Janssen Research & Development, LLC ("Janssen") today announced positive results from a pivotal Phase 2 global registration study (MCD2001) suggesting siltuximab, an investigational compound, along with best supportive care (BSC), exhibited statistically significant efficacy and a tolerable safety profile compared with placebo and BSC in treating patients with the rare disorder Multicentric Castleman's Disease (MCD) who are HIV-negative and human herpes virus-8 (HHV-8)-negative. MCD is a disorder in which lymphocytes, a certain type of white blood cells, are over-produced and lead to enlargement of lymph nodes.
These data supported the recent regulatory filings of siltuximab in the United States and European Union. Interim findings from a separate Phase 2 study (MCD2002) reinforce the safety profile of siltuximab. The studies were featured in an oral presentation (MCD2001) and poster presentation (MCD2002) at the 55th American Society of Hematology (ASH) Annual Meeting in New Orleans, USA.
"MCD is a devastating disease that weakens the immune system and may lead to life-threatening infections," said Raymond S. Wong, MBChB, M.D., Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong and lead study investigator. "These results are encouraging and from my perspective support the potential for siltuximab as a new treatment for these patients who previously had no approved treatment options."
The MCD2001 study found more than one-third of patients in the siltuximab arm had a durable tumor and symptomatic response to treatment, compared to none of the patients who received placebo plus BSC (34 percent versus 0 percent). The median time to treatment failure was not reached for patients who received siltuximab plus BSC versus 134 days for who received placebo plus BSC. In looking at the response rate to treat MCD-related symptoms, 25 percent of patients who received siltuximab plus BSC had durable complete symptom resolution, defined as 100 percent of reduction of baseline overall symptom scores for at least 18 weeks, compared to none of the patients who received placebo plus BSC.
The safety profile, defined by frequencies of treatment-emergent adverse events (AEs), Grade 3 or higher AEs and serious adverse events (SAEs), was similar between siltuximab and placebo even with the duration of treatment being twice as long for those in the siltuximab arm. The most frequently reported Grade 3 or higher AEs with siltuximab were fatigue (9 percent), night sweats (8 percent), hyperkalemia (high levels of potassium in blood), hyperuricemia (high levels of uric acid in blood), localized edema (swelling at a specific site in the body), hyperhidrosis (excessive sweating), neutropenia (an abnormally low number of neutrophils, a type of white blood cell), thrombocytopenia (a decrease of platelets in the blood), hypertension (high blood pressure), and weight increase (4 percent each).
In addition, an interim analysis of the Phase 2 study MCD2002 was presented on December 7 in a poster titled:
An Open-Label, Phase 2, Multicenter Study Of The Safety Of Long-Term Treatment With Siltuximab (an Anti-Interleukin-6 Monoclonal Antibody) In Patients With Multicentric Castleman's Disease (Abstract #1806)
This ongoing extension study assessed the safety of long-term treatment with siltuximab in 19 patients with MCD whose disease was controlled for an extended period of time in a Phase 1 study. At the time of study analysis (January 2013), the patients had been treated with siltuximab for up to 7.2 years (median of 5.1 years) with no cumulative toxicity observed. At the data cutoff for this interim analysis of the extension study, all patients were alive and maintaining disease control. Findings suggest prolonged siltuximab treatment exhibited a tolerable side effect profile.
During a median treatment duration of 5.1 (range 3.4-7.2) years, the most commonly reported AEs included upper respiratory tract infection (89 percent); nausea (63 percent); vomiting (58 percent); diarrhea (53 percent); hypercholesterolemia (high levels of cholesterol in blood) (47 percent); hypertriglyceridemia (high levels of triglycerides in blood), pain in arms and legs, headache, rash and abnormal liver function (each 42 percent). However, the majority of them were low grade. Two patients had at least one serious infection during the Phase 1 study, and none were reported during the Phase 2 extension study.
These abstracts were also published online in the December 6 supplemental volume of Blood.
MCD2001 Study Design
MCD2001 is a Phase 2 multi-national, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of siltuximab plus best supportive care (BSC) versus placebo plus BSC in 79 patients with MCD who are HIV-negative and HHV-8-negative. MCD2001 is the first randomized study in MCD. Patients were randomized 2:1 to receive either siltuximab plus BSC or placebo plus BSC until protocol-defined treatment failure, after which patients taking the placebo could cross over to un-blinded siltuximab. Half of the patients on placebo (13 out of 26) crossed over to siltuximab.
The primary efficacy endpoint of the study was durable tumor and symptomatic response, defined as partial response or complete response (Cheson criteria) by independent radiological review, and improvement/stabilization in MCD-related symptoms for at least 18 weeks. Secondary endpoints included additional predefined efficacy measures and safety. The primary analysis occurred after the last treated patient completed assessments at 48 weeks.
Baseline MCD symptoms included fatigue (86 percent), malaise (61 percent), night sweats (52 percent), peripheral sensory neuropathy (nerve damage in the peripheral nervous system) (38 percent), anorexia and pruritus (itching) (37 percent each). Median treatment duration was 375 days with siltuximab versus 152 days with placebo, with 64 percent versus 27 percent completing 48 weeks of treatment, respectively.