The Generative Brain

NSC500 (pentamer formyl thiophene acetic acid), EU orphan designated anti-prion compound

NSC500 is the sponsor code under which NeuroScios GmbH, a small central nervous system drug development company at St. Radegund near Graz in Austria, obtained EU orphan designation EU/3/17/1883 for pentamer formyl thiophene acetic acid in the treatment of Creutzfeldt-Jakob disease, granted by the European Commission on 20 June 2017 after a positive COMP opinion on 12 May 2017. EMA's summary says the compound is expected to attach to misfolded prion protein in brain cells, make it more soluble and less harmful and so slow the disease, and that at designation it had only been studied in experimental models, with no patient trial started. The chemical name is the long form of pFTAA, a five ring luminescent conjugated oligothiophene made at Linkoping University in Sweden and first used as an amyloid and prion deposit stain. In 2012 the Zurich prion group of Adriano Aguzzi, with the Linkoping chemists, showed that pFTAA and related polythiophenes reduce prion infectivity in cell and cell-free assays by over-stabilising prion aggregates, and in 2015 a larger study showed that five ring carboxylated polythiophenes prolonged survival of prion-infected mice, with the best designed compound adding more than 80 percent when given before infection. No source read ties NeuroScios to that academic work, no trial of NSC500 is registered, and the EMA record has not changed since 2017. This is an experimental compound with animal data only. It is not an available treatment. Information only, not medical advice.

Key facts

  • The European Commission granted orphan designation EU/3/17/1883 on 20 June 2017 to NeuroScios GmbH, Willersdorfer Strasse 7, 8061 St. Radegund/Graz, Austria, for pentamer formyl thiophene acetic acid, also known as NSC500, for treatment of CJD, following a positive COMP opinion on 12 May 2017; the EMA page shows status positive, first published and last updated 17 July 2017, with no withdrawal or transfer noted.
  • EMA states the medicine is expected to bind misfolded prion protein in brain cells and make it more soluble and less damaging, that its effects were still being evaluated in experimental models, that no clinical trial in patients had started, and that CJD affected fewer than 0.1 in 10,000 people in the EU at the time.
  • An orphan designation is a regulatory status that gives incentives for development in a rare disease; it is not a marketing authorisation and says nothing about whether the medicine works.
  • pFTAA is defined in the Linkoping and Zurich literature as pentamer (or pentameric) formyl thiophene acetic acid, one of the luminescent conjugated oligothiophenes introduced in a 2009 ACS Chemical Biology paper as stains that could tell apart distinct prion deposits ex vivo and image protein aggregates in living transgenic mice.
  • In a 2012 J Biol Chem study by the Zurich Institute of Neuropathology and Linkoping University, pFTAA reduced prion infectivity in mouse prion brain homogenate in a cell based infectivity assay, with an effect similar to the polymer PTAA, and reduced aggregate signal in a misfolded protein assay; the authors proposed that these compounds work by hyperstabilising PrPSc aggregates and noted that the pentamers cross the blood-brain barrier, but pFTAA itself was not tested in treated animals in that paper.
  • The 2015 Science Translational Medicine study, a Zurich, ETH, Linkoping and Lyon collaboration with Aguzzi as last author, found that antiprion activity in prion-infected mice required at least five thiophene rings with regularly spaced carboxyl side groups; its redesigned lead extended survival by more than 80 percent, worked against mouse and hamster prions and had some effect when injected into the abdomen.
  • Per a news report of that study, the five ring compound LIN5001 prolonged survival by 36.5 percent when infused into the brain from before infection and by more than 15 days when started three weeks after infection, with only a hint of benefit at the symptomatic stage; the redesigned LIN5044 gave 87.5 percent before infection, 22 percent when started at day 50 into the brain and 14.5 percent when started at day 50 by intraperitoneal injection.
  • The LIN5001 ligand deposited in the Protein Data Bank (2MUS) is a quinquethiophene with two carboxymethyl side groups and two terminal carboxylic acids, formula C26H16O8S5, and PubChem's pFTAA record has the same formula and substitution pattern as its tetra-anion. On this comparison LIN5001 appears to be pFTAA, but that is an inference from two registry records and no source read says so.
  • The Zurich group said in 2015 that its own role in developing the compounds as drugs was finished and that pharmaceutical companies would need to take them forward.
  • NeuroScios presents itself in a vendor directory as a CNS drug development service provider (chemistry, pharmacology, toxicology, regulatory and clinical trial services) and lists no prion, CJD or NSC500 programme; a business register excerpt gives it as active and founded in 2013.
  • No trial of NSC500 or a formyl thiophene compound appears on ClinicalTrials.gov, and no NeuroScios sponsored study was returned.
  • The code NSC500 collides with an older US National Cancer Institute compound number for an unrelated phosphorothioic triamide, so chemical database searches on NSC500 alone return the wrong substance.
  • The European Commission Union Register entry for the designation did not render its data in the fetch tool, so the current Union Register status was not confirmed.

Timeline

  1. 2009ACS Chemical Biology paper from Linkoping and Zurich introduces pentameric thiophene derivatives including p-FTAA as imaging stains for prion and other protein deposits.
  2. 2012J Biol Chem paper shows polythiophenes including pFTAA reduce prion infectivity in vitro by stabilising prion aggregates.
  3. 2015Science Translational Medicine paper reports five ring carboxylated polythiophenes prolong survival of prion-infected mice.
  4. 2017EMA Committee for Orphan Medicinal Products gives a positive opinion on pentamer formyl thiophene acetic acid for CJD.
  5. 2017European Commission grants orphan designation EU/3/17/1883 to NeuroScios GmbH.
  6. 2017EMA publishes the designation page; it has not been updated since.
  7. 2026No registered trial found on ClinicalTrials.gov; Union Register status unconfirmed.
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