Interferon-targeted therapy in systemic lupus erythematosus: Is this an alternative to targeting B and T cells?

Abstract

Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE. Rontalizumab, an anti-interferon-α monoclonal antibody, was studied in patients who had discontinued immunosuppressants. This study failed to show efficacy as assessed by both two outcome assessments; however, in low interferon signature patients, response was higher and corticosteroid usage was less in rontalizumab-treated patients. Sifalimumab, another anti-interferon-α monoclonal antibody, was studied in patients who remained on standard of care therapy. This study showed significantly better efficacy in patients treated with two sifalimumab dosages; significant differences were seen in the high interferon signature group. In a similar design and in a similar population as the sifalimumab study, anifrolumab, a monoclonal antibody that binds to a type I interferon receptor, was studied in patients who remained on standard of care therapy. In this study, one dosage group demonstrated efficacy and statistically significant effects were achieved in both tested dosage groups with secondary end points. Oral corticosteroid reduction to ≤7.5 mg daily was achieved in one of the tested dosage groups and organ-specific outcomes were significantly improved in that same group. For all studies, no significant differences in serious adverse effects were seen; although, herpes zoster infections were increased in sifalimumab- and anifrolumab-treated patients and influenza rates were increased in anifrolumab-treated patients. Anifrolumab is currently in pivotal phase III studies. Data appear to support the concept that targeting type I interferon in SLE patients associates with clinical efficacy and safety. Further data are forthcoming from ongoing phase III clinical trials of anifrolumab. Other drug development efforts should be considered that target plasmacytoid dendritic cells and toll like receptors given the effects these components have on interferon production.

Keywords

Biologics interferon interferon signature plasmacytoid dentritic cells

Introduction

As dysregulation of the innate and adaptive immune systems are critical aspects to the pathogenesis of systemic lupus erythematosus (SLE),¹ novel therapeutic approaches that target these abnormalities have been investigated in hopes of developing more efficacious and safer therapies than the current standard of care modalities. A major focus of these efforts has concentrated on targeting dysregulated B and T cells as well as the interactions between these cellular abnormalities. Additionally, efforts to target the dysregulation of the innate immune system, abnormal cytokine response and peptide effects are gaining interest. In the last year, new evidence has emerged suggesting that therapeutic approaches that target the innate immune system through down-regulation of interferon-α (IFN-α) may be effective.

A plethora of data implicates IFN-α in the pathogenesis of SLE.^2,3 IFN-α, which is a type I interferon, is involved in breaking self-tolerance by activating antigen-presenting cells;⁴ IFN-α is produced when toll-like receptors 7 (TLR7) and 9 (TLR9) on B cells and plasmacytoid dendritic cells (pDCs) recognize self nucleic acids.⁵ IFN-α is produced by many cells but pDCs are of particular importance.⁶ High levels of IFN appear to be a heritable phenotype that associates with SLE with a polygenic form of inheritance.⁷ Increased IFN-regulated gene expression, which is termed the IFN signature, correlates with the presence of auto-antibodies and with SLE disease activity.^8,9 In cross-sectional studies, patients with SLE have been noted to have elevated serum levels of INF-α and levels of INF-α correlate with disease activity and flares.^10–15 Microarray analyses of mononuclear cell RNA has demonstrated IFN-inducible gene overexpression in both adult^16,17 and pediatric¹⁸ patients. Genome-wide association studies have noted SLE risk polymorphisms within IFN-regulated genes^19,20 and the use of therapeutic recombinant IFN-α has been implicated as a cause of drug-induced lupus.²¹

Both hydroxychloroquine and high dose corticosteroids have been noted to have therapeutic effects in SLE through their effects on the type I IFN system by down-regulating the type I IFN signature. Hydoxychloroquine downregulates IFN-α by blocking TLR7- and TLR 9-binding epitopes and thereby interferes with the activation of these toll-like receptors;²² it also inhibits IFN-β production by blocking cyclic GMP-AMP synthase-DNA interaction.²³ Whereas corticosteroids in low doses do not appear to affect pDC activation or have subsequent effects on IFN-α levels, intravenous pulse corticosteroid therapy (solumedrol 30 mg/kg per day for several days) can reduce pDCs and the IFN signature.⁵

In light of the abundance of data implicating the importance of IFN in SLE, three biologics have recently been developed to target IFN-α and have been tested for their efficacy and safety in moderate-to-severely active SLE patients without active lupus nephritis; these studies were all non-pivotal, phase II multi-center, placebo-controlled clinical trials.^24–26 Although all three trials demonstrated acceptable safety profiles with suggestions of efficacy in the tested patients, only one molecule has been selected to be studied in a pivotal phase III trial (see Table 1).

