Volanesorsen

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Volanesorsen
Clinical data
Trade namesWaylivra
Other namesISIS 304801, ISIS-APOCIIIRx
Routes of
administration
Subcutaneous injection
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [1]
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Identifiers
  • all-P-ambo-2'-O-(2-Methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2- methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyluridine[2]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC230H320N63O125P19S19
Molar mass7165.05 g·mol−1
  • Cc1cn(c(=O)[nH]c1=O)[C@H]2C[C@@H]([C@H](O2)COP(=O)(O[C@H]3C[C@@H](O[C@@H]3COP(=O)(O[C@H]4C[C@@H](O[C@@H]4COP(=O)(O[C@@H]5[C@H](O[C@H]([C@@H]5OCCOC)n6cc(c(=O)[nH]c6=O)C)COP(=O)(O[C@@H]7[C@H](O[C@H]([C@@H]7OCCOC)n8cc(c(=O)[nH]c8=O)C)COP(=O)(O[C@@H]9[C@H](O[C@H]([C@@H]9OCCOC)n1cc(c(nc1=O)N)C)COP(=O)(O[C@@H]1[C@H](O[C@H]([C@@H]1OCCOC)n1cnc2c1nc([nH]c2=O)N)COP(=O)(O[C@@H]1[C@H](O[C@H]([C@@H]1OCCOC)n1cnc2c1ncnc2N)CO)S)S)S)S)S)n1cc(c(nc1=O)N)C)S)n1cc(c(=O)[nH]c1=O)C)S)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cc(c(nc1=O)N)C)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cc(c(nc1=O)N)C)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1ncnc2N)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cnc2c1nc([nH]c2=O)N)OP(=O)(OC[C@@H]1[C@H](C[C@@H](O1)n1cc(c(nc1=O)N)C)OP(=O)(OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=O)(OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=O)(OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)OP(=O)(OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cnc2c1ncnc2N)OCCOC)OP(=O)(OC[C@@H]1[C@H]([C@H]([C@@H](O1)n1cc(c(=O)[nH]c1=O)C)OCCOC)O)S)S)S)S)S)S)S)S)S)S)S)S
  • InChI=1S/C230H320N63O125P19S19/c1-98-55-274(217(308)254-178(98)231)142-45-112(400-419(322,438)361-70-124-113(46-143(381-124)275-56-99(2)179(232)255-218(275)309)401-423(326,442)367-76-130-119(52-149(387-130)288-92-248-152-183(236)242-89-245-186(152)288)407-427(330,446)369-78-132-121(54-151(389-132)290-94-252-156-190(290)260-215(240)263-202(156)306)408-425(328,444)365-72-125-114(47-144(382-125)276-57-100(3)180(233)256-219(276)310)406-428(331,447)372-81-134-160(171(354-38-28-344-18)206(393-134)283-64-107(10)196(300)269-226(283)317)412-432(335,451)375-84-137-163(173(356-40-30-346-20)208(395-137)285-66-109(12)198(302)271-228(285)319)415-435(338,454)377-86-139-165(175(358-42-32-348-22)210(397-139)287-68-111(14)200(304)273-230(287)321)416-436(339,455)379-87-140-166(176(359-43-33-349-23)212(398-140)292-96-250-154-185(238)244-91-247-188(154)292)417-430(333,449)371-80-133-158(295)168(351-35-25-341-15)204(391-133)282-63-106(9)195(299)268-225(282)316)123(380-142)71-362-421(324,440)403-117-50-147(279-61-104(7)193(297)266-223(279)314)386-128(117)75-366-426(329,445)409-120-53-150(289-93-251-155-189(289)259-214(239)262-201(155)305)388-131(120)77-368-424(327,443)405-118-51-148(280-62-105(8)194(298)267-224(280)315)385-127(118)74-364-422(325,441)404-116-49-146(278-60-103(6)192(296)265-222(278)313)384-126(116)73-363-420(323,439)402-115-48-145(277-58-101(4)181(234)257-220(277)311)383-129(115)79-370-429(332,448)411-162-136(394-207(172(162)355-39-29-345-19)284-65-108(11)197(301)270-227(284)318)83-374-434(337,453)414-164-138(396-209(174(164)357-41-31-347-21)286-67-110(13)199(303)272-229(286)320)85-376-433(336,452)413-161-135(392-205(170(161)353-37-27-343-17)281-59-102(5)182(235)258-221(281)312)82-378-437(340,456)418-167-141(399-213(177(167)360-44-34-350-24)293-97-253-157-191(293)261-216(241)264-203(157)307)88-373-431(334,450)410-159-122(69-294)390-211(169(159)352-36-26-342-16)291-95-249-153-184(237)243-90-246-187(153)291/h55-68,89-97,112-151,158-177,204-213,294-295H,25-54,69-88H2,1-24H3,(H,322,438)(H,323,439)(H,324,440)(H,325,441)(H,326,442)(H,327,443)(H,328,444)(H,329,445)(H,330,446)(H,331,447)(H,332,448)(H,333,449)(H,334,450)(H,335,451)(H,336,452)(H,337,453)(H,338,454)(H,339,455)(H,340,456)(H2,231,254,308)(H2,232,255,309)(H2,233,256,310)(H2,234,257,311)(H2,235,258,312)(H2,236,242,245)(H2,237,243,246)(H2,238,244,247)(H,265,296,313)(H,266,297,314)(H,267,298,315)(H,268,299,316)(H,269,300,317)(H,270,301,318)(H,271,302,319)(H,272,303,320)(H,273,304,321)(H3,239,259,262,305)(H3,240,260,263,306)(H3,241,261,264,307)/t112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122+,123+,124+,125+,126+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141+,142+,143+,144+,145+,146+,147+,148+,149+,150+,151+,158+,159+,160+,161+,162+,163+,164+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,204+,205+,206+,207+,208+,209+,210+,211+,212+,213+,419?,420?,421?,422?,423?,424?,425?,426?,427?,428?,429?,430?,431?,432?,433?,434?,435?,436?,437?/m0/s1
  • Key:IJUQCWMZCMFFJP-GQSLRNSLSA-N

