The US Food and Drug Administration (US FDA) has approved Janssen Biotech's Sylvant (siltuximab) for the treatment of patients with multicentric castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Sylvant was not studied in patients with MCD who are HIV positive or HHV-8 positive because Sylvant did not bind to virally produced interleukin-6 (IL-6) in a nonclinical study.

Sylvant is an IL-6 antagonist biologic therapy administered as an intravenous (IV) infusion once every three weeks. Sylvant is the first approved treatment in the US for MCD.

MCD is a rare blood disorder with high morbidity in which lymphocytes, a type of white blood cell, 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.

"There has been a serious need for treatment options for patients with MCD," said Frits van Rhee, managing director, University of Arkansas for Medical Sciences, and MCD2001 study lead investigator. "MCD is a complex disease and up until this point, physicians have tried to reduce lymph node masses and put the disease in remission through a combination of treatments, but MCD often returns. Today's approval of Sylvant gives physicians a long-awaited treatment option for a group of patients who has been suffering with this chronic, serious and debilitating disease."

"Today's approval of a treatment for patients with multicentric Castleman's disease marks a significant milestone for patients living with this rare disease and underscores the importance of ongoing research and development in areas where there are so few patients with such a high unmet medical need," said Peter L. Saltonstall, president and chief executive officer, National Organisation of Rare Disorders (NORD), a federation of health organisations dedicated to helping people with rare diseases.

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.

"Sylvant exemplifies Janssen's approach to research and development, as well as our commitment to patients," said Peter F. Lebowitz, managing director, Global Oncology Head, Janssen. "Our expertise in hematologic malignancies was key to recognising the potential for Sylvant in this rare disease. We're extremely proud to be the first company with an approved medicine to treat MCD in the 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 randomized study in MCD.8 Fifty-three patients were randomised to the Sylvant arm at a dose of 11 mg/kg and 26 patients were randomised to the placebo arm. Patients had symptomatic MCD and were HIV negative and HHV-8 negative.1

Treatment of MCD tumors and related symptoms is an important treatment goal for these patients. In this pivotal study, which led to the FDA 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 per cent;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 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<0.05). Efficacy results from MCD2001 also showed tumour response for those in the Sylvant arm was 38 per cent versus four per cent for those in the placebo arm (p<0.05). Among ananaemic patients, an increase in haemoglobin of 1.5 g/dL was seen in 61 per cent of patients in the Sylvant arm versus 0 per cent in patients who received placebo and BSC (p<0.05).

Sylvant is an anti-interleukin-6 (IL-6) chimeric monoclonal antibody that binds to human IL-6.1 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.

On September 3, 2013, Janssen announced simultaneous submissions of a Biologic License Application (BLA) to the United States Food and Drug Administration (US FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for siltuximab for the treatment of patients with MCD who are HIV negative and HHV-8 negative. The FDA granted the siltuximab BLA priority review in the US and the EMA has granted Accelerated Assessment of the MAA. Siltuximab has been granted orphan drug status in MCD in the US and European Union.

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. Signs and symptoms are driven by dysregulated IL-6 production.Common symptoms include enlarged lymph nodes (appearing as lumps under the skin), fever, weakness, fatigue, night sweats, weight loss, loss of appetite, nausea, vomiting and nerve damage that leads to numbness and weakness.2 Some symptoms can be life threatening. Infections, multisystem organ failure and malignancies including malignant lymphoma are common causes of death in patients with MCD.