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An investigational therapy for long COVID failed to improve measures of mitochondrial function in a small randomized study, but the oral drug did show potential for easing patients' fatigue.

Four weeks of treatment with the endogenous metabolic modulator AXA1125 showed no benefit over placebo for the study's primary outcome, a measure of mitochondrial oxidative capacity following exercise (P=0.24), or for boosting distance on 6-minute walk tests, reported Betty Raman, MBBS, of Oxford University Hospitals NHS Foundation Trust in England, and colleagues.

But AXA1125 was associated with a reduction in self-reported fatigue scores from baseline to day 28 on the Chalder Fatigue Questionnaire (CFQ-11), according to the findings in .

Total scores on the CFQ-11, where higher scores on a 0-33 Likert scale indicate worse fatigue (≥24 for moderate-to-severe), dropped from an average of 26.2 to 21.0 with AXA1125, as compared with 28.1 to 26.5 with placebo group, for a least squares (LS) mean difference of -4.30 (95% CI -7.14 to -1.47, P=0.0039).

And significant improvements favoring the investigational drug were seen in physical and mental fatigue scores as well (P=0.0097 for both).

The 41-patient, single-center was conducted in the U.K. and enrolled long COVID patients with fatigue (moderate-to-severe in most cases) and clear signs of impaired mitochondrial function.

While treatment-emergent adverse events (TEAEs) were more than twice as frequent with the study drug (52.4% vs 20.0%), most events were mild and none led to stoppage of treatment, according to the researchers.

"The reduction in patients' own reports of fatigue is really positive news, and we hope that further work will help us understand the underlying processes behind this improvement too," Raman said in a following publication of the results, which were also presented at the in Copenhagen, Denmark.

"There is still some way to go in treating all patients with long COVID -- our results focus specifically on fatigue, rather than the breathlessness and cardiovascular issues that other long COVID patients have reported," Raman noted.

To date, no drugs are approved for treating long COVID, though metformin has demonstrated potential for preventing onset of the sometimes debilitating condition. While long COVID, or post-COVID syndrome, can encompass a wide range of symptoms, prior studies estimate that fatigue is involved in anywhere from to of cases.

"Mounting evidence suggests a for and impaired cellular bioenergetics," explained Raman and colleagues. "The SARS-CoV-2 virus is thought to 'hijack' the host mitochondria to facilitate viral replication, compromising function, increasing inflammation and oxidative stress. Subsequent energy dysregulation triggered by metabolic reprogramming (a switch from oxidative phosphorylation to glycolysis) is proposed to manifest as chronic fatigue."

AXA1125, which is comprised of multiple amino acids, has shown effects on cellular energetics and inflammation in preclinical models and clinical trials in liver disease. Combined, "these findings suggest that AXA1125 might offer therapeutic benefits in patients with long COVID," the researchers asserted.

Based on the study results, developer Axcella Therapeutics is planning a phase III trial for AXA1125 in long COVID patients with fatigue, with the FDA recently the company's investigational new drug application in this setting.

The phase IIa pilot study screened 60 individuals, ultimately randomizing 41 adults with fatigue-dominant long COVID who met eligibility criteria to either AXA1125 (33.9 g of orange-flavored powder dissolved in water) or placebo matched for taste and color. Treatment was administered twice-daily with an oral suspension for 4 weeks, with 2 weeks of additional follow-up. Those with other possible causes of fatigue were excluded.

Included participants were 44 years of age on average, about two-thirds were women, and 90% were white. Mean BMI was 26.4, and long COVID symptoms had been present for an average of about 17-18 months.

The study's primary endpoint was mean change in post-exercise skeletal muscle phosphocreatine recovery time constant (τPCr). To assess this, patients calf muscles were measured by phosphorus magnetic resonance spectroscopy (³¹P-MRS) as they bent and straightened their leg against mild resistance. In the study arm, τPCr increased from 96.8 to 118.0 per second, while the measure increased from 87.9 to 91.9 in the placebo arm, with no significant between-group differences.

On the 6-minute walk test, both groups showed similar mean improvements from baseline to day 28 (increases of 25-26 m in each group).

Addressing the lack of significant effect on the primary endpoint, the researchers suggested this was "likely due to the variability seen in this parameter in this patient population. Nonetheless, the majority of patients had a prolonged τPCr at baseline, an important finding indicative of significant impairment of mitochondrial metabolism ... and energetics." They added that this could signal a potential mechanism for ongoing symptoms.

In post hoc analyses, patients in the AXA1125 arm who qualified as physical fatigue responders were more likely to have corresponding effects on τPCr (P=0.0024) and improvements in walking distance at day 28 (P=0.045) compared with non-responders, associations not seen among placebo responders.

"The positive trend in τPCr which accompanied fatigue reduction suggests that treatment response may be due to improvements in metabolism and oxidative stress," according to Raman and co-authors.

Common TEAEs with AXA1125 included diarrhea (14.3%) and nausea (9.5%), with only two cases deemed to be treatment related. One grade 3 case of syncope related to the imaging procedure was reported in the AXA1125 group.

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