How debilitating are the effects of long COVID?
When Axcella Health CEO Bill Hinshaw discusses the disorder, he mentions a competitive college skier who needs to be dropped off at her house. Not at her driveway—but all the way to her front door.
“She’s like a 90-year-old lady,” said Hinshaw in an interview. “That’s devastating.”
Conquering the fatigue and muscle weakness that strikes more than half of those with long COVID is the goal of Hinshaw and his Massachusetts-based biotech, which was established by research and venture capital incubator Flagship Pioneering.
Visiting Washington, D.C., last week, Hinshaw is trying to enlist congressional allies for the cause. He’s the first to admit that it’s not an easy sell.
“People are tired of COVID, and we understand that,” Hinshaw said. “The government did a remarkable job looking forward and being outcome-oriented when we talk about the pandemic … But frankly, this is still part of the pandemic. We need the same energy to address this.”
Roughly 24 million people in the U.S. have developed long COVID. In the U.K., 45% of those who have had long COVID have had to modify their work schedule, and 22% have not returned at all.
With its range of difficult symptoms—shortness of breath, brain fog, dizziness and headaches—the cause of long COVID has been difficult to pinpoint. But at least in the case of muscle weakness and fatigue, recent data point to mitochondrial dysfunction and inflammation.
This is an area Axcella knows well through its development of AXA1125, a powdered oral drug to combat the same symptoms in the liver condition nonalcoholic steatohepatitis (NASH)—a tricky indication that has stymied many a Big Pharma.
“We’re prepared to lead in this area with a product that’s already got an IND, already in global phase 2b for NASH and already has significant safety and activity information,” Hinshaw said. “So that allows us to work with the experts and proceed very rapidly, hopefully to bring this as quickly as possible.”
AXA1125 is an endogenous metabolic modulator composed of six amino acids and derivatives. In NASH, it has been shown to effect pathways related to metabolism, inflammation and fibrosis.
Now Axcella, along with the University of Oxford, will conduct a placebo-controlled phase 2a trial of AXA1125 against long COVID fatigue. The company expects to present results in the third quarter of this year.
In revealing last month the completion of enrollment in the midstage study, Axcella also unveiled a reshuffle of its portfolio. A trial for another asset, AXA1665 against overt hepatic encephalopathy (OHE), will be shut down. Hinshaw said the problem isn’t with the drug; it was the design of the phase 2 study.
Axcella was looking to find a neurological impact with AXA1665. OHE is a brain condition caused by liver insufficiency that can cause symptoms such as confusion, loss of small hand movements and severe personality changes. The company had already conducted two clinical trials for AXA1665, finding the therapy safe and well tolerated, and getting a hit on some biomarker data that suggested efficacy. The now-shuttered phase 2 trial was looking for 150 patients who had experienced at least one prior OHE event and had neurocognitive dysfunction.
Ultimately, the enrollment goals were just too difficult, according to Hinshaw. Axcella decided that the trial could not be executed as designed in the near term, so they cut their losses. The reprioritization allows Axcella to fully focus on NASH and long COVID.
In the long COVID trial, Axcella will assess mechanistic information on mitochondrial function and inflammation. The company will also look at key biomarkers such as lactate levels and functional measures—for example, a fatigue score in a six-minute walk.
Only a few companies are even taking a run at long COVID, and, among that small group, little progress has been made. Last week, PureTech Health announced the failure of a phase 2 trial for its candidate, bringing home the challenge Axcella is up against.
“Long COVID is complex,” Hinshaw said. “Our products have a very distinct profile. We are working with the body systems to address multiple dysregulated pathways at the same time and that’s unique.”
The multiple pathways approach also is the key to solving NASH, Hinshaw believes, giving Axcella a chance to succeed where others have failed.
“What I think we’ve seen in the field is people doing it through a modality of single-targeted therapies where they’ve been able to show target engagement but not on the disease to the level they would like,” Hinshaw said.
It was Axcella’s focus on developing a new class of products to rebalance the metabolic state of patients that compelled Hinshaw to leave Novartis, where he was the company’s oncology chief.
“I’ve worked on some amazing products—Gleevec, Kymriah, Afinitor—things that were true paradigm shifts,” Hinshaw said of his years at the Swiss pharma. “And that’s what Flagship-founded companies try to do. We’re looking at transformational technology.”