Early in the Covid-19 crisis, we’d all heard the hopeful news that, even though a vaccine was more than a year away, we did have promising therapies in the form of drugs that had already been approved for other uses. Even before it became clear last month that one favorite candidate, hydroxychloroquine, was far from a panacea, the research community realized the unfortunate truth: when it comes to Covid-19, there is no magic bullet among existing monotherapies. A “cocktail approach” of multiple drugs is required.
But how do we make it work? In pharmaceutical research, our goal is to “fail faster” and eliminate what won’t be effective. As of June 11th, there were 1,166 clinical interventional studies registered in clinicaltrials.gov, with therapies targeting Covid-19. Had there been an individual candidate among approved drugs that could treat Covid-19, we would know about it by now.
In contrast, a cocktail combines multiple drugs, not individually powerful enough to arrest the virus, to create a synergistic antiviral response. The value of this approach was proven against HIV/AIDS. Using an anti-retroviral cocktail of existing medications — going to war with the army we had— revolutionized patient outcomes in the ‘90s; now patients have normal life expectancies and a high quality of life. Progress in treating hepatitis C repeated the HIV story; with drug combinations, we went from a 50% cure rate to 100%.
The lessons from HIV and hepatitis C have direct impact on how we fight today’s pandemic. Applying an understanding of “opportunity points” can help us design therapeutic combinations that target different parts of a virus’s life cycle and understand which may have the best chance for success.
The challenge with developing cocktail therapies is that the number of potential drug choices, combinations, and dosing regimens is staggering. We need to cut our possibilities to the fewest, most likely to be effective treatments as quickly as possible, and traditional clinical trials aren’t practical, as they waste time we don’t have. But through computer modeling and simulation, which offers a quick, reliable method to triage therapeutics entering assessment with simulations that test drug combinations, we can accelerate cocktail development to determine their probability of safety and efficacy to support a rationale for clinical trial evaluation.
Our team’s modeling investigations have determined that, in combination therapy, earlier intervention improves outcomes. We’re also confirming that targeting multiple points in the SARS-CoV-2 life cycle – points important to viral replication within a host cell and release from infected host cells, with modest drug effects is a good strategy for reducing viral load and host cell infection, and can be more effective than targeting one point with a strong drug effect. This finding is critical; combining a handful of modest therapies that promote virion kill and infected cell death, and which inhibit virion release, has potential to be effective for the cessation of viral shedding and addressing the issue of “super spreaders” — patients who act as highly active vectors of the disease.
Repurposing approved drugs has the advantages of speed and safety, and the viral life cycle model provides a framework to guide the selection of therapeutic combinations. To illustrate this, we draw from current Covid-19 trial literature. For example, remdesivir alone is proving to improve median recovery time in patients hospitalized with lower respiratory tract impact from 15 to 11 days. A triple combination of interferon-b-1b with ribavarin and lopinavir/ritonavir decreases both productive cell death and virion release, reducing viral shedding by five days, vs. lopinavir/ritonavir alone, aligning with our findings that combinations can prove more effective than single therapies. We found that building on this kind of combination by adding convalescent plasma or monoclonal antibodies to remdesivir or lopinavir/ritonavir, and interferon would target three parts of the viral life cycle— virion release, productive cell death and target cell infection— at the same time.
This is extremely promising. While the world needs vaccines for Covid-19, drug cocktail therapies have been effective against HIV/AIDS and hepatitis C and should be investigated and employed against what has proven to be a difficult foe. Harnessing the incremental impact of a cocktail of drugs will fill the gap until vaccines are successfully developed, tested, approved, and manufactured at a scale that can stop this pandemic.
Realistically, developing a vaccine may take longer than expected, so we need to move quickly. A successful cocktail would also serve us in the long-run to treat the impacts of Covid-19 and keep those who are most vulnerable, the elderly and those with pre-existing conditions, more resilient against serious illness or death. This approach should prove successful and assist greatly in fighting Covid-19 and reducing mortality.
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