A new phase II clinical trial designed to evaluate the safety and efficacy of brentuximab vedotin (Adcetris®; Seattle Genetics) in systemic lupus erythematosus also known as SLE or lupus, has been initiated by researchers at Seattle Genetics.

Systemic lupus erythematosus is a chronic autoimmune rheumatic disease in which the body’s own immune system, the part of the body that identifies and fights off foreign invaders such as viruses and bacteria, overreacts, creating autoantibodies (antibodies directed against self, or host proteins) and other autoimmune responses that attack multiple healthy organs, causing inflammation, pain and permanent organ damage. Without proper treatment the the disease is often fatal. There is no currently known cure for the disease.

Fig 1.0. Innate immunity – the first line of defense – refers to nonspecific defense mechanisms which follows immediately or within hours of an antigen’s appearance in the body. The innate immune response is activated by chemical properties of the antigen. The adaptive immune response – the second line of defense – is more complex than the innate immune response. In this case, the antigen must first be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity also includes a “memory” that makes future responses against a specific antigen more efficient.

Systemic lupus erythematosus is caused by pathogenic autoantibodies and involves various facets of both the innate and adaptive immune system.  Studies have also shown that approximately 35 genes
are associated with development of the disease, underscoring the complexity of inheritance that probably contributes to its development. In patients with a genetic predisposition to autoimmunity and systemic lupus erythematosus, normal immune responses become dysregulated. This leads to an increase of the production of autoantibody. [1] [2]

Furthermore, environmental triggers include Epstein–Barr virus infection [3], exposure to ultraviolet light, estrogen-containing medications, silica dust, and smoking tobacco. [4]

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Involvement of cytokines
Emerging evidence suggests that cytokines play a key role in the differentiation, maturation and activation of immune cells – and are involved in immune dysregulation of systemic lupus erythematosus as well as the local inflammatory response which leads to tissue damage. Various studies have shown that an imbalance in cytokine production and cytokine levels  – including an altered balance of Th1-/Th2-type cytokines, with an overproduction of Th2-type cytokines such as IL-4 and IL-6 – directly correlates with disease progression. Hence, researchers believe that a better understanding of cytokines and their interactions is an important factor in the treatment strategy as well as an avenue for new drug development. [5][6][7]

Effect of hormones
Some evidence suggests that pregnancy is a factor in the development systemic lupus erythematosus and may aggravate the diseases. Although it is not yet clear whether rising levels of estradiol or progesterone play a role, a link between pregnancy outcome and the status of the disease at conception has been noted in some studies. Interestingly, levels estradiol or progesterone are lower during the second and third trimesters in patients with systemic lupus erythematosus than in healthy pregnant women. [8][9] Some studies have also shown that there is an increased risk of developing the disease in postmenopausal women who received estrogen replacement therapy. [10]

The  cell-surface glycoprotein Cluster of Differentiation 30 or CD30, which is a member of the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily, is expressed on activated lymphocytes that are thought to play a key role in the development of autoimmune diseases, including systemic lupus erythematosus.

On normal – healthy – cells, expression of CD30, which has a molecular weight of 120 kDa, is highly restricted. In contrast, expression of CD30 is upregulated in various hematological malignancies and originally described as a marker of Hodgkin’s disease (HD) and Reed-Sternberg cells in Hodgkin’s lymphoma, anapestic large cell lymphoma (ALCL) and subsets of Non-Hodgkin’s lymphoma (NHL). It’s  preferentially expressed on CD4− and CD8+ T-cell clones that produce T helper 2 (Th2)-type cytokines and released in a soluble form by these cells. Interestingly, elevated serum levels of soluble CD30s have been found in a number of conditions in which a pathogenic role for Th2 cells has been suggested.

These conditions include systemic lupus erythematosusatopic dermatitis, asthma, allergic rhinitis and localized scleroderma. [11] CD30+ cells and soluble CD30s have also been detected in the circulation of some patients with rheumatoid arthritis. [12] Finally, soluble CD30s has been detected in the peripheral blood of patients with localized scleroderma and primary progressive multiple sclerosis. [13][14]

The evaluation of Soluble CD30s serum levels has been recognized as a predictor of (good) respons in the treatment of rheumatoid arthritis and may, in this disease, represent a simple method to assess the anti-inflammatory activity of Th0/Th2 cells in early disease.

Given the fact that CD30 is involved in important regulatory functions of the immune system, their low expression in normal conditions, as well as increased expression in malignancies, autoimmune and inflammatory disease, it is an attractive target for ongoing research in systemic lupus erythematosus.

