Hey team,
I figure I should also weigh in with a bit of a summary of the current Covid-19 ARDS scenario.
I am a translational scientist/business analyst that specialises in the development of novel drugs/therapies (new molecular entities, biologics, cellular therapies). My role is to come into early-stage biotech companies, generally via a venture capital firm or technology transfer office, and take an 'agent' through a cost-effective de-risking process to develop it to a clinical-stage. My training is in physiology, patent law, regulations and early tech commercialisation.
Here is some of my analysis that may help people get their head around the Covid-19 opportunity:
Acuterespiratory distress syndrome (ARDS) is a serious immunological and inflammatory condition characterized by widespread inflammation in the lungs.ARDS can be triggered by pneumonia, sepsis, or trauma and represents a majorcause of morbidity and mortality in the critical care setting. It hassignificant implications, as it may result in the prolonged intensive care unit(ICU) and hospital stays and may also require convalescence in the hospital andrehabilitation. ARDS is the leading cause of death among COVID-19 patients thatbecome seriously or critically ill.
Pathogen-inducedlung injury can progress into ARDS, as seen with SARS-CoV and influenza virusinfections. IL-1β is a key cytokine driving proinflammatory activity inbronchoalveolar lavage fluid of patients with lung injury (Pugin, Ricou,Steinberg, Suter, & Martin, 1996). Intense inflammation in the lungs alsocan have other systemic effects on other organs, as the combination of severeHCl injury in the lungs and mechanical ventilation in rabbits leads to renaldysfunction and evidence of apoptosis in renal tubular epithelial cells (Imaiet al., 2003).
Mortalityin COVID-19 infected patients with the inflammatory lung condition, ARDS isreported to approach 50%, and is associated with older age, co-morbidities suchas diabetes, higher disease severity, and elevated markers of inflammation.Currently, the only therapeutic interventions that are offering any promise ofimproving in-hospital survival are steroids, although the most successfultherapy only reduces mortality by ~30% (Mahase, 2020).
There is a pressing need for a safe and effective treatment for ARDS and attention has turned to the use of cell therapy. The first successful use of cell therapy involved the use of bone marrow (BM) aspirates in a transplant procedure for leukaemia patients that developed GvHD (Thomas et al., 1977). Originally thought to be the definitive solution for the replacement of damaged tissues by differentiating to replace the damaged cells, further investigations have highlighted that in fact, this is not a major mechanism of adult stromal/stem cell action. Their immune-modulating effects, anti-bacterial action, lack of rejection molecules as well as the relative ease of isolation and characterisation make these cells an ideal therapeutic for ARDS. In fact, several different cell types have been examined for therapeutic potential.
MSCs have some common morphological and immunophenotypic properties and studies have shown that MSCs derived from UC and AD tissue among others have demonstrated therapeutic efficacy in pre-clinical models of ARDS (Mao et al., 2015; Min, Gao, Li, & Liu, 2015; Pedrazza et al., 2017; C. Wang et al., 2018; S. Zhang et al., 2018). It was recently demonstrated that UC-MSCs could protect against LPS-induced lung injury in a mouse model, with examination of the MSC secretome and identification of factors responsible for the immune regulation leading to a beneficial outcome (H. Zhu et al., 2017).
MSCs secrete a plethora of paracrine soluble factors including keratinocyte growth factor (KGF), angiopoietin-1 (Ang-1), prostaglandin E2 (PGE2), interleukin-10 (IL-10), and other trophic cytokines (Han, Liu, Liu, & Li, 2019). These paracrine factors can increase alveolar fluid clearance, regulate lung epithelial and endothelial permeability, facilitate endothelial repair, and reduce inflammation (J. W. Lee, Fang, Krasnodembskaya, Howard, & Matthay, 2011). MSCs can also release extracellular vesicles (EVs), which envelop cytokines, growth factors, signalling lipids, functional mRNAs and microRNAs (Abreu, Weiss, & Rocco, 2016). EVs participate in cell-to-cell communication, cellular signal transduction, cellular metabolism, and immune modulation both locally and at a distance in the body. Furthermore, Islam et al. (2012) demonstrated that MSCs transferred mitochondria to the injured alveolar epithelium gave rise to increased alveolar ATP concentrations, thereby restituting alveolar bioenergetics and improving organ function.Figure X below displays the mechanisms that MSCs are believed to improve lung injury / ARDS.
