COVID-19 and NAS150

 

Maintaining Redox Balance is Critical for Offsetting the Development of COVID-19 Cytokine Release Syndrome  

An Imbalanced Cellular Redox State Can Trigger Hyperinflammation: Role in COVID-19 Pathophysiology 

There are many host-cell factors which can directly or indirectly affect viral infection in humans and influence the development and outcome of disease. Key among these is a balanced state between pro-oxidant and antioxidant (redox statefactors which keep reactive oxygen species (ROS)/oxidative stress from causing cellular damage to ensure the normal functioning of host cells.  

 While a transient increase in ROS is essential to trigger the immune system upon viral infection, there are situations where the immune response becomes more generalized and leads to an uncontrolled systemic level of inflammation causing massive tissue and organ damage which can progress to death if left untreated.  In this hyperinflammatory state known as Cytokine Release Syndrome (CRS), the redox balanced is tipped to a massively pro-oxidant state where extremely high levels of ROS are produced from damaged tissues and infiltrating immune cells leading to a self-perpetuating feedback loop of more ROS productioninflammation, and tissue damage.  It is this hyperinflammatory state where the body’s own natural antioxidant defenses are wholly overwhelmed and cannot restore a normal redox balance.   

 Therefore, maintaining control and balance of ROS production and reduction sits at the nexus of antiviral defense, immune response, and patient outcome.  This insight has created a focal point of interest in developing and testing of antioxidant compounds which may mitigate the hyperinflammatory response and offset the resulting tissue and organ damage observed in cases where COVID-19associated CRS is involved. 

 Current Strategies on Leveraging Therapeutic Antioxidants for COVID-19 

 Current efforts by many groups are underway to explore the potential of using antioxidant compounds to treat COVID-19 in the early stages of disease as a possible intervention to stop viral replication and in the later stages to mitigate the hyperinflammatory state.  There is evidence that antioxidants can directly inhibit viral replication. For example, several antioxidants, among them N-acetyl-L-cysteine (NAC), glutathione, resveratrol, and ascorbic acid reduce ROS and have been shown to directly inhibit the proliferation of influenza virus.   

 Given the central role of ROS in both the early and later stages of COVID-19, it is not surprising that clinical studies are underway to examine possible therapeutic synergies of antioxidants with antiviral drugs and drugs that can interfere with inflammatory processes.  With targets from viral replication, immune system response and local redox imbalance all implicated in the multi-system failures observed in COVID-19 patients, it is reasonable that multiple anti-inflammatory agents are undergoing testing against the SARS-CoV-2 virus infection in human studies. These include tocilizumab (Actemra®, Roche) with remdesivir (Veklury®, Gilead) as well as JAK-STAT signaling inhibitors baricitinibfedratinib, and ruxolitinib.  Of note, oxidative stress stimulates JAK-STAT kinase activity.   

 Of relevance, a collaborative group of researchers from the US and China acknowledge excessive ROS drives oxidative stress, promotes viral replication and induces a systemic hyperinflammatory state. They are pursuing a stabilized catalase therapeutic which would also drive SOD detoxification of superoxide anion and decrease oxidative damage. Also, under active investigation is melatonin, a known inhibitor of ROS and an anti-inflammatory agent.   

Taken together, these efforts and findings support our hypothesis that therapeutically mitigating deleterious ROS production at different stages of COVID-19 could lead to improved patient outcomes. 

 NAS150 Can Reduce ROS and Inflammation to Rebalance the Cellular Redox State 

 We believe our Phase 2 clinical stage antioxidant and anti-inflammatory agent, the superoxide dismutase (SOD) mimetic NAS150, can be an effective treatment and adjuvant therapeutic for SARS-CoV-2 infection and COVID-19.  NAS150 is a Mn-metalloporphyrin SOD mimetic with demonstrated antioxidant and anti-inflammatory activities.  NAS150 acts catalytically to destroy multiple ROS including superoxide anion, hydrogen peroxide, peroxynitrite, and inhibits lipid peroxidation to downregulate expression of inflammatory cytokines which are triggered by ROS. Unlike other antioxidants which are often consumed in detoxifying reactions, NAS150 will continue to inactivate ROS.   

 In models of radiation injury where high levels of ROS and ROS-triggered cytokines perpetuate acute and long-term damage, NAS150 was shown to be extremely effective in mitigating injury pathologies and other radiation exposure-related sequelae. In support of our candidate, the Federal government has provided substantial financial support for early research and development efforts. This has led to Phase 1 clinical administration in patients and completion of multiple studies showing safety with subcutaneous administration. 

