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Background Analysis: US FDA Advisory Committee to Review Volanesorsen by Akcea Therapeutics for Familial Chylomicronemia Syndrome – MAY 10, 2018 (EMDAC)


The US FDA has scheduled an Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting for Thursday, May 10, 2018 to discuss the safety and efficacy of a new drug application (NDA) for volanesorsen solution for subcutaneous injection, submitted by Akcea Therapeutics, Inc. (Akcea). The proposed indication is as an adjunct to diet for the treatment of patients with familial chylomicronemia syndrome.

Volanesorsen was discovered by Ionis Pharmaceuticals, Inc. (Ionis),  co-developed by Ionis and Akcea, and, if approved, will be commercialized by Akcea.

Indication Background

Description of Indication

Familial chylomicronemia syndrome (FCS) is a rare genetic metabolic disorder characterized by improperly-functioning lipoprotein lipase (LPL), an enzyme that is responsible for the breakdown of triglycerides and chylomicrons (lipoprotein transporters of dietary fat and cholesterol). The resulting buildup of triglycerides (TG) and chylomicrons can lead to clinical manifestations that include abdominal pain and acute pancreatitis, and progressively can lead to chronic pancreatic insufficiency and diabetes.

Product Background

Description of Product

Volanesorsen (formerly ISIS-APOCIIIRx) is an antisense oligonucleotide designed to bind to the mRNA of apoC-III and inhibit its translation. ApoC-III is a protein produced in the liver that is also involved in the regulation of TG levels.

In clinical trials, volanesorsen was administered subcutaneously, once-weekly, at a dose of 300 mg.

Clinical Trials of Proposed Indication

Akcea says the submission of volanesorsen for the treatment of FCS is based on data from the Phase 3 APPROACH and COMPASS studies (ClinicalTrials.Gov IDs: NCT02211209 and NCT02300233). The company reports that the pivotal APPROACH study, a one-year, randomized, placebo-controlled study in 66 patients with FCS (average baseline triglycerides of 2,209 mg/dL, or 25.0 mmol/L), achieved its primary endpoint of reduction in TG at three months, with a 77% mean reduction in TG, which translated into a 1,712 mg/dL (19.3 mmol/L) mean absolute TG reduction in volanesorsen-treated patients. The treatment difference is 94% compared to an 18% increase for placebo. In addition, in the APPROACH study, the company says that treatment with volanesorsen was associated with a statistically significant reduced rate of on-study pancreatitis attacks in the group of patients who had multiple pancreatitis events during the 5 years prior to screening and reduced abdominal pain in patients reporting pain during the screening period.

In addition, Akcea has reported that the COMPASS study, a six-month randomized placebo-controlled study in 113 patients with very high TG (>500 mg/dL), also achieved its primary endpoint of reduction in TG at three months, with a 71% mean reduction in TG. Furthermore, the company says that in the COMPASS study, treatment with volanesorsen was associated with a statistically significant reduction in on-study pancreatitis attacks.

According to Akcea, the most common adverse event in the studies was injection site reactions, which were mostly mild. Platelet count reductions were observed in many patients. The company says these platelet declines were not clinically significant in most patients and were generally well managed with monitoring and dose adjustment. Five patients discontinued participation in the APPROACH study due to platelet count reductions, two of which were severe; four patients discontinued due to other nonserious adverse events, says Akcea.

Regulatory Background

US Regulatory Background

August 30, 2018 – PDUFA date

August 31, 2017 – NDA 210645 submission date

Orphan Drug

Ex-US Regulatory Background

September 12, 2017 – Akcea announced the filing of a New Drug Submission (NDS) for volanesorsen for the treatment of FCS to Health Canada (HC)

Priority review (HC)

July 27, 2017 – Akcea announced the submission of a Marketing Authorization Application (MAA) for volanesorsen for the treatment of FCS to the European Medicines Agency (EMA)

Orphan Drug (EMA), Promising Innovative Medicine (UK Medicines and Healthcare products Regulatory Agency)

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Akcea Therapeutics, Inc.  Drug Name: volanesoren Drug Class: Antisense Inhibitor of apo-CIII Indication: familial chylomicronemia syndrome

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.