Off-Label: Can Drugs Developed For Other Diseases Treat COVID-19?

woman with mask off, in sun

Do we already have a treatment for coronavirus (COVID-19)? Was President Trump right about chloroquine or was remdesivir more promising for coronavirus? With such an urgent need for treatments, researchers and the biopharmaceutical industry have been working to determine if currently available medications can treat COVID-19. Treatment has improved during that time, but randomized clinical trials of various interventions remain a challenge. Still, researchers have banded together the data they can collect, and one group has created a registry of more than 350 drugs being tested to treat the disease or its symptoms. Additionally, on March 15, 2021, the FDA launched FAERS (FDA Adverse Event Reporting System) public dashboard. There, patients, healthcare providers, and manufacturers can report and review adverse events associated with drugs and therapies that have received Emergence Use Authorizations for COVID-19. Vaccines are not included; adverse reactions to vaccines are reported through the Vaccine Adverse Event Reporting System (VAERS.)

Here are the highlights of what researchers have found so far.

A Two-Pronged Approach

One approach to treat COVID-19-related illness is to find medications that slow down — or even stop — the virus’s ability to reproduce. This could shorten the length of illness and prevent it from becoming severe or critical.

Researchers are also investigating drugs that reduce the body’s immune response in the critical stages of illness. An overzealous immune response can cause inflammation that damages cells and organs throughout the body.

It’s important to note that there isn’t enough scientific evidence about the safety or effectiveness of most of these drugs for them to have been approved by the U.S. Food & Drug Administration (FDA) to treat COVID-19. Larry Sasich, PharmD, MPH, a consultant for the FDA and the Saudi Arabian Food and Drug Authority, and co-author of Worst Pills, Best Pills, also pointed out that for the most part, we only really know about side effects in patients who don’t have COVID-19.

It’s important to talk to your doctor about any medication that you’re considering using for COVID-19. Not only is there the possibility for dangerous side effects, but there are also potential drug interactions to consider, so you should have medical supervision.

Potentially Promising Treatments

Here’s a look at some of the drugs scientists are researching to see if they could be effective in treating COVID-19-related illness.

IL-6 Receptor Inhibitors

IL-6 (interlueukin-6) receptor inhibitors tocilizumab and sarilumab are both injections and “they are quite potent in reducing inflammation,” said Hana Akselrod, MD, an assistant professor of medicine in the infectious diseases division at the George Washington University School of Medicine and Health Sciences in March 2020.

Tocilizumab

What it’s currently used for: Tocilizumab (Actemra/RoActemra) is FDA-approved to treat active rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis, and cytokine release syndrome. It works by decreasing the overactive inflammatory response found in these conditions.

Clinical trials: Researchers have conducted several trials yielding mixed results. The NIH recommended against their use this summer. However, a new study posted on a preprint server suggested that the both tocilizumab and sarilumab may reduce the mortality rate of patients in the intensive care unit from 36% to 27%. Scientists note that the main difference between this and previous studies is that the current study was conducted only in critically ill patients.

In the study, patients received the drugs within 24 hours of entering the ICU. While the study hasn’t yet been peer-reviewed, U.K. regulators found the evidence compelling enough to authorize the drugs for critically ill patients.

Known serious side effects: Tocilizumab has multiple potential side effects, the most serious of which is a black box warning. “A boxed warning is the most serious warning that the FDA can require in the professional product label for a drug,” said Sasich. “Usually it involves deaths in human beings.” In this case, the boxed warning is for an increased risk of developing serious infections that can lead to hospitalization or death.

Other severe adverse reactions include tears in the stomach or intestines, liver issues, low platelet count, higher blood cholesterol levels, low neutrophil (white blood cell) count, allergic reactions, and an increased risk of cancer.

Sarilumab

What it’s currently used for: Sarilumab (Kevzara) is FDA-approved to treat active rheumatoid arthritis (RA), particularly in people who haven’t responded to other medications for RA or who can’t use other types of medication.

