While the coronavirus epidemic is gaining momentum due to the relaxation of social distancing, researchers are working tirelessly on developing a drug to combat SARS-Cov-2, and a team of scientists is hoping to initiate a clinical trial for a dual therapy combining the Remdesivir molecule used to treat Ebola with the antihypertensive diltiazem. This combination has shown encouraging results in the laboratory.
As part of the REACTING program coordinated by INSERM, the Virpath team, led by INSERM researcher Manuel Rosa-Calatrava at the International Centre for Research in Infectiology, is working on repurposing drugs already on the market for viral infections for new therapeutic indications.
To test the therapeutic efficacy of these molecules against COVID-19, the team has been developing experimental models of viral infections since February. The results are published in Cell Reports Medicine. To this end, they have reconstituted in vitro human respiratory epithelia of nasal and bronchial origin, which are as close as possible to human physiology. “We have been using these pre-clinical infection models for several years, which allow a high prediction of infection in vivo,” says Manuel Rosa Calatrava.
Researchers have also developed several protocols to quantify the viral genome and infectious particles. Their observations and analyses have confirmed and completed current knowledge of the mechanisms of SARS-CoV-2 infection and the interactions between the virus and its host. “In our virus-infected models, we observe in particular the induction of Il6 interleukin production, which is one of the markers of disease severity,” says Manuel Rosa-Calatrava.
Together, these two molecules have an encouraging potential
In these models, a large number of drug candidates were evaluated, including two interesting molecules: Remdesivir and Diltiazem, alone and in combination. Remdesivir has antiviral activity against RNA viruses including SARS-CoV-2. In vitro and in animal models several ongoing clinical studies have shown the first positive results against this virus.
Diltiazem is an antihypertensive medication used to treat angina pectoris. It has already been repurposed by VirPath researchers because it can stimulate the innate antiviral immune response especially against influenza viruses and pneumovirus.
The human toxicity of these two repurposed molecules has also been studied, significantly reducing the clinical development time for their new therapeutic indication against SARS-CoV-2
The results of this study show a significant reduction in viral load in SARS-CoV-2 infected epithelia when treated with Remdesivir. This effect is reinforced when diltiazem is added in combination.
“By stimulating the innate immune response of the epithelium, Diltiazem increases the effect of Remdesivir and offers the possibility of reducing the doses needed. Remdesivir has some toxicity in vivo and is a very expensive drug,” says Manuel Rosa-Calatrava. The team will continue its pre-clinical studies with this dual therapy in animal models and hopes to start a clinical trial next winter if positive results are confirmed.