Assessing the efficacy, safety and tolerability of AXA1125 in long COVID patients

By Bhavana KunkalikarApr 19 2023Reviewed by Lily Ramsey, LLM

In a recent study published in the eClinicalMedicine Journal, researchers evaluated the effectiveness and tolerability of an endogenous metabolic modulator AXA1125, in individuals with long coronavirus disease (COVID).

Study: Association between hearing aid use and all-cause and cause-specific dementia: an analysis of the UK Biobank cohort. Image Credit: DmitryDemidovich/Shutterstock.com

Background

Long COVID refers to symptoms that persist for more than 12 weeks after a person has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with fatigue being a common symptom.

Reduced cellular bioenergetics and mitochondrial function are among the potential causes. AXA1125, an endogenous metabolic modulator, has shown potential in preclinical models and certain clinical conditions to improve bioenergetics and elevate β-oxidation, which may help reduce long-COVID-related fatigue.

About the study

In the present study, researchers evaluated the effectiveness, safety, and tolerability of AXA1125 against long COVID.

The study included individuals who were aged between 18 and 64 years and had clinically suspected COVID-19 at least 12 weeks before the screening. They reported fatigue-predominant long COVID with a total fatigue score of eight or more on the Chalder Fatigue Questionnaire (CFQ-11) and had a post-exertional skeletal muscle phosphocreatine recovery rate constant (τPCr) of over 50 seconds.

Patients who met the criteria were randomly assigned to receive either oral AXA1125 or a placebo that appeared and tasted the same and had a similar smell.

The study conducted a screening visit in a hospital setting to evaluate prospective patients using various tests such as patient-reported fatigue assessment and blood tests. Physical activity was evaluated quantitatively using the venous serum lactate levels, six-minute walk test (6MWT), and CFQ-1111 at both clinic visits.

The study conducted pre- and post-exercise measurements of τPCr during the screening visit and on day 28. On Day 14, a follow-up fatigue assessment was performed over the telephone. Treatment-emergent adverse events (TEAEs) were monitored throughout the study period, including the final telephone visit on day 35.

The adverse events were categorized based on their seriousness, severity, and association with the study drug and were obtained through non-leading questions. The Common Terminology Criteria for Adverse Events (CTCAE) was used to categorize adverse events (AE) into grades one to five.

The study's primary endpoint was to measure the average difference in τPCr levels between the start of the study and day 28, which could indicate alterations in mitochondrial oxidative metabolism.

Secondary efficacy endpoints were the changes in pre-exercise CFQ-11 fatigue score from baseline, the number of patients with improved pre-exercise fatigue severity as per CFQ-11 on day 28, the change in distance covered during a 6MWT, and the difference in post-6MWT peak serum lactate level from baseline.

Results

Patients were recruited between 15 December 2021 and 23 May 2023. Almost 41 eligible patients out of 60 were randomly assigned to receive either AXA1125 twice daily or a placebo twice daily.

All participants in the intent-to-treat (ITT) population received at least one dose of the study treatment and successfully finished the study. The average age of the study population was 43.6 years. 

The study found that post-exertional τPCr was high and varied among subjects on day one and remained elevated and variable on day 28. There was no significant difference in the average variation in post-exertional τPCr between baseline and Day 28 in the placebo and AXA1125 treatment cohorts.

The AXA1125 treatment cohort showed a positive correlation between the difference in pre-exertional physical fatigue score and the change in τPCr, while the placebo group did not. AXA1125 showed significant reductions in pre-exercise CFQ-11 total physical and mental fatigue scores compared to the placebo on day 28.

Almost 71% of AXA1125-treated patients experienced an improvement in pre-exercise physical fatigue, and 33% experienced an improvement in pre-exercise mental fatigue, while only 20% and 5% of patients in the placebo arm experienced an improvement in these areas, respectively.

AXA1125 showed notable decreases in post-exercise CFQ-11 scores compared to the placebo, which was like the reductions noted in the pre-6MWT fatigue evaluation. Patients treated with AXA1125 exhibited a tendency towards decreased post-exertional peak serum lactate level on day 28 in comparison to those who received placebo from baseline.

There was no significant difference in the percentage change of post-exertional peak serum lactate between the two treatment cohorts.

Out of the 11 TEAEs in the AXA1125 group, 10 were mild, and one was severe. TEAEs in the placebo group were mild or moderate in severity. Diarrhea, abdominal distension, and nausea were the frequently reported TEAEs. Among these, two cases were related to the treatment. Additionally, one grade three TEAE was observed in the AXA1125 cohort.

Conclusion

The study findings showed that AXA1125 treatment did not lead to a significant τPCr increase. However, the studies showed enhancements in both physical and mental fatigue, evaluated through a verified questionnaire.

AXA1125 was well tolerated with few treatment-emergent adverse events reported. A phase three evaluation of AXA1125 against long COVID is being planned, which will include assessments of mental, physical, and cognitive health, as well as health-related quality-of-life estimates to better understand the therapy's benefits.