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. 2024 May 3;11(6):ofae233.
doi: 10.1093/ofid/ofae233. eCollection 2024 Jun.

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

Jeff Kingsley  1 , Nagalingeswaran Kumarasamy  2 , Luis Abrishamian  3 , Marc Bonten  4 , Awawu Igbinadolor  5 , Martha Mekebeb-Reuter  6 , Jennifer Rosa  7 , Damodaran Solai Elango  8 , Patricia Lopez  9 , Pierre Fustier  10 , Susana Goncalves  9 , Charles G Knutson  11 , Petra Kukkaro  9 , Philippe Legenne  10 , Krishnan Ramanathan  9 , Shantha Rao  12 , Evgeniya Reshetnyak  12 , Vaia Stavropoulou  10 , Nina Stojcheva  10 , Michael T Stumpp  10 , Andreas Tietz  9 , Marianne Soergel  10 , Richa Chandra  12
Affiliations

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

Jeff Kingsley et al. Open Forum Infect Dis. .

Abstract

Background: The coronavirus disease 2019 (COVID-19) pandemic was characterized by rapid evolution of severe acute respiratory syndrome coronavirus 2 (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 multispecific designed ankyrin repeat protein (DARPin) with multivariant in vitro activity, in ambulatory patients with mild to moderate COVID-19.

Methods: Nonhospitalized, 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 = .002), -0.33 (P = .014), and -0.59 (P < .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% confidence interval, 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 nonhospitalized patients with COVID-19.

Keywords: COVID-19; DARPin; SARS-CoV-2; ensovibep; randomized clinical trial.

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Conflict of interest statement

Potential conflicts of interest. J. K. reports receiving grants or contracts from Pfizer, Regeneron, Lilly, Novavax, Boehringer Ingelheim, GlaxoSmithKline, Merck, Clear Creek, National Institute of Allergy and Infectious Diseases, and Azur. N. K. reports receiving grants or contracts from Hetero Labs, Viatris, Emcure, Johnson & Johnson, National Institutes of Health, Indian Council of Medical Research, and the World Health Organization. L. A. reports payment for expert testimony by individual law firms and insurance companies. M. B. reports receiving grants or contracts from Janssen Vaccines, Novartis, and CureVac; consulting fees from AstraZeneca, Pfizer, Janssen Vaccines, and Novartis; participation on a data and safety monitoring board or advisory board for Sanofi (all payments to University Medical Center Utrecht); and honoraria for lectures by Takeda. E. R. is an employee of Novartis. R. C., D. S. E., S. G., P. K., P. L., A. T., C. G. K., and S. R. are employees at Novartis and hold stock or stock options in the company. P. L., P. S., M. S., and N. S. are employees at Molecular Partners AG and hold stock or stock options in the company. M. T. S. is an employee at Molecular Partners AG, is a member of its executive management, and owns shares in the company. At the time of writing this manuscript, P. F. was an employee at Molecular Partners AG and K. R. was an employee at Novartis. All other authors report no potential conflicts.

Figures

Figure 1.
Figure 1.
Study disposition in the Ensovibep Multicenter Placebo-controlled study in Ambulatory patients with symTomatic COVID-19 (pHase 2 and 3 for efficacY and safety) (EMPATHY) study. Patients could discontinue from study treatment but continue participating in the study. Two patients randomized to ensovibep 75 mg did not receive the treatment they were randomized to: 1 due to screening failure and the other was denied for dosing after randomization. Two patients randomized to ensovibep 225 mg did not receive the treatment they were randomized to: 1 patient received no active study drug because the infusion bag was not prepared correctly, and 1 patient received a lower dose (<75 mg) as the infusion was interrupted. For the safety set, these 2 patients were analyzed in the placebo and ensovibep 75 mg arms, respectively. In the placebo arm, 3 patients did not receive the treatment they were randomized to: 1 patient was never dosed due to randomization failure, and 2 withdrew consent before dosing.
Figure 2.
Figure 2.
A, Mean change from baseline in viral load to day 15 with ensovibep versus placebo. Vertical bars represent standard deviation. B, Kaplan-Meier curve for the time to sustained clinical recovery in patients treated with ensovibep versus placebo up to day 29 (full analysis set). The full analysis set includes all patients in the randomized set for whom intravenous infusion of study treatment was initiated during the treatment period, excluding misrandomized patients. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation.
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