The Pitfalls and Promise of Using Repurposed Drugs for COVID-19

Even amid the expanding use of COVID-19 vaccines, clinicians can expect a steady stream of news in the months ahead about efforts to repurpose approved drugs as treatments for SARS-CoV-2 infections.

But experts who spoke to Medscape Medical News caution that physicians and patients facing a deluge of treatment information should try to adhere to guidelines and good advice while avoiding the temptation of quick fixes, often fueled by misinformation.

Studies are underway around the world to test whether approved drugs, including statins, antivirals, and rheumatoid arthritis medications might help people with SARS-CoV-2 infection, as shown by listings on the National Institutes of Health’s ClinicalTrials.gov website.

The projects range in scale from small studies centered around a single medicine or even a single hospital to wide-scale and multidrug trials such as the UK’s Randomised Evaluation of COVID-19 Therapy (RECOVERY) program and the Solidarity program launched by the World Health Organization.

Among the most closely watched efforts is a program within the NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV).

The NIH in April said the ACTIV-6 component will study a pool of up to seven drugs approved by the US Food and Drug Administration (FDA) as potential treatments for mild to moderate COVID-19. Drugs to be tested in ACTIV-6 will be ones that study participants can easily take at home, such as pills or medicines given by inhaler.

This study intends to enroll up to 13,500 participants who are at least 30 years old, have tested positive for SARS-CoV-2 infection and have experienced two or more mild-to-moderate symptoms of COVID-19 for no more than 7 days, the NIH said in the April announcement.

An NIH spokesperson told Medscape Medical News the first drugs selected for this test are likely to be announced next month.

David Fajgenbaum, MD, MBA, MSc, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, told Medscape Medical News that he was among those who advised on the selection for ACTIV-6. Although he doesn’t know which drugs were chosen, he said he hopes the antidepressant fluvoxamine, the antiparasitic drug ivermectin, and inhaled budesonide will be included.

ACTIV-6 will be done on a scale that should allow it to answer questions about whether these medicines work for COVID patients, Fajgenbaum said.

“When you do a large study on a few drugs, you can really feel confident in the results,” said Fajgenbaum, who is the project director and lead investigator for the COvid19 Registry of Off-label & New Agents (CORONA) project.

He was among the first researchers to try to capture a broad view of the rapid and varied global attempts to reposition existing medicines to treat COVID-19. In May 2020, just months into the pandemic, he and his co-authors published a paper, “Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review” in the journal Infectious Diseases and Therapy.

Finding a new use for an existing drug was already an expert skill for Fajgenbaum, who has a rare disorder of the lymph nodes called Castleman disease. In his 2019 book, “Chasing My Cure,” Fajgenbaum details how he discovered that the drug sirolimus (Rapamune), used to prevent rejection of kidney transplant, kept his life-threatening disease at bay.

The nature of COVID-19 complicates efforts to prove medicines are effective, as opposed to testing in a disease that more often proves fatal such as Castleman disease, Fajgenbaum said. As most people will recover from a COVID-19 infection, larger studies are needed to spot the difference.

“It’s really hard to do a clinical trial and to show that your treatment works right if most people are getting better without that treatment,” he said.

The race to find treatments for COVID-19 led to initial missteps, Janet Woodcock, MD, the acting director of the FDA, said during a March webinar hosted by the American Medical Association.

It usually takes 18 months or longer to get a major study of a medicine organized and running, a timeline compressed during the pandemic. That made it difficult to decipher the effects of approved drugs on COVID-19, a condition that led to varied courses of illness in patients. And some studies were too small to truly gauge the value of approved drugs in this disease.

“The heterogeneous outcomes of this disease were really challenging,” Woodcock said. “This led to underpowered studies and false conclusions from either observational trials or case series for these small studies,”

“The field was led astray, or misled I think, by conclusions from studies that just weren’t capable of giving answers in this disease,” she added.

“Infodemic of Misinformation”

Even with improvements in the quality of studies, questions remain about many drugs for which their supporters have had high hopes, particularly ivermectin.

The NIH’s treatment guidelines for COVID-19 says there is insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19.

“Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19,” NIH’s guideline says.

The guideline from the Infectious Diseases Society of America (IDSA) for treatment of COVID-19 suggests against ivermectin for the treatment of hospitalized patients and those being seen outside of hospitals, unless the drug is given in the context of a clinical trial. Like the writers of the NIH guidelines, the IDSA’s experts also saw a need for further study.

“Well-designed, adequately powered, and well-executed clinical trials are needed to inform decisions on treating COVID-19 with ivermectin,” IDSA says in its guidelines.

Ivermectin has been used broadly in some places around the world, including India. Use of this drug in Brazil was among the concerns raised by the nonprofit Doctors Without Borders (Médecins Sans Frontières) in an April statement.

“Fuelling sickness and death in Brazil is the overwhelming amount of disinformation circulating in communities across the country,” Doctors Without Borders said, noting a lack of mask use and physical distancing. “In addition, hydroxychloroquine (an anti-malarial medication) and ivermectin (an anti-parasitic drug) are touted by politicians as the panacea to the COVID-19 pandemic and prescribed by doctors as both COVID-19 prophylaxis and treatment.”

US health officials have warned about the risks of off-label use of ivermectin. In March, the FDA said there had been multiple cases of patients who have required medical support and hospitalization after self-medicating with ivermectin intended for horses.

The agency noted that some research is underway to see if ivermectin might aid in COVID-19, with such studies also likely to identify how the drug should be administered if proven successful. But the FDA urged people not to buy into false reports about a proven benefit.

