A drug effective against long covid and fatty liver disease has entered final trials. The process of drug-discovery is just as amazing as the drug itself.
By Dona Suri
A new drug, rapidly approaching final approval, may successfully treat both long covid and fatty liver disease. Researchers say test results are encouraging. The drug, AXA 1125, is the creation of a Cambridge, Massachusetts-based biotech firm, Axcella Health Inc. So far, two advanced human trials have been carried out: one looked at the effect the drug on patients of long covid and the other focused on patients suffering from fatty liver disease (medical name – Non-Alcoholic Steato-Hepatitis – NASH).
AXA 1125 is a biologic drug (meaning that is produced from living organisms or contain components of living organisms) and is described as a mitochondrial enhancer; it is composed of five amino acids and the mitochondrial booster N- acetylcysteine. Trial results found that AXA1125 increased energy production in cells and reduced inflammation.
Before getting into what AXA1125 does and how it does it, let’s check out what’s going on in our cells. Actually, not just in our cells, but all cells – animal and plant.
Inside the cell are membrane- bound organelles called mitochondria. It takes an electron microscope to see a mitochondrion; it’s nano-scale in size – but mega-scale in importance. Cells run on adenosine triphosphate (ATP). ATP molecules are like super-tiny button cells – they store energy.
Mitochondria make ATP; the scientific name for this process is oxidative phosphorylation. The mitochondria take in nutrients and put out energy-rich molecules. It’s an electrical process: when mitochondria run an electrical voltage across their membranes, they give off ATP.
Mitochondria are not only the “Powerhouses of the Cell”, they carry out many other important biological processes and are central to cell functioning. These other functions and processes are massive topics, but, we will focus only on mitochondria, energy levels, inflammation, long covid and fatty liver disease – which is more than enough to bite off for one small blog post.
Now about fatty liver disease… It is chronic, often asymptomatic and affects some 16.5 million people in the USA alone – and this number is rapidly increasing. Sufferers not only have fatty livers, their livers are inflamed and fibrotic (hard, tough and stringy).
At present, the only way to restore the liver to health is by lifestyle changes such as avoiding unhealthy foods, losing weight and exercising. There are no approved medicines for it in the USA. If left untreated, fatty liver is likely to spiral into cirrhosis and hepatocellular carcinoma.
About 80 percent of people with Type 2 diabetes suffer from fatty liver disease. It commonly affects obese people but even people whose weight is within normal range may have this condition.
Why does it strike some people and not others? The needle of suspicion points to a metabolic problem, which means that the search for a remedy ultimately leads down to cell level. When something’s not right with the mitochondria, the result is liver fat and insulin resistance, inflammation and fibrosis. As for long covid treatment, by the end of 2022, out of more than 500 million people infected by covid-19 reported across the world, about 10 per cent developed long covid. One of the symptoms is extreme and constant exhaustion throughout the day. The abnormal fatigue is the result of impaired functioning of the mitochondria in the muscles.
Researchers have figured out enough about long covid to know that the virus targets the mitochondria, so a drug that cures long covid has to overcome the effect of the virus at the mitochondrial level.
The initial investigation of AXA 1125 effect on the symptoms of long covid was a short duration trial conducted at Oxford University’s Radcliffe School of Medicine. This trial did not go entirely as expected. The drug’s makers were interested in seeing what effect the drug would have on phosphor-creatine, or creatine-P, or PCr, in the muscles of the long Covid patients after moderate exercise.
Creatine is a small molecule synthesized in the liver from glycine. The creatine is transported through the bloodstream to skeletal and heart muscles. It enters the mitochondria in the muscles, which add a phosphate group molecule and produce ATP (the fuel that powers the muscles). When the muscle works, it uses up phosphor-creatine; when the work stops, the phosphor-creatine level comes up again to its normal resting level. Researchers time how long it takes for the PCr to get back to normal; this is the PCr recovery rate. Short PCr recovery time means improved muscle function.
As it turned out, the long covid patients who had AXA 1125 had the same PCr recovery rate as those who didn’t get it. No score for AXA 1125.
BUT … those who got AXA 1125 were not as tired, physically or mentally as the placebo group and they did better on the six-minute walk test. Goal!
Associate Professor Betty Raman, the study’s principal investigator clarified: “Our results focus specifically on fatigue, rather than the breathlessness and cardiovascular issues that other long covid patients have reported. We found that AXA1125’s combination of five amino acids and an amino acid derivative appears to improve power output through multiple biological pathways.” The study was double-blind, that is, neither the patients nor the researchers working with the patients knew which patients had the treatment and which patients had a placebo.
In subsequent trials, AXA 1125 substantially restored the livers of those who got the drug: liver fat and insulin resistance, inflammation and fibrosis all came down. Notably, the improvement was consistently greater in the subgroup of subjects with Type 2 diabetes.
The AXA 1125 – NASH trials continued through 2023. By now, the data has made it clear that AXA1125 does indeed help the liver get back to normal. As a result of the positive test results, the Federal Drug Administration has granted a Fast-Track Designation to the new drug. The FDA okays Fast-Track when the drug under trial has the potential to cure a serious or life-threatening condition treatment.
The news about AXA 1125 is something to celebrate, but an equally remarkable aspect is the process by which AXA 1125 was identified.
Think way, way back to 1928 — the year of one of the greatest pharmaceutical breakthroughs in history.
Alexander Fleming returned from a two-week vacation to find that a mold had developed on an accidentally contaminated staphylococcus culture plate left out on the lab counter.
Upon examination, he noticed that the mold prevented the growth of staphylococci. Hello, Penicillin !
The discovery of AXA 1125 was the result of big data analysis and a systems biology approach: machine learning meets amino acid behavior. Axcella scientists screened more than 30 MILLION possible Endogenous Metabolic Modulator (EMM) combinations to identify candidates with the potential to effect multiple targeted pathways.
Today, the process of discovery is just as amazing as the discoveries themselves.