Faster clinical recovery with ensovibep compared to placebo in patients with mild-to-moderate COVID-19: interim results from the EMPATHY Phase 2 trial

Background: Ensovibep is a multi-specific DARPin (designed ankyrin repeat protein) therapeutic in clinical development for treatment of COVID-19. In Part A (Phase 2) of the EMPATHY study, ensovibep treatment demonstrated greater viral load decline versus placebo (Pbo), and a relative risk reduction for hospitalization, ER visits and death. We report the sustained clinical recovery data from Phase 2 of EMPATHY. Method(s): Patients (pts) were eligible for EMPATHY (NCT04828161) when presenting >=2 mild-to-moderate COVID19 symptoms (onset within 7 days) and a positive SARS-CoV-2 rapid antigen test on day of dosing. 407 pts were randomised (1:1:1:1) to ensovibep (600, 225 or 75mg) or Pbo as single, IV infusion. The FDA COVID-19 symptom questionnaire was used (daily to Day 15, and on Days 22, 29) to assess time to sustained clinical recovery (secondary endpoint). Result(s): Ensovibep treatment was associated with a shorter time to sustained clinical recovery versus Pbo (Fig 1). The median time to sustained recovery were 23 days, 15 days, 14 days, and 29 days in 600mg, 225mg, 75mg, placebo arms, respectively. The cumulative proportion of patients with sustained clinical recovery by Day 15 were 44%, 54%, 55% and 36% in 600mg, 225mg, 75mg, and placebo arms, respectively. Conclusion(s): Ensovibep administration was associated with earlier sustained clinical recovery versus placebo.

Ensovibep antiviral activity in ambulatory patients with COVID-19 is independent of baseline anti-SARS-CoV-2 antibodies and exhibits minimal selective pressure - Results from the placebo-controlled EMPATHY trial

Background. Ensovibep is a multi-specific DARPin (designed ankyrin repeat protein) antiviral in clinical development for treatment of COVID-19. In the Phase 2 EMPATHY study, ensovibep demonstrated greater viral load decline versus placebo. Here we report (1) the efficacy of ensovibep in patients with and without anti-SARS-CoV-2 antibodies at baseline and (2) SARS-CoV-2 mutation emergence data with treatment. Methods. Eligible ambulatory patients with >=2 COVID-19 symptoms (onset within 7 days) and positive SARS-CoV-2 rapid antigen test on day of dosing, were randomized (1:1:1:1) to ensovibep (600, 225 or 75 mg) or placebo as single, IV infusion. Chemiluminescent immunoassays were used for antibody detection (SARS-CoV-2 S1/S2 IgG and SARS-CoV-2 IgM). A pre-specified subgroup analysis was performed based on baseline anti-SARS-CoV-2 antibody status. Analysis of changes in viral genome from baseline to post baseline was performed to evaluate treatment-emergent mutations. Results. Of the patients analyzed, 48.5% had anti-SARS-CoV-2 antibodies at baseline. Baseline log10 SARS-CoV-2 viral load (mean +/-SD) was similar across groups [ensovibep (all doses) 6.5 +/-1.5, placebo 6.2 +/-1.5];> 90% were infected with the Delta (B.1.617.2) variant. SARS-CoV-2 viral load reduction up to Day 8 showed similar effects in favor of ensovibep compared with placebo regardless of the presence of anti-SARS-CoV-2 antibodies (Figure 1). Patients in ensovibep 75 mg, 600 mg, and placebo groups had comparable incidences of emergent mutations, with a higher incidence in the 225 mg group. Based on analysis of 70% of the expected viral sequencing data, two mutations in the key binding residues of ensovibep were observed (Y489H and F486L) in a total of three patients treated with ensovibep. These patients either cleared virus by Day 8 or mutations were transient (occurred at a single time point but not later in the course of infection). (Figure Presented) Conclusion. Ensovibep effectively reduces SARS-CoV-2 viral load regardless of the presence of anti-SARS-CoV-2 antibodies at baseline. Furthermore, there were no emerging mutations of concern, indicating that a single dose administration of ensovibep is associated with minimal selective pressure.