Rontalizumab

Rontalizumab, a humanized IgG1 anti-IFN-α monoclonal antibody, was studied in patients with disease activity in systems other than the kidney.²⁴ It prevents signaling through the type I IFN receptor by neutralizing all 12 subtypes of IFN-α but does not bind to IFN-β or IFN-ω. Patients were randomized (2:1) to receive 750 mg of rontalizumab or placebo intravenously every 4 weeks (part 1) and 300 mg or placebo subcutaneously every 2 weeks (part 2). Patients were allowed to use hydroxychloroquine and corticosteroids but immunosuppressants used at baseline were discontinued. Outcome efficacy at 24 weeks was assessed with the primary efficacy end point being reduction in disease activity assessed by the British Isles Lupus Disease Activity Group (BILAG)-2004 instrument and the secondary end point being the Systemic Lupus Erythematosus Response Index (SRI). An exploratory efficacy outcome was IFN-regulated gene expression (the IFN signature metric (ISM)), which was based on three genes.

In this study, 238 patients were randomized with 159 receiving rontalizumab and 79 receiving placebo. High IFN-regulated gene expression as assessed by the ISM was seen in 75.6% of treated patients. Safety appeared to be acceptable as adverse events were similar in both the rontalizumab and placebo groups. The mean disease activity was similar in both cohorts as assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI); both groups had mean SELENA-SLEDAI scores of approximately 10. Efficacy was similar in both the rontalizumab and placebo groups as assessed by both BILAG-2004 and the SRI. However, in an exploratory analysis of the patients with low IFN-regulated gene expression measured by ISM, SRI response was higher and corticosteroid usage was less in the patients treated with rontalizumab. This patient group also had significantly reduced flare rates assessed by the SELENA-SLEDAI flare instrument. These disparate findings of efficacy between the ISM-high and ISM-low groups seemed counterintuitive as the expectation was that ISM-high patients would have responded better than ISM-low patients; perhaps the opposite effect was seen because of the choice of a suboptimal dosage. Perhaps a higher dosage would have had a greater effect on ISM-high patients, but only one dosage was explored in this phase II trial. Despite the demonstration of efficacy in a subset of patients, this molecule was not selected to be tested in a pivotal study by the sponsoring biopharmaceutical company.

Sifalimumab

Sifalimumab, a fully human IgG1κ monoclonal antibody, was also studied in patients with moderate-to-severe disease activity but without active lupus nephritis.²⁵ This molecule binds and neutralizes most subtypes of IFN-α. Patients who were felt to be inadequate responders to standard of care therapy were randomized to three fixed intravenous dosages of sifalimumab or placebo. In this study, 431 patients were randomized to monthly intravenous sifalimumab 200 mg, 600 mg or 1200 mg or placebo plus standard of care therapy. Stratification of patients at baseline by disease activity, geographic region and IFN-regulated gene expression was undertaken. As opposed to the rontalizumab study, which used three genes for their ISM, this study utilized four genes for determination of their IFN-regulated gene expression signature. Outcome efficacy at 52 weeks was assessed, with the primary efficacy end point being the percentage of patients achieving an SRI response.

At all dosages of sifalimumab, a greater percentage of patients achieved the primary end point compared to placebo (1200 mg, 59.8%; 600 mg, 56.5%; 200 mg, 58.3%; placebo, 45.4%) with significant differences noted in the 200 mg and 1200 mg dosage groups. These effects were significant in the IFN-high but not in the IFN-low groups at these dosages. Other significant responses were seen in several dosage treatment groups compared to placebo, including the 200 mg and 1200 mg dosage groups using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score, which is a secondary efficacy end point that assesses skin disease activity, and in several treatment dosage groups using predefined outcome efficacy end points, such as physician’s global assessment, the BILAG-composite index and the percentage of patients who achieved different levels of reductions in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000 score. In a post hoc analysis of the reduction in numbers of tender and swollen joints, there were significant differences between all sifalimumab dosage groups and placebo. There were no significant differences in the percentage of patients with serious adverse events between the sifalimumab treatment groups and the placebo group; although, sifalimumab-treated patients more frequently had herpes zoster infections. Although this molecule appeared to demonstrate significant clinical effects across several different validated end points and in organ-specific assessments of disease activity, it was not chosen by its sponsoring pharmaceutical company to proceed with development.

Table 1

Phase II studies for Type I IFN-targeted therapeutic agents in SLE.

