ECE2020 Oral Communications Diabetes, Obesity, Metabolism and Nutrition (7 abstracts)
Efficacy and safety of volanesorsen for the treatment of metabolic complications in patients with familial partial lipodystrophy: results of the BROADEN study
Louis O’Dea 1 , Joseph Tami 2 , Veronica Alexander 2 , Lynnetta Watts 2 , Eunju Hurh 1 , Brant Hubbard 1 , Hartmut Schmidt 3 , Anatoly Tiulpakov 4 , Ann Mertens 5 , Abhimanyu Garg 6 & Elif Oral 7
1Akcea Therapeutics, Boston, United States; 2Ionis Pharmaceuticals, Carlsbad, United States; 3Universitaetsklinikum Muenster, Gastroenterology, Hepatology, Endocrinology, Diabetology, and Infectology, Münster, Germany; 4Moscow, Moscow, Russian Federation; 5KU Leuven, Department of Chronic Diseases, Metabolism, and Ageing, Leuven, Belgium; 6University of Texas Southwestern Medical Center, Internal Medicine, Dallas, United States; 7University of Michigan, Metabolism, Endocrinology, and Diabetes Division, Ann Arbor, United States
Introduction: Familial Partial Lipodystrophies (FPLD) are rare genetic disorders characterized by marked loss of subcutaneous fat from the extremities with variable fat loss from the face and trunk. Patients with FPLD develop metabolic abnormalities including hypertriglyceridemia, insulin resistance, and diabetes mellitus, which are difficult to manage with conventional therapies including fibrates, statins and insulin. The BROADEN study evaluated the efficacy and safety of volanesorsen, an antisense inhibitor of apolipoprotein C-III, to improve the metabolic abnormalities of patients with FPLD consuming a low-fat diet.
Methods: BROADEN was a 52-week phase 2/3 study of volanesorsen in 40 patients (11 males, 29 females) with FPLD, randomized 1:1 to weekly administration of volanesorsen (300 mg) or placebo. Enrollment criteria included FPLD by genetic, familial or phenotypic criteria; fasting plasma triglycerides ≥ 2.3 mmol/l (200 mg/dl) and diabetes mellitus. The primary efficacy endpoint, mean percent change in fasting plasma triglycerides from baseline, was evaluated at 3 months and other secondary endpoints were evaluated at 12 months.
Results: The median age of the participants was 49 years (range 28 – 68), and they had a BMI of 29.8 kg/m2 (range 21.0 – 44.2), fasting plasma triglycerides of 8.6 mmol/l (range 2.4–60.4) and HgbA1c of 8.2 % (range 4.8–10.5) at baseline. Volanesorsen treatment resulted in an 88% reduction in fasting plasma triglycerides as compared to 22% reduction in placebo-treated patients (P = 0.0009) and this reduction remained significant for the entire duration of the study. As compared to placebo, volanesorsen treatment significantly reduced hepatic fat fraction at 12 months (+1.5% vs −51.9%, respectively; P = 0.004) but did not improve HgbA1c levels (−0.2% vs 2.3%, respectively; P = 0.77). The most common adverse event for volanesorsen-treated patients was injection site reactions, which were predominately mild in severity. While reductions in blood platelet count were seen in volanesorsen-treated patients, no one developed severe thrombocytopenia (platelet count < 50,000/mm3). Five patients treated with volanesorsen discontinued treatment due to a mild or moderate adverse event, while no patient on placebo treatment discontinued treatment.
Conclusions: In patients with FPLD, as compared to placebo, volanesorsen therapy results in significant reductions in serum triglycerides and hepatic fat fraction but glycemic control remains unchanged. The prevalence of side effects of volanesorsen was comparable to that reported previously in patients with familial chylomicronemia syndrome, but without any reports of severe thrombocytopenia.
Volume 70
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Endocrine Abstracts
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