Service delivery challenges in HIV care during the first year of the COVID-19 pandemic: results from a site assessment survey across the global IeDEA consortium.

INTRODUCTION: Interruptions in treatment pose risks for people with HIV (PWH) and threaten progress in ending the HIV epidemic; however, the COVID-19 pandemic's impact on HIV service delivery across diverse settings is not broadly documented. METHODS: From September 2020 to March 2021, the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium surveyed 238 HIV care sites across seven geographic regions to document constraints in HIV service delivery during the first year of the pandemic and strategies for ensuring care continuity for PWH. Descriptive statistics were stratified by national HIV prevalence (<1%, 1-4.9% and ≥5%) and country income levels. RESULTS: Questions about pandemic-related consequences for HIV care were completed by 225 (95%) sites in 42 countries with low (n = 82), medium (n = 86) and high (n = 57) HIV prevalence, including low- (n = 57), lower-middle (n = 79), upper-middle (n = 39) and high- (n = 50) income countries. Most sites reported being subject to pandemic-related restrictions on travel, service provision or other operations (75%), and experiencing negative impacts (76%) on clinic operations, including decreased hours/days, reduced provider availability, clinic reconfiguration for COVID-19 services, record-keeping interruptions and suspension of partner support. Almost all sites in low-prevalence and high-income countries reported increased use of telemedicine (85% and 100%, respectively), compared with less than half of sites in high-prevalence and lower-income settings. Few sites in high-prevalence settings (2%) reported suspending antiretroviral therapy (ART) clinic services, and many reported adopting mitigation strategies to support adherence, including multi-month dispensing of ART (95%) and designating community ART pick-up points (44%). While few sites (5%) reported stockouts of first-line ART regimens, 10-11% reported stockouts of second- and third-line regimens, respectively, primarily in high-prevalence and lower-income settings. Interruptions in HIV viral load (VL) testing included suspension of testing (22%), longer turnaround times (41%) and supply/reagent stockouts (22%), but did not differ across settings. CONCLUSIONS: While many sites in high HIV prevalence settings and lower-income countries reported introducing or expanding measures to support treatment adherence and continuity of care, the COVID-19 pandemic resulted in disruptions to VL testing and ART supply chains that may negatively affect the quality of HIV care in these settings.

PHASE III TRIAL of MOLNUPIRAVIR in ADULTS with MILD SARS-CoV-2 INFECTION in INDIA

Background: To improve the management of SARS-Co2 infection there is an urgent unmet need for an orally administered antiviral drug to prevent disease progression, hospitalization, and clinical complications. Molnupiravir was developed in response to this need. This study assesses its efficacy and safety in Indian patients with mild SARS-CoV2 infection. Methods: This study is a phase III multi-centre open label randomized controlled trial of oral molnupiravir plus standard of care (MOL/SOC) versus SOC alone in Indian adults with mild SARS-CoV2 infection. The molnupiravir formulation used was developed and manufactured by HETERO LABS LTD, Hyderabad, India, under license from MERCK INC, NJ, USA. Eligible patients with RT PCR-confirmed mild SARS CoV2 infection, uncomplicated upper respiratory tract infection, with mild symptoms without any evidence of breathlessness, were randomized 1:1 to either oral MOL 800 mg b.i.d. for 5 days plus SOC or SOC alone. The primary endpoint was rate of hospitalization up to day 14. Secondary endpoints included proportion with a 2-point improvement in WHO 11-Point Clinical Progression Scale and rate of SARS CoV2 RT PCR negativity in naso/oropharyngeal swab at day 5, 10 and 14 and incidence of adverse events. Results: Of 1284 patients screened, 1218 were eligible and randomized, 608 to MOL+SOC, and 610 to SOC. The population consisted mainly of male patients (68%). Both arms were well balanced for age, height and weight. In the MOL/SOC arm 9 patients (1.5%) required hospitalisation vs. 26 (4.3%) in the SOC arm (p<0.01). In the MOL/SOC arm 80.8%, 95.6% and 97.4% had clinical improvement by Day 5, 10 and 14, respectively, compared to 32.1%, 74.3% and 94.1% in the SOC arm (p<0.0001 at day 5 and 10, and <0.01 at day 14). The rate of SARS CoV2 negativity was 77.1%, 91.3% and 93.9% in MOL/SOC vs. 29.3%, 70.2% and 89.0% in SOC at day 5, 10 and 14, respectively (p<0.001). There were no serious adverse events. Mild and self-limiting adverse events occurred in 4.8% of MOL/SOC and 2.6% of SOC participants. The most common adverse events were neurological (headache, somnolence) and gastrointestinal. Conclusion: A lower rate of hospitalisation, earlier clinical improvement, and earlier SARS CoV2 RT PCR negativity document superiority of Molnupiravir to SOC in mild SARS-CoV2 infection in this trial in India. Molnupiravir was well tolerated: adverse events were mild and rare.

