The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recommended that siltuximab (Sylvant, Janssen) be granted marketing authorization for the treatment of multicentric Castleman's disease (MCD). The approval is specifically for the treatment of adults who test negative for HIV and human herpesvirus 8 (HHV-8).
Currently, there are no approved treatments in the United States or European Union for MCD, so this go-ahead from CHMP is likely to lead to the first worldwide approval of a drug to treat the disorder.
The product is under review at the US Food and Drug Administration, but a decision is not expected until later this year.
Siltuximab has already been granted orphan drug status for MCD in both the European Union and the United States. The regulatory submissions included data from a randomized multinational double-blind placebo-controlled study (MCD2001) and from 2 nonrandomized supportive studies.
Castleman's disease is a heterogenous group of rare lymphoproliferative disorders and is associated with, in a subset of cases, HIV and HHV-8. It can be differentiated into at least 2 distinct diseases — unicentric and multicentric. The signs and symptoms of Castleman's disease are driven by dysregulated interleukin (IL)-6 production. The multicentric form of this disease, although not a malignancy, has similarities to lymphoma, and patients can progress to non-Hodgkin's lymphoma.
Siltuximab is a novel chimeric immunoglobulin G1 kappa monoclonal antibody that binds to human IL-6 with high affinity, preventing IL-6 from interacting with the IL-6 receptor.
Results from the MCD2001 study were presented at the 2013 annual meeting of the American Society of Hematology, and reported at that time by Medscape Medical News. The phase 2 randomized double-blind controlled multicenter study involved 79 patients with MCD who were symptomatic, had measurable disease, and were negative for HIV and HHV-8.
Newly diagnosed or pretreated patients were randomized in a 2:1 ratio to an intravenous infusion of siltuximab 11 mg/kg every 3 weeks or placebo. All patients received best supportive care to manage their MCD symptoms.
In the siltuximab group, there was 1 complete response and 17 partial responses; in the placebo group, there were no responses. There was a higher percentage of durable tumor and symptomatic response with siltuximab than with placebo (34% vs 0%; P = .0012), and the median duration of tumor and symptomatic response of 340 days with siltuximab indicates prolonged disease control, according to the researchers.
"About 1 in 3 patients actually achieved a durable tumor response for at least 18 weeks," lead author Raymond S. Wong, MBChB, MD, from the Prince of Wales Hospital and the Chinese University of Hong Kong, said at the meeting. He added that "1 in 4 achieved a complete symptom response for at least 18 weeks in the siltuximab arm."
Patients who received siltuximab had a rapid and significant reduction of inflammatory parameters, such as C-reactive protein and fibrinogen, which was not observed in the placebo group. There was also a significant improvement in anemia and hemoglobin level. More patients in the siltuximab group than in the placebo group experienced improvement in hemoglobin of at least 15 g/L at week 13 (61% vs 0%; P = .0002).
Siltuximab was well tolerated. The most frequently occurring grade 3 events were fatigue (9%) and night sweats (8%) in the siltuximab group, and anemia (12%) in the placebo group.
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Cite this: Siltuximab for Castleman's Disease Recommended in EU - Medscape - Mar 21, 2014.