The first trial of a drug to target the fatigue and muscle weakness experienced by more than half of people with long Covid has been launched in the UK. It is also the first drug trial in long Covid patients who were not hospitalised during their initial infection.
The drug, called AXA1125, targets cellular power plants called mitochondria, which it is thought could be dysfunctional in the subset of long Covid patients with severe fatigue. If successful, it could pave the way for similar trials in patients with other forms of post-viral fatigue, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Mitochondria help to regulate various cellular processes, and play a crucial role in transforming the chemical energy from our diets into adenosine triphosphate (ATP) – the energy currency that cells depend on to drive essential reactions.
Supplies of ATP are quickly exhausted, so cells must constantly regenerate it. This can be done through a process called glycolysis, which produces lactic acid as a byproduct. But ATP is produced more efficiently through oxidative phosphorylation, which involves the mitochondria.
Mounting evidence suggests Sars-CoV-2 can hijack cells’ mitochondria, boosting viral replication but disrupting ATP production in the process.
“In essence, it’s a fuel switch. The virus invades the mitochondria and seeks to move it towards glycolysis to produce more viral particles, but it leaves the cell damaged,” said Bill Hinshaw, the president and chief executive of Axcella, which developed the new drug.
An estimated 56% of long Covid patients suffer from fatigue and many also struggle to exercise. “We originally thought that these symptoms were related to organ inflammation,” said Dr Betty Raman at the University of Oxford, who is researching the impact of Covid-19 on organ health. “But six months down the track, we found that although the heart and lungs were seen to be recovering, these people were still unable to exercise.”
Further investigation revealed that they were accumulating lactic acid in their muscles at a faster rate than healthy individuals – a possible sign of mitochondrial dysfunction. “In a normal, healthy person, the mitochondria will be very active in replenishing the ATP to sustain energy,” Raman said.
AXA1125 is designed to normalise mitochondrial metabolism in diseases where it may be out of balance. So far it has been tested in patients with non-alcoholic fatty liver disease, with some promising results.
Raman is launching a study in 40 patients with severe post-Covid fatigue to see if it can improve their exercise tolerance, reduce fatigue and improve mitochondrial metabolism in their muscle tissue – something that can be visualised using imaging techniques. Half will be given AXA1125 for 28 days, and the other half a placebo drug. Results are expected by mid-2022.
“I don’t think this one drug will be the solution to everything because long Covid is such a complex disease, but [if it works] it will benefit a significant proportion of patients,” Raman said.
Prof Amitava Banerjee, of University College London, who is spearheading a separate trial of long Covid diagnostics and treatments, said: “It is really good to be trialling different drugs and different mechanisms. Mitochondrial dysfunction in fatigue is something that’s been written about and studied for some time, but we don’t know how common it is in this patient population, or how it correlates with the severity of their symptoms.”
He is waiting for approval to begin trials of “repurposed” drugs such as antihistamines and aspirin in long Covid patients who were not hospitalised. A trial to identify treatments to boost recovery after Covid-19 patients are discharged from hospital is already under way.
Banerjee said: “Whatever we’re trialling, we know there’s tens of thousands of people either waiting to be seen or being seen in clinics. Any new treatments need to be translatable and accessible quickly.”
If AXA1125 does help to reduce fatigue in long Covid, there could also be important implications for people with ME/CFS, according to Dr Charles Shepherd, a medical adviser at the ME Association. “We now have a considerable amount of research evidence to indicate that there is mitochondrial dysfunction in ME/CFS, and that the effect this has on muscle energy metabolism appears to be a significant contributory factor in the activity induced-fatigue that occurs.”