TOCILIZUMAB (BIOSIMILAR) USE in CYTOKINE STORM of SEVERE COVID-19 PNEUMONIA

Background: Tocilizumab is an IgG1 class humanized monoclonal antibody targeting IL-6 receptor (IL-6R). IL-6 is a key cytokine involved in cytokine storm of severe COVID-19. Tocilizumab down-regulates IL-6 preventing fatal and permanent damage to vital organs, significantly preventing COVID-19 related mortality and morbidity. Therefore, this study aimed to compare the efficacy and safety of Tocilizumab (biosimilar) developed by Hetero Biopharma Ltd, India vs reference medicinal product (RMP)-Tocilizumab manufactured by Roche in cytokine storm of severe COVID-19 pneumonia. Methods: This multicenter, randomized, double-blind, active-controlled study enrolled patients aged 18 to 65 years, with laboratory-confirmed, hospitalized, severe COVID-19 disease with elevated inflammatory markers not on mechanical ventilation. Patients were randomized (3:1 ratio) to receive either Test-Tocilizumab (Test) 8 mg/kg or RMP-Tocilizumab 8mg/kg, maximum 800mg, administered once on day 1. The primary endpoint was the cumulative proportion of patients requiring mechanical ventilation by Day 14. Secondary endpoints included 28 day mortality rate, proportion of patients with a 2-point decrease in WHO ordinal scale, time to clinical failure (death or required mechanical ventilation or withdrawn), change in inflammatory markers (CRP, IL-6, Ferritin and D-dimer) and duration of hospital stay in days. Safety endpoints included the incidence of adverse events;the proportion of patients discontinued the study due to adverse events and the incidence of any post-treatment bacterial and/or fungal infection. Results: Out of 211 patients screened, 172 patients were randomized (131 to Test and 41 to RMP) to receive Tocilizumab 8mg/kg. Patients were similar in both groups at baseline in terms of age, gender, weight etc. Fourteen (10.69%) patients in Test and 5 (12.20%) patients in RMP progressed to mechanical ventilation by Day 14 (p=0.7789). Overall, 9 (7.83%) patients died in Test vs 5 (13.16%) in RMP during 28 days follow up (p=0.3382). Clinical improvement was seen 62.60% and 77.10% vs 53.66% and 73.17% in Test vs RMP at day 14 and 28 respectively. The time to clinical failure was 6 vs 5 days and time to clinical improvement was 11 vs 11.5 days. Hospitalization duration was 12.9 versus 13.8 days in the Test and RMP. ARDS, Insomnia and Pain were most commonly reported adverse events. Conclusion: Tocilizumab biosimilar is comparable with RMP-Tocilizumab in preventing mechanical ventilation in severe COVID19 pneumonia patients.