Votoplam

{{Short description|Small molecule drug }} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=July 2025}} {{Infobox drug | drug_name = Votoplam | INN = | type =  | image = Votoplam.svg | image_class = skin-invert-image | width = | alt = | caption = | image2 = | image_class2 =  | width2 = | alt2 = | caption2 = | imageL = | image_classL =  | widthL = | altL = | imageR = | image_classR =  | widthR = | altR = | captionLR =  | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA =  | licence_EU =  | DailyMedID =  | licence_US =  | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category= | dependency_liability = | addiction_liability = | routes_of_administration = Oral | class = | ATCvet = | ATC_prefix =  | ATC_suffix = | ATC_supplemental =  | legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US =  | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status = Investigational  | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action= | excretion =  | CAS_number = 2407849-89-0 | PubChem = 147894286 | IUPHAR_ligand = | DrugBank = | ChemSpiderID = 129432011 | UNII = D7EZ7B585X | KEGG = D12970 | ChEBI = | ChEMBL = 4850295 | NIAID_ChemDB = | PDB_ligand = | 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 | chemical_formula = | C=21 | H=25 | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I= | K= | Li= | Mg= | Mn= | N=9 | Na= | O=1 | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge= | molecular_weight = | SMILES = CC1(CC(CC(N1)(C)C)N2C3=NN=C(C=C3N=N2)C4=C(C=C(C=C4)N5N=CC=N5)O)C | Jmol = | StdInChI = 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 | StdInChI_comment = | StdInChIKey = ICZNVPJUHBURBG-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | solubility = | sol_units = | specific_rotation = }}

'''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).<ref name="synapse">{{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 }}</ref> The compound functions as a huntingtin (HTT) gene modulator and splicing factor modifier, designed to selectively reduce huntingtin mRNA and protein levels.<ref name="probechem">{{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}}</ref>

==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.<ref>{{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 }}</ref> It exhibits strong potency in lowering huntingtin protein levels, with an IC50 of ≤ 0.1 μM.<ref name="medchem">{{cite web | title = HTT Regulator | date = 2020-01-02 | website = MedchemExpress.com | url = https://www.medchemexpress.com/votoplam.html | access-date = 2025-07-21 }}</ref>

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.<ref>{{Cite web | title = Votoplam- PTC Therapeutics - AdisInsight | url = https://adisinsight.springer.com/drugs/800061227 | access-date = 2025-07-21 | website = adisinsight.springer.com }}</ref>

==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.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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}}</ref><ref name="ptc_press">{{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 }}</ref> 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.<ref name="ptc_press" />

The trial achieved its primary endpoint of reducing blood huntingtin (HTT) protein levels at 12 weeks (p<0.0001), demonstrating statistically significant efficacy.<ref name="ptc_press" /> 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.<ref name="Taylor_2025">{{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 }}</ref>

==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).<ref name="orphanet">{{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 }}</ref> As of September 2025, the drug is in Phase 2 clinical development, representing the highest research and development status globally for this compound.<ref name="synapse" />

== See also ==

* Huntington's disease

* Huntingtin

==References== {{Reflist}}

Category:Phenols Category:Piperidines Category:Triazolopyridazines Category:Triazoles Category:Experimental drugs Category:Huntington's disease Category:Orphan drugs