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| IUPAC_name = (6''E'')-3-(1''H''-Pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)oxy-1''H''-pyridazin-6-ylidene]cyclohexa-2,4-dien-1-one
| IUPAC_name = (6''E'')-3-(1''H''-Pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)oxy-1''H''-pyridazin-6-ylidene]cyclohexa-2,4-dien-1-one
| image = Branaplam skeletal.svg
| image = Branaplam skeletal.svg
| alt =
| alt =
| caption =
| caption =
<!-- Clinical data -->
<!-- Clinical data -->
| pronounce =
| pronounce =
| tradename =
| tradename =
| Drugs.com =
| Drugs.com =
| MedlinePlus =
| MedlinePlus =
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment =
| pregnancy_AU_comment =
| pregnancy_US = <!-- A/B/C/D/X/N -->
| pregnancy_US = <!-- A/B/C/D/X/N -->
| pregnancy_category=
| pregnancy_category=
| routes_of_administration =
| routes_of_administration =
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment =
| legal_AU_comment =
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| legal_NZ = <!-- Class A, B, C -->
| legal_NZ = <!-- Class A, B, C -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_US =
| legal_US =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_status = <!-- Free text -->
| legal_status = <!-- Free text -->
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| bioavailability =
| bioavailability =
| protein_bound =
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<!-- Identifiers -->
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| CAS_number = 1562338-42-4
| CAS_number = 1562338-42-4
| class =
| class =
| ATCvet =
| ATCvet =
| ATC_prefix =
| ATC_prefix =
| ATC_suffix =
| ATC_suffix =
| PubChem = 89971189
| PubChem = 89971189
| UNII_Ref =
| UNII_Ref =
| UNII = P12R69543A
| UNII = P12R69543A
| DrugBank =
| DrugBank =
| KEGG = D12272
| ChemSpiderID = 34980709
| ChemSpiderID = 34980709
| synonyms = LMI070; NVS-SM1
| synonyms = LMI070; NVS-SM1
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| StdInChIKey2 = STWTUEAWRAIWJG-UHFFFAOYSA-N
| StdInChIKey2 = STWTUEAWRAIWJG-UHFFFAOYSA-N
}}
}}
'''Branaplam''' (development codes '''LMI070''' and '''NVS-SM1''') is a [[pyridazine]] [[derivative (chemistry)|derivative]] that is being studied as an [[experimental drug]]. It was originally developed by [[Novartis]] to treat [[spinal muscular atrophy]] (SMA); since 2020 it was being developed to treat [[Huntington's disease]] (HD) but the trial ended in 2023 with harmful side effects.<ref>https://www.fiercebiotech.com/biotech/novartis-cans-branaplam-after-seeing-huntingtons-safety-signal-delays-orphan-drug-over-slow</ref>


'''Branaplam''' (development codes '''LMI070''' and '''NVS-SM1''') is an [[experimental drug]] being developed by [[Novartis]] to treat [[spinal muscular atrophy]] (SMA). It is a [[pyridazine]] [[derivative (chemistry)|derivative]] that works by increasing the amount of functional [[survival of motor neuron]] protein produced by the [[SMN2|''SMN2'' gene]] through [[alternative splicing|modifying its splicing pattern]].<ref>{{cite journal | vauthors = Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R | display-authors = 6 | title = SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice | journal = Nature Chemical Biology | volume = 11 | issue = 7 | pages = 511–7 | date = July 2015 | pmid = 26030728 | doi = 10.1038/nchembio.1837 }}</ref><ref name=smanewstoday>{{cite web | url=https://smanewstoday.com/lmi070-novartis/ | title=LMI070 | publisher=SMA News Today | access-date=2017-03-10}}</ref>
As a treatment for SMA, branaplam increases the amount of functional [[survival of motor neuron]] protein produced by the [[SMN2|''SMN2'' gene]] through [[alternative splicing|modifying its splicing pattern]].<ref>{{cite journal |display-authors=6 |vauthors=Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, Sivasankaran R |date=July 2015 |title=SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice |journal=Nature Chemical Biology |volume=11 |issue=7 |pages=511–7 |doi=10.1038/nchembio.1837 |pmid=26030728}}</ref><ref name="smanewstoday">{{cite web |title=LMI070 |url=https://smanewstoday.com/lmi070-novartis/ |access-date=2017-03-10 |publisher=SMA News Today}}</ref> It was studied since 2014 in a [[clinical trial]] in children with SMA type 1<ref>{{cite web| url=https://clinicaltrials.gov/ct2/show/NCT02268552 |title=An Open Label Study of LMI070 in Type 1 Spinal Muscular Atrophy (SMA) | publisher=[[ClinicalTrials.gov]] | access-date=2017-03-10}}</ref><ref>{{cite web | url=http://www.curesma.org/news/novartis-branaplam-update.html | title=Novartis Releases Update on LMI070 (Branaplam) Clinical Trial | publisher=CureSMA | date=2017-09-20 | access-date=2017-10-07 | archive-url=https://web.archive.org/web/20171125171712/http://www.curesma.org/news/novartis-branaplam-update.html | archive-date=2017-11-25 | url-status=dead }}</ref><ref>{{Cite web|url=https://www.sma-europe.eu/news/novartis-announced-that-enrollment-for-the-ongoing-clinical-trial-of-branaplan-is-now-closed/|title={{!}} Novartis announced that enrollment for the ongoing clinical trial of branaplan is now closed|date=20 May 2019|language=en|access-date=2019-07-12}}</ref> until the programme was discontinued in 2021.


