More than half a million new Covid-19 cases are still being registered worldwide every day resulting in more than 10,000 deaths daily. India, Argentina, Brazil, Thailand – amongst others – are struggling to cope with new waves of Covid-19. Emerging variants continue to cause fear and trepidation, even in well-vaccinated countries, where the specter of a resistant strain causing a resurgence hangs overhead like a Sword of Damocles.
The unprecedented progress made in the development and availability of Covid-19 vaccines has been game-changing for those fortunate enough to be able to access them – but the reality is that more of the world remains unvaccinated than vaccinated. The urgent need for a highly effective and safe Covid-19 treatment, which would be easy to distribute and easy to take by patients worldwide is as acute as ever.
Unfortunately, while vaccine development broke speed records, the development of such treatments lagged in its wake. Few drugs have received FDA emergency use authorization to treat Covid-19, with limited overall benefit and with constraints as to when and to whom they can be administered.
With the possible exception of dexamethasone, the real-world levels of effectiveness of these approved medications are underwhelming, with mixed, equivocal, marginal and sometimes contradictory outcomes. Accessibility to therapy also remains a problem, particularly for non-hospitalized patients, with the vast majority of treatments requiring intravenous administration. The verdict in terms of real-world use is indicative – with significant supplies of drug having been left unused on clinic shelves.
So, while vaccination rightly continues to be a global priority, it is clear that to properly manage this likely endemic virus, and reduce the burden of disease, there is an urgent need to support the rapid development of safe and effective and easy to use treatments for Covid-19.
Combatting Covid-19 – A Diverse and Differentiated Approach Needed
Approaches to treating Covid-19 have focused, broadly speaking, on one of two main approaches: 1. Antiviral – attempting to stop the virus in its tracks and prevent it from replicating, or 2. Anti-inflammatory – attempting to interrupt the cascade of damaging immune response to infection. More than one year into the pandemic, the results have proven underwhelming.
Addressing a viral pandemic that is driving a complex disease which is still far from being well understood, is an extraordinary challenge. It is growing clearer that rapidly and rigorously evaluating diverse and differentiated approaches, beyond conventional treatment categories such as direct acting antiviral antibodies or specific anti-inflammatory targets (such as IL6), is needed. By covering a more extensive range of differentiated potential mechanisms, and drug categories, and by rapidly evaluating them in a scientifically rigorous and controlled framework of studies, we could considerably increase the odds of finding a much-needed beneficial therapy. The more diverse shots on goal there are, the more likely one is to score.
Sphingosine kinase-2 (SK2) inhibition is one such promising differentiated approach. SARS-CoV-2, the virus which causes Covid-19, is one of a wide range of viruses known as positive-sense single-stranded RNA (+ssRNA) viruses, which make up more than one-third of all known virus genera. These types of viruses use host factors in various steps of viral infection, such as cell entry and replication. A key human cell factor involved in this process is sphingosine kinase-2 (SK2), potentially making it a broad-spectrum antiviral target. SK2 also happens to be active in the modulation of certain pro-inflammatory cytokines. So, drugs that can inhibit SK2 may deliver a 2-pronged antiviral and anti-inflammatory effect – highly desirable in the case of Covid-19. Moreover, the targeting of a human cell host factor, such as SK2, is expected to uphold antiviral activity irrespective of the worrisome mutations in the SARS-CoV-2 spike protein and the emergence of new strains which may develop resistance to direct anti-viral antibodies and vaccines.
Another important aspect of an effective therapy for use in response to an infectious pandemic is its distribution and administration. The burden on healthcare systems due to the complexities of current intravenously administered treatment options is significant. They require hospital- or clinic-based drug delivery, with doctors and nurses to administer and manage dosing, and with dedicated appropriately equipped areas to administer the drugs. Added to that are the issues of highly complex manufacturing and supply chain processes. All of which hamper global access to these therapies.
In this respect also, diversification of approach might provide important advantages, and orally available alternatives should be high on the list of priorities. Small molecules provide the potential for easily administering therapy in capsule or tablet form which would alleviate a significant level of resource pressure. This benefit is further enhanced in an outpatient setting, where ease of distribution and administration are all the more critical for effectively preventing hospitalization and reducing the risks of virus exposure and spread in the community.
With further waves of infections currently sweeping over many countries, and with continuously emerging variants neither this virus, nor its effects, are likely to disappear quickly. The vaccination programs must continue unabated. But to complement this there is an urgent need to support the development of diverse and differentiated, multi-mechanistic and potentially complementary therapies, that are effective against both the cause and the effects of Covid-19, are unaffected by the threat of viral mutation and, more critically than ever, are easy to make, easy to distribute to the countries that need it and easy to take by the patient.
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