FROM THE ANALYST’S COUCH

Systemic lupus erythematosus and lupus nephritisToli Koutsokeras and Tina Healy Isolated couch over white background, from fckncg/Alamy

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is characterized by systemic chronic inflammation that can affect multiple major organ systems. A major contributor to morbidity and mortality among patients with SLE is renal involvement, known as lupus nephritis (LN). The aetiology of SLE and LN is incompletely understood, but a combination of genetic and environmental factors are thought to be involved1.

The clinical course of SLE can vary from mild symptoms to life-threatening multi-organ disease. We estimate that there were approximately 0.45 million diagnosed cases of SLE in 2012 in the seven major markets (United States, France, Germany, Italy, Spain, United Kingdom and Japan), a number that is expected to grow steadily to 0.48 million by 2022 owing to increases in the population and life expectancy, and improvements in disease awareness and diagnosis1.

Current therapiesThe overall goal of disease management in SLE is to suppress chronic inflammation and prevent organ damage. Therapy revolves around five drug classes: non-steroidal anti-inflammatory drugs, antimalarials, steroids, immunosuppressives and biologics.

Although patients with SLE are routinely prescribed antimalarials such as hydroxychloroquine, the exact mechanism by which these drugs modulate the immune response remains unclear. The most commonly used steroid is oral prednisone. Immunosuppressives such as methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide are routinely prescribed off-label. Steroids and immunosuppressives are generally effective but have serious side effects.

Biologics include rituximab (Rituxan; Roche), an anti-CD20 therapy that is prescribed off-label, and belimumab (Benlysta; GlaxoSmithKline), which was approved in 2011 and targets B lymphocyte stimulator (BLYS; also known as BAFF), a protein that is often increased in patients with SLE. Belimumab was the first drug to

be approved for SLE in more than 50 years and is the only approved disease-modifying biologic for SLE. Biologics are expensive add-on therapies and are mainly reserved for patients with high disease activity or who are unresponsive to other available therapies. Significant unmet needs in SLE still remain, particularly for LN, because the induction of disease remission is slow, patients are exposed to substantial toxicity and it is estimated that only 25% of patients achieve a complete renal response with existing treatments2.

Emerging therapiesHistorically, drug development within this therapy area has been challenging and lengthy, and has a high rate of attrition. This is due to difficulties in selecting appropriate clinical end points and background treatments, the high degree of heterogeneity among patients with SLE, and competition for patient recruitment. Diverse R&D strategies are being pursued, and 17 products are in Phase II and III development. These comprise anti-BLYS therapies as well as products that have novel targets in inflammatory pathways (TABLE 1).

Products targeting novel inflammatory pathways include epratuzumab (UCB/Immunomedics), a CD22-specific monoclonal antibody (mAb) that depletes B cells, and rigerimod (Lupuzor; ImmuPharma), a synthetic peptide that modulates the responses of CD4-expressing T cells by binding to heat shock cognate protein 70 (HSC70). Both are in Phase III development. Agents in Phase II development include the mAbs sifalimumab (MedImmune) and rontalizumab (Genentech/Roche), which both target interferon-α; MEDI-546 (MedImmune), a mAb targeting type I interferon receptors; PF-04236921(Pfizer), an interleukin-6 (IL-6)-specific mAb; SM-101 (SuppreMol), which is a soluble version of Fcγ receptor IIB (FcγRIIB) and acts as an FcγRIIB agonist; and the biologic INV-103 (Invion), a modified version of the heat shock protein chaperonin 10 (also known as HSP10).

Anti-BLYS therapies in Phase III development include tabalumab (Eli Lilly), blisibimod (Anthera) and atacicept

(Merck Serono). Unlike belimumab, tabalumab and blisibimod can bind to both membrane-bound and soluble BLYS, and atacicept can also bind to the BLYS family member APRIL (a proliferation-inducing ligand). Blisibimod has shown promising efficacy data in its Phase IIb trial. Interestingly, the development of tabalumab progressed directly to Phase III, bypassing Phase II, therefore efficacy data for patients with SLE are currently unavailable. A safe efficacious dose for atacicept has yet to be established, because the high dose (150 mg) evaluated in its Phase IIb clinical trial demonstrated efficacy but was associated with safety concerns, while the lower dose (75 mg) did not show any efficacy. It remains to be seen whether any of these anti-BLYS products can demonstrate superiority to belimumab.

For LN, GlaxoSmithKline is seeking label expansion for belimumab, and a Phase III programme is underway for this indication. Abatacept (Orencia; Bristol-Myers Squibb), an anti-CD80/CD86 therapy in Phase III, is the most promising pipeline product for LN. A post-hoc analysis of Phase IIb data showed a positive relationship between abatacept as an add-on treatment to immunosuppressive and steroid therapy and the probability of achieving complete renal response at 12 months. Further products for LN in Phase II include BIIB-023 (Biogen Idec), a tumour necrosis factor-like weak inducer of apoptosis (TWEAK)-specific mAb; sirukumab (Johnson & Johnson/GlaxoSmithKline), an IL-6-specific mAb; and the immunomodulator laquinimod sodium (Teva/Active Biotech).

