{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:10:57Z","timestamp":1787796657139,"version":"build-2784847793"},"reference-count":21,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,8,18]],"date-time":"2024-08-18T00:00:00Z","timestamp":1723939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013223","name":"PTC Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013223","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      PTC518 is an orally administered, centrally and peripherally distributed huntingtin (\n                      <jats:italic>HTT<\/jats:italic>\n                      ) pre\u2010mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease\u2010modifying treatments. This first\u2010in\u2010human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This phase 1, single\u2010centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by\n                      <jats:italic>HTT<\/jats:italic>\n                      mRNA and HTT protein levels after single and multiple doses, and food effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PTC518 demonstrated a favourable safety profile. The majority of treatment\u2010emergent adverse events were mild and transient. PTC518\n                      <jats:italic>T<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      was reached at 6\u20137\u00a0h and the terminal\n                      <jats:italic>T<\/jats:italic>\n                      <jats:sub>1\/2<\/jats:sub>\n                      was 54.0\u201375.3\u00a0h following a single oral dose. Exposure increased with dose though less than dose proportionally. The PTC518 concentrations in cerebrospinal fluid were approximately 2.6\u2010fold higher than the unbound free\u2010drug concentrations in plasma. A significant dose\u2010dependent reduction of up to approximately 60% in\n                      <jats:italic>HTT<\/jats:italic>\n                      mRNA and a significant dose\u2010dependent, time\u2010dependent and sustained reduction in HTT protein levels of up to 35% were observed after PTC518 treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      PTC518 was well tolerated, and proof of mechanism of this novel splicing modifier was demonstrated by the dose\u2010dependent decrease in systemic\n                      <jats:italic>HTT<\/jats:italic>\n                      mRNA and HTT protein levels. Results from this first\u2010in\u2010human study support further studies in patients with HD and demonstrate the potential for PTC518 as a breakthrough treatment for HD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bcp.16202","type":"journal-article","created":{"date-parts":[[2024,8,18]],"date-time":"2024-08-18T22:03:20Z","timestamp":1724018600000},"page":"3242-3251","source":"Crossref","is-referenced-by-count":15,"title":["Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first\u2010in\u2010human study"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2528-7656","authenticated-orcid":false,"given":"Lan","family":"Gao","sequence":"first","affiliation":[{"name":"PTC Therapeutics  Warren New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Bhattacharyya","sequence":"additional","affiliation":[{"name":"PTC Therapeutics  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