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Lupus – a 'great imitator'

Presenting with symptoms common to a range of diseases, Systemic Lupus Erythematosus is hard to diagnose and treatments are difficult to develop

Butterfly imitating a leafLupus is an autoimmune disease characterised by inflammation and tissue damage, caused by the body's immune system mistakenly attacking healthy cells. Lupus encompasses a collection of diseases caused by problems with immunity. However, it is most often used to refer to Systemic Lupus Erythematosus (SLE) and affects around nine times more women than men. Approximately one in 750 women in Europe has SLE and, if it is left untreated, many sufferers do not live beyond the age of 50.

SLE is a systemic disease which can affect any part of the body and is a difficult disease to diagnose due to its heterogeneity. It is one of several diseases known as 'the great imitators'. The disease manifests as a myriad of symptoms, including fatigue, fever, loss of appetite, alopecia and joint pain, which are common to many other diseases. A facial rash over the bridge of the nose is often seen in patients with SLE.

Hereditary component
Its causes are unknown; a hereditary component is suspected as the disease is found more often among relatives than in the general population and environmental factors, such as sun exposure, may play a part in the progression of the disease. The female predominance of SLE suggests that female hormones contribute to its expression. SLE can also be triggered by the use of certain medications known to stimulate the immune system. However, this is relatively rare and the effects are often reversible through discontinuation of the medication.

SLE is widely thought to be a B-cell mediated disease and approved therapies in use today were developed based on this hypothesis. Current research suggests that T-cells may also play an important role in the pathophysiology of SLE, fuelling research efforts for this alternative target. However, despite continued research into this complex disease, effective treatment remains undefined and largely determined by specific organ involvement.

Current treatments include immunosuppressive and cytotoxic agents, such as high-dose glucocorticoids, cyclophosphamide, methotrexate, as well as mycophenolate mofetil. However, the side effects of these treatments are often intolerable and results can vary between patients.

Immunosuppressants such as mycophenolate mofetil (CellCept, Roche) and tacrolimus (Prograf, Astellas Pharma) are used to inhibit the body's production of auto-antibodies, which are responsible for the classical symptoms of SLE.

These drugs have proved effective in the treatment of very active SLE, particularly in patients with kidney or neurological manifestations, as well as acute blood vessel inflammation. They can also eliminate the need for corticosteroids, long term use of which can produce side effects such as osteoporosis.

However, mycophenolate mofetil and tacrolimus were initially developed for patients undergoing organ transplantation.

Therefore, their use in the treatment of SLE can lead to life-threatening complications related to depression of blood cell counts, such as opportunistic infections and bleeding.

It is clear that the future development of targeted therapies will be hugely beneficial to patients with SLE.

Most current therapies seek to correct imbalances in the immune system broadly and are usually developed for other autoimmune disorders, such as rheumatoid arthritis (RA), and then extended to SLE. However, this approach is understandable for a disease which shares the same characteristics as many others. The challenge remains to develop a drug which is effective for all patients.

Newly launched drug
A new drug which has been launched recently in the US for the treatment of SLE is belimumab (Benlysta, Human Genome Sciences/GlaxoSmithKline). Belimumab is a monoclonal antibody which specifically recognises and inhibits the biological activity of B-lymphocyte stimulator (BLyS), thereby dampening the B-cell response in patients with autoimmune diseases such as SLE. Approval was based on results from the largest phase III trial programme for a lupus drug to date, demonstrating an improvement in patient response rate compared with placebo.

Despite its success, belimumab's efficacy profile is still considered to be modest; only a little over half of patients respond at all. Nevertheless, it is not expected that this will affect the demand for the drug among patients, considering the limited treatment options available for SLE. The safety profile of belimumab does appear to be more favourable than alternative existing therapies. The potential exists for the use of belimumab in combination with other lupus drugs, which may result in increased efficacy.

Following in the footsteps of belimumab is tabalumab (Eli Lilly), another anti-BLyS monoclonal antibody, currently in phase III clinical trials for the treatment of SLE and rheumatoid arthritis. Eli Lilly chose to bypass phase II trials of tabalumab in SLE, apparently due to the success of belimumab. Data has not yet been published, but it is unlikely that tabalumab will be able to compete directly with belimumab, unless the drug can offer a significantly better efficacy profile.

