Inotersen

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Inotersen
Names
Trade namesTegsedi
Other namesGSK-2998728, ISIS-420915
Clinical data
Drug classAntisense oligonucleotide[1]
Main usesHereditary transthyretin-mediated amyloidosis (hATTR)[1]
Side effectsRedness and pain at the site of injection, nausea, headache, tiredness, low platelets, fever[2]
Pregnancy
category
  • US: N (Not classified yet)
Routes of
use
Subcutaneous injection
External links
AHFS/Drugs.comMonograph
US NLMInotersen
Legal
License data
Legal status
Chemical and physical data
FormulaC230H318N69O121P19S19
Molar mass7183.08 g·mol−1
3D model (JSmol)
  • CC1=CN(C(=O)NC1=O)C2CC(C(O2)COP(=S)(O)OC3CC(OC3COP(=S)(O)OC4CC(OC4COP(=S)(O)OC5C(OC(C5OCCOC)N6C=NC7=C6N=C(NC7=O)N)COP(=S)(O)OC8C(OC(C8OCCOC)N9C=C(C(=O)NC9=O)C)COP(=S)(O)OC1C(OC(C1OCCOC)N1C=C(C(=O)NC1=O)C)COP(=O)(OC1C(OC(C1OCCOC)N1C=C(C(=NC1=O)N)C)COP(=S)(O)OC1C(OC(C1OCCOC)N1C=C(C(=O)NC1=O)C)CO)S)N1C=NC2=C1N=C(NC2=O)N)N1C=C(C(=O)NC1=O)C)OP(=S)(O)OCC1C(CC(O1)N1C=NC2=C(N=CN=C21)N)OP(=S)(O)OCC1C(CC(O1)N1C=C(C(=NC1=O)N)C)OP(=S)(O)OCC1C(CC(O1)N1C=NC2=C(N=CN=C21)N)OP(=S)(O)OCC1C(CC(O1)N1C=C(C(=O)NC1=O)C)OP(=S)(O)OCC1C(CC(O1)N1C=NC2=C1N=C(NC2=O)N)OP(=S)(O)OCC1C(CC(O1)N1C=NC2=C(N=CN=C21)N)OP(=S)(O)OCC1C(CC(O1)N1C=NC2=C(N=CN=C21)N)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C(N=CN=C21)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)O
  • InChI=1S/C230H318N69O121P19S19/c1-98-53-280(219(312)262-178(98)231)140-43-110(121(382-140)66-364-425(328,444)406-114-47-144(292-90-254-150-183(236)244-85-249-188(150)292)387-126(114)71-368-423(326,442)404-112-45-142(282-59-104(7)197(303)274-225(282)318)383-122(112)67-363-421(324,440)403-111-44-141(281-58-103(6)196(302)273-224(281)317)385-124(111)69-366-427(330,446)410-119-52-149(297-95-260-156-194(297)268-217(242)271-204(156)310)391-130(119)75-372-431(334,450)419-167-139(401-215(177(167)362-42-32-352-22)299-97-261-157-195(299)269-218(243)272-205(157)311)84-381-438(341,457)418-165-136(398-213(175(165)360-40-30-350-20)291-64-109(12)202(308)279-230(291)323)82-379-437(340,456)417-163-135(397-211(173(163)358-38-28-348-18)289-62-107(10)200(306)277-228(289)321)81-378-435(338,454)414-161-132(394-209(171(161)356-36-26-346-16)286-56-101(4)181(234)265-222(286)315)78-375-433(336,452)412-159-120(65-300)392-207(169(159)354-34-24-344-14)288-61-106(9)199(305)276-227(288)320)402-422(325,441)367-70-125-115(48-145(386-125)293-91-255-151-184(237)245-86-250-189(151)293)407-426(329,445)365-68-123-113(46-143(384-123)283-60-105(8)198(304)275-226(283)319)405-424(327,443)371-74-129-118(51-148(390-129)296-94-259-155-193(296)267-216(241)270-203(155)309)409-429(332,448)370-72-127-116(49-146(388-127)294-92-256-152-185(238)246-87-251-190(152)294)408-428(331,447)369-73-128-117(50-147(389-128)295-93-257-153-186(239)247-88-252-191(153)295)411-430(333,449)374-77-138-166(176(361-41-31-351-21)214(400-138)298-96-258-154-187(240)248-89-253-192(154)298)420-439(342,458)380-83-137-164(174(359-39-29-349-19)212(399-137)290-63-108(11)201(307)278-229(290)322)416-436(339,455)377-80-134-162(172(357-37-27-347-17)210(396-134)287-57-102(5)182(235)266-223(287)316)415-434(337,453)376-79-133-160(170(355-35-25-345-15)208(395-133)285-55-100(3)180(233)264-221(285)314)413-432(335,451)373-76-131-158(301)168(353-33-23-343-13)206(393-131)284-54-99(2)179(232)263-220(284)313/h53-64,85-97,110-149,158-177,206-215,300-301H,23-52,65-84H2,1-22H3,(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)(H,341,457)(H,342,458)(H2,231,262,312)(H2,232,263,313)(H2,233,264,314)(H2,234,265,315)(H2,235,266,316)(H2,236,244,249)(H2,237,245,250)(H2,238,246,251)(H2,239,247,252)(H2,240,248,253)(H,273,302,317)(H,274,303,318)(H,275,304,319)(H,276,305,320)(H,277,306,321)(H,278,307,322)(H,279,308,323)(H3,241,267,270,309)(H3,242,268,271,310)(H3,243,269,272,311)/t110-,111-,112-,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+,158+,159+,160+,161+,162+,163+,164+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,206+,207+,208+,209+,210+,211+,212+,213+,214+,215+,421?,422?,423?,424?,425?,426?,427?,428?,429?,430?,431?,432?,433?,434?,435?,436?,437?,438?,439?/m0/s1
  • Key:KLEGMTRDCCDFJK-XDQSQZFTSA-N

