Long Covid: A call to action for drug developers

According to the National Institutes for Health, some form of long Covid affects around 10% of people infected with Covid-19, with fatigue being the most common symptom. Despite the size of the market and the global impact, there are currently no effective treatments. Diana Spencer caught up with Bill Hinshaw, President & CEO of Axcella Therapeutics, to find out why.

DS: A paper in Science showed this month how mitochondrial function in the organs is impaired by Covid-19, potentially after the infection has cleared, causing long Covid. Can you explain this mechanism?

BH: The scientific findings published by Science from Joseph W Guarnieri and his colleagues link alterations in the function of mitochondria, the cell’s central energy unit, to acute infection with Covid-19, and post-viral clearance, as is the case for long Covid. Akin to a computer’s central processing unit, mitochondria orchestrate broad ranging processes pertaining to cellular health, including metabolism, energy, and immune regulation. In their paper, Guarnieri et al. highlight the impact of viral infection on several facets of this central mitochondrial organelle, including bioenergetics, metabolism, inflammation, and oxidative stress, with downregulation of these processes across several organ systems both in the presence of the virus (and correlated with severity) and after the virus is not detected. In short, the virus crashes the CPU, and the whole system slows down significantly. These results represent a significant step forward in further elucidating the mechanism of disease (MOD) of Covid-19 and long Covid, building on previous research that highlights similar impact on mitochondrial and cellular metabolism and comparable pathogenesis of other post-acute infection syndromes, and heighten the call to action for mitochondrial based therapeutics for long Covid.

The system needs a reboot. Intervening with these perturbations in mitochondrial function is consistent with the mechanism of action (MOA) of Axcella Therapeutics’ investigational product for long Covid fatigue, AXA1125. The authors’ results support Axcella’s hypothesis for the origin/drivers of long Covid fatigue, data from our studies on the MOD of long Covid, and AXA1125’s multi-targeted action. In particular, the report by Guarnieri et al. provides basic insights into potential mechanisms for how AXA1125 restores mitochondrial bioenergetics; reduces inflammation and oxidative stress; and improves endothelial and vascular inflammation markers. The reported MOD framework advances the mechanistic rationale of the clinical benefits on fatigue observed in our clinical trial with AXA1125 in the context of the combination’s mechanism of action.

DS: As new variants begin circulating, what impact could this finding have on our understanding and the potential treatment of long Covid?

BH: These variants have demonstrably allowed for improved viral growth, antigenicity and ultimately transmissibility, resulting in more people being infected. As new variants emerge, we continue to learn about SARS-CoV-2’s evolutionary and adaptation strategy and the corresponding mechanisms that are harnessed by the virus. While new variants may evade immunity from vaccination or prior infection, and may demonstrate enhanced infectivity, there are core underlying mechanisms and processes that the virus utilise to hijack the cell and replicate.

Dysregulations in core processes such as mitochondrial energetics and metabolism are unfortunately sustained post-infection and implicated in long Covid fatigue, and therefore carry through across variants.This is why we believe AXA1125 has the potential to be an important treatment, as it is targeting multiple mechanisms of disease that are fundamental and shared across variants.

DS: Why do you think we are no closer to treatments for long Covid? What is needed to encourage innovation in this area?

BH: There are several reasons, with key ones being: One, the focus on acute infection: It was necessary to focus on addressing the short-term impact of the pandemic and those in life sciences, medicine, government, and more achieved remarkable progress in that effort.  Unfortunately, long Covid has been in the shadows of the pandemic and did not receive enough effort even though these are the same patients who suffered from the acute infection. The very large numbers, the devastating impact on patients, their families, the health care system, and our economies is now starting to be understood.

Second is the incomplete understanding of the drivers and nature of the disease: long Covid is a complex set of symptoms and manifestations and understanding it is important. We have started to make real progress in understanding key parts such as the mitochondrial role and how that translates to fatigue. Steps need to be taken to bring those efforts together in a thoughtful and organised fashion, like was done for the acute infections. This is a new dynamic and efforts on research, clinical trials regulatory, and financial support are required. To date there is a significant lag and deficit in funding of therapeutics trials, and most of the focus has been on elucidating mechanisms of disease. Clinical trials that could lead to near-term therapeutic treatments are needed. A recent investigation from STAT News found that the National Institutes of Health is out of money for further research on long Covid fatigue, having exhausted over a billion dollars since 2020 without advancing potential treatments – the majority of spending was directed to observational research and behaviour methods, rather than to clinical trials that could lead to near term therapeutic treatments. We all agree that patients and our society need to advance treatments as rapidly as possible, and we remain open to the opportunity to collaborate with the NIH to advance clinical trials.

DS: A Phase IIa trial of your long Covid candidate AXA1125 has demonstrated ‘significant improvements in fatigue-based symptoms’. Can you explain how it works?

BH: We announced the promising results of our Phase IIa trial in August 2022.  AXA1125 is a combination product with a multi-targeted activity that is well matched to the emerging mechanism of disease for long Covid fatigue. It works by improving cellular metabolism and rescuing a hypo-metabolic state, increasing fatty acid oxidation and therefore restoring a cellular bioenergetics balance that favors cellular function and ultimately capacity to respond to daily metabolic and energetic demands, therefore reducing fatigue and restoring normative function, as well as reducing markers of inflammation, oxidative stress, and endothelial function, which taken together allow for a healthy and oxygenated cellular environment and matched cellular function.

DS: Do you think we will be able to successfully treat long Covid in the future? Where do you see these treatments coming from?

BH: It is critical that we find a way to successfully treat long Covid fatigue. Long Covid fatigue is a large, important, ongoing, and as-yet untreated complication of Covid-19 infection. There are millions of people currently suffering who need relief now, and unfortunately, even more who will in the future, as the virus continues to mutate and spread. We encourage continued efforts to understand and approach treatments for long Covid. It is also important to recognise and appreciate the need more broadly for post-acute infection syndromes, like chronic fatigue syndrome (CFS), which Covid-19 and the magnitude of this pandemic has shed light on. Given the shared canonical pathways and processes that viruses hijack, we hold on to the potential that successful treatments for long Covid have an opportunity for success in treating other post-acute infection syndromes.


Bill HinshawBill Hinshaw joined Axcella as CEO in May 2018. He was formerly Executive Vice President of US Oncology at Novartis Pharmaceuticals Corporation, where he served for 15 years and led more than a dozen product launches, including Tasigna, Gleevec, and Kymriah. Hinshaw also played a key role on the Global Oncology Executive Committee, including leading key strategic programmes to maximise the portfolio and pipeline development. He holds a BS in Molecular Biology from the University of Wisconsin.

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