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Volanesorsen helped to significantly improve triglyceride levels in people with the rare familial chylomicronemia syndrome (FCS), according to the .

In the 66-patient, double-blind study, those on the novel therapy saw a 77% drop in mean triglyceride levels compared with an 18% increase in the placebo group, reported Joseph Witztum, MD, of the University of California San Diego in La Jolla, and colleagues.

After 3 months of treatment -- the study's primary endpoint -- this equated to an average 1712 mg/dL drop in triglyceride levels for those on volanesorsen (19.3 mmol/L, 95% CI 1330-2094 mg/dL) versus an increase of 92.0 mg/dL (1.0 mmol/L, 95% CI -301.0 to 486 mg/dL) seen among those on placebo, they stated in the .

A total of 77% of those on volanesorsen achieved levels (<750 mg/dL, 8.5 mmol/L) versus only 10% of those on placebo.

Over the entire 52-week trial, those on treatment had a 40% decrease in fasting triglyceride levels from baseline (986 mg/dL, 11.1 mmol /L) versus a 9% increase for the placebo group (39 mg/dL, 0.44 mmol/L).

The volanesorsen group also saw an 84% decrease -- equivalent to a 25.7 mg/dL decrease from baseline -- in mean plasma apolipoprotein C-III levels, whereas the placebo group saw a 6.1% increase (1.9 g/dL). This was maintained, with the volanesorsen group seeing an average reduction of 83% (25.6 mg/dL) from baseline after 6 months of therapy, the authors reported.

However, thrombocytopenia and injection-site reactions were common adverse events (AEs) in the volanesorsen group,, the authors noted.

Volanesorsen works as an antisense-mediated inhibitor of hepatic APOC3 mRNA. The gene encodes apolipoprotein C-III, which, when overexpressed, leads to high triglyceride levels and atherosclerosis by inhibiting certain lipase enzymes.

"Familial chylomicronemia syndrome is a rare disorder that results in marked hypertriglyceridemia and high risk of acute pancreatitis," explained Robert Rosenson, MD, of the Icahn School of Medicine at Mount Sinai in New York City.

Rosenson, who was not involved with the study, told MedPage Today that the trial "supports the concept that inhibited production of an inhibitor of lipoprotein lipase (LPL), the rate limiting step in triglyceride catabolism, lowers triglycerides by 77%."

But he pointed out that "the clinical significance of triglyceride lowering cannot be ascertained as the study did not evaluate episodes of acute pancreatitis. However, it potentially fills a major unmet need for patients with this rare disorder."

Currently, there is no approved treatment for FCS after the the agent in August 2018. This rejection came after an advisory committee . The drug was earlier this year under the brand name Waylivra.

The APPROACH trial included adults diagnosed with FCS confirmed by genetic testing or low lipoprotein lipase activity, defined as <20% of the normal range. Triglyceride levels also had to be at least 750 mg/dL for inclusion. Over 75% of the entire cohort had a history of pancreatitis, while baseline triglycerides averaged 2,209 mg/dL. More than half of participants also possessed mutated LPL genes.

Participants went through a 6-week diet stabilization run-in period prior to treatment initiation, which was comprised of a diet containing <20 g of fat per day. Those randomized to the volanesorsen group received 300 mg/week of the treatment in a single subcutaneous injection.

AEs were high among the volanesorsen group, with 61% experiencing an injection-site reaction versus none in the placebo group. A third of participants on treatment also saw a decrease in platelet count, and several also experienced abdominal pain, fatigue, headache, and nausea.

Nearly half of the volanesorsen group saw platelet counts <100,000 per microliter, whereas no individuals on placebo saw these low levels. Two patients on the treatment even saw platelet counts drop <25,000 per microliter. After the study investigators implements new enhanced platelet-monitoring rules, consisting of assessment of counts every 2 weeks, there were no further reports of counts dropping <50,000 per microliter, they reported.

"The major limitation of this intervention is the reduction in platelet count in nearly 50% of study participants," Rosenson pointed out. "Based on the thrombocytopenia, it is unlikely that the FDA will approve this medication."

He added that "since the initiation of this trial, more targeted approaches for delivering antisense mediated inhibitors to the liver have been developed. The new approach reduces systemic exposure to the inhibitor and potentially the risk of thrombocytopenia."

In a joint statement after the FDA turn down, Akcea Therapeutics and Ionis Pharmaceuticals stated they plan to "continue to work with the FDA to confirm the path forward [for volanesorsen]."

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