Figure X: The Mechanisms by Which MSCS Improve Lung Injury (Han et al., 2019).MSCs secrete an abundance of paracrine soluble factors increase as well as releasing a great quantity of extracellular vesicles (EVs), exerting beneficial effects against lung injury. MSCs can also transfer mitochondria to the injured alveolar epithelium and macrophage, thereby restituting alveolar bioenergetics and enhancing phagocytic activity, respectively. KGF, keratinocyte growth factor; Ang-1, angiopoietin-1; PGE2, prostaglandin E2; IL-10, interleukin-10; HGF, hepatocyte growth factor; RNA, ribonucleic acid; DNA, deoxyribonucleic acidWith the Covid-19 pandemic, ARDS has become a significant unmet medicalneed that overloads health systems, is extremely economically costly and has asignificant mortality rate approaching 50%.MSC therapies have been investigated around the world in a desperate attempt to curb the damage being done by Covid-19 ARDS, and the early results are extremely promising.Various companies and their productsare involved including the Abu Dhabi Stem Cell Centres’ (ADSCC) UAECell19, Athersys’ Multistem and Mesoblast’s Remestemcel-L.Athersys presented their phase I/2 study results investigating their product Multistem in non-COVID-19 ARDS in May 2019.They demonstrated a mortality rate of 25%vs 40% in the placebo group, and reduced hospital time, ventilator time, and a rapid improvement in pulmonary function.ADSCC’s trial has now treated more than 2000 patients and researched have concluded thatthe average duration of hospitalisation with the treatment has been reduced from 22 days to just 6. The early analysis seems to indicate that patients on the therapy were 3.1 times more likely to recover in seven days than those on standard therapy.Compassionate use of remestemcel-L in 12 patients within New York saw 9/12 patients successfully come off ventilator support within a median of 10 days and 10/12 survive during the period of March-April 2020.This is in contrast to a major hospital network in New York City where there was only a 12% survival (38/320) and 9% came off ventilators (38/445). While this does not serve as a true control, it does show a stark contrast that is unlikely to be due to chance. Opportunity Non-Covid-19 ARDS is a severely debilitating disease with a significant mortality rate that corresponds to its severity level.The mortality for non-Covid-19 ARDS is 27%, 32% and 45% for mild, moderate and severe respectively.Covid-19 ARDS is more severe, with mortality rates closer 50%.There are currently no recommended specific anti-Covid-19 therapies and so there is a heavy reliance on supportive treatment, which is a significant economic burden on hospitals. The average total hospital costs non-Covid-19 ARDS were Can$128,860 in 2002 (US$128967 in 2020), with the majority of this cost born in the ICU ($97,810). Of these costs, the largest contributor was nursing care, which accounted for over 75% of the costs incurred. Of survivors at 2 years, 39% had been hospitalized, 20% more than once. Post-discharge costs were $28,350 by year two (2002 Can$), and totalled Can$49,572 by year 5 (2009) (US$43042 2020). The first year after discharge was the most expensive, responsible for nearly half the 5-year total.The true costs for Covid-19 ARDS are yet to be realised, but the economic costs surrounding the management of the spread of the disease has proved too much for many countries, leading them to allow the spread of the disease.
So far, promising therapeutic options arelimited.A randomized, controlled, open-label (RECOVERY) trial in the UK found that the steroid dexamethasone reduced deaths by one third in patients receiving invasive mechanical ventilation (Mahase, 2020).Dexamethasone is currently the only therapy that has been shown to have a meaningful impact on mortality for people on mechanical ventilation.