Volanesorsen, sold under the brand name Waylivra, is a triglyceride-reducing drug. It is a second-generation[3] 2'-O-methoxyethyl (2'-MOE) chimeric antisense therapeutic oligonucleotide (ASO)[4] that targets the messenger RNA for apolipoprotein C3 (apo-CIII).

The most common side effects include reduced platelet levels and reactions at the site of the injection such as pain, swelling, itching, or bruising.[5]

Volanesorsen, is an 'antisense oligonucleotide,' a very short piece of synthetic RNA (a type of genetic material).[5] It has been designed to block the production of a protein that slows down the breakdown of fats called apolipoprotein C-III.[5] By blocking the production of this protein, the medicine reduces the level of triglycerides in the blood and, as a result, fat accumulation in the body, which is expected to reduce the risk of pancreatitis.[5]

Medical uses

Familial chylomicronaemia syndrome (FCS) (also known as type I hyperlipoproteinaemia) is an inherited disease where people have abnormally high levels of some types of fat called triglycerides in their blood.[5] The excess fat accumulates in organs such as the spleen and liver, which become abnormally enlarged.[5] Fat accumulation can also cause repeated bouts of pancreatitis (inflammation of the pancreas) and xanthomas (formation of yellow fatty deposits just under the skin, generally around joints)[5]

Volanesorsen is indicated as an adjunct to diet in adults with genetically confirmed familial chylomicronemia syndrome (FCS) and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.[5]

History

It is in Phase III clinical trials for the treatment of hypertriglycidemia,[when?] familial chylomicronemia syndrome and familial partial lipodystrophy.[6][7]

The drug was discovered and developed by Ionis Pharmaceuticals.

Volanesorsen was designated an orphan drug by the European Medicines Agency (EMA) in February 2014, for phosphorothioate oligonucleotide targeted to apolipoprotein C-III for treatment of familial chylomicronaemia syndrome.[8]

Volanesorsen was approved for medical use in the European Union in May 2019.[5]

Volanesorsen was effective in reducing triglycerides in the blood in a study of 67 participants with familial chylomicronemia syndrome (FCS).[5] After three months, participants given volanesorsen had an average 77% reduction in the level of triglycerides compared with an average 18% increase in participants given placebo (a dummy treatment).[5] All participants in the study were on a low-fat diet in addition to receiving volanesorsen or placebo.[5]

Chemistry

The complete sequence of volanesorsen is:[2]: 165–166 

3'—A*—G*—mC*—T*—T*—dmCdTdTdGdTdmCdmCdAdGdmCT*—T*—T*—A*—T*—5'
* = 2'-O-(2-methoxyethyl)
m = 5-methyl
d = 2'-deoxy
Chemical structure[2]: 165–166 

Names

Volanesorsen is the International nonproprietary name (INN).[2]

References

  1. ^ "Waylivra (volanesorsen) 285 mg solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 28 August 2019. Retrieved 19 May 2020.
  2. ^ a b c d World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1): 165–6. hdl:10665/331046.
  3. ^ Pechlaner R, Tsimikas S, Yin X, Willeit P, Baig F, Santer P, et al. (February 2017). "Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III". Journal of the American College of Cardiology. 69 (7): 789–800. doi:10.1016/j.jacc.2016.11.065. PMC 5314136. PMID 28209220.
  4. ^ Graham MJ, Lee RG, Bell TA, Fu W, Mullick AE, Alexander VJ, et al. (May 2013). "Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans". Circulation Research. 112 (11): 1479–90. doi:10.1161/CIRCRESAHA.111.300367. PMID 23542898.
  5. ^ a b c d e f g h i j k l "Waylivra EPAR". European Medicines Agency (EMA). Retrieved 19 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ^ Taylor NP (20 December 2016). "Ionis' volanesorsen hits efficacy endpoint in phase 3". www.fiercebiotech.com. Retrieved 22 December 2016.
  7. ^ Digenio A, Dunbar RL, Alexander VJ, Hompesch M, Morrow L, Lee RG, et al. (August 2016). "Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes". Diabetes Care. 39 (8): 1408–15. doi:10.2337/dc16-0126. PMID 27271183.
  8. ^ "EU/3/14/1249". European Medicines Agency (EMA). Retrieved 19 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

  • "Volanesorsen". Drug Information Portal. U.S. National Library of Medicine.