UPDATED: Axcella flunks long Covid PhII primary goal — but plots a path into PhIII
As Covid-19 cases mount once again and millions of people experience lingering symptoms months after diagnosis, Axcella Therapeutics wants to treat long Covid, but like others in the past, it has failed to meet the primary goal of a mid-stage study.
The biotech isn’t giving up on the pandemic disease’s long-term effects, unlike the move that PureTech Health made after missing the beat in its own Phase II last month. Axcella will attempt to persuade regulators in the US and UK with fatigue scores from the Phase IIa, rather than the missed primary goal, in discussions about a potential registrational Phase III study following.
Axcella’s shares $AXLA rose about 15% before the opening bell Tuesday and ended up closing the day lower, at an 8.5% hike over Monday, but the stock is still more than $1 below its price this time last year.
The main goal of phosphocreatine recovery rate (PCr) after moderate exercise was not achieved in the relatively small 41-patient study. The biotech thinks clinically and statistically significant improvements in self-reported mental and physical fatigue can get the drug toward the finish line, as there are no currently approved treatments for the pandemic disease’s long-term impacts.
Conducted in the UK, the study looked at a variety of measures, including the PCr, fatigue scores, a six-minute walk test and serum lactate levels, which represent a measure of muscle health. The PCr is used to assess improvement of mitochondrial function, which creates most of the chemical energy, in the so-called powerhouse of the cell in skeletal muscle.
The median age of patients was 43 years old and, to be enrolled, the patients had to have severe fatigue for at least three months, CMO Margaret Koziel told Endpoints News. No patients in the trial had been on any other Covid-19 therapies, she said.
For four weeks, researchers gave 21 patients 67.8 grams of AXA1125 divided into two doses per day, and gave a placebo to 20 randomized patients. All 41 completed the trial, which included a one-week safety follow-up period.
Regarding the primary outcome, Axcella’s medical chief said the drug developer was expecting baseline PCr to be around 50 seconds, but the figure was “sky-high” in the patients who actually took part in the study, conducted in conjunction with the University of Oxford.
“Instead, the baseline value was 92 seconds, which is like people who have severe peripheral arterial disease, like they are not getting blood flow to their lower legs,” Koziel said.
“The real killer for us was that the standard deviation was much higher than we anticipated — it was 38%, not 15 to 20%, so within the sample size, we couldn’t possibly demonstrate statistically significant change in treatment groups,” she continued. The ability to walk and the expected higher PCr levels of elderly patients are why the median age of the trial was optimized for middle age, the medical chief said.
As long Covid impacts millions of people, the biopharma industry has only a dozen or so companies looking at the condition. Tonix Pharmaceuticals will begin a mid-stage test this quarter after a few other biotechs have flamed out in their attempts. Atea’s antiviral, AT-527, failed a mid-stage test last year, and the company subsequently ditched a six-month follow-on study looking at the drug’s impact on long Covid in up to 1,000 patients. PureTech Health has also gotten out of long Covid after its drug LYT-100-COV did not pass muster in a Phase II study looking at respiratory complications.
For its part, Axcella will move forward with its long Covid program, looking to emphasize the clinically and statistically significant improvements on mental and physical fatigue seen in its study. The mean change in total fatigue score versus placebo was -4.30, good for a p-value of 0.0039. The figures for physical and mental scores were -2.94 (p=0.0097) and -1.32 (p=0.0097), respectively.
Three patients on the study drug normalized their physical fatigue scores, the CMO said, meaning their fatigue was similar to before getting infected with SARS-CoV-2.
Fatigue is a major concern for patients who experience the lingering effects of Covid-19. Axcella noted its impact on the workforce, citing recent congressional subcommittee data that say almost one in five adults with Covid will go on to have long Covid, and that about one million Americans are out of work because of the condition. A Brookings Institution report estimates four million full-time equivalent workers are out of work because of the condition that can be a disability under federal law.
Given the drug is already being tested in patients with non-alcoholic steatohepatitis, or NASH, and is in an ongoing global Phase IIb clinical trial in that condition, Axcella thinks its historical safety data on the oral therapeutic can be a boon to its discussions with regulators.
“The types of confounders that often lead to long Covid and Covid, in general, are often characterized in the NASH population, so we already know that it’s working preclinically and clinically in that setting based on our previous data, so this gives us a lot of optimism and confidence as we go forward,” CEO Bill Hinshaw said in a joint interview.
While Omicron and other variants and sublineages of the coronavirus have limited the impact of vaccines and therapies, Axcella doesn’t expect that to be the case for AXA1125 in long Covid.
“I don’t anticipate that this is going to be sensitive to variants. We’re not an antiviral where nucleotide substitution is really going to result in resistance,” Koziel said.
The goal is to “take this forward as rapidly as possible,” the medical chief said, with the CEO anticipating the regulatory talks to be a “favorable discussion.” While the endpoints are yet to be hashed out, Koziel expects general quality of life and improvements in physical activities to be studied in the trial.
If the drug makes it into a Phase III study in long Covid, the biotech thinks it can be “efficient” and will then “work with the right parties to help us develop and capitalize the company,” Hinshaw said. The company tuned its pipeline in May by suspending a global Phase II trial of another drug, AXA1665, in patients with overt hepatic encephalopathy.
SVB Securities analysts pegged AXA1125 with a 45% probability of success at getting approved in long Covid. If greenlit, the analysts project about $500 million in peak sales for the condition.
At the end of March, Axcella had about $63 million at its disposal. The company will report second quarter earnings in the coming weeks.
Editor’s note: This article was updated with information from an SVB Securities analyst note.