The DARPin antiviral ensovibep for non-hospitalized patients with COVID-19: Results from EMPATHY, a randomized, placebo-controlled Phase 2 study

Abstract Background 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. Methods 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. Results 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 < 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. Conclusions 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).