Dexamethasone as an Emerging COVID-19 Therapy

This week the SOLIDARITY trial published their official report on Dexamethasone as a therapy for hospitalized COVID-19 patients in the New England Journal of Medicine (Horby P, et al., NEJM, 2020). This report was previously summarized in a press release prior to publication and as a pre-print on medRxiv with a smaller number of participants which has expanded in the NEJM version (Horby P, et al., medRxiv, 2020). As shown in Figure 1, dexamethasone reduced 28 day mortality and is the first COVID-19 therapy to do so. However, it was only effective in patients requiring mechanical ventilation and supplemental oxygen as summarized by Figure 2. Thus, while this treatment will work for severe, critical, and perhaps some moderate cases, mild cases may not benefit from this therapy. This relationship and efficacy has been hypothesized to be a result of the timing of the therapy in disease course. In early stages of COVID-19, the immune system is fighting the virus and actively reducing viral loads, but in severe and critical cases the immune system has a prolonged activation leading to severe inflammation. Dexamethasone is anti-inflammatory and helps to dampen the immune system, which may be beneficial in the severe and critical COVID-19 patients with an over activated immune system. However, patients with mild symptoms are likely earlier in disease course, and in this earlier stage of disease slowing and reducing immune system activation may hamper the fight against the virus. This could possibly explain the trend towards a higher risk ratio in the “no oxygen received patients” which would reflect a more milder disease with earlier treatment intervention (Figure 2).

Recently, there have also been several details released on operation warp speed (OWS), a government-run program that seeks to fast track vaccine development and therapies for COVID-19. Of note, the COVID-19 Prevention Trials Network (COVPN), a unified portal for the collection of information from willing potential participants in clinical trials, was announced to help facilitate expedite the clinical trials. This portal will be key in helping to find and enroll the thousands of participants needed for each trial.

An interesting trial has started in Argentina using non-invasive Vagus nerve stimulation to treat COVID-19 (cite). Vagus nerve stimulation has been suggested to suppress inflammation and sequester hyper-immune responses; thus, it may be of use in severe and critical COVID-19 patients who often develop a cytokine storm.

COVID-19 has brought about many changes to clinical trial procedures and has prompted massive procedural changes from the FDA in response to the pandemic. Perhaps one of the largest changes has been emergency use authorizations or EUAs. For therapies, EUAs have only been given to both Remdesivir and Hydroxychloroquine with the latter having its EUA revoked after numerous studies demonstrated no beneficial effect in COVID-19. However, Hydroxychloroquine has continued to hold the spotlight despite the lack of efficacy across the many trials looking at this drug. In response to the early testing of hydroxychloroquine, the government acquired millions of doses preemptively which are currently sitting in warehouses. However, with the retraction of the EUA from the FDA, these stockpiles can not be accessed or distributed. This led to a recent call from the presidential trade advisor which requested the reapproval of Hydroxychloroquine’s EUA as to be able to distribute the drug. However, due to the overwhelming evidence on the lack of efficacy this request is unlikely to be granted and emphasizes the political controversy invading the current scientific landscape.

Finally, for this week’s update, Regerneron has entered Phase III trials with its antibody therapy REGN-COV2 at the beginning of July. This cocktail was developed from the company’s VelocImmune® mice and consists of two antibodies that target the spike protein’s receptor-binding domain (RBD). For this phase of the trial, they will be enrolling participants at approximately 100 sites with an end enrollment of 2000 patients.