Market outlookWe anticipate that tabalumab, blisibimod, atacicept, epratuzumab, rigerimod and abatacept will potentially enter the SLE and LN market between 2017 and 2022.

Despite the initial excitement for belimumab prior to its 2011 launch, this product has not delivered the expected commercial gains. The uptake for this drug has been low, owing to its expense (an approximate annual cost of US$45,000 ▶

Nature Reviews Drug Discovery | AOP, published online 14 February 2014; doi:10.1038/nrd4227

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Nature Reviews | Drug Discovery

Market volume for SLE2012 2022

Market value for SLE2%

34%

35%

6%

36%

38%

20%29%

20122% 1%

39%

58%

Total:US$473.6

million

2022

80.2%

1.3% 0.4%

18.1%

Total:US$1,158.6

million

Antimalarials Steroids Immunosuppressives Biologics

FROM THE ANALYST’S COUCH

in the United States), mild clinical benefits and physicians’ lack of clinical experience with the drug. However, owing to its high price tag, belimumab has achieved the second highest revenue in the SLE market, having generated approximately $107 million in 2012 in the seven major markets. The top-selling drug is off-label rituximab, which generated approximately $170 million in the same year. Overall, we estimate that drug sales for SLE were over $473 million, and drug sales for LN were over $216 million across the seven major markets in 2012.

On the basis of currently available clinical trial data, upcoming biologics will primarily target patients with high disease activity: that is, approximately 10–15% of patients with SLE. As a result, we anticipate that only a small percentage of the overall patient population will use these treatments. Nevertheless, biologics will shape the SLE and LN markets owing to their associated high treatment costs (FIG. 1). By 2022, we predict the SLE market to be worth approximately $1.1 billion and the LN market $505 million in the seven major markets1.

Toli Koutsokeras is an analyst at GlobalData, 40–42 Hatton Garden, London EC1N 8EB, UK.

Tina Healy is Director, Immunology at GlobalData, 40–42 Hatton Garden, London EC1N 8EB, UK.

e-mails: tkoutsokeras@globaldata.com; thealy@globaldata.com

doi:10.1038/nrd4227 Published online 14 February 2014

1. Koutsokeras, T. & Healy, T. PharmaPoint: Systemic Lupus Erythematosus and Lupus Nephritis — Global Drug Forecast and Market Analysis to 2022 (GlobalData, 2013).

2. Lateef, A. & Petri, M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res. Ther. 14, S4 (2012).

Competing interests statement The authors declare no competing interests.

Figure 1 | Drug sales for SLE in the seven major markets in terms of market value and volume in 2012 and 2022 (estimated). Drug classes

include antimalarials, steroids, immuno suppressives and biologics. SLE, systemic lupus erythematosus.

Table 1 | Systemic lupus erythematosus and lupus nephritis therapeutics — pipeline products in Phase II and III (2013)

Molecule (brand) Company Mechanism of action Molecule type Phase

Systemic lupus erythematosus

Blisibimod Anthera Anti-BLYS (soluble and membrane-bound BLYS) Recombinant protein III

Epratuzumab UCB/Immunomedics Anti-CD22 Monoclonal antibody III

Rigerimod (Lupuzor) ImmuPharma CD4 modulator Synthetic peptide III

Tabalumab Eli Lilly Anti-BLYS (soluble and membrane-bound BLYS) Monoclonal antibody III

Atacicept Merck Serono Anti-BLYS, anti-APRIL Recombinant protein II

GSK-2586184 GSK/Galapagos JAK1 inhibitor Small molecule II

INV-103 Invion Modified chaperonin 10 Recombinant protein II

PF-04236921 Pfizer Anti-IL-6 Monoclonal antibody II

Rontalizumab Genentech-Roche Anti-IFNα Monoclonal antibody II

Sifalimumab MedImmune Anti-IFNα Monoclonal antibody II

MEDI-546 MedImmune Anti-IFNα receptor Monoclonal antibody II

SM-101 SuppreMol FcγRIIB agonist Recombinant protein II

Lupus nephritis

Abatacept (Orencia) Bristol-Myers Squibb Anti-CD80, anti-CD86 Recombinant protein III

Belimumab (Benlysta) GSK Anti-BLYS (soluble BLYS) Monoclonal antibody III

BIIB-023 Biogen Idec Anti-TWEAK Monoclonal antibody II

Laquinimod sodium Teva/Active Biotech Immunomodulator Small molecule II

Sirukumab Johnson & Johnson/GSK Anti-IL-6 Monoclonal antibody II

Source: GlobalData, Pharma eTrack (accessed October 2013). APRIL, a proliferation-inducing ligand; BLYS, B lymphocyte stimulator; FcγRIIB, Fcγ receptor IIB; GSK, GlaxoSmithKline; JAK, Janus kinase; IL, interleukin; IFNα, interferon-α; TWEAK, tumour necrosis factor-like weak inducer of apoptosis.

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