000096046 001__ 96046
000096046 005__ 20201030123623.0
000096046 0247_ $$2doi$$a10.1056/NEJMoa1715944
000096046 0248_ $$2sideral$$a112971
000096046 037__ $$aART-2019-112971
000096046 041__ $$aeng
000096046 100__ $$aWitztum, J.L.
000096046 245__ $$aVolanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
000096046 260__ $$c2019
000096046 5060_ $$aAccess copy available to the general public$$fUnrestricted
000096046 5203_ $$aBackground
Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.
Methods
We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months.
Results
Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). 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). 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). 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.
Conclusions
Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, .) This phase 3 trial showed that treatment with volanesorsen, an antisense oligonucleotide drug complementary to mRNA encoding apolipoprotein C-III, resulted in a mean reduction in triglyceride levels of 77% over the course of 3 months.
000096046 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000096046 590__ $$a74.699$$b2019
000096046 591__ $$aMEDICINE, GENERAL & INTERNAL$$b1 / 165 = 0.006$$c2019$$dQ1$$eT1
000096046 592__ $$a18.291$$b2019
000096046 593__ $$aMedicine (miscellaneous)$$c2019$$dQ1
000096046 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000096046 700__ $$aGaudet, D.
000096046 700__ $$aFreedman, S.D.
000096046 700__ $$aAlexander, V.J.
000096046 700__ $$aDigenio, A.
000096046 700__ $$aWilliams, K.R.
000096046 700__ $$aYang, Q.
000096046 700__ $$aHughes, S.G.
000096046 700__ $$aGeary, R.S.
000096046 700__ $$aArca, M.
000096046 700__ $$aStroes, E.S.G.
000096046 700__ $$aBergeron, J.
000096046 700__ $$aSoran, H.
000096046 700__ $$0(orcid)0000-0001-7043-0952$$aCiveira, F.$$uUniversidad de Zaragoza
000096046 700__ $$aHemphill, L.
000096046 700__ $$aTsimikas, S.
000096046 700__ $$aBlom, D.J.
000096046 700__ $$aO'Dea, L.
000096046 700__ $$aBruckert, E.
000096046 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina
000096046 773__ $$g381, 6 (2019), 531-542$$pN. Engl. j. med.$$tNEW ENGLAND JOURNAL OF MEDICINE$$x0028-4793
000096046 8564_ $$s297676$$uhttps://zaguan.unizar.es/record/96046/files/texto_completo.pdf$$yVersión publicada
000096046 8564_ $$s44094$$uhttps://zaguan.unizar.es/record/96046/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000096046 909CO $$ooai:zaguan.unizar.es:96046$$particulos$$pdriver
000096046 951__ $$a2020-10-30-09:58:12
000096046 980__ $$aARTICLE