Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study.

Elif A Oral, Abhimanyu Garg, Joseph Tami, Eric A Huang, Louis St L O'Dea, Hartmut Schmidt, Anatoly Tiulpakov, Ann Mertens, Veronica J Alexander, Lynnetta Watts, Eunju Hurh, Joseph L Witztum, Richard S Geary, Sotirios Tsimikas

Journal: Journal of clinical lipidology 2023;16(6):833-849

PMID: 36402670

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Volanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations.

OBJECTIVE

The present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes.

METHODS

BROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods. Patients received weekly subcutaneous volanesorsen 300 mg or placebo. The primary endpoint was percent change from baseline in fasting triglycerides at 3 months. Secondary endpoints included relative percent change in hepatic fat fraction (HFF), visceral adiposity, and glycated hemoglobin levels.

RESULTS

Forty patients (11 men, 29 women) were enrolled, majority of whom were aged <65 years (mean, 47 years) and White. Least squares mean (LSM) percent change in triglycerides from baseline to 3 months was -88% (95% CI, -134 to -43) in the volanesorsen group versus -22% (95% CI, -61 to 18) in the placebo group, with a difference in LSM of -67% (95% CI, -104 to -30; P=0.0009). Volanesorsen induced a significant LSM relative reduction in HFF of 53% at month 12 versus placebo (observed mean [SD]: 9.7 [7.65] vs. 18.0 [8.89]; P=0.0039). No statistically significant changes were noted in body volume measurements (fat, liver, spleen, visceral/subcutaneous adipose tissue) or glycated hemoglobin. Serious adverse events in patients assigned to volanesorsen included 1 case each of sarcoidosis, anaphylactic reaction, and systemic inflammatory response syndrome.

CONCLUSION

In BROADEN, volanesorsen significantly reduced serum triglyceride levels and hepatic steatosis in patients with FPLD.

Address: Metabolism, Endocrinology and Diabetes Division and Brehm Center for Diabetes, University of Michigan, Ann Arbor, MI, USA (Dr Oral). Electronic address: [email protected].; Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA (Dr Garg).; Ionis Pharmaceuticals, Carlsbad, CA, USA (Drs Tami, Alexander, Watts, Geary, and Tsimikas).; Akcea Therapeutics, Inc., Boston, MA, USA (Drs Huang, O'Dea, and Hurh).; University Hospital Muenster, Muenster, Germany (Dr Schmidt).; Endocrinology Research Centre, Moscow, Russian Federation (Dr Tiulpakov).; Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium (Dr Mertens).; School of Medicine, University of California San Diego, San Diego, CA, USA (Drs Witztum and Tsimikas).; Ionis Pharmaceuticals, Carlsbad, CA, USA (Drs Tami, Alexander, Watts, Geary, and Tsimikas); School of Medicine, University of California San Diego, San Diego, CA, USA (Drs Witztum and Tsimikas).

DOI: 10.1016/j.jacl.2022.08.008

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MeSH Terms: Female, Humans, Male, Apolipoprotein C-III, Glycated Hemoglobin, Lipodystrophy, Familial Partial, Triglycerides