ABSTRACT
Rationale: LAU-7b is developed as a broadly effective oral COVID-19 therapeutic targeting membrane lipids to exert dual antiviral and inflammation-controlling activity. SARS-CoV-2 reprograms host cellular lipid metabolism to favor entry and replication, a mechanism shared by all lipid-enveloped viruses. LAU-7b decreases host cell membrane lipids fluidity, inhibits de-novo cell lipogenesis, and modulates phospholipid signaling promoting resolution of inflammation. Due to its host-directed mutation-agnostic mechanism, LAU-7b utility could span across future variants, as demonstrated in-vitro against multiple SARS-CoV-2 strains and MERS-CoV. RESOLUTION, a large Phase 2/3 study evaluating LAU-7b in hospitalized COVID-19 patients, is ongoing in the US and Canada, and preliminary Phase 2 results are presented. Methods: RESOLUTION is a placebocontrolled study of oral LAU-7b, once-a-day for 14 days on top of standard of care, in hospitalized COVID-19 patients at risk of developing pulmonary complications. The Phase 2 portion of the study randomized 148 patients with moderate-to-severe COVID-19 and 84 patients in critical condition, but not on invasive ventilation. Key endpoints included proportion of patients alive and free of respiratory failure at Day 29, rates of progression to mechanical ventilation and all-causes death by Day 60, time to recovery and length of hospitalization. Results: Both study arms were highly comparable in terms of mean age, number of comorbidities and concomitant medications. LAU-7b demonstrated a 100% reduction in the risk of progressing to mechanical ventilation or death by Day 60 in moderate-to-severe COVID-19 patients. None of the 76 patients on LAU-7b required mechanical ventilation and none died, while 5 out of 72 patients on placebo progressed to mechanical ventilation (6.9% difference, p=0.025), and 4 patients died (5.6% difference, p=0.053). LAU-7b group also showed an increase of 6.9% (p=0.055) in the proportion of patients alive and free of respiratory failure at Day 29, versus placebo. Patients on LAU-7b tended to recover more rapidly and leave hospital faster. LAU-7b was well-tolerated, with safety comparable to placebo. Critically ill patients treated with LAU-7b did not show improvement over placebo, suggesting that COVID-19 patients in respiratory failure at baseline are too severely affected to benefit. Conclusion: LAU-7b showed positive results in the trial's Phase 2 portion on both survival and avoidance of mechanical ventilation in moderate-to-severe COVID-19. The confirmatory Phase 3 portion was triggered and received approval from the FDA and Health Canada, focusing on moderate-to-severe COVID-19 and using the “Proportion of patients requiring mechanical ventilation and/or death by Day 60” as primary efficacy endpoint.
ABSTRACT
At the end of 2019, a new pathogen, coronavirus SARS-CoV2, was identified. The virus has infected more than 30 million people worldwide with lethality close to 5 %. SARS-CoV2 is an RNA virus. The viral genome contains 29 891 nucleotides which encode 9 889 amino acids;5´-replicase (orf1/ab) four main structural proteins [Spike (S) -Envelope (E) - Membrane (M) -Nucleocapsid (N)] and open reading frame proteins. MicroRNAs (miRNA) are potent post-transcriptional regulators of gene expression and hence can control viral infection and replication. In silico and bioinformatics assessments revealed that host miRNA (15b-5p, 15a-5p, 197-5p, 548c-5p, 548d-5p, 409-3p, 30b-5p, 505-3p) may be involved blocking viral replication. Also, viral miRNA are shared with cells miRNA (8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p), which may modulate cell response and facilitate SARS-CoV2 infection. Even though, these targets have to be validated with studies in vitro and in vivo, there is a high therapeutic potential involved which has been proposed and tested in other viral infections. More studies on the molecular mechanism of this complex viral infection are required to understand viral pathogenesis. © 2020 Academia Nacional de Medicina. All rights reserved.