Long COVID but short on treatment options

With COVID-19 vaccines and therapeutics developed in rapid time, Ben Hargreaves investigates why this has not been the case with the creation of a treatment for Long COVID. The condition is more common than might be thought and presents a significant burden to patients, and yet the pipeline of potential therapies remains relatively sparse.

When the pandemic first struck, the gravity of the situation did not take long to set in. Once the scale of the threat was understood, the pharmaceutical industry reacted with a rapidity and agility that allowed vaccines to be developed at a record rate. To understand how quickly the industry responded, one need only look at the development history of Moderna’s COVID-19 vaccine: the company took all of two days to transition from receiving the genetic sequence of the virus to creating a vaccine candidate.

Anyone living with Long COVID would likely be interested in knowing why the same urgency is not being shown to develop a treatment for this condition. There is currently no approved treatment for Long COVID, and advice on how to treat the illness varies. With no specific medication available, doctors are likely to recommend exercise and self-management of the condition, through rest and reduced workload. The bad news for those living with the condition is that the pipeline of possible treatments is virtually empty.

A serious and poorly understood problem

According to the US Centers for Disease Control and Prevention, approximately 7.5% of the adult population of the US have symptoms of Long COVID, which works out at 24.75 million individuals. The range of symptoms of the condition includes extreme tiredness, shortness of breath, chest pain, problems with memory, difficulty sleeping, heart palpitations, and dizziness – though the exact symptoms can vary between individuals. A study of 47,910 patients that experienced a COVID-19 infection found that 80% developed one or more long-term symptoms, with more than 50 different symptoms associated with infection.

The recovery time is also an individual process that can endure for differing periods of time – from a few weeks, to months or even upwards of a year. Certain people who have experienced Long COVID are unable to work their regular jobs or to work at the same capacity as prior to infection, placing a significant burden on financial and general wellbeing.

In truth, one of the difficulties facing those with Long COVID and the scientific community is the lack of knowledge of the condition. Research into coronaviruses has been happening for decades, and this facilitated the development of the vaccines against COVID-19. With Long COVID, there are a myriad of factors involved, while even the definition of Long COVID is still evolving. It is this uncertainty that is putting off big pharma from investing heavily into research, especially as the condition, in many cases, resolves with time.

Enter biotech

As in many areas of drug development, when the hopes of finding a treatment are more speculative, biotech companies often make the initial breakthroughs on the way to finding a solution. This is likely to be the case with Long COVID, as the pipeline of potential therapies for the condition is mainly occupied by biotechs.

Two such companies are Axcella Health and AIM Immunotech, which are progressing AXA1125 and Ampligen (rintatolimod) as potential treatments for Long COVID, respectively.  Earlier this month, Axcella revealed that AXA1125 had missed its primary endpoint in a phase 2a trial, but that it had managed to improve patients’ fatigue compared against the placebo. As a result, CEO of Axcella, Bill Hinshaw, told pharmaphorum that the company will continue to move forward with the potential treatment but with a focus on treating severe fatigue. The latter company, AIM Immunotech, was able to report positive preliminary pilot study data for its trial into Ampligen as a treatment for chronic fatigue.

When the spokesperson for AIM Immunotech was asked why so few companies are working in the space, they responded: “We really can’t completely know what other companies are working on behind closed doors, but we do know that Long COVID is a complex disorder. There are 28 different recognized symptoms of Long COVID and different combinations are found in different individuals. Some patients have severe symptoms, and some have mild symptoms.”

For his part, Hinshaw explained, “Most biopharma companies have an approach to understanding the target, endpoints, and nature of the market, with a single target approach to treat conditions separately. Long COVID is complicated and manifests in many different ways, resulting in little research to date and leaving patients still in hope of answers.”

Next steps

Part of the challenge that saw Axcella’s AXA1125 miss its primary endpoint was due to this variety of potential endpoints facing drugmakers, Hinshaw outlined. With each patient reacting differently and exhibiting various symptoms, the difficulty becomes selecting which symptom a treatment could make a material impact on.

The benefit of progressing treatments through the pipeline and working with patients is the added learning about the condition being treated. For Axcella, the results of the phase IIa trial demonstrated that “that the baseline phosphocreatine recovery time following moderate exercise among all subjects was both significantly higher and had a higher degree of inter-subject variability (92.46 seconds +/- 35.3 seconds) than previously reported in the literature,” Hinshaw stated.

As a result, this supports the hypothesis that there is mitochondrial dysfunction due to Long COVID, and though this discovery did not end up proving useful to Axcella as a primary endpoint, it could prove invaluable to a long-term understanding of the condition.

For AIM, the biotech is still in the discussion phase with the FDA to gain approval for a placebo-controlled, double-blind investigatory clinical trial to study the efficacy of Ampligen in treating fatigue from Long COVID. Explaining why Ampligen may prove effective, the spokesperson said, “Ampligen is a selective TLR3 agonist which — to put it very simply — works to activate immune cells, shut down protein replication and chew-up viral RNA, all of which can help stop the virus from replicating and hopefully even eradicate it. The presumed aetiology of latent viral infection and the antiviral and immunomodulatory mechanism of Ampligen may explain why patients in studies with Ampligen have shown clinical improvement for fatigue.”

Despite the positive signs for both biotechs, an approval in Long COVID remains some time away. However, after posting its results, despite the miss on its primary endpoint, the share price of Axcella has risen by approximately 32%, at the time of writing. With there being a financial interest in developing a Long COVID treatment, should there be further signs of progress, it might not be long before larger pharma companies begin to make moves in the area. With the numbers of people living with Long COVID only increasing, this could come as a welcome development in a space currently lacking many options.