Paridiprubart for COVID-19

ABSTRACTBackgroundCoronavirus disease 2019 (COVID-19) mortality is predominantly due to acute respiratory distress syndrome (ARDS). There are currently limited treatment options for ARDS, a life-threatening condition with different etiologies, secondary to inflammation-induced lung injury. Paridiprubart is a monoclonal antibody that inhibits Toll-like Receptor 4 (TLR4), a key player in ARDS pathophysiology.MethodsThis was a prespecified sub-study of a randomized, double-blind, placebo-controlled, Phase 2 trial evaluating the efficacy and safety of paridiprubart in COVID-19 patients with ARDS receiving invasive mechanical ventilation and additional organ support. Efficacy outcomes were 28- and 60-day all-cause mortality, and improvement in COVID-19 severity and ventilation-free days at 28-days post-treatment.ResultsThirteen (13) and twenty (20) patients received paridiprubart and placebo, respectively. The groups were comparable for demographics and baseline parameters, except for higher kidney failure incidence and use of immune modulators and antivirals, and lower corticosteroids use in the paridiprubart group. Mortality at 28-days post-treatment was 7.7% (1/13) in the paridiprubart group versus 40.0% (8/20) for placebo (OR=0.125; 95% CI, 0.013-1.160; P=0.067; P[bootstrap]=0.011). 60-day mortality was 23.1% (3/13) in paridiprubart-treated patients and 45.0% (9/20) in placebo patients (OR=0.367; 95% CI, 0.077-1.749; P=0.208; P[bootstrap]=0.162). Mean survival time was 55.78 days for paridiprubart recipients compared to 41.44 days for placebo patients (HR=0.386; 95% CI, 0.077-1.436; P=0.156; P[bootstrap]=0.083). Although not statistically significant, results for other efficacy measures favored paridiprubart. Incidence of adverse events was similar in both groups.ConclusionsIn COVID-19 patients with ARDS requiring invasive ventilation and organ support, paridiprubart was efficacious in preventing mortality and improving clinical outcomes, with no safety concerns.

Innate immunity is the first line of defense against infections, including the detection and response to SARS-CoV-2. Cells of the innate system are usually activated within hours after pathogen exposure and do not generate conventional immunological memory. In this review, the current knowledge of the innate immune cells and of pattern-recognition receptors in sensing and responding to SARS-CoV-2 to mount a protective response has been shortly reviewed. Subsequently, the evasion strategies of the virus, as the inhibition of IFN-I/III production and autophagic response, counteracting the innate cell activity (including NK cells), have been briefly outlined. In the course of the infection, these strategies are also capable of rendering dysfunctional most innate cells, thus deeply interfering with the onset and maintenance of adaptive immunity. Possible mechanism(s) for the maintenance of dysfunctional innate immune response are also discussed. In this context, the importance of a rapid and robust activation of innate immunity through toll-like receptor (TLR) 4 as a key paradigm central to host defense against COVID-19 pathogenesis is also illustrated. We also discuss how the viral excess plus inflammatory signals upregulating TLR4 on innate cells may initiate a vicious loop which maintains and improves hyperinflammation, leading to the most critical outcomes. Targeting the TLR4 or its signaling pathway may be a promising therapeutic strategy, offering the dual benefits of viral suppression and decreasing inflammation.