An FDA advisory committee voted 12-8 on Thursday to recommend the approval of Akcea Therapeutics’ volanesorsen, an RNAi drug for rare lipid disorder familial chylomicronemia syndrome. The FDA is expected to make a decision by Aug. 30.

Of course, the panel vote is not binding, but the FDA tends to follow committee recommendations, especially for rare diseases. Familial chylomicronemia syndrome (FCS) is caused by a genetic mutation that causes deficient triglyceride processing and, in some patients, leads to potentially life-threatening pancreatitis. It tends to show up in childhood or adolescence but is typically diagnosed late because it is so rare. There are no FDA-approved therapies for the disorder, with a restrictive low-fat diet being the go-to treatment.

Volanesorsen is an antisense oligonucleotide that inhibits apolipoprotein C-III (ApoC-III), a protein made in the liver that regulates triglyceride metabolism. Akcea is seeking approval for the drug as an adjunct to diet in patients with FCS.

Besides safety and efficacy, the draft questions for the panel included the risk of thrombocytopenia—low blood platelet count—and serious bleeding associated with volanesorsen, whether a risk evaluation and mitigation strategy is necessary, and if FCS is a specific enough description of the the target population for the drug’s approval.

"It is important to ensure that the appropriate patient population is targeted, given the serious risks that may be associated with [volanesorsen] therapy. Considering that the onset of clinical symptoms frequently occurs in childhood, the potential for off-label use in a pediatric population is significant and it is concerning, especially if frequent laboratory monitoring is required for safe use," FDA staff wrote in a briefing document (PDF).

It filed the NDA in August with a dosing schedule of 300 mg/week delivered subcutaneously for three months, after which the dose will be adjusted according to body weight and platelet count. But in January, after the "NDA review was well-underway, the applicant unexpectedly submitted an amendment that proposed a new dosing and platelet monitoring strategy for labeling that had not been implemented in any of the clinical trials," the FDA said.

The new dosing regimen "may be reasonable, but it has not been systematically evaluated, and it is not yet clear that it would substantially improve the safety profile for use of VLN in this patient population."

Ionis Pharma spun out its lipid disorder subsidiary Akcea in early 2017, handing over responsibility for four programs, including volanesorsen. And in March, the pair became commercialization partners for inotersen, an antisense drug for hereditary transthyretin amyloidosis (hATTR). The deal came seven months after Ionis’ initial partner, GlaxoSmithKline, decided to drop their collaboration.

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