 In the context of ROS-induced CRS in COVID-19, we believe NAS150’s multiple antioxidant capabilities in combination with its continuous catalytic activity will be effective in downregulating deleterious ROS production within overstimulated infiltrating immune effectors such as activated macrophages and neutrophils as well as down regulating ROS produced by and around damaged tissues; factors that perpetuate and amplify CRS.  Modulating the cellular redox status with NAS150 within these compartments would alter the energy balance and push for an overall less inflammatory state by reducing ROS-induced cytokine expression and subsequent activation and infiltration of ROS-producing immune effectors. 

 New Amsterdam Sciences View Looking Forward 

 As of this writing we are now more than one year out since the World Health Organization (WHO) officially declared COVID-19 a pandemic.  Based on global spread of this virus and the prevalence of multiple variants of concern arising a consequence of replication and selection pressures driven by vaccines and immune evasion, it is highly probable that some level of SARS-CoV-2 persistence and COVID-19 illness will remain in the human population going forward.  Additionally, the continuation with haphazard implementation and/or deliberate disregard for public health guidelines, pandemic fatigue, resistance towards perceived infringement on civil liberties, lack of appropriate public health infrastructure inside and outside of US borders, and the possibility of short-term immunity conferred by previous SARS-CoV-2 infection and/or vaccines will ensure that COVID-19 remains a persistent health burden.  Finallyit should be noted that SARS-CoV-2 arose out of a recombination event between coronaviruses in non-human hosts prior to spillover transmission into humans which implies the possibility of new SARS-CoV strains emerging with additional traits that could compromise existing approaches to effectively diagnose and combat this virus.  How much longer the current pandemic will last or whether we will have regular COVID-19 flareups caused by SARS-CoV-2, its variants, and/or emerging recombinant strains derived from SARS-CoV-2 with other coronaviruses will be apparent as time passes.  However, it is reasonable to say there will be a continuing need to address the near-term cases of severe COVID-19 as well as the ever-growing population of “Long Haulers.”  Taken together, these factors support the need for industry to come together to develop an appropriate therapeutic armamentarium for medical practitioners to leverage for combatting this disease. 

 While vaccines are a great medical first line of defense, the need for therapeutics is paramount as the number of people who have been infected domestically and globally is rising. Current therapeutic strategies which have shown success are primarily focused on treating the early to moderate stages of COVID-19 with an emphasis on targeting the virus which include antiviral compounds and select monoclonal antibodies.  While there is some therapeutic efficacy for the early stages of COVID-19, these approaches have showed little impact in late-stage infections.  Once the virus has been cleared and/or a CRS is underway, these therapeutics are of minimal utility.  Therefore, the need to treat late-stage COVID-19 is paramount. There are thrusts exploring different immunomodulating therapeutic strategies in treating CRS in COVID-19 patients including neutralizing antibodies targeting pro-inflammatory cytokines such as IL-6 and GM-CSF (granulocyte macrophage colony stimulating factor), kinase inhibitors, corticosteroids, pathway checkpoints (CD24Fc), interferons, and others.  These approaches are beneficial as they target individual components involved in CRS; however, neither really addresses the fundamental component that starts and facilitates the perpetuation of CRS and that is ROS.  Therefore, the need for a therapeutic such as NAS150 remains critical. 

 Taking the above into consideration, New Amsterdam Sciences views the need for effective, life-saving therapeutics will continue to grow.  As an exemplar, consider the persistent and expanding multi-billion dollar market for therapeutics against influenza virus (Tamiflu®, Relenza®, Rapivab®Xofluza®) and rhinovirus (nasal decongestants, antihistaminesZinc, etc.despite there being years of experience with multiple marketed brands and formulations of influenza vaccines and common cold medications Due to the prospect of emerging SARS-CoV-2 variants and the threat of recombination with other circulating coronaviruses, one can expect that more severe illness and outcomes following SARS-CoV-2 infection will continue to drive the need for effective therapeutic options for years to come. 

 NAS150 Is The Logical Choice 

 One would expect that treatment with this Phase 2 ready, GMP-compliant clinical trial material would both reduce viral load and virus-related inflammation in COVID-19, therefore reducing symptoms and mitigating severe patient outcomes.  NAS150’s anti-oxidant and anti-inflammatory actions would lead to a measurable reduction in cytokine production and subsequent decrease in morbidity and mortality to viral infection. Considering the current dearth of effective agents against SARS-CoV-2, our clinic-ready, multipronged therapeutic deserves swift and rigorous evaluation. 

 Given NAS150’s unique therapeutic capabilities, one could predict that prophylactic administration prior to or shortly after exposure to SARS-CoV-2 with our potent systemic antioxidant could act at the onset of infection to block viral replication while simultaneously minimizing the probability of progression to more serious disease.  Towards these ends New Amsterdam Sciences is exploring additional delivery methods of NAS150 including a dermal patch or use of a microneedle array.  In patients able to self-administer a daily subcutaneous injection, an autoinjector delivery system is also in consideration.   

 

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