Incidence and mortality
According to the Lupus Foundation, an estimated 5 million people throughout the world have various forms of lupus and at least 1.5 million people in the United States are living with the disease. While men may develop the disease, approximately 70 – 90% of all lupus-patients are women with disease onset during the childbearing age (15 – 44 year of age).

The prevalence of the disease also varies according to race and ethnic background.  Statistical data shows a higher prevalence rates among latinos, blacks, and afro-caribbeans, and a lower prevalence rates are among whites and asians. [15]  Overall survival (OS) also vary by race and ethnic background, with an average 5-year survival rate of approximately 95% among whites, 90% among blacks and afro-caribbeans, and 87% among latinos. The 10-year survival rate is about 70%. [15] But according to the available literature, men as well as people in lower socioeconomic groups and Lupus-patients with nephritis have a much lower survival rates than other patients with the disease.

Approximately 80% of patients with systemic lupus erythematosus have persistently active disease or frequent flares with irreversible organ damage generally developing over a period of 6+ years in the majority of these patients. A particular high mortality rate is seen in active disease (particularly nephritis), infections, and accelerated atherosclerosis. [16]

Cost of disease
In the United States, one third of patients with musculoskeletal manifestations of lupus are unable to work. In 2011, the annual individual direct health related costs of systemic lupus erythematosus of these patients in the United States were estimated to be between $13,735 to $20,926. [17] In addition to the direct costs, indirect costs and loss of productivity also contribute greatly to the total economic burden of the disease.

Limited treatment options
Despite enormous efforts in finding real and conclusive answers regarding the etiology and pathogenesis of systemic lupus erythematosus, treatment is still complex and treatment options remain limited.

Treatment for patients systemic lupus erythematosus often complicated by the fact that the clinical spectrum of the disease is rather diverse, and patients often present with very vague manifestations (including fever, fatigue, and arthralgia) which can pose a real diagnostic challenge for clinicians who may not recognize the systemic nature of the disease. In addition to the complexity of diagnosis, adequate treatment requires finding a balance between immunosuppression and immune dysregulation. A real challenge for physicians indeed.

The current recommended treatments aims to restore the balance in a dysregulated immune system and the treatment choice is generally determined by the severity of the disease and the function of the involved organ. [18]

Since the 1950’s glucocorticoids – which still forms the mainstay of treatment – has changed the management of most rheumatic diseases including systemic lupus erythematosus.  The use of glucocorticoids has led to a gradual improvement in disease management as well as improvements of the health related Quality of Life (hrQoL) of patients with the disease. And at the right individualized dose, glucocorticoids are rapid in onset and – in most cases – nearly universally effective, regardless of the organ activity that has manifested. Unfortunately, the long-term use of these drugs is associated with major toxicities, involving increased risk of infection, bone health, and glucose homeostasis (the balance of insulin and glucagon to maintain blood glucose).

Based on the European League Against Rheumatism (EULAR) treatment recommendations, patients with mild, non-organ threatening disease, can, in most cases, be effectively treated with steroid-sparing treatments, including antimalarials, in particular hydroxychloroquine (Plaquenil®; Clovis Pharma)[*] and transient use of nonsteroidal anti-inflammatory drugs (NSAIDs; this may provide symptomatic relief for arthralgias, fever, headache, and mild serositis).

For patients with organ threatening disease or illness that is not responding to an acceptable dose of steroids, or in cases in which treatment with steroids is not possible as a result of co-morbidities [**], immune suppressants are often initiated. Mycophenolate mofetil (MMF; CellCept®, Genentech/Roche) or cyclophosphamide (Cytoxan®; Bristol-Myers Squibb Company) are usually used as the first line treatment for lupus nephritis (inflammation of the kidney that is caused by systemic lupus erythematous which, if uncontrolled, can lead to kidney failure), and in either case, corticosteroids are added. Patients requiring maintenance therapy are generally treated with either mycophenolate mofetil or azathioprine (Imuran®; Prometheus Labs).

