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

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.

A randomized, double-blind, Phase 2 study to evaluate subjective and objective outcomes in patients with acute bacterial skin and skin structure infections treated with delafloxacin, linezolid or vancomycin.

OBJECTIVES: Delafloxacin is an investigational anionic fluoroquinolone being developed to treat infections caused by Gram-positive and -negative organisms. This clinical trial evaluated the efficacy and safety of delafloxacin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs). METHODS: In a double-blind, Phase 2 trial, 256 patients were randomized (1 : 1 : 1) to 300 mg of delafloxacin, 600 mg of linezolid or 15 mg/kg vancomycin (actual body weight), each administered intravenously twice daily for 5-14 days. Randomization was stratified by infection category. The primary endpoint was the investigator's assessment of cure, defined as complete resolution of baseline signs and symptoms at follow-up. Secondary endpoints included reductions in the total areas of erythema and induration and assessments of bacterial eradication. This trial has been registered at ClinicalTrials.gov under registration number NCT01283581. RESULTS: Cure rates were significantly greater with delafloxacin versus vancomycin (mean difference: -16.3%; 95% CI, -30.3% to -2.3%; P = 0.031); differences were significant for obese patients (BMI ≥30 kg/m(2); mean difference: -30.0%; 95% CI, -50.7% to -9.3%; P = 0.009), but not for non-obese patients. Cure rates with delafloxacin and linezolid were similar. Using digital measurement, the percentage decrease in total erythema area was significantly greater with delafloxacin versus vancomycin at follow-up (-96.4% versus -84.5%; P = 0.028). There were no differences in bacterial eradication among the treatment groups. The most frequently reported treatment-emergent adverse events were nausea, diarrhoea and vomiting. CONCLUSIONS: These data show that delafloxacin is effective in the treatment of ABSSSIs and is well tolerated.

A randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections.

BACKGROUND: A randomized, double-blind, multicenter trial was done to compare two doses of delafloxacin with tigecycline in patients with various complicated skin and skin-structure infections (wound infections following surgery, trauma, burns, or animal/insect bites, abscesses, and cellulitis). METHODS: Patients were randomized 1:1:1 to receive delafloxacin 300mg intravenous (IV) every 12h, delafloxacin 450mg IV every 12h, or tigecycline 100mg IV×1, followed by 50mg IV every 12h; randomization was stratified by infection type. Duration of therapy was 5-14 days. The primary efficacy analysis, performed on the clinically evaluable (CE) population at the test-of-cure (TOC) visit (14-21 days after the final dose of study drug), compared clinical response rates in the delafloxacin and tigecycline arms. Clinical response rates in the two delafloxacin arms were also compared. RESULTS: Among CE patients, clinical cure rates at TOC visit were similar in the delafloxacin and tigecycline arms (94.3%, 92.5%, and 91.2%, respectively in delafloxacin 300-mg, delafloxacin 450-mg, and tigecycline arms). Overall, the most frequent adverse events were nausea, vomiting, and diarrhea; the 300-mg delafloxacin arm was the best-tolerated regimen. CONCLUSIONS: Delafloxacin was similarly effective as tigecycline for a variety of complicated skin and skin-structure infections and was well tolerated. (Clinicaltrials.gov NCT 0719810).

TD-1792 versus vancomycin for treatment of complicated skin and skin structure infections.

TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of -7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistant Staphylococcus aureus at baseline (n = 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n = 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.

Neuropathologic and neuroinflammatory activities of HIV-1-infected human astrocytes in murine brain.

The balance between astrocyte and microglia neuroprotection and neurotoxicity defines the tempo of neuronal dysfunction during HIV-1-associated dementia (HAD). Astrocytes maintain brain homeostasis and respond actively to brain damage by providing functional and nutritive neuronal support. In HAD, low-level, continuous infection of astrocytes occurs, but the functional consequences of this infection are poorly understood. To this end, human fetal astrocytes (HFA) and monocyte-derived macrophages (MDM) were infected with HIV-1DJV and HIV-1NL4-3 (neurotropic and lymphotropic strains respectively) and a pseudotyped Vesicular Stomatitis Virus (VSV/HIV-1NL4-3) prior to intracranial injection into the basal ganglia of severe combined immunodeficient mice. Neuropathological and immunohistochemical comparisons for inflammatory and neurotoxic activities were performed amongst the infected cell types at 7 or 14 days. HIV-1-infected MDM induced significant increases in Mac-1, glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1, and proinflammatory cytokine RNA and/or protein expression when compared with HSV/HIV-1- and HIV-1-infected HFA and sham-operated mice. Levels of neuron-specific nuclear protein, microtubule-associated protein 2, and neurofilament antigens were reduced significantly in the brain regions injected with human MDM infected with HIV-1DJV or VSV/HIV-1. We conclude that HIV-1 infection of astrocytes leads to limited neurodegeneration, underscoring the early and active role of macrophage-driven neurotoxicity in disease.