Direct target
Atacicept (Merck Serono) is a soluble fusion protein, based on two TNF receptor family members, TACI and BCMA, expressed on the surface of B-cells, which bind growth factors and, when stimulated, induce the production of antibodies.

Atacicept is unique in that it is being developed solely for the treatment of lupus. It was tested in a phase III clinical trial as an adjunctive therapy to mycophenolate mofetil for the treatment of lupus nephritis. However, this trial was discontinued owing to an apparent increased risk of severe infection. Almost concurrently, Merck Serono initiated a phase II/III trial of atacicept in reducing the number of flares in patients with SLE; this trial appears to be ongoing.

Lupus nephritis trials have largely been unsuccessful, therefore it is hoped that, with the change in patient population, atacicept will show some efficacy in these patients. Even so, like many agents in the same class, atacicept is predicted to have only a 50 per cent probability of approval in SLE, at best.

Targeting B-cell activation appears to be the chosen route for the majority of treatments for SLE, including epratuzumab (Epratucyn, Immunomedics/UCB). This antibody targets the CD22 receptor, which is present on the surface of mature B-cells and on many types of malignant B-cells. Combined data from 90 patients from two discontinued phase III trials (SL0003 and SL0004) demonstrated that epratuzumab 360 or 720 mg/m2 IV was associated with improvements in British Isles Lupus Assessment Group Index (BILAG) score and reductions in steroid use from weeks four to 48, with an overall incidence of adverse events similar to placebo. Phase III clinical trials are ongoing. However, B-cell depleting therapies such as epratuzumab have been known to show little effect in patients with SLE.

Lack of clarity
It is unclear why B-cell modification appears to be more effective than B-cell depletion, although past experience has demonstrated that the benefit of rituximab, a B-cell depleting therapy, is offset by its significant adversity profile, making it unsuitable for approval in SLE.

An alternative approach to the treatment of SLE comes in the form of forigerimod (Lupuzor, ImmuPharma/Cephalon). This compound modulates the signalling of a specific subset of CD4 T-cells through a reportedly unique and poorly characterised mechanism of action. Initial results have been promising: forigerimod 200 ug once-a-month for three months achieved a clinically significant improvement in response rate versus placebo in a phase IIb trial. A phase III programme is expected to commence shortly, with similar positive results anticipated.

Another therapy targeting T-cell proliferation is abatacept (Orencia, Bristol-Myers Squibb). Approved for the treatment of RA, abatacept is a genetically-engineered fusion protein of human CTLA4 and the IgG1 Fc region, which prevents T-cell proliferation by binding with high affinity to CD80. A phase II/III clinical trial is underway in patients with active proliferative glomerulonephritis due to SLE.

However, despite its success in RA, abatacept faces significant obstacles in its path to approval for SLE. A phase II study of abatacept in 175 patients with SLE did not meet its primary or secondary efficacy endpoints related to the proportion of patients with a new SLE flare after the start of prednisone taper over one year. It is uncertain whether the company's commitment to testing abatacept in patients with SLE will result in a viable treatment option. Nevertheless, results will help determine whether targeting T-cell proliferation is an acceptable approach in the treatment of this disease.

Looking forward, scientists are considering alternative targets and novel mechanisms of action, such as inhibition of interferons like IL-6 and IL-17, which are responsible for inflammation and immunomodulation, respectively. Antibodies against IL-17 are being developed separately by Novartis, Amgen and Eli Lilly for the treatment of autoimmune conditions, but not yet for SLE. Syk inhibition is also considered to be a promising target in the treatment of SLE. Fostamatinib (Rigel/AstraZeneca) was being evaluated in SLE, but the phase II trial was terminated.

Nevertheless, syk remains a valuable target, due to its expression in B-cells and monocytes. It is not anticipated that development of drugs for the treatment of SLE will be as active as other areas such as RA. SLE is comparatively rare. It is considered to be an orphan indication, with approximately 10 times fewer patients than RA. However, for reasons that are poorly understood, the incidence of SLE has nearly tripled in the last 40 years, indicating that a demand clearly exists for effective treatments.

The Author
R&D Pipeline was written by Chin-Hang Kong of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or Email:

15th September 2011


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