The Designed Ankyrin Repeat Protein Antiviral Ensovibep for Nonhospitalized Patients With Coronavirus Disease 2019: Results From EMPATHY, a Randomized, Placebo-Controlled Phase 2 Study

Kingsley et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofae233, EMPATHY, NCT04828161

May 2024

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RCT 407 mild to moderate COVID-19 outpatients showing faster viral clearance, lower risk of hospitalization/ER visits, and shorter time to sustained recovery with ensovibep treatment (75/225/600mg single infusion). There were 2 COVID-19 related deaths in the placebo group and none in the ensovibep groups.

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risk of death, 89.0% lower, RR 0.11, p = 0.06, treatment 0 of 301 (0.0%), control 2 of 99 (2.0%), NNT 49, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).

risk of hospitalization/ER, 78.1% lower, RR 0.22, p = 0.02, treatment 4 of 301 (1.3%), control 6 of 99 (6.1%), NNT 21.

risk of hospitalization, 86.8% lower, RR 0.13, p = 0.01, treatment 2 of 301 (0.7%), control 5 of 99 (5.1%), NNT 23.

ER visit, 86.8% lower, RR 0.13, p = 0.01, treatment 2 of 301 (0.7%), control 5 of 99 (5.1%), NNT 23.

risk of no recovery, 29.6% lower, HR 0.70, p = 0.13, treatment 100, control 99, inverted to make HR<1 favor treatment, Cox proportional hazards, 600mg.

risk of no recovery, 39.4% lower, HR 0.61, p = 0.03, treatment 100, control 99, inverted to make HR<1 favor treatment, Cox proportional hazards, 225mg.

risk of no recovery, 39.4% lower, HR 0.61, p = 0.03, treatment 101, control 99, inverted to make HR<1 favor treatment, Cox proportional hazards, 75mg.

risk of PASC, 0.9% higher, RR 1.01, p = 1.00, treatment 146 of 243 (60.1%), control 50 of 84 (59.5%), day 91.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Kingsley et al., 3 May 2024, Double Blind Randomized Controlled Trial, placebo-controlled, multiple countries, peer-reviewed, 23 authors, study period 10 May, 2021 - 21 October, 2021, trial NCT04828161 (history) (EMPATHY). Contact: richa.chandra@novartis.com, andreas.tietz@novartis.com.

This Paper Ensovibep All

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..

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DOI record: { "DOI": "10.1093/ofid/ofae233", "ISSN": [ "2328-8957" ], "URL": "http://dx.doi.org/10.1093/ofid/ofae233", "abstract": "Abstract\n \n Background\n 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.\n \n \n Methods\n Non-hospitalized, symptomatic patients (N = 407) with COVID-19 were randomized to receive single-dose intravenous ensovibep (75, 225, or 600 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.\n \n \n Results\n 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 = 0.002), –0.33 (p = 0.014), and –0.59 (p &lt; 0.001) for 75, 225, and 600 mg, 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.\n \n \n Conclusions\n 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).\n ", "author": [ { "affiliation": [ { "name": "IACT Health DBA Centricity Research , Columbus, GA , USA" } ], "family": "Kingsley", "given": "Jeff", "sequence": "first" }, { "affiliation": [ { "name": "VHS Infectious Diseases Medical Centre, Chennai Antiviral Research and Treatment Clinical Research Site , Chennai , India" } ], "family": "Kumarasamy", "given": "Nagalingeswaran", "sequence": "additional" }, { "affiliation": [ { "name": "South Bay Clinical Research Institute , Redondo Beach, CA , USA" } ], "family": "Abrishamian", "given": "Luis", "sequence": "additional" }, { "affiliation": [ { "name": "UMC Utrecht , Utrecht , The Netherlands" } ], "family": "Bonten", "given": "Marc", "sequence": "additional" }, { 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"given": "Evgeniya", "sequence": "additional" }, { "affiliation": [ { "name": "Molecular Partners AG , Zurich-Schlieren , Switzerland" } ], "family": "Stavropoulou", "given": "Vaia", "sequence": "additional" }, { "affiliation": [ { "name": "Molecular Partners AG , Zurich-Schlieren , Switzerland" } ], "family": "Stojcheva", "given": "Nina", "sequence": "additional" }, { "affiliation": [ { "name": "Molecular Partners AG , Zurich-Schlieren , Switzerland" } ], "family": "Stumpp", "given": "Michael T", "sequence": "additional" }, { "ORCID": "http://orcid.org/0009-0006-1223-2118", "affiliation": [ { "name": "Novartis Pharma AG , Basel , Switzerland" } ], "authenticated-orcid": false, "family": "Tietz", "given": "Andreas", "sequence": "additional" }, { "affiliation": [ { "name": "Molecular Partners AG , Zurich-Schlieren , Switzerland" } ], "family": "Soergel", "given": "Marianne", "sequence": "additional" }, { "affiliation": [ { "name": "Novartis Pharmaceuticals Corporation , East Hanover, NJ 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