{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:51:19Z","timestamp":1779346279325,"version":"3.51.4"},"reference-count":40,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti\u2010tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Phase 2a patients (<jats:italic>n<\/jats:italic>\u2009=\u2009134) received 1800\u2009mg MTPS9579A or placebo intravenously every 4\u2009weeks for 48\u2009weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (<jats:italic>n<\/jats:italic>\u2009=\u200927) received one intravenous dose of 300 or 1800\u2009mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>MTPS9579A did not meet the primary endpoint (hazard ratio\u2009=\u20090.90; 95% CI: 0.55\u20131.47; <jats:italic>p<\/jats:italic>\u2009=\u20090.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8\u2010fold lower, and bronchial active and total tryptase levels were higher (119\u2010fold and 30\u2010fold, respectively). Pharmacokinetic\/pharmacodynamic modeling predicted intravenous doses of 3800\u2009mg every 4\u2009weeks would be necessary to achieve 95% active tryptase inhibition from baseline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.16309","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T15:23:42Z","timestamp":1725895422000},"page":"2993-3004","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor <scp>MTPS9579A<\/scp> in asthma"],"prefix":"10.1111","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4388-2208","authenticated-orcid":false,"given":"Horace","family":"Rhee","sequence":"first","affiliation":[{"name":"Early Clinical Development, Ophthalmology, Metabolism, Neurology, Immunology (OMNI) Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsay M.","family":"Henderson","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca N.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kit","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracy L.","family":"Staton","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David F.","family":"Choy","sequence":"additional","affiliation":[{"name":"Human Pathobiology and OMNI Reverse Translation Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prajna","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor","family":"Poon","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Data and Statistical Sciences Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keyi","family":"Long","sequence":"additional","affiliation":[{"name":"Data and Statistical Sciences Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gizette","family":"Sperinde","sequence":"additional","affiliation":[{"name":"Department of BioAnalytical Sciences Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven T.","family":"Laing","sequence":"additional","affiliation":[{"name":"Safety Assessment Pathology Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas S.","family":"Jones","sequence":"additional","affiliation":[{"name":"Early Clinical Development, Ophthalmology, Metabolism, Neurology, Immunology (OMNI) Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara B.","family":"Glickstein","sequence":"additional","affiliation":[{"name":"Early Clinical Development, Ophthalmology, Metabolism, Neurology, Immunology (OMNI) Genentech, Inc.  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parul","family":"Dayal","sequence":"additional","affiliation":[{"name":"Real World Data Science Enabling Platform, Product Development Data Sciences Genentech, Inc.  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