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As the pandemic wears on, with new concerns and uncertainty around the Omicron variant, attention toward therapeutics is intensifying — particularly oral medications that could be offered readily to outpatients to keep their disease from worsening.
“An effective oral agent has been a holy grail,” Acting FDA Commissioner Janet Woodcock, MD, told Medscape Medical News. Monoclonal antibodies work, but “you need more fuss and bother to get set up to have an infusion. Oral drugs would obviously be much more accessible.”
Many patients are “very scared,” said emergency medicine physician Barbara Kilian, MD, who serves as medical director for CityHealth, a San Francisco Bay Area company that offers COVID-19 testing and urgent care services. “I can’t tell you how much I want there to be an easy medication out there that I could just start giving people.”
Experts are evaluating safety and efficacy data for three oral drugs: antiviral pills being developed by Merck (molnupiravir) and Pfizer (Paxlovid), and a decades-old generic drug (fluvoxamine) that typically treats obsessive-compulsive disorder and depression but has shown benefits in several published trials of COVID-19 outpatients — and costs under $10.
What helps determine whether these drugs enter clinical practice?
The fate of Merck’s drug remains uncertain amid muted support from a US Food and Drug Administration (FDA) advisory panel, which voted 13 to 10 last month to recommend the pill’s emergency use authorization (EUA).
This week Pfizer announced the full analysis of its antiviral pills, which the company says are still nearly 90% effective in preventing hospitalization and deaths in high-risk patients when taken for 5 days along with the older antiviral ritonavir. Based on earlier interim data for this drug combination, Paxlovid, the company filed an EUA application in mid-November and told CNBC recently that it would release the full results to the FDA “in the coming days.”
The FDA issues EUAs to authorize unapproved medical products or unapproved uses of approved products during a declared public health emergency. The EUA process is faster than a regular approval, and “depending on the situation, the evidentiary requirements might be different,” Woodcock said.
She did note that clinical and safety evaluation is more rigorous with EUAs for vaccines than for therapeutics, given that therapeutic drugs are generally prescribed to sick patients whereas vaccines are given to hundreds of millions of people who are healthy.
Compared to novel pharmaceuticals, off-patent drugs such as fluvoxamine face a much tougher path toward emergency use authorization. To study these drugs, “you have to get a placebo, an investigational drug supply, you need cooperative manufacturing,” said Woodcock. For a generic manufacturer, that’s a lot of time and effort without a big payoff.
“There’s less incentive, perversely,” she told Medscape Medical News. “And so the government often will have to do it.”
This April, more than a year into the pandemic, the National Institutes of Health (NIH) launched ACTIV-6 — a placebo-controlled, phase 3 study of repurposed drugs that it ships free of charge to COVID-19 outpatients nationwide.
With an initial NIH investment of $115 million provided through the American Rescue Plan Act, the trial is enrolling patients aged 30 years and older who have tested positive for COVID-19 and had at least two symptoms for less than a week.
ACTIV-6 uses a single master protocol to test multiple medications, as they become available, across multiple sites nationwide. Its adaptive design allows investigators to drop treatments for futility or add in new ones during the course of the study — similar to platform trials such as the United Kingdom’s RECOVERY, which showed that the common steroid dexamethasone could be repurposed to treat hospitalized COVID-19 patients.
The NIH trial is currently testing the controversial drug ivermectin, fluvoxamine, and the inhaled steroid fluticasone — up to 1200 participants per group — said principal investigator Susanna Naggie, MD, vice dean for clinical research at Duke University. “We had our first interim analysis already and expect multiple interim analyses in the first quarter of 2022.”
Several ACTIV-6 medications are also being evaluated, along with metformin, in a separate at-home clinical trial, COVID-OUT, coordinated by Carolyn Bramante, MD, MPH, and colleagues at the University of Minnesota in Minneapolis.
After an initial investment by the university and UnitedHealth, the study is funded primarily by philanthropy — totaling around $2 million from the Parsemus Foundation, the Rainwater Charitable Foundation, and FastGrants. People from 30 to 85 years old who just tested positive for COVID-19 and meet other criteria may be eligible, and participants who complete the study receive $400.
“OK, What Now?”
With data still to come from these ongoing studies, some fluvoxamine results have already been published — including a 2020 phase 2 study and the phase 3 TOGETHER trial, which enrolled nearly 1500 newly symptomatic COVID-19 patients in Brazil.
In the phase 3 platform study, published in October in The Lancet Global Health, a 10-day course of fluvoxamine cut hospitalizations by 66% and reduced deaths by 91% in high-risk COVID-19 outpatients who took most of their pills.
Accumulated evidence from these trials, along with preclinical and observational data, is compelling enough for some doctors to prescribe fluvoxamine off label — especially in the absence of other easy, accessible, authorized options in the outpatient setting.
Family medicine physician Brandon Shumway, MD, began seeing COVID-19 patients as soon as he started practice this summer at Central Valley Indian Health in Clovis, California. As the new doctor, he ended up seeing a lot of the walk-ins, and most had COVID-like symptoms.
After getting rapid testing in the parking lot behind the clinic, “a few were testing positive each day,” Shumway said. “Then the question is always, OK, what now?”
In residency, the standard of care was to “do nothing,” he told Medscape Medical News. “It was frustrating.” Shumway started researching treatment options to determine “what I would do if I was the one calling the shots,” he said. “And then suddenly I was.”
