{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:55:44Z","timestamp":1776405344659,"version":"3.51.2"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Zapnometinib (ATR-002) is a selective MEK inhibitor designed to modulate the MAPK\/ERK pathway, which plays a key role in viral infections and inflammatory diseases. Clinical characterization of its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) is essential to support further development. This Phase I clinical trial was registered under EudraCT number 2021-005225-25.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a Phase I, single-center, randomized, double-blind, placebo-controlled trial conducted in healthy adults. The study included three parts: a single ascending dose (SAD) phase, a multiple ascending dose (MAD) phase, and a drug\u2013drug interaction (DDI) as well as a food-drug interaction (FDI) phase. In the SAD phase, 42 participants received single oral doses of 600, 900, 1,200, or 1,500\u00a0mg. In the MAD phase, 29 participants received daily oral doses of 900, 1,200, or 1,500\u00a0mg for 7\u00a0days. The DDI phase assessed the effect of zapnometinib on CYP2C8 and CYP2C9 activity using repaglinide and celecoxib as probe substrates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Zapnometinib was well tolerated with no serious adverse events reported. Most treatment-emergent adverse events (TEAEs) were mild to moderate, including gastrointestinal symptoms (e.g., diarrhea, nausea) and headache. PK analysis showed dose-proportional increases in C\n                      <jats:sub>max<\/jats:sub>\n                      and AUC, with a notable food effect that increases bioavailability. PD evaluation demonstrated significant MEK inhibition, evidenced by reduced ERK phosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion\/Conclusion<\/jats:title>\n                    <jats:p>This phase 1 study demonstrates that zapnometinib has a favorable safety and tolerability profile, predictable pharmacokinetics, and potent pharmacodynamic activity. The results support further clinical development of zapnometinib for therapeutic indications involving dysregulated MAPK\/ERK signaling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1743230","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:19:50Z","timestamp":1776403190000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Safety, tolerability, pharmacokinetics, and pharmacodynamics of zapnometinib: results from a phase I clinical study"],"prefix":"10.3389","volume":"17","author":[{"given":"Stephan","family":"Stenglein","sequence":"first","affiliation":[{"name":"Institute of Immunology, University and University Hospital of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Atriva Therapeutics GmbH","place":["Martinsried, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Volk","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University and University Hospital of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvonne","family":"F\u00fcll","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University and University Hospital of T\u00fcbingen","place":["T\u00fcbingen, Germany"]},{"name":"Atriva Therapeutics GmbH","place":["Martinsried, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Reh","sequence":"additional","affiliation":[{"name":"Nuvisan GmbH","place":["Neu-Ulm, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steffen","family":"Haffner","sequence":"additional","affiliation":[{"name":"Nuvisan GmbH","place":["Neu-Ulm, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Canisius","sequence":"additional","affiliation":[{"name":"ACliRA Consulting ApS","place":["T\u00f8nder, Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Overend","sequence":"additional","affiliation":[{"name":"Atriva Therapeutics GmbH","place":["Martinsried, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Planz","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University and University Hospital of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. 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