2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2) and severe acute respiratory syndrome coronavirus (SARS-CoV) are human coronaviruses (HCoVs) causing global epidemics with high morbidity and mortality. Presently, there are no effective drugs to treat 2019-nCoV. As the number of deaths increases rapidly, the standard drug development pathway is not really an option for countering this virus. We need to use already known drugs by doing drug repurposing, as that can shorten the time and reduce costs compared to current drug development procedures.
One important way is to start with existing antivirals and our knowledge of SARS and MERS outbreaks. The general genomic structure among all the three family members — MERS, SARS and SARS-CoV-2 — is same, suggesting a similar replication cycle and the potential use of broad drugs to target them. From the start of the 2019-nCoV outbreak, China has been using alpha-interferon in combination with lopinavir and ritonavir, which are HIV protease inhibitors. This combination of lopinavir and ritonavir repurposed drugs are also used on other combinations like that of gaunosine analogue and RNA synthesis inhibitor ribavirin with reverse transcriptase inhibitors (like emtricitabine/tenofovir alafenamide fumarate).
However, 2019-nCoV RNA dependent RNA polymerase suggests that above modalities may fail in long term clinical outcomes. To this extent, a 199-patient clinical trial — reported on 18 March 2020 in New England Journal of Medicine by Xia J et al on lopinavir-ritonavir combination — failed to give any clinical improvement in outcomes for patients in comparison to standard care.
In this study, 99 patients were assigned to the lopinavir-ritonavir group and 100 to the standard care group. The results after 28 days show that 19.2% of patients in the treatment group died, versus 25% in the standard care group — a difference of -5.8% percentage points. No detectable differences in viral loads were observed. Gastrointestinal adverse events were more common in lopinavir-ritonavir treatment and 13.8% patients stopped therapy due to adverse events. The data clearly suggests that there is no greater observed benefit with lopinavir-ritonavir treatment beyond standard care.
Importance of RNA-polymerase drugs
Therefore, there is an urgent need to evaluate RNA-dependent RNA polymerase inhibitors for viral cycle inhibition in combination with interferon-alpha to tackle inflammation and last for the reduction of lung abnormality progression. In this article, we present potential combinations which can help in drug repurposing for combating 2019-nCoV. We searched for clinical trials associated with 2019-nCoV from clinicaltrials.gov and found 93 results (only active, recruiting, not yet recruiting, enrolling by invitation, active not recruiting and completed trials were considered as on 19th March 2020). Of these, 42 clinical trials were using small molecules, 22 were biological (cell-based or biomolecules such as monoclonal antibodies or vaccines) and the remaining 29 were diagnostics or other applications. We focused on the 43 small molecule studies and selected those with outcomes mentioned such as “clinical recovery or survival or mortality reduction or normalization of fever and oxygen saturation”, which were 14 in total. Upon further analysis, we found that 4 out of 11 trials in phase II were focused on combinatorial therapies of lopinavir-ritonavir with or without interferon alpha or beta. Four phase II studies were using nitric oxide, while there was one study each in phase 2 for tetrandrine, thalidomide, aviptadil, and methylprednisolone. Remdesivir is the only RNA dependent RNA polymerase (RdRp) inhibitor in the list. It was initially designed for Ebola virus and was targeting viral replication. It is in phase 3, along with pirfenidone, which has demonstrated activity in multiple fibrotic conditions, including those of the lung, kidney and liver.
Sequence or structural analysis of RNA dependent RNA polymerases of pathogens which have small molecules could be easily done to understand the homology between them. For example, the polymerase domain homology between hepatitis C and 2019-nCoV RdRp was observed to be high, suggesting that sofosbuvir can potentially be repurposed for 2019-nCoV infection for stopping the viral cycle.
A similar analysis is needed for Ebola and 2019-nCoV to understand sequence or structural homology between them and repurpose remdesivir. In all these analyses, a potential three-pronged study will give a good answer to the search for a therapy for 2019-nCoV infections: First a standard care group, second sofosbuvir, prifenidone and interferon alpha (SPI), and a third group testing remdesivir, prifenidone and interferon alpha (RPI).
In this kind of a study, outcomes can be measured in several ways as deemed fit by clinicians. It can be done by measuring a reduction in viral load, a reduction in inflammation or an improvement of lung function. The important point is that such approaches can truly help in using already available drugs in clinical implementation, especially in a country like India, before the outbreak becomes a stage 3 level community infection.