Clinical trials: Researchers have conducted several trials yielding mixed results. The NIH recommended against their use this summer. However, a new study posted on a preprint server suggested that the both tocilizumab and sarilumab may reduce the mortality rate of patients in the intensive care unit from 36% to 27%. Scientists note that the main difference between this and previous studies is that the current study was conducted only in critically ill patients.

In the study, patients received the drugs within 24 hours of entering the ICU. While the study hasn’t yet been peer-reviewed, U.K. regulators found the evidence compelling enough to authorize the drugs for critically ill patients.

Known serious side effects: Sarilumab, too, has a black box warning about an increased risk of developing serious infections that can lead to hospitalization or death. It also has the same potential serious adverse reactions as tocilizumab, including tears in the stomach or intestines, liver issues, low platelet count, higher blood cholesterol levels, low neutrophil (white blood cell) count, allergic reactions, and an increased risk of cancer.

How IL-6 inhibitors could help COVID-19 patients: The theory is that these medications “try to block parts of that severe immunologic inflammatory cascade in order to reduce the severity of the pneumonia that happens after the virus (COVID-19) has already caused the infection,” said Akselrod.

“There do appear to be some data that suggest that (Il-6 inhibitors) might be effective as adjuncts to treatment in patients with severe COVID-19 pneumonia, reducing some of the inflammation and some of the other complicating factors, hopefully, to improve oxygenation,” said Michael Klepser, PharmD, FCCP, a professor at Ferris State University’s College of Pharmacy, in March.“They’re not going to necessarily cure the virus, but they may help patients improve clinically.”

Potential risks for COVID-19 patients:

“The trick is to figure out if IL-6 inhibitors can be used safely to tone down the damaging parts of the immune response without shutting down the parts of the response that are needed to fight infection,” said Akselrod.

The infection risk also means that “these are probably not going to be what you see used in the majority of patients, but maybe in the sickest of the sick,” noted Klepser. He also points out that these drugs are quite expensive, though he acknowledges that “at this point in time, I’m not sure that cost is really that big of a consideration.”

Antiviral Drugs

Remdesivir

Remdesivir was originally formulated to fight Ebola. However, it was found to be basically ineffective against the Ebola virus during the 2019 outbreak in the Democratic Republic of the Congo.

What it’s currently used for: Remdesivir works by inhibiting a virus’s ability to replicate, but it isn’t approved to treat any type of condition or disease.

Clinical trials: Remdesivir was the first (and only) drug fully approved by the FDA to treat COVID-19 in October 2020, though it had received emergency use authorization before that in May. It was one of the drugs used to treat Donald Trump when he contracted the illness. Trials showed that the drug shortened recovery times from 15 days to 10 days for certain hospitalized patients and that the drug was most effective in those who were receiving oxygen but were not ventilated.

Known serious side effects: Not a lot of information is available for this drug because it wasn’t previously approved. “One concerning bit about it is it does have a solubilizing agent in it called sulfobutylether-beta-cyclodextrin (SBECD),” said Klepser. “We’ve seen that solubilizer used with other medications and sometimes in patients with renal dysfunction, it can cause some problems because (the SBECD) can accumulate and cause kidney damage. That would be the major thing to keep an eye on.”

Remdesivir’s manufacturer lists allergic reactions, nausea, and liver damage as possible side effects, but it’s noted that there may be more we don’t yet know about.

How it could help COVID-19 patients: In 2017, researchers found that remdesivir was effective against many different coronaviruses — including the ones that cause severe acute respiratory syndrome (SARS) — in both a mouse and in cell cultures.

“The idea is treating with remdesivir would prevent the viral infection from becoming established and would also shorten its duration once it’s already happening,” said Akselrod.

