Q&A: Forthcoming trial will examine drug’s ‘great potential’ in long COVID

Axcella Therapeutics announced that it is recruiting for a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of AXA1125 in patients with exertional fatigue related to long COVID.

AXA1125 (Axcella Therapeutics) is an “endogenous metabolic modulator composition of six amino acids and derivatives,” that has shown promise in treating metabolism, inflammation and fibrosis related to non-alcoholic steatohepatitis (NASH), the company said on its website.

“With no approved long COVID therapies, the need for continued innovation is urgent,” Betty Raman, MBBS, DPhil, FRACP, a trial investigator and intermediate fellow from Oxford University’s Radcliffe Department of Medicine, said in a press release.

Axcella Therapeutics’ president of research and development, Alison Schecter, MD, provided more details about long COVID and the upcoming trial in an interview with Healio Primary Care.

Healio Primary Care: What is currently known about the underlying pathophysiology of long COVID?

Schecter: To date, more than 240 million cases of COVID-19 have been reported globally and of that, nearly a quarter of people are estimated to suffer from long-term effects known as long COVID.

Until recently, drivers of the disease have been mostly unknown. We are working with researchers at Oxford University’s Radcliffe Department of Medicine to better understand the science around long COVID and evaluate the efficacy of AXA1125 to alleviate symptoms for patients.

The emerging science in long COVID has uncovered mitochondrial dysfunction as a likely driver of fatigue and muscle weakness, and based on our data to date, we believe AXA1125 holds great potential to address this underlying bioenergetic issue.

Healio Primary Care: How does AXA1125 work? What symptoms could it potentially alleviate?

Schecter: AXA1125 has demonstrated the potential to boost fatty acid oxidation, improve mitochondrial respiration and reduce inflammation. Axcella Therapeutics has generated preclinical data demonstrating AXA1125’s ability to restore mitochondrial function and cellular homeostasis.

This in-vitro data are reflected in our compelling clinical data in NASH, where we have seen notable reductions in key markers of liver fat, inflammation and fibrosis. These data also position AXA1125 very well given that mitochondrial dysfunction and inflammation are being implicated as drivers of long COVID.

Healio Primary Care: Which patients are you targeting for enrollment? How many will be included in the trial?

Schecter: We will be enrolling subjects who have had COVID symptoms for more than 12 weeks, which is the point at which patients who remain symptomatic are considered to have long COVID.

The phase 2a trial will be a randomized, double-blind, placebo-controlled investigation to evaluate the efficacy and safety of AXA1125 in approximately 40 patients with chronic fatigue related to long COVID.

Healio Primary Care: Can you discuss the primary and secondary endpoints? How do they indicate whether a patient has recovered?

Schecter: The primary endpoint in our phase 2a trial is the change in phosphocreatine recovery time as measured by 31-phosphorus magnetic resonance spectroscopy.

Phosphocreatine recovery time is a direct, highly reproducible and FDA-approved measure of mitochondrial oxidative function that has been strongly correlated with the 6-minute walk test, which can be used as an endpoint for registration in a number of other exertional fatigue-related conditions, including pulmonary hypertension and interstitial lung disease.

Secondary endpoints will include other biomarkers such as lactate levels and outcomes and functional measures such as the 6-minute walk test and validated patient reported outcome measure, such as fatigue scores.

We would like to see a concordance of effect in these measures, which one would expect to then translate into improved outcomes for these patients.

Healio Primary Care: AXA1125 is also being studied in patients with NASH. What evidence is there to suggest that an investigational treatment for liver disease could help treat long COVID symptoms?

Schecter: Preclinical evidence of AXA1125 increasing fatty acid oxidation and ATP production is translating into clinical findings that have demonstrated reductions in liver fat, inflammation and glucose homeostasis in subjects with NASH. Having demonstrated the potential to boost fatty acid oxidation, improve mitochondrial respiration and reduce inflammation, AXA1125 is uniquely suited as a potential treatment for the debilitating symptoms of long COVID.

References

Axcella Therapeutics launches clinical program to develop treatment for patients with long COVID. https://ir.axcellatx.com/news-releases/news-release-details/axcella-therapeutics-launches-clinical-program-develop-treatment. Published Oct. 26, 2021. Accessed Nov. 12, 2021.

Axcella Therapeutics. Endogenous metabolic modulators. https://axcellatx.com/endogenous-metabolic-modulators/. Accessed Nov. 12, 2021.

Axcella Therapeutics. Pipeline. https://axcellatx.com/pipeline/axa1125/. Accessed Nov. 12, 2021.