Inotersen, sold under the brand name Tegsedi, is a medication used to treat nerve damage in hereditary transthyretin-mediated amyloidosis (hATTR).[1] It is used in people who are still able to walk.[6] It is given by injection under the skin.[1]

Common side effects redness and pain at the site of injection, nausea, headache, tiredness, low platelets, and fever.[2] Other side effects may include kidney inflammation, stroke, vitamin A deficiency, allergic reactions, and liver problems.[2][1] It is a antisense oligonucleotide.[1]

Inotersen was approved for medical use in the United States and Europe in 2018.[1][6] In the United Kingdom it costs the NHS about £332,000 per year as of 2021.[7] In the United States this amount costs about 521,000 USD while in Canada it is about 420,000 CAD.[8][9]

Medical use

Dosage

It is given at a dose of 284 mg once per week.[7]

Because of these serious side effects, inotersen is available in the United States only through a restricted program called the Tegsedi Risk Evaluation and Mitigation (REMS) Program.[2]

Chemistry

It is a antisense oligonucleotide.[1] The sequence is TCTTG GTTACATGAA ATCCC, where C is methylated C, and the first and third section (bases 1-5 and 16-20, separated from the middle section by spaces) are MOE-modified.[10]

History

Inotersen was approved for medical use in the European Union in July 2018.[5]

The U.S. Food and Drug Administration (FDA) approved inotersen in October 2018.[2] The application for inotersen was granted orphan drug designation.[11]

The FDA approved inotersen based on evidence from one clinical trial (Trial 1/NCT01737398) that included 172 patients with hereditary transthyretin-mediated amyloidosis.[2] The trial was conducted at 24 sites in Australia, Europe, South America, and the United States.[2]

The benefits and side effects of inotersen were evaluated in one clinical trial that enrolled patients with hereditary transthyretin-mediated amyloidosis.[2] Patients were randomly assigned to receive inotersen or placebo by subcutaneous injection given once a week for 65 weeks.[2] During the first week of treatment, patients received three doses of treatment, followed by once weekly subcutaneous injections for 64 weeks.[2] Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed.[2]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[12]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Inotersen Monograph for Professionals". Drugs.com. Retrieved 26 November 2021.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "Drug Trial Snapshot: Tegsedi". U.S. Food and Drug Administration (FDA). 23 July 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  3. "Tegsedi 284 mg solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 15 October 2019. Retrieved 3 October 2020.
  4. "Tegsedi- inotersen injection, solution". DailyMed. 2 September 2020. Retrieved 3 October 2020.
  5. 5.0 5.1 "Tegsedi EPAR". European Medicines Agency (EMA). Retrieved 3 October 2020.
  6. 6.0 6.1 "Tegsedi". Retrieved 26 November 2021.
  7. 7.0 7.1 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1109. ISBN 978-0857114105.
  8. "Tegsedi Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 26 November 2021.
  9. "CADTH Canadian Drug Expert Committee Recommendation" (PDF). CADTH. Retrieved 26 November 2021.
  10. "Nucleid Acid Ther". Retrieved 26 July 2021.
  11. "Inotersen Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 July 2012. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  12. New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.

External links

Identifiers: