# Votoplam
> Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Votoplam
> Markdown URL: https://mediated.wiki/source/Votoplam.md
> Source: https://en.wikipedia.org/wiki/Votoplam
> Source revision: 1329897807
> License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/)
{{Short description|Small molecule drug }}
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{{Infobox drug
| drug_name = Votoplam
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| routes_of_administration = Oral
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| legal_status = Investigational
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| CAS_number = 2407849-89-0
| PubChem = 147894286
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| ChemSpiderID = 129432011
| UNII = D7EZ7B585X
| KEGG = D12970
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| ChEMBL = 4850295
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| synonyms = PTC518
| IUPAC_name = 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)triazolo[4,5-c]pyridazin-6-yl]-5-(triazol-2-yl)phenol
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| SMILES = CC1(CC(CC(N1)(C)C)N2C3=NN=C(C=C3N=N2)C4=C(C=C(C=C4)N5N=CC=N5)O)C
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'''Votoplam''' (also known as '''PTC518''') is an investigational oral small molecule drug being developed by [PTC Therapeutics](/source/PTC_Therapeutics) for the treatment of [Huntington's disease](/source/Huntington's_disease) (HD).[{{Cite web | title = Delving into the Latest Updates on Votoplam with Synapse | url = https://synapse.patsnap.com/drug/3d8accbe86ab40148bb51bcef2b6dee0 | access-date = 2025-07-21 | website = synapse.patsnap.com | language = en }}] The compound functions as a [huntingtin](/source/huntingtin) (HTT) gene modulator and splicing factor modifier, designed to selectively reduce huntingtin mRNA and protein levels.[{{Cite web | title = Votoplam (PTC518) {{!}} HTT splicing modulator {{!}} Probechem Biochemicals|url=https://www.probechem.com/products_Votoplam.aspx|access-date=2025-07-21|website=www.probechem.com}}]
==Mechanism of action==
Votoplam functions as a splicing modulator of the HTT gene by promoting the inclusion of a [pseudoexon](/source/exon) that harbors a premature [termination codon](/source/termination_codon), leading to degradation of HTT mRNA and a consequent decrease in HTT protein expression.[{{cite web | title = PTC518 PIVOT-HD Study Achieves Primary Endpoint | url = https://ir.ptcbio.com/news-releases/news-release-details/ptc518-pivot-hd-study-achieves-primary-endpoint?mobile=1 | publisher = PTC Therapeutics | access-date = 5 May 2025 }}] It exhibits strong potency in lowering huntingtin protein levels, with an [IC50](/source/IC50) of ≤ 0.1 μM.[{{cite web | title = HTT Regulator | date = 2020-01-02 | website = MedchemExpress.com | url = https://www.medchemexpress.com/votoplam.html | access-date = 2025-07-21 }}]
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.[{{Cite web | title = Votoplam- PTC Therapeutics - AdisInsight | url = https://adisinsight.springer.com/drugs/800061227 | access-date = 2025-07-21 | website = adisinsight.springer.com }}]
==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.[{{Cite report | title = A Phase 2A, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of PTC518 in Subjects With Huntington's Disease | issue = NCT05358717 | date = 2025-02-19 | url = https://clinicaltrials.gov/study/NCT05358717 | last = PTC Therapeutics | publisher = clinicaltrials.gov | archive-date = 27 March 2025 | access-date = 21 July 2025 | archive-url = https://web.archive.org/web/20250327094726/https://clinicaltrials.gov/study/NCT05358717 | url-status = live }}][{{Cite web | title = PTC's Novartis-partnered Huntington's drug disappoints in mid-stage data reveal | url = https://firstwordpharma.com/story/5956490 | access-date = 2025-07-21 | website = firstwordpharma.com }}][{{Cite web|vauthors=MS MW|title=PTC518 found to reduce huntingtin protein levels in 1 year in trial {{!}} Huntington's Disease News|date=2025-05-05|url=https://huntingtonsdiseasenews.com/news/ptc518-pivot-hd-study-achieves-primary-endpoint/|access-date=2025-07-21|website=huntingtonsdiseasenews.com|language=en-US|archive-date=24 May 2025|archive-url=https://web.archive.org/web/20250524123317/https://huntingtonsdiseasenews.com/news/ptc518-pivot-hd-study-achieves-primary-endpoint/|url-status=live}}][{{cite press release | title = PTC518 PIVOT-HD Study Achieves Primary Endpoint | date = May 5, 2025 | url = https://ir.ptcbio.com/news-releases/news-release-details/ptc518-pivot-hd-study-achieves-primary-endpoint | publisher = PTC Therapeutics | access-date = 2025-07-21 | archive-date = 20 May 2025 | archive-url = https://web.archive.org/web/20250520103036/https://ir.ptcbio.com/news-releases/news-release-details/ptc518-pivot-hd-study-achieves-primary-endpoint | url-status = live }}] 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.[{{Cite web | vauthors = Taylor P | title = PTC's Huntington study was positive. Why did its stock fall? | date = 6 May 2025 | url = https://pharmaphorum.com/news/ptcs-huntington-study-was-positive-why-did-its-stock-fall | access-date = 2025-07-21 | website = pharmaphorum | language = en }}]
==Regulatory status==
Votoplam has received [orphan drug](/source/orphan_drug) designation for the treatment of Huntington's disease from both the [European Medicines Agency](/source/European_Medicines_Agency) (December 13, 2024) and the [Food and Drug Administration](/source/Food_and_Drug_Administration) (October 25, 2024).[{{Cite web | title = Orphanet: Votoplam | url = http://www.orpha.net/en/drug/substance/689618 | access-date = 2025-07-21 | website = www.orpha.net | language = en }}] As of September 2025, the drug is in Phase 2 clinical development, representing the highest research and development status globally for this compound.