Through a physicians’ Facebook group, Shumway learned that the TOGETHER Trial stopped its fluvoxamine arm in August after preliminary results showed the drug worked better than placebo.
Reading more about this drug and learning it had been used safely since the 1980s, Shumway felt “it was at least something I could offer to patients” — particularly those who were not eligible for monoclonal antibody treatment or didn’t want the infusions. He explains the risks and benefits, “being clear up front that this is not something with an official recommendation by NIH or FDA,” and lets patients “decide if it’s something they want to try.”
Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston, Massachusetts, said in a December 16 tweet: “With nirmatrelvir (Paxlovid) and molnupiravir not yet available, and the most widely used monoclonal antibodies lacking activity against Omicron (+ other issues), is it time to bump up fluvoxamine at least to ‘consider use’ status on the treatment guidelines?”
With nirmatrelvir (Paxlovid) and molnupiravir not yet available, and the most widely used MAbs lacking activity against Omicron (+ other issues), is it time to bump up fluvoxamine at least to "consider use" status on the treatment guidelines? Two well-done RCTs show benefit. https://t.co/AWFxWmfS6a
— Paul Sax (@PaulSaxMD) December 16, 2021
The COVID-19 treatment guidance group at Johns Hopkins Medicine added fluvoxamine to its recommended treatments in November, stating the drug “may be considered for outpatient management of COVID-19 within 7 days of symptom onset when timely administration of monoclonal antibodies is not possible or is unlikely to occur.”
But often, guideline groups and large government organizations “prefer to wait — for more data, more advocacy, someone else to come on board,” said Jeff Klausner, MD, professor of preventive medicine at the University of Southern California. “When I was a health official in San Francisco, I learned that we never want to be the first [to make a recommendation]” because “if we’re wrong, we’re going to erode public trust.”
The Infectious Diseases Society of America guidelines recommend fluvoxamine to COVID-19 outpatients “only in the context of a clinical trial.” In a similar vein, the latest version of the NIH COVID-19 treatment guidelines, released December 16, states that the evidence to date is “insufficient” to recommend “either for or against” using fluvoxamine as an early COVID-19 treatment.
“That’s not a recommendation against,” said Cliff Lane, MD, a co-chair for the NIH guidelines panel, which sprang into action in March 2020 leveraging the infrastructure created in the 1990s to develop treatment guidelines for antiretroviral drugs during the HIV pandemic. “I think that ‘insufficient evidence’ provides that sort of flexibility for the treating clinician to go either way.”
For some physicians, though, the lack of consensus among COVID-19 treatment guideline groups can be unnerving.
While fluvoxamine is “a very safe drug” that has been used for decades treating mental health problems, “then you add in a crazy viral infection like COVID, which we still don’t completely understand,” and there could theoretically be “complications that you can’t anticipate,” Kilian said.
Plus, fluvoxamine doesn’t have an EUA — which matters in the US “because we live in a very litigious society,” she told Medscape.
“I don’t want to be the person who prescribes a medication that kills a loved one. But neither do I want to not give a medication that helps people,” Kilian said. Having guidelines that are supported by multiple organizations and endorsed in medical journals “certainly makes it easier for practitioners to feel comfortable adopting a new practice.”
Under the Public Readiness and Emergency Preparedness (PREP) Act, medical measures with an EUA “have liability protection if you stay within the authorized use and the conditions of use,” Woodcock said.
But she was quick to note that lack of EUAs hasn’t deterred physicians who are “still prescribing azithromycin, ivermectin, hydroxychloroquine, and corticosteroids to outpatients, along with zinc and a bunch of things” that are explicitly not recommended.
For effective drugs, even FDA authorizations and treatment guidelines don’t ensure timely access. Look at Tamiflu. That took years and years, and even now it’s probably not used as often as it should be, said Norman Hearst, MD, a family doctor at the University of California, San Francisco.
Given their narrow window of use, early COVID-19 treatments should be “directly integrated into the testing process, so that when someone calls with results, they’re doing follow-up and assessing whether they are candidates for treatment,” Hearst said.
David Boulware, MD, MPH, an infectious disease physician-researcher at the University of Minnesota, agrees. When he got results from a COVID-19 test he took in the United Kingdom, “the bottom of the email was like, if you want to participate in a clinical trial, go to this link — which is really slick,” he said. “Imagine if we could actually do this here” — providing treatment advice or referring people to studies “instead of, ‘hey, you’re positive, talk to your doctor.’ “
For their part, investigators on the philanthropy-funded COVID-OUT trial have contracted with several companies to couple positive COVID-19 test results with invitations to enroll, said Boulware, who is working with the COVID-OUT drug supplier, as well as TOGETHER Trial investigators and funders, to submit a fluvoxamine EUA application.
Woodcock agrees that connecting testing with treatments is key. Since outpatient drugs work best when given early and most people don’t get tested until they’ve developed symptoms, “the ideal is, OK, you get the test and you immediately start taking the pills. Certainly that’s been talked about for a long time, how that would be managed,” she said. “But our health system in this country is very fragmented, and that makes it difficult.”
Klausner is a paid medical consultant for Curative and CityHealth and has received financial support from Danaher, Roche, Cepheid, Abbott, Tailis Bio, Visby Medical, and Phase Scientific. Boulware, Hearst, Lane and Shumway report no relevant financial relationships.
Esther Landhuis is a freelance science journalist in the San Francisco Bay Area. She can be found on Twitter @elandhuis.
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