⚫
In October 2020, Novartis announced that branaplam lowers the level of [[huntingtin protein]], which is one of the major therapeutic approaches in Huntington's disease. In 2021, [[U.S. Food and Drug Administration]] (FDA) granted an orphan drug status to branaplam for treatment of Huntington’s disease, and Novartis announced that they will set up clinical trials in 2021.<ref>{{cite web| url=https://www.novartis.com/news/media-releases/novartis-receives-us-food-and-drug-administration-fda-orphan-drug-designation-branaplam-lmi070-huntington%27s-disease-hd |title=Novartis receives US Food and Drug Administration (FDA) Orphan Drug Designation for branaplam (LMI070) in Huntington's disease (HD) | publisher=[[novartis.com]] | access-date=2020-10-24}}</ref> In August 2022, Novartis temporarily halted the dosing with branaplam in its clinical studies, and in December 2022 Novartis announced that they canceled the HD program because of severe side effects in the clinical trials.<ref>https://hdsa.org/wp-content/uploads/2022/12/Novartis-VIBRANT-HD-Community-Letter-FINAL-PDF.pdf</ref>
{{As of|2019|07}}, branaplam is in a phase-II [[clinical trial]] in children with SMA type 1.<ref>{{cite web| url=https://clinicaltrials.gov/ct2/show/NCT02268552 |title=An Open Label Study of LMI070 in Type 1 Spinal Muscular Atrophy (SMA) | publisher=[[ClinicalTrials.gov]] | access-date=2017-03-10}}</ref><ref>{{cite web | url=http://www.curesma.org/news/novartis-branaplam-update.html | title=Novartis Releases Update on LMI070 (Branaplam) Clinical Trial | publisher=CureSMA | date=2017-09-20 | access-date=2017-10-07 | archive-url=https://web.archive.org/web/20171125171712/http://www.curesma.org/news/novartis-branaplam-update.html | archive-date=2017-11-25 | url-status=dead }}</ref><ref>{{Cite web|url=https://www.sma-europe.eu/news/novartis-announced-that-enrollment-for-the-ongoing-clinical-trial-of-branaplan-is-now-closed/|title={{!}} Novartis announced that enrollment for the ongoing clinical trial of branaplan is now closed|date=20 May 2019|language=en|access-date=2019-07-12}}</ref>


⚫
In October 2020, Novartis stated that the running trials for SMA showed that branaplam lowers the level of [[huntingtin protein]] as well. Lowering huntingtin protein is one of the major approaches researched by different companies to cure [[Huntington's disease]]. [[U.S. Food and Drug Administration]] granted an orphan drug status to branaplam for treatment of Huntington’s disease, and Novartis announced that they will set up trials for HD patients in 2021.<ref>{{cite web| url=https://www.novartis.com/news/media-releases/novartis-receives-us-food-and-drug-administration-fda-orphan-drug-designation-branaplam-lmi070-huntington%27s-disease-hd |title=Novartis receives US Food and Drug Administration (FDA) Orphan Drug Designation for branaplam (LMI070) in Huntington’s disease (HD) | publisher=[[novartis.com]] | access-date=2020-10-24}}</ref>
[[File:Branaplam tautomers.svg|thumb|left|upright=2|[[Keto-enol tautomerism]] of branaplam]]
[[File:Branaplam tautomers.svg|thumb|left|upright=2|[[Keto-enol tautomerism]] of branaplam]]
{{clear left}}
{{clear left}}


