The European Commission (EC) has approved the use of Janssen-Cilag International's Sylvant (siltuximab) for the treatment of adult patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpes virus-8 (HHV-8) negative.

Sylvant is a monoclonal antibody (a specialised type of protein) that binds selectively to an antigen in the body called interleukin-6 (IL-6). Sylvant is administered as an intravenous (IV) infusion once every three weeks and is the first medicine to receive regulatory approval in the EU for the treatment of MCD patients.

MCD is a rare blood disorder with high morbidity in which lymphocytes, a type of white blood cells, are over-produced, leading to enlarged lymph nodes. MCD can also affect lymphoid tissue of internal organs, causing the liver, spleen, or other organs to enlarge. Infections, multisystem organ failure and malignancies including malignant lymphoma are common causes of death in patients with MCD. It is classified as a rare disease by the European Commission, meaning that it affects fewer than five in 10,000 people. In fact, MCD is so rare that it is difficult to track the number of cases across Europe. As the majority of publications on MCD are based on case reports, epidemiological evidence is very scarce. However, a recent study from the US estimated the 10-year prevalence of MCD to be 2.4 cases per million inhabitants.

"The approval of Sylvant means that there is now an EU approved treatment for patients with MCD who are HIV negative and HHV-8 negative. Sylvant will provide an urgently needed treatment option that will make a significant difference to the way that MCD is managed," said Professor Pier Luigi Zinzani, Associate Professor of Hematology, University of Bologna, Italy. "It has the potential to become a new standard of care for patients, providing an important new therapeutic option to those suffering with this chronic, serious and debilitating disease."

While the cause of MCD currently is unknown, overproduction of IL-6 is considered a key mechanism in MCD. Sylvant works by binding to human IL-6, a multifunctional cytokine produced by various cells such as T cells, B cells, monocytes, fibroblasts and endothelial cells.

Jane Griffiths, company group chairman of Janssen Europe, the Middle East and Africa (EMEA) said, "Janssen is committed to developing compounds in areas of unmet medical need and our expertise in haematologic malignancies was key to recognising the potential of Sylvant. As the first company with an approved medicine to treat MCD in Europe, we are very proud to be able to offer an effective treatment option for eligible patients with this rare and challenging disease and further demonstrate our commitment to patients."

The EC approval was based on the results of the MCD2001 Pivotal Study and follows the accelerated assessment and recommendation from the CHMP to approve Sylvant on March 20, 2014. The US Food and Drug Administration's approval of Sylvant was announced on April 23, 2014. Sylvant has been granted orphan drug status for MCD in both the EU and the United States (US).

The efficacy and safety of Sylvant were evaluated in a multi-national, randomised, double-blind, placebo-controlled pivotal study in 79 patients with MCD (MCD2001). MCD2001 is the first randomised study in MCD. Fifty-three patients were randomised to the Sylvant arm at a dose of 11 mg/kg every 3 weeks and 26 patients were randomised to the placebo arm. Patients had symptomatic MCD and were HIV negative and HHV-8 negative.

Treatment of MCD tumours and related symptoms is an important treatment goal for these patients. In this pivotal study, which led to the European Commission approval, more than one-third of patients in the Sylvant arm had a durable tumour and symptomatic response to treatment plus best supportive care (BSC), compared to none of the patients who received placebo plus BSC (34 per cent versus 0 percent according to stringent criteria; 95 per cent CI: 11.1, 54.8; p=0.0012). A durable response was defined as tumour and symptomatic response (reduction in tumour size and complete resolution or stabilisation of disease symptoms) that persisted for a minimum of 18 weeks without treatment failure. The median time to treatment failure was not reached for patients who received Sylvant plus BSC; those who received placebo plus BSC experienced treatment failure at a median of 134 days (p=0.0084). Efficacy results from MCD2001 also showed tumor response for those in the Sylvant arm was 37.7 per cent versus 3.8 per cent for those in the placebo arm (p=0.0022). Among anaemic patients, an increase in hemoglobin of at least 15 g/L at week 13 was seen in 61.3 per cent of patients in the Sylvant arm versus 0 percent in patients who received placebo and BSC (p=0.0002).

Sylvant is an anti-interleukin-6 (IL-6) chimeric monoclonal antibody that binds to human IL-6.2 IL-6 is a multifunctional cytokine produced by various cells such as T cells, B cells, monocytes, fibroblasts and endothelial cells. Dysregulated overproduction of IL-6 from activated B cells in affected lymph nodes has been implicated in the pathogenesis of, or mechanism causing, MCD.

MCD is a rare blood disorder with high morbidity in which lymphocytes, a type of white blood cell, are over-produced and lead to enlargement of lymph nodes. MCD can also affect lymphoid tissue of internal organs, causing the liver, spleen or other organs to enlarge. MCD signs and symptoms are driven by dysregulated IL-6 production. Some symptoms can be life threatening.

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