Scanning the horizon for future Covid-19 treatments

Hopes of finding a magic bullet against Covid-19, at least within the next few months, rest on the outcomes of a small number of clinical trials. Beyond these leading antibody and vaccine approaches, few large clinical programmes of other novel mechanisms are under way.

True, there is a huge amount of early-stage research going on, and hopes are high that antibody and vaccine research will yield important new options. But a scan for ongoing trials robust enough to generate the sort of data that could get a product on the market reveals little on the near-term horizon.

Some of the biggest Covid-19 trials concern drugs already on the market, largely sponsored by academia. Several repurposing attempts have already fired blanks, however; the cheap steroid dexamethasone is arguably the biggest success story so far. 

Earlier this month the Solidarity trial authors concluded that four known antivirals, including Gilead’s Veklury, offer little or no benefit to hospitalised Covid-19 patients. Academic-led trials of other HIV agents like Truvada are ongoing, but it seems more likely that research into experimental antivirals will yield new and improved options.

Merck's MK-4482 is the furthest along, with phase II data due before year end on a Ridgeback-licensed candidate that is already in registrational studies. And last month Roche paid $350m up front for ex-US rights to Atea's phase II project, AT-527, while Novartis took an option over two preclinical candidates from Molecular Partners.

Pfizer also recently put an experimental antiviral into phase I. This all points to a rapidly advancing pipeline, albeit one that is slightly behind that for vaccines and antibodies. The longevity of previous pandemic antivirals, particularly Tamiflu, shows why big pharma is interested in this space – Roche has booked cumulative sales of $15.9bn of Tamiflu since it was launched in 1999, according to EvaluatePharma (Previous pandemic antiviral demand spike sees Biocryst jump aboard, March 5, 2020)

Coming behind

In terms of large trials of other novel agents, much effort is still going into cytokine-dampening MAbs, despite the disappointment with existing anti-IL-6 products. Drugs like Roche's Actemra were hypothesised to reduce the inflammatory response seen in very ill Covid-19 patients, although results published recently in two major journals surely confirm this as a dead end.  

Attention has now largely turned to anti-granulocyte-macrophage colony-stimulating factor MAbs. Glaxosmithkline has moved into a large trial with its rheumatoid arthritis project otilimab, an anti-GM-CSF antibody licensed from Morphosys. Like IL-6, GM-CSF is a cytokine thought to be involved in the dangerous hyperinflammatory stage of Covid-19; Kiniksa’s mavrilimumab and Humanigen’s lenzilumab are similarly targeted projects in Covid-19 trials.

Roche, meanwhile, has started a Covid-19 trial with two other cytokine blocking antibodies it has in its pipeline. Astegolimab (RG6149) inhibits the binding of IL-33 to ST2, a pathway thought to be involved in various lung diseases, while RG7880 hits IL-22.

Other late-stage Covid-19 trials are largely being conducted by smaller developers, and the table above highlights a selection of contenders.

Synairgen’s interferon approach is not technically novel, although formulating interferon beta-1a for inhalation is certainly unique. The pilot phase of a potentially large study is ongoing in high-risk patients; early data were considered encouraging, and further evidence is awaited (Synairgen joins the 2020 coronavirus winners club, July 20, 2020).

Algernon, meanwhile, is poised to release data before the end of the year from the phase IIb portion of its trial of NP-120. Also called ifenprodil, the company believes the NMDA receptor antagonist might work by dampening cytokines.

And Fulcrum has put its MAPK inhibitor, losmapimod, into a trial in hospitalised patients, the hypothesis being that the acute inflammatory response seen in severe patients is mediated by p38 mitogen-activated protein kinase.

A new purpose

In terms of repurposing existing medicines, much work is going on with anti-clotting agents, to treat or prevent the thromboses that Covid-19 can trigger. The most notable of these efforts is a 4,000-patient trial sponsored by Johnson & Johnson, to see if Xarelto can reduce the risk of clotting events, hospitalisation or death in high-risk patients.

A couple of trials are investigating whether BCG vaccination might reduce the risk of infection by the coronavirus that causes Covid-19. Elsewhere, some research groups are exploring the role that androgens might play in disease expression, which might in turn explain the imbalance of severe disease seen in men. Astellas is collaborating on a large trial of Xtandi in this area.

The rationale behind some other repurposing trials is less obvious. A 2,000-patient trial of Prozac, investigating whether the antidepressant can reduce intubation and death, falls into this camp.

The fact that big pharma is largely focused on novel antibodies, vaccines and antivirals speaks to where the big hopes lie in Covid-19 research. While the complete failure of these efforts seems unlikely, mediocre effectiveness cannot be ruled out – a situation that might leave the door open for some of these other approaches.