{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T18:06:03Z","timestamp":1780077963049,"version":"3.54.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012331","name":"Agentschap Innoveren en Ondernemen","doi-asserted-by":"publisher","award":["HBC.2020.3083"],"award-info":[{"award-number":["HBC.2020.3083"]}],"id":[{"id":"10.13039\/100012331","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Service Public de Wallonie-Recherche","award":["8495"],"award-info":[{"award-number":["8495"]}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101045949"],"award-info":[{"award-number":["101045949"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ExeVir Bio BV"}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Variable Heavy domain of Heavy chains (VHH) are innovative tools to target unique epitopes, yet few have been developed as heavy chain-only antibodies for clinical use. Rimteravimab (referred to here as XVR011) is a humanized antibody developed for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19), consisting of two identical VHHs targeting the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, with a human immunoglobulin (Ig) G1 fragment constant of antibody (Fc), silenced for Fc effector functions. We conducted two Phase 1 studies in healthy volunteers or hospitalized COVID-19 patients to evaluate its safety, tolerability, pharmacokinetics and immunogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>A randomized, double-blinded, single-center, placebo-controlled, single ascending dose study was performed in healthy volunteers (Phase 1a, EXEVIR0102, EudraCT 2021-003707-17), in parallel to an open-label, multi-center, single ascending dose study in patients hospitalized for mild to moderate COVID-19 (Phase 1b, EXEVIR0101, EudraCT 2020-005299-36, NCT04884295). Participants received a single intravenous infusion of 250, 500 or 1,000\u2009mg of XVR011. The primary objective for both trials was the safety and tolerability of XVR011. Pharmacokinetics were evaluated as a secondary objective in Phase 1a and as an exploratory objective in Phase 1b. Efficacy (evaluated as respiratory parameters and COVID-19 clinical status) and antiviral activity in patients were evaluated as a secondary objective in Phase 1b. Immunogenicity was evaluated as an exploratory objective. Part 2 of the EXEVIR0101 study (initially a phase 1b\/2 study) was not conducted due to the loss of XVR011 potency against SARS-CoV-2 Omicron BA.2. Demographics, safety, efficacy, and immunogenicity were analyzed using descriptive statistics, while pharmacokinetics were analyzed with noncompartmental pharmacokinetics (PK) modeling.<\/jats:p>\n                    <jats:p>\n                      In the Phase 1a study, there were no infusion-related reactions, serious treatment-emergent adverse events (TEAEs) or TEAEs grade \u22653. 22\/30 volunteers (73.3%) reported 53 TEAEs (49 Grade 1, 4 Grade 2) with none being related to XVR011. The most common TEAE was headache (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098, 26.7%) in various treatment groups. In the Phase 1b study, 27 hospitalized patients were enrolled, and followed up to 30 days. Seven patients (25.9%) reported a total of 15 TEAEs, the majority (80%) being mild to moderate (Grade 1\u20132). There were no treatment-related serious TEAEs. All TEAEs resolved by the end of the study. Peak exposure (maximal concentration, C\n                      <jats:sub>max<\/jats:sub>\n                      ) and systemic exposure (area under the curve, AUC\n                      <jats:sub>0-t<\/jats:sub>\n                      , and AUC\n                      <jats:sub>0-inf<\/jats:sub>\n                      ) for XVR011 increased dose-proportionally. Geomean half-life ranged from 15.4 to 17.0 days in Phase 1a, while individual half-life ranged from 11.4 to 15.6 days in Phase 1b. SARS-CoV-2 viral load, as detected in nasopharyngeal samples by reverse transcription and quantitative polymerase chain reaction (RT-qPCR), decreased similarly in all cohorts compared to baseline. No treatment-induced anti-drug antibodies (ADA) were detected in Phase 1a. In Phase 1b, higher XVR011 concentrations increased the likelihood of ADA formation, without impacting pharmacokinetics and pharmacodynamics. No obvious dose-response in COVID-19 clinical status or respiratory parameters was observed.\n                    <\/jats:p>\n                    <jats:p>Technological limitations included study size, absence of placebo for the Phase 1b, absence of repeated dosing, evolving SARS-CoV-2 variants and standard-of-care.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>XVR011 displayed a favourable safety, tolerability, pharmacokinetics, and immunogenicity profile, both in healthy volunteers and in patients hospitalized for mild to moderate COVID-19. These data pave the way for the design and clinical development of VHH-Fc constructs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1004609","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:27:56Z","timestamp":1780075676000},"page":"e1004609","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of the VHH-Fc construct rimteravimab in healthy adults and patients hospitalized for mild-to-moderate COVID-19: Two Phase 1 randomized clinical trials"],"prefix":"10.1371","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4596-7679","authenticated-orcid":true,"given":"Ellen","family":"Jansen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viki","family":"Bockstal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5094-1990","authenticated-orcid":true,"given":"Florence","family":"Herschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0706-8783","authenticated-orcid":true,"given":"Per","family":"Olsson Gisleskog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Rinaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9454-2663","authenticated-orcid":true,"given":"Ang\u00e9lique","family":"Boerboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salah","family":"Hadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Gaibu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6405-1785","authenticated-orcid":true,"given":"Michel","family":"Moutschen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9541-8644","authenticated-orcid":true,"given":"Dominique","family":"Tersago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"pmed.1004609.ref001","unstructured":"COVID-19 cases | WHO COVID-19 dashboard. 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