Molecule	Molecular design	Results	Future plans
Rontalizumab	Humanized anti-IFN-α monoclonal antibody	• Did not meet primary efficacy endpoint • In an exploratory analysis of IFN-low patients, higher SRI response and less corticosteroid usage seen • IFN-low group had significantly reduced flare rates • No safety signals noted	No further studies planned
Sifalimumab	Fully human anti-IFN-α monoclonal antibody	• Primary efficacy endpoint met in several dosage groups • Efficacy seen in IFN-high patients • Efficacy seen in organ-specific outcomes • No increase in serious adverse effects but increased herpes zoster risk	No further studies planned
Anifrolumab	Fully human type I IFN receptor monoclonal antibody	• Primary efficacy endpoint met in one dosage group and secondary efficacy endpoint met in both tested dosages • Significant difference in ability to achieve tapering to daily oral corticosteroid dosages of 7.5 mg in one dosage group • Efficacy seen in organ-specific outcomes • No increase in serious adverse effects but increased herpes zoster risk and more influenza infections seen	Pivotal phase III studies underway

Anifrolumab

Anifrolumab, a fully human IgG1κ monoclonal antibody, was also studied in SLE patients with moderate-to-severely active disease activity but without active lupus nephritis and who had had inadequate responses to standard of care medications.²⁶ This molecule prevents signaling by all types of type I IFNs, including IFN-α, IFN-β, IFN-ɛ, IFN-κ and IFN-ω, by binding to a type I IFN receptor.²⁷ In this study, 305 patients were randomized to receive either intravenous anifrolumab 300 mg, anifrolumab 1000 mg or placebo monthly for 48 weeks. Stratification of patients was undertaken based on baseline SLEDAI score, baseline oral corticosteroid dosage and IFN gene signature (IFN-high vs. IFN-low based on the same four-gene expression assay used in the sifalimumab study discussed previously). The primary end point was a composite of SRI response at day 169 using a four-point improvement in SLEDAI and a sustained reduction of oral corticosteroid to less than 10 mg daily and at least the same day 1 corticosteroid dosage or less maintained between days 85 and 169. Secondary end points assessed at 52 weeks included a composite of SRI using a four-point improvement in SLEDAI and sustained reduction of oral corticosteroids maintained between days 281 and 365 and a separate end point that required reduction of oral corticosteroids to 7.5 mg daily of prednisone or equivalent by day 365 in those taking 10 mg daily or more at baseline. Other efficacy outcome assessments included measurements of organ-specific disease activity at day 365.

The primary efficacy end point was met by a greater percentage of anifrolumab-treated patients compared to placebo (1000 mg, 28.8%; 300 mg, 34.3%; placebo, 17.6%) with the 300 mg dosage group achieving statistical significance (p = 0.014). The secondary SRI end point was achieved by a statistically significant greater percentage of anifrolumab-treated patients (1000 mg, 38.5%; 300 mg 51.5%; placebo, 25.5%); 1000 mg group vs. placebo, p = 0.048 and 300 mg group vs. placebo, p < 0.001. Oral corticosteroid reduction to 7.5 mg daily or less was achieved at day 365 by 26.6% of placebo-treated patients, 56.4% of patients in the 300 mg dosage group (p < 0.001 vs. placebo) and 31.7% % of the 1000 mg dosage group (p = 0.595 vs. placebo). In organ-specific assessments of outcome, the percentage of patients with a baseline CLASI activity score of 10 or greater who had a 50% or greater reduction in this score by day 365 was significantly greater in the 300 mg dosage group compared with placebo. For patients with eight or more tender and eight or more swollen joints at baseline, a significantly greater percentage of patients in the 300 mg treatment group had a 50% or greater decrease in both the tender and swollen joint counts compared with placebo (p = 0.038). In both dosage groups of anifroluab, median suppression of 21 INF-regulated genes was approximately 90% in IFN-high patients. Improvements across multiple end points were even more pronounced in the IFN-high patients treated with anifrolumab. There were no significant differences in the percentage of patients with serious adverse events between the anifrolumab treatment groups and the placebo group, but there was a higher frequency of influenza in the anifrolumab groups and a dose-dependent increase in herpes zoster infection.

Anifrolumab appeared to significantly reduce disease activity across multiple global and organ-specific efficacy end points. Enhanced clinical effects in IFN-high patients appear to support the pathobiological effects of this targeted therapy. The lack of a dose-related response might be explainable on the bases of the near identical degree of IFN-regulated gene inhibition achieved by the two explored dosages. Given these efficacy data and the adequate safety patterns seen, this molecule was chosen for further development and pivotal phase III studies are now underway.

Conclusion

There appears to be emerging data to support the concept of targeting type I IFN in SLE patients based on the efficacy and safety data seen in three separate phase II randomized, multi-center clinical trials. Data related to the clinical effects of targeting the IFN-a receptor will be forthcoming through the ongoing phase III clinical trials of anifrolumab. Further drug development efforts should be also considered, which target pDCs and TLR7 and TLR9 given the effects these components have on the production of type I IFN.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KC Kalunian has acted as consultant for Medimmune and Genentech and has received research funding support for the conduct of clinical trials from Medimmune and Genentech.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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