Baricitinib, Nebulized Remdesivir, and Dexamethasone Preliminary Data in COVID-19 Clinical Trials Released

This week the NIH halted its ORCHID Trial which was studying hydroxychloroquine in severe and moderate COVID-19. Following the termination of hydroxychloroquine in the WHO solidarity trial, the scientific community is moving forward  with new therapies.

Gilead has begun its trials on nebulized Remdesivir delivery in healthy individuals. This antiviral therapy is currently administered by IV in the hospital which makes mass distribution and administration more difficult. By testing in healthy individuals and then transitioning to COVID-19 patients in August, Gilead hopes to determine initial safety before progressing into later trials to determine efficacy of the therapy compared to its IV delivery. Of note, other antiviral therapies such as interferons have been found to have increased efficacy in respiratory infection and Remdesivir may hold the same potential in COVID-19. Also of note, Gilead recently announced its CARAVAN trial which will study Remdesivir in pediatric patients with moderate and severe COVID-19 (NCT04431453).

The anti-inflammatory JAK inhibitor Baricitinib is currently being evaluated with Remdesivir in the ACTT-2 trial sponsored by the NIH and will be compared to a Remdesivir and standard of care group (NCT04401579). The pharmaceutical company behind Baricitinib, Lilly, announced they would also begin a clinical trial to study the drug without administration of Remdesivir in hospitalized COVID-19 patients. This trial will provide very valuable information in combination with ACTT-2 and will allow for comparisons of the combination therapy to both drugs individually.

Recently, the RECOVERY trial out of the UK found that Dexamethasone, a low cost steroid, reduced 28 day mortality by one-third in patients with ventilation (p=0.0003), one-fifth in patients with supplemental oxygen (p=0.0021), and no benefit in patients with no respiratory intervention (p=0.14) as shown in Figure 1 (Horby P, et al., 2020). This large study (n=11,550) has been the first therapy to report reduced mortality compared to the reduced time to recovery that has been found with Remdesivir. However, these findings will need to be further validated despite the large size of the study with special consideration for the timing of steroids during COVID-19 as early studies debated the efficacy of steroids with some papers reporting an increase in mortality with the therapy (Veronese N, et al., 2020; Lu X, et al., 2020; Wu C, et al. 2020; Fadel R, et al., 2020). It is likely that the timing of this anti-inflammatory therapy is key to its success, as early dosing versus later dosing seem to have different efficacies and contribute to the variety of results between trials (Veronese N, et al., 2020; Lu X, et al., 2020; Wu C, et al. 2020; Fadel R, et al., 2020). On the other hand, many complications from COVID-19 come from an over activated immune system in the later stages of disease which may be the optimal time for steroid administration. As shown in Figure 2, the benefits of Dexamethasone were exclusive to severe patients. In milder patients (who may be earlier in disease course) there was a trend towards an increased risk ratio which was not statistically significant. Moving forward, other studies will be needed on Dexamethasone and potentially other steroids, such as solumedrol and prednisone,  with attention to timing of administration.