Branaplam

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]

Branaplam

Clinical data
Other names	LMI070; NVS-SM1
Identifiers
IUPAC name (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	1562338-42-4
PubChem CID	89971189
ChemSpider	34980709
UNII	P12R69543A
KEGG	D12272
CompTox Dashboard (EPA)	DTXSID801337133
Chemical and physical data
Formula	C22H27N5O2
Molar mass	393.491 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1(CC(CC(N1)(C)C)Oc2ccc(nn2)c3ccc(cc3O)c4c[nH]nc4)C
InChI 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

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]

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 ^{[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): 511–7. 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 ^{[bare URL PDF]}