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Even after recovery from COVID-19, many patients are left with long-term health problems, including breathlessness and fatigue.(Source:Getty Images)

As COVID-19 continues to spread worldwide, ‘long Covid’, where people recover from the infection but are left with long-lasting health problems, is becoming a global public health concern.

However, the many unknowns around long Covid – including how to characterize and target it - mean only a few biopharma companies have moved into clinical studies for potential therapies.

Far from being a single disease, long Covid covers a huge range of symptoms that persist after a minimum of four weeks from the onset of a diagnosed COVID-19 infection, ranging from breathlessness and fatigue to ‘brain fog’ and digestive problems.

One company, PureTech Health, has decided to take the plunge with trials to investigate a respiratory therapy, LYT-100 (deupirfenidone).

PureTech launched a Phase II trial of LYT-100 in December, recruiting people suffering from Long COVID respiratory complications and related sequelae, with the hope of improving their long-term recovery and limiting the damage to their lungs caused by SARS-CoV2 infection.

LYT-100 is closely related to Roche’s Esbriet pirfenidone) an anti-fibrotic treatment for rare lung disorder idiopathic pulmonary fibrosis (IPF), but includes a chemical tweak to reduce gastrointestinal side-effects seen in the older drug.

PureTech in-licensed the drug from Auspex Pharmaceuticals in July 2019, having spotted its potential as a treatment for lymphatic flow disorders, including lymphedema. But when the pandemic struck last year, the company saw that it might also help post-COVID-19 patients.

LYT-100 is designed to block fibrosis, the scarring process which can permanently damage lungs, and which was observed in earlier novel coronaviruses, namely SARS and MERS.

PureTech’s head of innovation Michael Chen told Scrip that the company “connected the dots” last year and saw the drug’s potential in patients recovering from COVID-19.

“We realised that some of the mechanisms of long COVID were reminiscent of those in SARS and MERS, and those were driven by inflammation and fibrosis. That was especially residual inflammation in the lungs and eventually the deposition of scar tissue and irreversible scarring.”

Building on positive signs from a Phase I study conducted last year, the Phase II placebo-controlled trial is now fully enrolled with 126 patients, and its primary endpoint is change in distance walked on the six-minute walk test.

The trial’s principal investigator is Toby Maher, professor of clinical medicine and director of interstitial lung disease at Keck School of Medicine of the University of Southern California. He said the six-minute walk test was chosen as a pragmatic endpoint, helping to establish quickly if those receiving the drug see more improvement than those on the placebo arm.

Toby Maher

Secondary endpoints include pharmacokinetics, inflammatory biomarkers, imaging and patient-reported outcomes such as dyspnea and self-reported quality of life measures.

The trial’s outcome is naturally not a foregone conclusion, not least because of remaining uncertainties about the progression of long Covid in patients. This includes questions about how big a role fibrosis plays alongside other factors such as persistent inflammation and loss of muscle strength caused by the infection and long hospital stays.

Maher acknowledges there are lots of uncertainties but hopes the trial can deepen understanding of the condition and the role of fibrosis, and whether or not it could be progressive or self-limiting.

“As with everything in COVID, we're sort of learning as we go along. If you look at [SARS and MERS] in many cases the fibrosis was self-limiting, but that didn't mean it didn't cause significant morbidity.”

It remains difficult to gauge how much of the post-hospital disability is caused by permanent loss of lung function, but these post-COVID patients are unlikely to be at the advanced stage of irreversible lung scarring seen in the average IPF patient.

If that is the case, Maher expects that LYT-100 treatment can be relatively short, at around six-12 months, rather than the lifelong treatment needed in IPF, and could be enough to facilitate post-COVID recovery and prevent development of significant fibrosis.

Chen also acknowledges that being first in the field brings with it novelty and uncertainty but asserts that PureTech’s decisions will be driven by the data.

The wait for data will not be long, as PureTech expects initial results from the study sometime in the second half of 2021.

If those results are not compelling enough to take LYT-100 into a pivotal trial in long Covid, the compound is also in an ongoing Phase II study in breast cancer related lymphedema, with late-stage trials in IPF and other interstitial lung diseases in the planning stage. 

More basic research to better understand long Covid is needed and one such initiative is the US National Institutes of Health’s 900-patient longitudinal study of COVID-19 sequelae and immunity. But in the meantime, the urgency and scale of the unmet need could attract other companies to follow PureTech.

Chen agrees that the company’s pioneering study in long Covid lung disease is just scratching the surface of a very complex phenomenon.

“I think the lung mechanisms, the respiratory complications of COVID are [among the best] understood because of SARS and MERS, and the precedent we have in inflammatory lung conditions.

“But we are talking about a disease that can make people's hair fall out, or cause inflammation in the toes. So it's literally a head-to-toe effect, and it will take years to unravel every mechanism of long Covid.”

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