Votoplam

Last updated

Votoplam
Votoplam.svg
Clinical data
Other namesPTC518
Routes of
administration 		Oral
Legal status
Legal status
  • Investigational
Identifiers
  • 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)triazolo[4,5-c]pyridazin-6-yl]-5-(triazol-2-yl)phenol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C21H25N9O
Molar mass 419.493 g·mol−1
3D model (JSmol)
  • CC1(CC(CC(N1)(C)C)N2C3=NN=C(C=C3N=N2)C4=C(C=C(C=C4)N5N=CC=N5)O)C
  • InChI=1S/C21H25N9O/c1-20(2)11-14(12-21(3,4)27-20)29-19-17(25-28-29)10-16(24-26-19)15-6-5-13(9-18(15)31)30-22-7-8-23-30/h5-10,14,27,31H,11-12H2,1-4H3
  • Key:ICZNVPJUHBURBG-UHFFFAOYSA-N

Votoplam (also known as PTC518) is an investigational oral small molecule drug being developed by PTC Therapeutics for the treatment of Huntington's disease (HD). [1] The compound functions as a huntingtin (HTT) gene modulator and splicing factor modifier, designed to selectively reduce huntingtin mRNA and protein levels. [2]

Contents

Mechanism of action

Votoplam functions as a splicing modulator of the HTT gene by promoting the inclusion of a pseudoexon that harbors a premature termination codon, leading to degradation of HTT mRNA and a consequent decrease in HTT protein expression. [3] It exhibits strong potency in lowering huntingtin protein levels, with an IC50 of ≤ 0.1 μM. [4]

The drug is an orally bioavailable small molecule that specifically targets the huntingtin gene through splicing modification, leading to selective reduction of both mutant and wild-type huntingtin mRNA and protein. [5]

Clinical development

PIVOT-HD Phase 2 trial

The primary clinical evaluation of votoplam has been conducted through the Phase 2 PIVOT-HD study, which enrolled patients with Stage 2 and Stage 3 Huntington's disease. [6] [7] [8] [9] The study was initially designed to include only Stage 2 patients, but a Stage 3 cohort was subsequently added to help identify the optimal study population for future trials. [9]

The trial achieved its primary endpoint of reducing blood huntingtin (HTT) protein levels at 12 weeks (p<0.0001), demonstrating statistically significant efficacy. [9] Dose-dependent reductions in HTT protein were observed, with a 23% reduction at the 5 mg dose for both Stage 2 and Stage 3 patients, increasing to 39% and 36% respectively at the 10 mg dose. [10]

Regulatory status

Votoplam has received orphan drug designation for the treatment of Huntington's disease from both the European Medicines Agency (December 13, 2024) and the Food and Drug Administration (October 25, 2024). [11] As of September 2025, the drug is in Phase 2 clinical development, representing the highest research and development status globally for this compound. [1]

See also

References

  1. 1 2 "Delving into the Latest Updates on Votoplam with Synapse". synapse.patsnap.com. Retrieved 21 July 2025.
  2. ↑ "Votoplam (PTC518) | HTT splicing modulator | Probechem Biochemicals". www.probechem.com. Retrieved 21 July 2025.
  3. ↑ "PTC518 PIVOT-HD Study Achieves Primary Endpoint". PTC Therapeutics. Retrieved 5 May 2025.
  4. ↑ "HTT Regulator". MedchemExpress.com. 2 January 2020. Retrieved 21 July 2025.
  5. ↑ "Votoplam- PTC Therapeutics - AdisInsight". adisinsight.springer.com. Retrieved 21 July 2025.
  6. ↑ PTC Therapeutics (19 February 2025). A Phase 2A, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of PTC518 in Subjects With Huntington's Disease (Report). clinicaltrials.gov. Archived from the original on 27 March 2025. Retrieved 21 July 2025.
  7. ↑ "PTC's Novartis-partnered Huntington's drug disappoints in mid-stage data reveal". firstwordpharma.com. Retrieved 21 July 2025.
  8. ↑ MS MW (5 May 2025). "PTC518 found to reduce huntingtin protein levels in 1 year in trial | Huntington's Disease News". huntingtonsdiseasenews.com. Archived from the original on 24 May 2025. Retrieved 21 July 2025.
  9. 1 2 3 "PTC518 PIVOT-HD Study Achieves Primary Endpoint" (Press release). PTC Therapeutics. 5 May 2025. Archived from the original on 20 May 2025. Retrieved 21 July 2025.
  10. ↑ Taylor P (6 May 2025). "PTC's Huntington study was positive. Why did its stock fall?". pharmaphorum. Retrieved 21 July 2025.
  11. ↑ "Orphanet: Votoplam". www.orpha.net. Retrieved 21 July 2025.
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