Revisiting the 'cytokine storm' in ARDS; the painful wait for anti-inflammatory drugs/targets that solve Covid-19 deaths
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I am a pulmonary and critical care physician-scientist with substantial expertise in critical care medicine, particularly in the inflammatory pathways involved in the acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI).
As a result, my laboratory has been pursuing mechanistic insights and effective therapies for ARDS and VILI for several decades. Over this expanded time horizon, there is abundant support for the contributory role of the much discussed “cytokine storm,” long associated with fatal ARDS and now with Covid-19-associated ARDS.
The essential nature of the elaborated cytokines to Covid-19 ARDS outcomes has been questioned in the media and were initially voiced in an editorial by UCSF ARDS experts. It is appropriate to consider this point of view; however, it must be recognized that the primary basis for this sentiment is related to observations centered on the interleukin-6 (IL-6) pathway, well-recognized to be involved in ARDS pathobiology.
One observation is that median circulating IL-6 levels in five Covid-19 cohorts were lower when compared to cohorts of non-Covid-19 ARDS, and the second observation is that several high-profile trials targeting IL-6 receptor antagonism in Covid ARDS failed to improve COVID-19 ARDS mortality. Specifically, the IL-6 receptor antagonists tocilizumab (Roche/Sanofi) and sarilumab (Regeneron/Sanofi), both failed to improve mortality in Phase II/III clinical trials of Covid-19 patients with severe disease (“Cleanup on IL-6”).
In fact, trial evidence suggested that drug recipients may be at increased risk for other infections, a particular risk in regions where drug-resistant bacteria are common. The accumulated failure of targeting the IL-6 pathway may reflect several factors that are of specific relevance to IL-6, including the downstream nature of this cytokine in the inflammatory cascade, as well as the complex role of IL-6 in innate immunity, i.e. exerting both anti-inflammatory and pro-inflammatory effects.
Overall, I believe there is wide acceptance that ARDS pathobiology is fundamentally related to massive activation of evolutionarily-conserved inflammatory networks by sepsis (infection in the blood), severe trauma, and severe bacterial or viral pneumonias including SARS-CoV-2. This inflammatory activation is substantially amplified when patients are placed upon mechanical ventilation, a potent inflammatory stimulus and contributor to ARDS mortality.
Thus, targeting of the unremitting inflammation remains a critical component to addressing ARDS mortality, albeit unlikely as a sole therapeutic strategy. This was supported by the United Kingdom trials demonstrating benefit of the potent, non-specific anti-inflammatory steroid, dexamethasome, in severe Covid-19 ARDS.
Clearly, ARDS is a vexing disorder without FDA-approved therapies and a staggering unmet need in the current Covid-19 pandemic landscape. The failure of many promising inflammation-focused ARDS drugs in Phase II and III trials, such as IL-6 antagonists and gamma interferon analogues, may reflect issues in: 1) target selection, i.e. cytokines downstream in the inflammatory cascade; or 2) delays in administration of the anti-inflammatory therapeutic, thereby reducing its influence on dampening inflammatory activation is minimal.
As a physician-scientist and ICU caregiver, I have been long searching for novel approaches to reducing ARDS mortality. When serving as the Director of Pulmonary and Critical Care Medicine at Johns Hopkins in 2005, I first reported the identification of eNAMPT (extracellular nicotinamide phosphoribosyltransferase) as a master regulator of innate immunity-driven inflammation that contributes to ARDS mortality and is essentially involved in VILI pathobiology.
Our substantial preclinical data support the targeting of eNAMPT with a humanized monoclonal antibody (ALT-100 mAb) to significantly impact human Covid-19- and non-Covid ARDS/VILI. We are making excellent progress in moving ALT-100 mAb down the drug development pipeline and to ARDS Clinical Trial evaluation.
I am totally convinced that the increasing availability of novel strategies (such as ALT-100 mAb) will ultimately allow for successful trials with drugs that reduce ARDS severity and mortality, particularly when we begin to employ personalized medicine strategies in trial design.
I do believe, however, similar to the management of many cancers, that to dramatically move the needle on reducing ARDS/VILI mortality, will require a combination of therapeutic approaches (including an anti-inflammatory drug). The wait for an FDA-approved ARDS therapy or therapies has been a frustrating reality. I am certain many will agree that given the current Covid pandemic and likelihood of future pandemics, we simply cannot afford to wait any longer.
Dr. Joe G.N. Garcia is an elected member of the National Academy of Medicine and CEO of Aqualung Therapeutics, an early-stage biotech company developing an immune-focused, anti-inflammatory platform centered around novel therapeutic humanized antibodies for ARDS/VILI patients.
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