== References==
==References==
{{reflist}}
{{reflist}}
{{Other drugs for disorders of the musculo-skeletal system}}
{{Other drugs for disorders of the musculo-skeletal system}}
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[[Category:Spinal muscular atrophy]]
[[Category:Spinal muscular atrophy]]
[[Category:Experimental drugs]]
[[Category:Experimental drugs]]
[[Category:Novartis brands]]
[[Category:Drugs developed by Novartis]]
[[Category:Pyrazoles]]
[[Category:Pyrazoles]]
[[Category:Piperidines]]
[[Category:Piperidines]]

Revision as of 03:54, 9 May 2024

Branaplam
Clinical data
Other namesLMI070; NVS-SM1
Identifiers
  • (6E)-3-(1H-Pyrazol-4-yl)-6-[3-(2,2,6,6-tetramethylpiperidin-4-yl)oxy-1H-pyridazin-6-ylidene]cyclohexa-2,4-dien-1-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC22H27N5O2
Molar mass393.491 g·mol−1
3D model (JSmol)
  • CC1(CC(CC(N1)(C)C)Oc2ccc(nn2)c3ccc(cc3O)c4c[nH]nc4)C
  • InChI=1S/C22H27N5O2/c1-21(2)10-16(11-22(3,4)27-21)29-20-8-7-18(25-26-20)17-6-5-14(9-19(17)28)15-12-23-24-13-15/h5-9,12-13,16,25,27H,10-11H2,1-4H3,(H,23,24)/b18-17+
  • Key:YIFFDXMJVNKGBL-ISLYRVAYSA-N

  • InChI=1S/C22H27N5O2/c1-21(2)10-16(11-22(3,4)27-21)29-20-8-7-18(25-26-20)17-6-5-14(9-19(17)28)15-12-23-24-13-15/h5-9,12-13,16,27-28H,10-11H2,1-4H3,(H,23,24)
  • Key:STWTUEAWRAIWJG-UHFFFAOYSA-N

Branaplam (development codes LMI070 and NVS-SM1) is a pyridazine derivative that is being studied as an experimental drug. It was originally developed by Novartis to treat spinal muscular atrophy (SMA); since 2020 it was being developed to treat Huntington's disease (HD) but the trial ended in 2023 with harmful side effects.[1]

As a treatment for SMA, branaplam increases the amount of functional survival of motor neuron protein produced by the SMN2 gene through modifying its splicing pattern.[2][3] It was studied since 2014 in a clinical trial in children with SMA type 1[4][5][6] until the programme was discontinued in 2021.

In October 2020, Novartis announced that branaplam lowers the level of huntingtin protein, which is one of the major therapeutic approaches in Huntington's disease. In 2021, U.S. Food and Drug Administration (FDA) granted an orphan drug status to branaplam for treatment of Huntington’s disease, and Novartis announced that they will set up clinical trials in 2021.[7] In August 2022, Novartis temporarily halted the dosing with branaplam in its clinical studies, and in December 2022 Novartis announced that they canceled the HD program because of severe side effects in the clinical trials.[8]

Keto-enol tautomerism of branaplam

References

  1. ^ https://www.fiercebiotech.com/biotech/novartis-cans-branaplam-after-seeing-huntingtons-safety-signal-delays-orphan-drug-over-slow
  2. ^ Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, et al. (July 2015). "SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice". Nature Chemical Biology. 11 (7): 511–7. doi:10.1038/nchembio.1837. PMID 26030728.
  3. ^ "LMI070". SMA News Today. Retrieved 2017-03-10.
  4. ^ "An Open Label Study of LMI070 in Type 1 Spinal Muscular Atrophy (SMA)". ClinicalTrials.gov. Retrieved 2017-03-10.
  5. ^ "Novartis Releases Update on LMI070 (Branaplam) Clinical Trial". CureSMA. 2017-09-20. Archived from the original on 2017-11-25. Retrieved 2017-10-07.
  6. ^ "| Novartis announced that enrollment for the ongoing clinical trial of branaplan is now closed". 20 May 2019. Retrieved 2019-07-12.
  7. ^ "Novartis receives US Food and Drug Administration (FDA) Orphan Drug Designation for branaplam (LMI070) in Huntington's disease (HD)". novartis.com. Retrieved 2020-10-24.
  8. ^ https://hdsa.org/wp-content/uploads/2022/12/Novartis-VIBRANT-HD-Community-Letter-FINAL-PDF.pdf
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