Treating Fatigue in COVID Long-Haulers

Understanding mitochondrial dysfunction in Long COVID

While mitochondria play a role in inflammation and cellular signaling, the primary role of these organelles is to produce energy. The so-called powerhouses of the cell control cellular respiration, in which oxygen and metabolites/substrates are converted to adenosine triphosphate (ATP), the energy currency of the cell. Energy is stored in the high-energy phosphate bond of ATP. As that chemical bond is broken and converted to energy, ATP loses one of its three phosphates, becoming adenosine diphosphate (ADP). ADP can then be phosphorylated again to regenerate ATP in a cyclical process similar to recharging a battery. The high-energy phosphate is shuttled back to the mitochondria where it can combine with creatine, producing phosphocreatine. The phosphocreatine can subsequently lend its phosphate to ADP to rapidly produce ATP.

Metabolites for cellular respiration include fatty acids, from triglycerides and other lipids, pyruvate, produced from glucose during glycolysis, and amino acids, from proteins. While metabolism of these molecules dominates cellular energetics, there are other ways to generate ATP. Although it is less efficient than cellular respiration, glycolysis is another metabolic pathway that can rapidly produce ATP within the cell cytoplasm without the need for oxygen.

Mitochondrial dysfunction involves energetic and lipid dysregulation, as well as inflammation. It underlies many diseases and conditions, from those affecting the central nervous system, to the muscle, heart, and kidneys. Cardiopulmonary testing has shown that impaired exercise tolerance and post-exercise fatigue in Long COVID patients may be driven by skeletal muscle abnormalities, suggesting phosphocreatine recycling is delayed. This leads to impaired oxidative capacity, as well as an inability for the cell to keep up with energetic demand during exertion, especially in tissues with a high metabolic demand like muscles. Rate of recovery of phosphocreatine is a good measure of mitochondrial oxidative capacity and correlates with measures of exercise tolerance (e.g., six-minute walk test).

Viruses are known to hijack mitochondrial function, exploiting the cell for the energy they need to metabolize proteins, generate new viral particles, and replicate, as well as evade antiviral surveillance by the immune system. Preclinical and clinical work has shown that during the acute phase of COVID-19 infection, the virus upregulates glycolysis to rapidly produce more virus particles and downregulates more-efficient oxidative phosphorylation pathways. This shift throws the cell into a state of crisis, in which its functionality degrades, increasing oxidative stress (imbalance of between oxidants and antioxidants in favor of oxidants), inflammation, and immune impairment, as well as reducing muscle oxidative capacity and function.

To enter a cell, SARS-CoV-2 exploits the angiotensin-converting enzyme 2 (ACE2) receptor. This transmembrane protein is key to regulation of the renin-angiotensin-aldosterone system that regulates blood volume and systemic vascular resistance, but it also plays a role in mitochondrial functions. Disruption of this receptor impacts cell energetics and antioxidant response, as well as vascular perfusion (i.e., blood flow through the circulatory system to organs).

Although SARS-CoV-2 is a new virus, it modulates existing mechanisms that are well elucidated and studied extensively (e.g., viral entry via the ACE2 receptor). The difference with SARS-CoV-2 is the multitude of mechanisms it modulates, simultaneously impacting the ACE2 receptor and downstream biology, vascular perfusion and endothelial function, oxidative stress, proinflammatory processes, immune function and surveillance, and cellular bioenergetics.

Treating a complex disease

A potential treatment for mitochondrial dysfunction involves endogenous metabolic modulators (EMMs), which encompass a broad set of molecular families, including amino acids, bile acids, other intermediary substrates, and hormones. EMMs act as regulators and signaling agents in highly orchestrated networks of metabolic pathways within the body. These pathways control a host of cell and organ functions, including selecting fuel sources, creating biomolecules (e.g., nucleic acids, proteins, lipids, carbohydrates), sensing available nutrients, eliminating waste, triggering immune responses, and activating signaling pathways. As the name suggests, EMMs are native to the body and thus are generally recognized as safe (GRAS) and well tolerated in therapeutic applications. They can be used in combination to serve as multitargeting agents to restore the various biological processes that are dysregulated in complex diseases.

Flagship-founded Axcella Therapeutics (Nasdaq: AXLA) is pioneering EMM therapies to treat complex conditions such as nonalcoholic steatohepatitis (NASH). The clinical-stage company has more recently expanded its focus to Long COVID, launching a Phase 2a trial in December 2021 for the treatment of Long COVID-induced fatigue. The trial investigates the efficacy and safety of an oral product candidate AXA1125 — an EMM composition of six amino acids and derivatives. A key design feature of AXA1125 is its potential to reverse the effects of SARS-CoV-2 on the energetics of a cell, restoring preference for oxidative phosphorylation over glycolysis. Thus, the 28-day trial focuses on a primary endpoint of phosphocreatine recovery time as a measure of mitochondrial function. Data have also shown AXA1125 improves antioxidant response, inflammation, insulin sensitivity, vascular perfusion, and lipid metabolism, all important biologies in the context of Long COVID. AXA1125 therefore holds the potential to improve functional clinical outcomes through a multi-targeted mechanism of action.

With the success of the Phase 2a trial, Axcella plans to seek regulatory path(s) to expeditiously advance AXA1125 toward approval. This could be critical. While the recent decline of acute COVID-19 cases could slow the emergency phase of the pandemic, it is likely that the Omicron surge of acute infections will also lead to a wave of new Long COVID cases, continuing to balloon a public health crisis. A therapy is critically needed to help the tens of millions of individuals impacted today, and potentially in the near future, by Long COVID.