The FDA has approved the anti-IL-6 chimeric monoclonal antibody siltuximab (Sylvant) as a treatment for HIV- and HHV-8-negative patients with multicentric Castlemanâ€™s disease (MCD).
Siltuximab is the first therapy to gain approval for the rare lymphoproliferative disorder. In the pivotal study, treatment with siltuximab plus best supportive care improved durable tumor and symptomatic response by 34% compared with no response with placebo plus best supportive care. Additionally, 25% of patients treated with siltuximab experienced complete symptom resolution for a minimum of 18 weeks. At a median 5.1-year follow-up, the median time to treatment failure with siltuximab had not been reached compared with a 134-day median for placebo.
“Sylvant is the first FDA-approved drug to treat patients with MCD,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval demonstrates the FDA’s commitment to approving drugs for rare diseases.”
In the study, 79 patients with HIV- and HHV-8-negative MCD were randomized in a 2:1 ratio to receive siltuximab plus best supportive care (n = 53) or best supportive care and placebo (n = 26). Intravenous siltuximab was administered at 11 mg/kg every 3 weeks. After treatment failure, approximately 50% of patients in the placebo arm crossed over to receive siltuximab. In total, 58% of patients received prior systemic therapy.
According to results presented at the 2013 ASH annual meeting, 1 patient treated with siltuximab experienced a complete response and 17 patients experienced a partial response. The overall response rate was 34% compared with 0% (P= .0012) and the durable symptomatic response rate was 57% versus 19% (P= .0018), for siltuximab and placebo, respectively. By central radiology review, response rates were 38% compared with 4% (P= .0022).
After 13 weeks of therapy, 61% of anemic patients treated with siltuximab experienced an improvement in hemoglobin levels of ≥15 g/L compared with 0% with placebo (P= .0002). Additionally, patients treated with siltuximab experienced a sustained reduction in inflammatory markers, such as CRP, ESR, and fibrinogen.
The median duration of treatment was 375 days with siltuximab compared with 152 days with placebo. The median time to next therapy was not reach in the investigational arm compared with 280 days for placebo (P= .0013). Treatment emergent adverse events were similar between the two arms, despite the substantially longer treatment duration for siltuximab.
Baseline symptoms included fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia (37%), and pruritus (37%). The most frequent all-grade adverse events experienced during the trial were rash (28%), pruritus (28%), upper respiratory tract infection (26%), increased weight (19%), and hyperuricemia (11%).
The most common adverse events greater than grade 3 associated with siltuximab were fatigue (9%) and night sweats (8%). Additionally, grade 3/4 hyperkalemia, hyperuricemia, localized edema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension, and weight gain were each experienced by 4% of patients.
"There has been a serious need for treatment options for patients with MCD," Frits van Rhee, MD, PhD, lead investigator of the MCD2001 study and professor of medicine at the University of Arkansas for Medical Sciences, said in a release. "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."
Siltuximab binds to IL-6, which is overproduced in patients with MCD. This mechanism reduces symptoms caused by high-levels of the cytokine. However, in nonclinical studies, siltuximab did not bind to IL-6 produced in response to HIV and HHV-8. As a result, the medication was not explored in this setting by its developer, Janssen Biotech Inc.