Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy

Figures & data

Figure 1 Apolipoproteins and other proteins influencing the clearance of chylomicrons or very-low-density lipoprotein particles and affecting the activity of lipoprotein lipase.

Abbreviations: ANGPTL, angiopoietin-like protein; Apo, apolipoprotein; CM, chylomicron; GPIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1; LMF-1, lipase maturation factor-1.

Table 1 Response of apoC3 and Triglyceride Levels to Volanesorsen Therapy in Patients with Hypertriglyceridaemia (Study CS2)⁷⁰

	Placebo	100mg	200mg	300mg	Fibrate-Placebo	Fibrate and 200mg	Fibrate and 300mg
ApoC3 Baseline (mg/dL)	22±8	22±8	23±5	23±6	19±6	16±4	18± 6
ApoC3 Treated (mg/dl)	22± 11	12± 5	8 ±4	4 ±2	18±4	6±3	5± 2
Change (least- squares mean %)	4±8	−39±9	−64±8	−80±9	−2± 6	−61±6	−72± 5
Triglycerides baseline mg/dl) Median & IQR	459(356–582)	558(351–825)	588(464–717)	566(355–702)	475(253–602)	272(230–295)	271(241–459)
Triglycerides baseline (mmol/L) median & IQR	5.2(4.02–6.58)	6.31(3.97–9.33)	6.64(5.24–8.10)	6.40(4.01–7.93)	5.37(2.86–6.80)	3.07(2.59–3.33)	3.06(2.72–5.19)
Triglycerides treated (mg/dl) Median & IQR	456(343–640)	277(226–394)	180(157–262)	120(115–185)	338(290–394)	120(103–172)	116(91–191)
Triglycerides treated (mmol/L) Median & IQR	5.15(3.86–7.23)	3.13(2.55–4.45)	2.03(1.30–2.96)	1.36(1.30–2.09)	3.82(3.28–4.45)	1.36(1.17–1.94)	1.31(1.03–2.16)
Change (least- squares mean %)	20±13	−31±15	−59±14	−71±15	−8±7	−52±7	−65±6

Table 2 Key Phase 3 Clinical Trials of Volanesorsen

Study/Study Population	Primary Objective	Study Design	Dose(mg)	Subjects	Parameters	Placebo Baseline mg/dl (mmol/L)	Placebo On-Treatment mg/dl (mmol/l)	Volanesorsen Baseline mg/dl (mmol/)	Volanesorsen On-Treatment mg/dl (mmol/L)	Change(%)
ISIS304801-CS6 (APPROACH)^Citation72 Patients with FCS	Efficacy Safety	Randomized, Double-Blind, Placebo Controlled,	300 mg Once weekly for 52 weeks	Volanesorsen: 33 Placebo: 33	TG CM-TG ApoB48 ApoB100 ApoC3	2152±1153 (24.3±13.0) 1785±1149 (20.2±13.0) 9.3±6.0 69.4±19.8 28.9±13.1	2367±1315 (26.7±14.9) 1991±1279 (22.5±14.5) 9.9±6.9 70.4±22.7 30.7±16.1	2267±1259 (25.6±14.4) 1913±1216 (21.6±13.7) 11.2±7.1 64.7±19.5 31.4±15.3	590±497 (6.7±5.6) 436±480 (4.93±5.4) 2.6±2.4 75.9±27.1 4.6±2.8	18 vs.-77 29 vs −83 14 vs −76± 4 vs 20 6 vs −84
ISIS 304801-CS7^a (APPROACH OLE)^Citation76 Patients with FCS	Safety	Open-Label Study.	300 mg Once weekly for 52 weeks	Volanesorsen: 67 50 naïve 14 CS6 continuing 3 CS16 continuing	Naïve TG CS6 TG CS16 TG			2317±1993 (26.1±22.5) 2641±1228 (29.8±13.9 2288±1524 (25.9± 17.2	979±683 (11.1±7.7) 1248±927 14.1±10.5) 1558±193 17.6±2.2)	−47 –55 -39
ISIS 304801-CS16^b (COMPASS)^Citation76 Patients with Hypertriglyceridaemia	Efficacy Safety	Randomized, Double-Blind, Placebo Controlled,	300 mg Once weekly for 26 weeks^c	Volanesorsen: 75 (5 FCS) Placebo: 38 (2 FCS)	TG	1414±1253 (16.0±14.2)	1406±1409 (15.9±15.9)	1183±759 (13.4±8.6)	294±245 (3.3±2.8)	−1 vs −71

Notes:^aThis is an open-label extension (OLE) study in patients from CS6, CS16, or newly included patients. Data at 6 months. ^bIncluded patients with FCS. ^cFor CS16, the protocol was amended so that patients that had not already completed ≥5 months of dosing as of 27 May 2016 had dose frequency reduced to 300 mg every 2 weeks or dose reduced to 150 mg per week after 13 weeks of treatment. A total of 39 patients had their dose or frequency of dosing changed as a consequence of this amendment.

GaudetD, AlexanderVJ, BakerBF, et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015;373(5):438–447. doi:10.1056/NEJMoa140028326222559

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WitztumJL, GaudetD, FreedmanSD, et al. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 2019;381(6):531–542. doi:10.1056/NEJMoa171594431390500

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European Medicines Agency. Volanesorsen (Waylivra): public assessment report Amsterdam, The Netherlands: European Medicines Agency; 2019 Available from: https;//www.ema.europa.eu/.

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