs. 31%, p = 0.0046). Ustekinumab was superior to placebo on individual organ-specific outcome metrics such as joint counts and the CLASI skin index. There was no difference among the groups in the BICLA, a more stringent outcome measure, raising some concerns about the overall effectiveness of this molecule. Ustekinumab was well tolerated, in line with previous experience with this medication. These data laid the ground work for the ongoing phase III trial that will address the effectiveness of IL-12/23 inhibition in SLE with active but not severe disease.

Interleukin-2 (IL-2)

Following clinical data on prevention of graft vs. host disease, IL-2 has been viewed increasingly as an anti-inflammatory cytokine with huge potential in various inflammatory diseases. IL-2 at low concentrations favors the expansion and survival of the anti-inflammatory Treg cells that express the IL-2 receptor at high levels. IL-2 production has long been known to be downregulated in SLE, and is linked to hyperactive effector T cells and defective Treg. Indeed, IL-2 can prevent the development of nephritis in murine lupus models. An open label study of low-dose IL-2 given subcutaneously in SLE patients resulted in 80% SRI-4 response rate at 12 weeks. This was associated with an increase in Treg and decrease in the proinflammatory T cell subtypes (Treg, follicular T helper cells, Tfh). Several placebo control trials are currently underway examining the effect of various formulations IL-2 (AMG 592, ILT-101, and Aldesleukin) on SLE disease activity.

Although only B cell targeting has been successful to date in alleviating SLE, targeting the T cell compartment by reducing pro-inflammatory T cells with IL-23 inhibition or boosting Treg by infusing low dose IL-2 appears quite promising.