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Votoplam
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
FormulaC21H25N9O
Molar mass419.493 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]

Mechanism of action

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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

[edit]

PIVOT-HD Phase 2 trial

[edit]

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

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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

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References

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  1. ^ a b "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. ^ a b c "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.