A trial of a novel designed ankyrin repeat protein, ensovibep, for the treatment of patients hospitalised with COVID-19 proved no better than placebo
Ensovibep treatment for patients hospitalised with COVID-19 was no better than placebo and, in fact, the trial was terminated early because of futility, according to the findings of randomised trial by researchers from the ACTIV-3/TICO group.
The early treatment of patients infected with COVID-19 using anti-virals such as molnupiravir reduces the risk of hospitalisation or death in at-risk, unvaccinated adults. However, to date, there are no effective anti-viral agents for those who have been hospitalised due to virus. One new class of treatment is designed ankyrin repeat proteins (DARPins), which represent a novel class of specific binding molecules, that can recognise targets with specificities and affinities that equal or surpass those of antibodies. One such DARPin is ensovibep, which has been found to simultaneously engage all three units of the COVID-19 spike protein trimer to potently inhibit ACE2 interaction and therefore prevent cellular entry of the virus. In a dose finding, efficacy trial with ensovibep (MP0420) in ambulatory, symptomatic COVID-19 patients, interim results showed that after a single dose, the drug reduced both viral load over a period of 8 days and hospitalisation and death.
Based on these early results, for the present study, researchers sought to determine whether ensovibep in combination to remdesivir and other standard care, improved clinical outcomes for patients hospitalised with COVID-19 in comparison to standard care alone. In this Phase III trial, hospitalised patients with a PCR or equivalent confirmed COVID-19 infection, were randomised 1:1 to ensovibep or placebo. A 600mg dose of the drug was administered intravenously on study day 0 and all participants received remdesivir as part of standard care, with dexamethasone also permitted if it formed part of the site’s standard care. Participants were assessed daily from randomisation to day 7 and then retrospectively on days 14, 28, 60 and 90. The primary efficacy outcome was the time to sustained clinical recovery up to day 90, which the researchers defined as the time to return home. However, a pre-specified futility assessment based on 7-category ordinal outcomes were collected at day 5; the pulmonary ordinal and pulmonary-plus scales. The former categorised individuals with respect to the intensity of respiratory support required whereas the latter assessed extra-pulmonary manifestations. The purpose of using these two scales was to ensure some minimal level of activity for ensovibep before continued enrolment.
Ensovibep and COVID-19 outcomes
A total of 485 participants with a median age of 57 years (43.3% female) were enrolled and randomised to ensovibep (247) or the control (standard care) arm. Among the complete cohort, 57.9% had a co-existing chronic illness including hypertension (39.4%) and diabetes (23.5%). Overall, 25.6% of participants had been fully vaccinated against COVID-19.
The adjusted odds ratio (OR) for having a better pulmonary score at day 5 was 0.93 (95% CI 0.67 – 1.30) for ensovibep vs control. Furthermore, a similar OR was obtained for the pulmonary-plus ordinal scale (OR = 0.95, 95% CI 0.69 – 1.32). After 90 days, sustained recovery was seen for 82% of those assigned ensovibep and 80% in the control arm (hazard ratio, HR = 1.06, 95% CI 0.88 – 1.28).
Because the futility assessment was not passed at day 5, further enrolment in the study was halted. The authors concluded that while ensovibep was well tolerated, it did not improve clinical outcomes over and above those of standard care.
ACTIV-3/TICO Study Group. Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19. A Randomized Controlled Trial Ann Intern Med 2022