The darpin antiviral ensovibep for non-hospitalized patients with COVID-19: Results from EMPATHY, a randomized, placebo-controlled Phase 2 study
Jeff Kingsley, Nagalingeswaran Kumarasamy, Luis Abrishamian, Marc Bonten, Awawu Igbinadolor, Martha Mekebeb-Reuter, Jennifer Rosa, Damodaran Solai Elango, Patricia Lopez, Pierre Fustier, Susana Goncalves, Charles G Knutson, Petra Kukkaro, Philippe Legenne, Krishnan Ramanathan, Shantha Rao, Evgeniya Reshetnyak, Vaia Stavropoulou, Nina Stojcheva, Michael T Stumpp, Andreas Tietz, Marianne Soergel, Richa Chandra
doi:10.1093/ofid/ofae2331
pandemic was characterized by rapid evolution of SARS-CoV-2 variants, affecting viral transmissibility, virulence, and response to vaccines/therapeutics.
Conflict of interest Dr Kingsley reports receiving grants or contracts from Pfizer, Regeneron, Lilly, Novavax, Boehringer Ingelheim, GlaxoSmithKline, Merck, Clear Creek, National Institute of Allergy and Infectious Disease, and Azur; Dr Kumarasamy reports receiving grants or contracts from Hetero Labs, Viatris, Emcure, Johnson & Johnson, NIH, ICMR, and WHO; Dr Abrishamian reports payment for expert testimony by individual law firms and insurance companies; Dr Bonten reports receiving grants or contracts from Janssen Vaccines, Novartis, and CureVac; consulting fees from AstraZeneca, Pfizer, Janssen Vaccines and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Sanofi (all payments to UMC Utrecht); and honoraria for lectures by Takeda; and participation in a Data Safety Monitoring Board or Advisory Board for Sanofi; Dr Igbinadolor, Dr Mekebeb-Reuter and Dr Rosa report no conflicts of interests; Reshetnyak is an employee of Novartis; Dr Chandra, Dr Solai Elango, Ms Goncalves, Dr Kukkaro, Dr Lopez, Dr Tietz, Dr Knutson, and Dr Rao are employees at Novartis and hold stock or stock options in the company; Dr Legenne, Dr Stavropoulou, Dr Soergel and Dr Stojcheva are employees at Molecular Partners AG and hold stock or stock options in the company; Dr Stumpp is an employee at Molecular Partners AG, a member of its executive management and owns shares in the company. At the time of writing this manuscript, Dr Fustier was an employee at Molecular..
References
Chen, Nirula, Heller, SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2029849Cromwell, Armer, Cormier, 22 -Evidence-Based Outcomes
Garcia-Beltran, Lam, Denis, Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity, Cell,
doi:10.1016/j.cell.2021.03.013Gobeil, Janowska, Mcdowell, Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity, Science,
doi:10.1126/science.abi6226Knutson, Claas, Gaudet, Ensovibep clinical dose selection rationale to treat COVID-19 in EMPATHY, Clin Pharmacol Ther
Otto, Day, Arino, The origins and potential future of SARS-CoV-2 variants of concern in the evolving COVID-19 pandemic, Curr Biol,
doi:10.1016/j.cub.2021.06.049Prins, Van Der Plas, Vissers, Viral clearance, pharmacokinetics and tolerability of ensovibep in patients with mild to moderate COVID-19: A phase 2a, open-label, single-dose escalation study, Br J Clin Pharmacol,
doi:10.1111/bcp.15560Stojcheva, Gladman, Soergel, Ensovibep, a SARS-CoV-2 antiviral designed ankyrin repeat protein, is safe and well tolerated in healthy volunteers: Results of a first-in-human, ascending single-dose Phase 1 study, Br J Clin Pharmacol,
doi:10.1111/bcp.15747The, Food and Drug Administration. Coronavirus (COVID-19) Update
Walser, Neutralisation of SARS-CoV-2 Omicron variants by ensovibep, a DARPin therapeutic candidate for the treatment of COVID-19, European Society for Clinical Virology Congress
Weinreich, Sivapalasingam, Norton, REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2035002Wen, Chen, Tang, Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis, Ann Med,
doi:10.1080/07853890.2022.2034936Zhou, Dejnirattisai, Supasa, Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera, Cell,
doi:10.1016/j.cell.2021.02.037Zhou, Tada, Dcosta, Landau, Neutralization of SARS-CoV-2 Omicron BA.2 by Therapeutic Monoclonal Antibodies, bioRxiv,
doi:10.1101/2022.02.15.480166{ 'indexed': {'date-parts': [[2024, 5, 4]], 'date-time': '2024-05-04T00:34:35Z', 'timestamp': 1714782875759},
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>The COVID-19 pandemic was characterized by rapid evolution of '
'SARS-CoV-2 variants, affecting viral transmissibility, virulence, and response to '
'vaccines/therapeutics. EMPATHY (NCT04828161), a Phase 2 study, investigated the '
'safety/efficacy of ensovibep, a multi-specific designed ankyrin repeat protein (DARPin) with '
'multi-variant in vitro activity, in ambulatory patients with mild-to-moderate '
'COVID-19.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>Non-hospitalized, symptomatic patients (N\u2009=\u2009407) with '
'COVID-19 were randomized to receive single-dose intravenous ensovibep (75, 225, or 600\u2005'
'mg) or placebo and followed until Day 91. The primary endpoint was time-weighted change from '
'baseline in log10 SARS-CoV-2 viral load through Day 8. Secondary endpoints included '
'proportion of patients with COVID-19-related hospitalizations, emergency room (ER) visits, '
'and/or all-cause mortality to Day 29; time to sustained clinical recovery to Day 29; and '
'safety to Day 91.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>Ensovibep showed superiority versus placebo in reducing log10 '
'SARS-CoV-2 viral load; treatment differences versus placebo in time-weighted change from '
'baseline were: −0.42 (p\u2009=\u20090.002), –0.33 (p\u2009=\u20090.014), and –0.59 (p\u2009'
'&lt;\u20090.001) for 75, 225, and 600\u2005mg, respectively. Ensovibep-treated patients '
'had fewer COVID-19-related hospitalizations, ER visits, and all-cause mortality (relative '
'risk reduction: 78%; 95% CI: 16–95%); and a shorter median time to sustained clinical '
'recovery than placebo. Treatment-emergent adverse events occurred in 44.3% versus 54.0% of '
'patients in the ensovibep and placebo arms; grade 3 events were consistent with COVID-19 '
'morbidity. Two deaths were reported with placebo and none with ensovibep.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>All 3 doses of ensovibep showed antiviral efficacy and clinical '
'benefits versus placebo and an acceptable safety profile in non-hospitalized patients with '
'COVID-19 (Funded by Novartis).</jats:p>\n'
' </jats:sec>',
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'title': 'The DARPin antiviral ensovibep for non-hospitalized patients with COVID-19: Results from '
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