Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. METHODS: We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. RESULTS: Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began. CONCLUSIONS: Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).

Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder caused by mutations in lipoprotein lipase (LPL) or genes required for LPL functionality and is characterized by hyperchylomicronemia that results in recurrent episodes of acute pancreatitis. Owing to the rarity of FCS, there are few case series describing the phenotypic variability in FCS patients in detail. OBJECTIVE: To provide baseline characteristics in the largest study population to date of patients with FCS. METHODS: We analyzed baseline demographic and clinical characteristics of adult FCS patients in the phase 3 APPROACH study of volanesorsen sodium (antisense inhibitor of apolipoprotein C-III). RESULTS: Sixty-six patients were included in the analysis. Mean (SD) age was 46 (13) years; and mean body mass index was 24.9 (5.7) kg/m2. We identified causal mutations in 79% (52) of patients, with LPL mutations accounting for 62% (41) of cases. Median age at diagnosis was 24 years, 54% were females, and 81% were Caucasian. All patients followed a low-fat diet, 43% received fibrates, 27% fish oils, and 21% statins. Median fasting triglyceride levels (P25, P75) were 1985 (1179, 3047 mg/dL). Overall, 76% of patients reported ≥1 lifetime episode of acute pancreatitis; 23 patients reported a total of 53 pancreatitis events in the 5 years before enrollment. CONCLUSIONS: Our data emphasize the severe hypertriglyceridemia characteristic of FCS patients despite restrictive low-fat diets and frequent use of existing hypolipemic therapies. Acute pancreatitis and recurrent acute pancreatitis are frequent complications of FCS. Diagnosis at an older age suggests likely underdiagnosis and underappreciation of this rare disorder.

The burden of familial chylomicronemia syndrome from the patients' perspective.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives. METHODS: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS. RESULTS: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS. CONCLUSIONS: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family.