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What is the future for covid drugs and treatments?


  1. Mun-Keat Looi, international features editor

  1. The BMJ
  1. mlooi{at}bmj.com

Mun-Keat Looi reports on where research is focused and what’s missing from the covid treatment pipeline

What new treatments or approaches are on the horizon?

It’s not so much about “new” treatments as continuing research to prove effectiveness of drugs we already know work in practice, says Janet Diaz, who leads clinical management at the World Health Organization’s Health Emergencies Programme.

“I think we’re still seeing a mixture of different types of products in regard to the immunomodulation type,” she says. “We have corticosteroids, IL-6 receptor tocilizumab, and then Janus kinase inhibitors, baricitinib.1 If we can really improve access to those and get clinicians to integrate them into covid-19 care pathways for severe and critical cases in hospitals, I think that would be a big advancement.”

That said, she sees potential for anticoagulants as a treatment, particularly for hospital inpatients with severe to critical covid-19. “We have recommendations for the prophylactic dose in those patients, but we are currently conducting a prospective meta-analysis and I hope to have those results [this year],” says Diaz. She also hopes to have more data soon around dosing of heparin in patients with severe to critical covid-19, to see if there’s any mortality benefit in those patients or a reduction in the need for basic ventilation.

Similarly, antiplatelet agents such as aspirin may be worth stronger recommendations. Diaz explains, “There are increasing numbers of studies being conducted on that, both in the acute phase and also potentially in the early recovery phase. I look forward to seeing what comes out with that, because we’ve heard a lot about the cardiovascular complications in that first year after acute illness.”

What role will combination therapies have in future covid treatment?

Experts who spoke to The BMJ are unanimous that combination therapies will help to keep current drug treatments going in the near future.

Stephen Griffin, reader at the University of Leeds, says, “Because of the prevalence and the huge amount of infection around the world that we’re seeing and then the increased use of antivirals, I think if we continue to use immunotherapy I can’t see how we can avoid resistance other than by using combination therapies.”

Diaz adds that combination therapies will be an avenue to look at for use in immunosuppressed patients or those who may not build an immune response, may not have a sufficient immune response with vaccines, or can’t take vaccines.

Chris Butler, clinical director of the University of Oxford’s Primary Care Clinical Trials Unit, says, “It might be that actually we need to use combinations even in the community early on. So, really thinking about next steps in the research of the combination of antiviral drugs that attack the virus in different ways [is key].”

Each of the currently recommended antivirals has drawbacks: different studies have warned that molnupiravir may be carcinogenic, Paxlovid has a large number of critical drug-drug interactions, and remdesivir is administered intravenously.2 The good news is that, currently, variants don’t seem to be affecting the efficacy of direct acting drugs. The reason for urgency with combination therapies is the risk of resistance as we continue to use drugs by themselves.

Butler explains, “It’s very different with HIV because there you have chronic illness, and you expose the virus to antiviral drugs over a long period. Whereas, typically for covid-19, you are giving people an antiviral drug for, say, five days. So, the chances of developing resistance as a result of the treatment are less, but nevertheless it might still be more therapeutic, as well as prudent from the resistance point of view, to give two drugs in combination. But we don’t know that yet in the primary care setting.”

What’s missing?

There’s always room for still more antivirals. Diaz points out that Paxlovid and molnupiravir “are for patients who are at high risk for severe disease, to reduce their need for hospitalisation.” She would also like to see at least two oral options and one intravenous antiviral option.

Butler would like to see early acting antiviral agents that attack preserved components of the virus—an enzyme, say, or an aspect of the virus that doesn’t change with the variant. “Then it’s probably more likely that an oral antiviral agent will be longer lasting than certain monoclonal antibody therapies,” he says, adding that we also need to be exploring combinations of orally acting agents.

He also highlights the immediate potential for interventions that are generic and topical and not directly antiviral, such as nasal treatments. “If you can find a treatment that’s cheap, effective, and with few or zero side effects that people can start using as soon as they feel unwell, then we could again further revolutionise this treatment,” he says. “I’m also excited about looking at agents—for example, topical treatments in the nose—that might reduce viral replication there and limit spread and so forth.”

Griffin wants research to explore whether combinations of direct antivirals, or monoclonal antibody therapies, provide not only improved activity but also longevity against SARS-CoV-2. He thinks that monoclonals targeting variant regions, for instance, would be the next step, as “you’re going to run out—you’re not going to win a race trying to develop monoclonals against different epitopes.”

With antivirals and with monoclonal antibodies, the science is still not clear on their efficacy against different variants. Speaking about the decision of the UK’s National Institute for Health and Care Excellence (NICE) not to license Evusheld in particular, Alex Richter, director of the Clinical Immunology Service at the University of Birmingham, says that monoclonal antibodies “have been proved to work well on previous covid-19 variants, both as a treatment when infected with the virus and as a preventive treatment.3 However, there is laboratory evidence that Evusheld doesn’t work against 85% of the covid-19 variants currently circulating in the UK4 . . . NICE recognises that the virus is evolving faster than the evidence can be produced and its assessment process can be undertaken.”

What treatments will we see for long covid?

Diaz says, “A lot of what we’re seeing studied in the long covid space is repurposed drugs but targeted towards what we think is the immunopathology, targeted to the coagulation problem. I think we’re still trying to target what we think is the immune pathology or pathophysiology of long covid [with repurposed drugs].”

Tari Turner, director of the National Covid-19 Clinical Evidence Taskforce at Monash University in Australia, says, “Research evaluating treatments for long covid is another area where substantially more progress is needed, and soon. It’s a complex area, effective treatments are unlikely to come in pill form, and many millions of people globally are likely to be impacted, so it’s vital that we get good information quickly to guide treatment. In the absence of information, people are already trying treatments for which there is no evidence and little biological plausibility, and that’s worrying.”

The BMJ, for instance, has exposed how patients with long covid are travelling long distances for expensive and ineffective “blood washing.”5

What drugs will there be for covid-19 prophylaxis?

The best treatments for prophylaxis are still being determined. Several studies have shown potential for current treatments in prophylaxis, including antivirals, but the only clarity so far is on what hasn’t worked.

In March 2023 WHO published the second version of its living guideline on drugs for preventing covid-19.6 It looked at 12 trials (9217 participants) comparing hydroxychloroquine with standard care/placebo, one trial (481 participants) comparing hydroxychloroquine with active interventions, and one trial (5197 participants) evaluating tixagevimab-cilgavimab, also known as Evusheld, compared with standard care/placebo. The conclusion was that hydroxychloroquine did not work for prophylaxis against covid, and the authors also advised against using tixagevimab-cilgavimab in individuals who don’t have covid-19.

Prophylaxis is the “next frontier” for treatments, says Butler. “The media love stories about bringing people back from a very grave situation, but in terms of impact and reach it’s critically important to prevent people from getting into hospital in the first place. That’s the biggest challenge.”

Griffin concludes that, without prophylaxis, we are “leaving those most vulnerable to infection high and dry, given the unmitigated prevalence and multiple waves we are experiencing at present.”

Do you have a “Covid Unanswered Question”? Email mlooi{at}bmj.com, and we’ll try to cover it in a future instalment.

This article is made freely available for personal use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://bmj.com/coronavirus/usage

References

  1. Suribhatla R, Starkey T, Ionescu M, Pagliuca A, Richter A, Lee L. Systematic review of the clinical effectiveness of tixagevimab/cilgavimab for prophylaxis of covid-19 in immunocompromised patients. MedRxiv [preprint] 2022:11.07.22281786. doi:10.1101/2022.11.07.22281786.



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