"The U.S. Food and Drug Administration today announced the approval of Lumizyme (alglucosidase alfa) for treatment of patients with infantile-onset Pompe disease, including patients who are less than 8 years of age. In addition, the Risk Evaluatio"...
Mechanism Of Action
Siltuximab binds human IL-6 and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors IL-6 has been shown to be involved in diverse normal physiologic processes such as induction of immunoglobulin secretion. Overproduction of IL-6 has been linked to systemic manifestations in patients with MCD.
Cardiac Electrophysiology: The effect of multiple doses of SYLVANT (15 mg/kg every 3 weeks for 4 cycles) on the QTc interval was evaluated in an open label, single arm study in 30 patients with Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study.
Measurement of IL-6 concentrations in serum or plasma during treatment should not be used as pharmacodynamic marker, as SYLVANT-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods.
The pharmacokinetics of siltuximab were evaluated in patients with multicentric Castleman's disease and hematological and non-hematological malignancies. The serum siltuximab pharmacokinetics are adequately described by a linear two-compartment intravenous model with first-order elimination.
Following SYLVANT administration (11 mg/kg, once every 3 weeks as 1-hour intravenous infusion) in patients with multicentric Castleman's disease, the maximum serum siltuximab concentration (Cmax) occurred close to the end of infusion. At steady state, the serum mean Cmax value for siltuximab is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV).
With the once every 3 week dosing regimen, siltuximab steady state is achieved by the sixth infusion, and siltuximab accumulates approximately 1.7-fold relative to a single dose. Following multiple dosing, siltuximab showed approximately dose proportional pharmacokinetics over the dose range of 2.8 to 11 mg/kg.
Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L (20% CV).
Based on the population pharmacokinetic analysis, the clearance of siltuximab in patients is 0.23 L/day (51% CV). Based on population pharmacokinetic analysis (n=378), body weight was identified as the only statistically significant covariate for siltuximab clearance. Therefore, the body weight based dosing is appropriate.
The mean terminal half-life (t½) for siltuximab in patients after the first intravenous infusion of 11 mg/kg is 20.6 days (range: 14.2 to 29.7 days).
Age and Gender
Based on population pharmacokinetic analysis, age [range: 18 to 85 years (n=378)] and gender [female (n=175), male (n=203)] do not affect exposure of siltuximab.
A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 377 patients enrolled in clinical trials, including 176 with normal renal function (CLCr ≥ 90 mL/min), 122 with mild renal impairment (CLCr 60 to < 90 mL/min), 75 with moderate renal impairment (CLCr 30 to < 60 mL/min), and 3 with severe renal impairment (CLCr 15 to 29 mL/min). The apparent clearance of siltuximab was similar in patients with preexisting mild, moderate and severe renal impairment (CLCr 15 to < 90 mL/min) compared to patients with normal renal function. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient.
A population pharmacokinetic analysis (based on pre-existing hepatic function) was carried out with data from 377 patients with enrolled in clinical trials, including 302 with normal hepatic function, 72 with mild hepatic impairment (Child-Pugh A), and 3 with moderate hepatic impairment (Child-Pugh B). The apparent clearance of siltuximab was similar in patients with pre-existing mild and moderate hepatic impairment (Child-Pugh Class A and B) compared to patients with normal hepatic function. The potential effect of severe hepatic impairment on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are not available.
The clinical efficacy and safety of SYLVANT for the treatment of patients with MCD was established in Study 1, a phase 2, multinational, randomized (2:1) double blind, placebo controlled study. In this study 53 patients were randomized to Best Supportive Care (BSC) and SYLVANT at a dose of 11 mg/kg every 3 weeks and 26 patients were randomized to BSC and placebo. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The histological subtype of MCD was similar in both treatment arms, with 33% hyaline vascular subtype, 23% plasmacytic subtype and 44% mixed subtype. Treatment was continued until treatment failure (defined as disease progression based on increase in symptoms, radiologic progression or deterioration in performance status) or unacceptable toxicity.
The major efficacy outcome of the study was durable tumor and symptomatic response, defined as tumor response (PR and CR based on modified International Working Group response criteria for malignant lymphoma) assessed by independent review and complete resolution or stabilization of MCD symptoms. Thirty-four MCD related symptoms were prospectively identified were collected and graded according to the NCI-CTCAE v 4, by investigator. A durable response was defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. The durable tumor and symptomatic response in the SYLVANT arm 34% compared to 0% in the placebo arm (95% CI: 11.1, 54.8; p=0.0012).
Other analyses included tumor response, time to treatment failure and an increase in hemoglobin of 1.5 g/dL or more, in patients who were anemic at time of study entry, at week 13. The results are summarized in Table 5.
Table 5: Efficacy Endpoints From Study 1
|Durable tumor and symptomatic response (independent review)||34%||0||0.0012|
|Tumor response||38%||4%||< 0.05|
|Median time to treatment failure (days)||NRb||134||< 0.05|
|≥ 1.5 g/dL increase in hemoglobin||61% (19/31)||0% (0/11)||< 0.05|
|a Adjusted for corticosteroid use at randomization
bNR= “Not Reached”
A consistent treatment effect was confirmed on subgroup analysis for all parameters evaluated with the exception of the hyaline vascular histological subtype. There were no patients with hyaline vascular histology who demonstrated a durable tumor and symptomatic response. However, activity was suggested in this subtype based on change in hemoglobin and median time to treatment failure.
At the time of the analysis, overall survival data were not mature. One year survival rate was 100% in the SYLVANT arm and 92% in the placebo arm.
Last reviewed on RxList: 5/12/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Sylvant Information
Report Problems to the Food and Drug Administration
Find out what women really need.