Branaplam

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 but the trial ended in 2023 due to toxicity concerns.[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 study was discontinued in 2021.

In October 2020, Novartis announced that branaplam reduces the amount 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 would start clinical trials in 2021.[7] In August 2022, Novartis temporarily halted the dosing with branaplam in its clinical studies, and in December 2022 the company discontinued the study due to negative safety signals.[8]

Use in biomedical research

Branaplam can be used as a so-called Xon inducer[9] of splicing for control of gene expression. For example, branaplam was used as an Xon inducer to tightly control Cas9 expression with a modified branaplam-sensitive splicing cassette from the SF3B3 gene.[10]

References

  1. ^ https://www.fiercebiotech.com/biotech/novartis-cans-branaplam-after-seeing-huntingtons-safety-signal-delays-orphan-drug-over-slow [bare URL]
  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): 511–517. 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. Archived from the original on 2020-10-27. Retrieved 2020-10-24.
  8. ^ "Status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington's Disease" (PDF). Community update. Novartis. December 8, 2022.
  9. ^ Monteys AM, Hundley AA, Ranum PT, Tecedor L, Muehlmatt A, Lim E, et al. (August 2021). "Regulated control of gene therapies by drug-induced splicing". Nature. 596 (7871): 291–295. doi:10.1038/s41586-021-03770-2. PMC 8966400. PMID 34321659.
  10. ^ Srinivasan R, Sun T, Sandles A, Wu D, Wang L, Heidersbach AJ, et al. (2024-12-28), "Chemically-inducible CRISPR/Cas9 circuits for ultra-high dynamic range gene perturbation", bioRxiv, doi:10.1101/2024.12.27.630546

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