Finally, in the case of refractory disease, any of the standard treatments is combined, with treatments including biologics and antibody inhibiting strategies, such a intravenous immunoglobulin (IVIG) or plasma exchange. Stem cell transplant is generally reserved for the refractory cases with very limited treatment options.[19]

Belimumab (LymphoStat-B; Benlysta®, GlaxoSmithKlein/GSK ) is a fully humanized immunoglobulin G (IgG) 1-λ monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). The drug, indicated for active, autoantibody-positive patients in whom standard therapy, including corticosteroids, antimalarials, immunosuppressives, and nonsteroidal anti-inflammatory drugs, has failed, was approved by the U.S. Food and Drug Administration (FDA) in 2011. [19] Although belimumab may clearly address an unmet need for some patients with systemic lupus erythematosus, the drug has only a limited efficacy, is expensive, requires intravenous administration and adverse effects lead to discontinuation of treatment in about 30% of patients.  An additional 30% of patients treated with this drug show neither a response nor adverse effects.  These incremental improvements in the treatment of the disease makes the development of therapeutic alternatives a necessity.

Ongoing trials
But not all clinical trials are successful. While B-cell depletion in the treatment of autoimmune and rheumatoid arthritis has shown some clinical efficacy, and a small study with the chimeric anti-CD20 antibody rituximab (Rituxan®; Genentech/Roche‎) has shown initial promise in patients with systemic lupus erythematosus, the large phase II/III EXPLORER trial of the drug in patients with moderate-to-severe systemic lupus erythematosus failed to reach its primary end points. [20][21][22]  

In contrast, results presented during the 73th Annual Scientific Meeting of the American College of Rheumatology, October 18, 2009, which was held in Philadelphia, PA, showed a significant drop in disease activity in one study which included 35 african-american and latino patients who received four weekly infusions and were followed for two years.  This even included patients with lupus nephritis. [23]  Results from another trial, presented during the same meeting, included 86 participating patients treated with rituximab with or without other lupus treatments for an average of 15 months. This study showed improvement in an estimated 73% of treated patients. Overall, in this study, 10 people had severe infections and one of these patients died from an infection. [24]  

Although rituximab has not been approved for the treatment of patients with systemic lupus erythematosus, the varying results show that it is quite likely that the drug works in certain populations of patients with the disease. Ongoing and future trials may shed more light of the efficacy of rituximab in this setting.

Brentuximab vedotin
The therapeutic potential of antibody-drug conjugates or ADCs has been realized with the approvals  ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) and brentuximab vedotin. Brentuximab vedotin comprises of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to the microtubule disrupting agent monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. This ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.

The trial is designed to assess the safety and activity of brentuximab vedotin in adult patients with lupus. The drug which is being evaluated broadly in more than 30 ongoing clinical trials, including four phase II studies, is approved for the treatment of Hodgkin Lymphoma (HL) and sALCL as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas. It is,however, currently not approved for the treatment of lupus.

“Lupus is a debilitating autoimmune disorder that can affect many of the body’s organ systems, causing a number of serious symptoms. Treatment options are limited, with few FDA-approved disease-modifying therapeutics available,” explained Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Based on a retrospective review of information collected from patients being treated with brentuximab vedotin in the U.S. for lymphoma, we noted some patients reported clinical improvement of concomitant autoimmune diseases, including lupus. Since elevated CD30 expression has been previously reported in lupus patients, we are enthusiastic to evaluate brentuximab vedotin as a potential treatment option for this [debilitating] disease.”

Trial design
The new study is a phase II randomized, double-blind, placebo-controlled dose-escalation clinical trial. The primary objective is evaluation of the safety of brentuximab vedotin in adults with active systemic lupus erythematosus.

In addition, the trial will evaluate the activity and pharmacokinetics of brentuximab vedotin in patients with the disease. In this clinical trial, brentuximab vedotin will be administered every three weeks and approximately 40 patients will be enrolled at multiple centers in the United States.

Given its complexity and the limited, effective, treatment options, the disease represents a real unmet need. Hence, solving the mystery of systemic lupus erythematosus, one of the world’s most cruel, most unpredictable, and most devastating diseases, and eliminating its brutal impact is a priority for many research teams.

The clinical improvement observed in lymphoma patients with of concomitant autoimmune diseases, including lupus, offers an interesting research direction which may potentially lead to a better treatment option. Based on this and similar data, it’s likely that CD30 be the focus of preclinical and clinical research in years to come.

[*] Antimalarials, in particular hydroxychloroquine (Plaquenil®; Clovis Pharma) may help prevent and treat lupus skin rashes, constitutional symptoms, arthralgias, and arthritis and is also associated with limiting lupus flares and reduced morbidity and mortality.

[**] Side effects of steroid use in the treatment of patients with SLE include severe toxicities and damage to the metabolic balance, cardiovascular system, eyes, and bones. Difficulty in tapering steroid use can be seriously detrimental. Steroids are responsible for many of the most severe comorbidities that threaten patients with lupus, and are considered a key factor in infection, one of the common causes of complications and death for lupus patients.


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