Lipid-efficacy RCT · N Engl J Med 2019
APPROACH trial
Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome.
The bottom line
In patients with familial chylomicronemia syndrome, volanesorsen substantially lowered triglyceride and apolipoprotein C-III levels compared with placebo but caused frequent injection-site reactions and thrombocytopenia.
Primary lipid endpoint metUS status: Not US-approved (EU)
At a glance
- Medicine
- Volanesorsen (antisense-mediated inhibition of hepatic APOC3 mRNA)
- Compared with
- Placebo
- People
- 66
- Who took part
- Patients with familial chylomicronemia syndrome, a rare genetic disorder caused by loss of lipoprotein lipase activity characterized by chylomicronemia and recurrent episodes of pancreatitis
- Design
- phase 3, double-blind, randomized 52-week trial
- Follow-up
- 52 weeks (primary endpoint assessed at 3 months)
- Main question
- Percentage change in fasting triglyceride levels from baseline to 3 months
Main result
Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% CI, 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001)
Effect on LDL cholesterol
Not reported for LDL; apolipoprotein C-III decreased from baseline by 25.7 mg per deciliter (84% decrease) at 3 months with volanesorsen vs. increase of 1.9 mg per deciliter (6.1% increase) with placebo (P<0.001)
Other results
At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter)
Safety
A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began.
In the trial's own words
“Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001).”
Quoted from the abstract of N Engl J Med 2019, checked word for word against PubMed. PubMed 31390500 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Olezarsen (Tryngolza) and volanesorsen
Common questions
What did the APPROACH trial find?
In patients with familial chylomicronemia syndrome, volanesorsen substantially lowered triglyceride and apolipoprotein C-III levels compared with placebo but caused frequent injection-site reactions and thrombocytopenia.
Who was in APPROACH?
66 people. Patients with familial chylomicronemia syndrome, a rare genetic disorder caused by loss of lipoprotein lipase activity characterized by chylomicronemia and recurrent episodes of pancreatitis.
What was APPROACH's main result?
Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% CI, 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001)
How much did LDL cholesterol change in APPROACH?
Not reported for LDL; apolipoprotein C-III decreased from baseline by 25.7 mg per deciliter (84% decrease) at 3 months with volanesorsen vs. increase of 1.9 mg per deciliter (6.1% increase) with placebo (P<0.001)
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- Balance (2024)In patients with familial chylomicronemia syndrome, olezarsen 80 mg significantly lowered triglycerides and markedly reduced acute pancreatitis episodes compared with placebo, with the 50-mg dose not reaching significance for the triglyceride endpoint.
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