“There’s a lot of misinformation around, and you may have heard that it’s okay to take large doses of ivermectin,” FDA said on its website. “That is wrong.”

Still, there remain adamant US backers of ivermectin, such as the controversial Front Line COVID-19 Critical Care Alliance. The current adamant support for ivermectin in some circles stems from heavy reliance on observational studies that are prone to bias and confounding, Adarsh Bhimraj, MD, of the Cleveland Clinic, told Medscape Medical News.

“Unfortunately people are not looking at data rigorously,” said Bhimraj, who is the lead author for the IDSA’s guidelines for treatment and management of patients with COVID-19.

Widespread use of ivermectin may complicate efforts to truly answer the question of how well it works, Bhimraj said. The drug is used so often in Latin America, for example, that it might be difficult to recruit patients for clinical trials. He compared this to the experience with hydroxychloroquine where observational studies suggested a benefit, but failed to be proved in a large randomized clinical trial.

The pace of research on COVID-19 has accelerated beyond what could have been imagined before the pandemic, along with faster dissemination of even the earliest findings. These factors contribute to what Bhimraj described as an “infodemic of misinformation” about which existing drugs might work against COVID-19.

“You Google and everybody’s got an opinion,” he said. “A lot of the reasoning is very mechanistic, based on what’s happened in the petri dish.”

Rapid Pace of Research

There’s been a near continual release of findings from studies of repurposed drugs, particularly through the medRxiv preprint server. It’s serving as something akin to a hotline for new research on COVID-19 that has not yet undergone peer review.

Consider some of the medRxiv postings seen in just the week of May 17 that focused on use of approved drugs as potential COVID-19 treatments:

• A retrospective analysis suggesting that metformin use by diabetics before hospitalization may confer increased survival in patients if they develop severe COVID-19.
• A posting reported on positive findings from an Egyptian trial of 250 patients who had moderate COVID-19 infections and were treated with the antiviral sofosbuvir/ledipasvir.

Also posted that week on medRxiv was a systematic review and meta-analysis of randomized controlled trials that concluded ivermectin was not a viable option to treat people with COVID-19, and it only should be used within clinical trials.

On May 18 alone, medRxiv posted a paper showing disappointing results for the inexpensive gout drug colchicine and another one with bullish findings for the rheumatoid arthritis drug anakinra.

Researchers had eyed colchicine as a potential COVID treatment due to its effect on an inflammatory pathway also linked to more severe cases of SARS-CoV-2, wrote University of Oxford scientists Martin Landray, MB ChB, PhD, and Peter Hornby, MD, PhD, in their paper.

But in a randomized trial involving over 11,000 patients from three countries and over 2000 deaths, allocation to colchicine was not associated with reductions in mortality, duration of hospitalization or the risk of being ventilated or dying for those not on ventilation at baseline.

Research done in Greece and Italy suggested that better screening of patients for use of anakinra may make a difference in COVID-19.

Evangelos J. Giamarellos-Bourboulis, MD, PhD, the coordinator of the Hellenic Sepsis Study Group, told Medscape Medical News promising results from a large trial he recently led indicate a more targeted approach to care could help with treating COVID-19.

He and his team used elevated readings of soluble urokinase plasminogen activator receptor (suPAR) as a sign that the patients’ course of disease might be tamped down by the immunomodulator anakinra, which is approved for use in rheumatoid arthritis.

In this trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and a plasma suPAR reading of 6 ng/ml or more who were receiving standard-of-care treatment were randomly assigned to either placebo or 100 mg anakinra once daily for 10 days. Of 189 patients in the placebo group, 50 (26.5%) were considered to have fully recovered, as opposed to 204 of the 405 in the anakinra group (50.4%).

Giamarellos-Bourboulis likened the approach used in this trial to acting early to prevent a forest fire from spreading.

“If you manage to stop the fire before the fire expands and burns all the trees, then you save the forest,” he said. “So imagine that the biomarker is the alarm sign telling [us] that the fire has started.”

“Less Is More Sometimes”

Guidelines such as the ones maintained by IDSA and NIH are critical for clinicians trying to keep up during the pandemic.

Most health systems have their own internal documents about COVID-19 protocols for repurposing drugs, which are aligned with guidelines from federal agencies, said Ebrahim Barkoudah, MD, MPH, associate director in the hospital medicine unit at Brigham and Women’s Hospital, Boston, Massachusetts. Barkoudah offered Medscape his views in an email exchange arranged by the Society of Hospital Medicine.

“Whereas the media outlets and various sources could amplify the findings and messages from clinical studies, we should follow clear evidence-based practices in our treatment protocol, specifically National Institute of Health guidance documents and internal” protocols, such as the one used at the Brigham and Women’s Hospital, he said.

The Cleveland Clinic’s Bhimraj also urged clinicians to look to guidelines as a tool to manage during a time of rapid information flow.

“There’s no way an individual provider has the time or resources to go back and look at each treatment and critically appraise them,” he said. “But the guidelines do that for them.”

Bhimraj said he was sympathetic with clinicians’ eagerness to find medications for patients infected with SARS-Cov-2. But he emphasized a need to stick with what’s been shown to be effective.

“Sometimes doing what we know works and not doing a lot of things is okay,” Bhimraj said. “We have to reiterate that less is more sometimes. More drugs don’t necessarily translate into better care.”

https://www.medscape.com/viewarticle/952037?src=soc_fb_210601_mscpedt_news_mdscp_covidtherapeutics&faf=1#vp_1

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Créditos: Comité científico Covid