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Volanesorsen decreases triglycerides in familial chylomicronemia syndrome
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Volanesorsen reduced triglycerides in 77% of patients with familial chylomicronemia syndrome to less than 750 mg/dL, according to a study published in The New England Journal of Medicine.
“Chylomicrons are what you see when you see cream form on the top of milk,” Joseph L. Witztum, MD, professor of medicine in the division of endocrinology and metabolism at the University of California San Diego School of Medicine, said in a press release. “For most people, when you eat a fatty meal for dinner at 6:00 p.m., the triglycerides are transported into the blood by chylomicrons and then lipoprotein lipase clears those out of the blood by 9:00 p.m. That’s definitely not the case for patients with familial chylomicronemia syndrome.”
Researchers analyzed data from 66 patients (mean age, 46 years; 36 women) with familial chylomicronemia syndrome. Patients had fasting baseline triglyceride levels of 750 mg/dL or higher after a 6-week diet stabilization run-in period.
Once that was completed, patients were assigned 300 mg per week volanesorsen (n = 33; Waylivra, Akcea Therapeutics) or placebo (n = 33). Treatment was administered for 52 weeks.
The primary endpoint was the change in fasting triglyceride levels form baseline to 3 months.
From baseline to 3 months, plasma apolipoprotein C-III decreased by 84% in patients assigned volanesorsen vs. an increase of 6.1% in patients assigned placebo (P < .001). Triglyceride levels also decreased by 77% in the volanesorsen group during this time frame (1,712 mg/dL; 95% CI, 1,330-2,094) and increased by 18% in the placebo group (92 mg/dL; 95% CI, –301 to 486). Triglyceride levels of less than 750 mg/dL were achieved in 77% of patients assigned volanesorsen at 3 months compared with 10% of those assigned placebo.
At least one mild to moderate injection-site reaction was seen in 61% of patients assigned volanesorsen, whereas none occurred in patients assigned placebo.
Nearly half of patients assigned volanesorsen (48%) had platelet counts below 100,000/µL compared with no patients assigned placebo. Two patients in the volanesorsen group had platelet levels below 25,000/µL. Once enhanced platelet monitoring was initiated, no patients had platelet counts below 50,000/µL.
“These data show that volanesorsen-mediated lowering of apolipoprotein C-III effectively enhances clearance of triglyceride-rich lipoproteins in patients without [lipoprotein lipase] activity,” Witztum and colleagues wrote. “Because traditional triglyceride-lowering therapies such as fibrates, [omega]-3 fatty acids and statins depend on [lipoprotein lipase] activity, inhibition of hepatic VLDL output or both, they are largely ineffective in familial chylomicronemia syndrome, as evidenced by the fact that half the patients in this trial were receiving one or more of these agents at the time they were recruited.”
“This publication of the APPROACH study results the recent EU approval of Waylivra clearly demonstrates Waylivra’s safety and efficacy profile for patients with FCS,” Brett P. Monia, PhD, chief operating officer of Ionis Pharmaceuticals, said in a press release from the company. “We and Akcea are focusing on delivering much-needed medicine to those patients living with this severe disease who are waiting to have Waylivra as a treatment option.” – by Darlene Dobkowski
Disclosures: The trial was funded by Ionis Pharmaceuticals and Akcea Therapeutics. Witztum reports he received personal fees from Ionis Pharmaceuticals, other fees from Oxitope and has a patent for Modulation of Apolipoprotein CIII Expression in Lipoprotein Lipase Deficient Populations. Monia is an employee of Ionis. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC
The findings are more confirmatory that volanesorsen is an immensely effective drug at dramatically reducing triglycerides in the familial chylomicronemia syndrome patient population in which no therapy is currently available. It’s the only therapy that works in that patient population.
These findings will have significant implications for clinical practice if and when the drug gets FDA approval.
With regard to this drug in general, I believe we have enough data to proceed. It’s now in the hands of the FDA to make the drug available for clinical practice.
This is a really challenging patient population. The lives of patients with familial chylomicronemia syndrome are totally consumed by this disease. They have to eat a diet that is essentially devoid of fat, which is an almost impossible diet. Even when adhering to this Spartan diet, they have triglycerides in the thousands and they remain at great risk for developing pancreatitis. Very frequently, they do develop pancreatitis, putting them at high risk for death. They typically suffer from brain fog, emotional issues, relationship issues and work issues because of this disease. I mean this. I know these people.
These patients have had no options. Now we have a drug with a known side effect of thrombocytopenia; yet, it’s immensely effective at lowering triglycerides and it seems to lower the risk for pancreatitis as well. It would be great if they had access to this drug.
I have had a good deal of experience treating patients with volanesorsen. Some have not had any recurrence of pancreatitis for well over 1 year compared with the four to six episodes per year to which they had become accustomed.
Here’s the thing: thrombocytopenia does put people at risk for bleeding, but in the volanesorsen trials, there were no patients who experienced a serious bleed. That is because we can catch platelet declines early, usually preventing severe thrombocytopenia and thereby preventing the occurrence of significant life-threatening bleeds. To me, based on my experience and interpretation of the literature, a risk-benefit analysis favors use of the medication in the right patients. At present, the mitigation strategies have been effective at avoiding serious bleeds. The FDA is assessing volanesorsen, and I’m an advocate for getting the drug approved with proper risk mitigation strategies in place and appropriate physician training utilized to optimize patient safety.
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