Scanning the horizon for future Covid-19 treatments

Outside of vaccines and antibodies, few experimental agents have made it into large, robust clinical trials.

Spotlight

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 mavrilimab 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.

Selected commercially sponsored large/late-stage Covid-19 trials
Product (company) Mechanism Detail NCT ID
ABX464 (Abivax) RNA CBC regulator; miRNA-124 expression stimulant; Rev inhibitor Preventing acute respiratory failure in high-risk patients. Interim analysis due by year end.  NCT04393038
SNG001 (Synairgen) Inhaled interferon-β1a Prevention of disease progression in high-risk patients. Next data due in 120 home-dosed patients. NCT04385095
Otilimab (Glaxosmithkline)
 
Anti-GM-CSF Mab Survival of severe Covid-19 patients. Primary completion date Dec 2020. NCT04376684
NP-120 (Algernon Pharmaceuticals) NDMA inhibitor  Disease progression in hospitalised patients. Read out from initial 150 patients due by YE 2020.  NCT04382924
Mavrilimumab (Kiniksa Pharmaceuticals) Anti-GM-CSF Mab Mortality in severe Covid-19 patients with pneumonia and hyper-inflammation. Data due from phase II portion.  NCT04447469
RTB101 (Restorbio) PI3K & Mtor inhibitor  Reducing disease severity in nursing homes. No recent update, Restorbio became a reverse merger target in September. NCT04409327
CX-01 (Chimerix) HGMB 1 antagonist Severe patients at high risk of respiratory failure. Phase II portion to complete enrolment in Q4'20.  NCT04389840
Losmapimod (Fulcrum Therapeutics) MAPK inhibitor Mortality in hospitalised patients. Top-line date due Q1'21. NCT04511819
RG7880 & RG6149 (Roche) Anti-IL 22 & anti-IL33 Mabs Disease progression in patients with severe Covid-19 pneumonia. Primary completion Jan 2021. NCT04386616
PTC299 (PTC Therapeutics) DHODH inhibitor  Respiratory improvement in hospitalised patients. Results due H1'21. NCT04439071
Lenzilumab (Humanigen) Anti-GM-CSF Mab Time to recovery in severe or critical patients. Read out due by YE 2020.  NCT04351152
Asunercept (Apogenix) CD95L inhibitor  Disease progression in severe patients. Started enrolling October 2020.  NCT04535674
Source: EvaluatePharma, clinicaltrials.gov, company statements. List not exhaustive.

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. 

Seeking a new purpose – existing drugs in large Covid-19 trials 
Product (company) Detail  Enrollment NCT ID
BCG vaccine (unclear) Prevention of respiratory tract infections, including Covid-19, in older adults. Academic led.  5,200 NCT04537663
Xarelto (Johnson & Johnson) Reducing the risk of clots in high-risk Covid-19 patients. J&J study.  4,000 Recruiting
Prozac (generic) Reducing intubation and death. Academic led.  2,000 NCT04377308
Metformin (generic)  Prevention and treatment of Covid-19. Academic led.  1,522 NCT04510194
Vascepa (Amarin) High-dose Vascepa to prevent and reduce severity of Covid-19 in healthcare workers. Academic study.  1,500 NCT04460651
Ultomiris (Alexion); Olumiant (Lilly)  To reduce disease severity in hospitalised patients. Academic study, TACTIC-R. 1,167 NCT04390464
Farxiga, Volibris, EDP1815* (Astrazeneca, generics, Evelo Biosciences)  To reduce disease severity in hospitalised patients. Academic study, TACTIC-E. 1,407 NCT04393246
Olumiant (Eli Lilly) Olumiant to reduce disease severity in hospitalised patients. Lilly study. 600 NCT04421027
Xtandi (Astellas Pharma) Xtandi to reduce disease severity in hospitalised patients. Astellas collaborating.  500 NCT04475601
Jakafi (Incyte) Jakafi to reduce mortality in ventilated patients. Incyte sponsored.  500 NCT04377620
Tavalisse (Rigel); Jakafi (Novartis) Tavalisse and Jakafi to reduce progression to severe pneumonia. Academic study.  456 NCT04581954
*Experimental microbial based product. Source: EvaluatePharma, clinicaltrials.gov. List not exhaustive. 

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