Potential risks for COVID-19 patients: “There are questions of what (remdesivir’s) potential toxicities and side effects will be, how it’s metabolized, what’s the correct dose to give, and when in the course of illness it would be most effective. And would it possibly interact with other drugs that the person is receiving?” Akselrod said.

Ritonavir and Lopinavir

Ritonavir and lopinavir are antivirals used in a combination drug called Kaletra.

What it’s currently used for: Kaletra is FDA-approved to treat human immunodeficiency virus (HIV). This medication blocks the virus’s ability to copy its genetic material, said Akselrod. “This is a medication we’ve been using for many, many, many years to treat HIV and it’s a potent and effective antiviral, but for a virus that’s not in the same family as COVID-19,” she said.

Clinical trials: Unfortunately, trials have not demonstrated that the drug helps patients with COVID-19.

Known serious side effects: There are a number of other medications that shouldn’t be taken with Kaletra because of the risk for serious drug interactions. Kaletra can also lead to pancreatitis, liver damage, heart rhythm abnormalities, increased cholesterol levels, and new or worsened diabetes.

Anti-Parasitic Drugs

Chloroquine and Hydroxychloroquine

What they’re currently used for: Chloroquine & Hydroxychloroquine medications are both approved by the FDA to treat and prevent malaria. “Remember that malaria is not a virus or a bacterium, it’s a parasite,” said Sasich. Because parasites have cells that are similar to human cells, a drug that’s used to treat a parasitic infection like malaria may cause more serious adverse effects, he says.

Chloroquine is also approved to treat amebiasis, a gastrointestinal infection caused by an amoeba. Hydroxychloroquine is approved for systemic lupus erythematosus and rheumatoid arthritis in patients whose symptoms haven’t improved with other medications.

Clinical trials: On March 30, 2020 the FDA granted chloroquine and hydroxychloroquine emergency use authorization for the treatment of COVID-19. While clinical trial were still ongoing, the approval was made so that the government could add it to the Strategic National Stockpile and it would be available for hospitals to request and to supply for clinical trials. However, in June, after the trials ended and demonstrated that drug did not benefit patients with COVID-19, the authorization was revoked.

In a November 2020 study in the New England Journal of Medicine, scientists reported that the drug also does not prevent COVID-19 when taken after close contact with an infected person.

Known serious side effects: Chloroquine’s potential adverse effects include cardiomyopathy (heart muscle disease) that can result in heart failure, heart rhythm abnormalities, severe hypoglycemia (low blood sugar), permanent eye damage, muscle weakness, and many adverse effects on the central nervous system. Using chloroquine with certain other medications can lead to serious drug interactions. Other side effects have been reported since this medication was approved too.

Hydroxychloroquine has a risk of similar serious side effects such as permanent eye damage, cardiac effects like cardiomyopathy with a risk for heart failure and heart rhythm abnormalities, severe hypoglycemia, and muscle atrophy. It can also cause suicidal behavior. Other serious effects have been reported since this medication was approved as well, including disorders of the blood, heart, ear, eye, immune system, metabolism, and skin.

How antimalarials were thought to help COVID-19 patients: Akselrod said the theory was “essentially (that) those drugs would make the cell less hospitable to the virus by interfering with some of the mechanisms that are involved in both the virus entering the cell and then possibly with the inflammation that occurs around the infection.”

Like remdesivir, chloroquine and hydroxychloroquine have been found to be effective against coronaviruses in cell cultures, including ones that cause SARS.

Potential risks for COVID-19 patients: Not everyone can take these drugs, Akselrod said. “Chloroquine and hydroxychloroquine can cause quite severe poisoning and even fatalities if they’re not taken under the supervision of a doctor or if they’ve taken in the wrong dose or if they’re taken by someone with a heart condition that’s predisposed to an irregular rhythm. These drugs can cause an unstable heart rhythm, which can cause the heart to stop, which is why it’s so concerning that right now there seems to be a worldwide rush on these drugs.”

“The major concerns with these medications are their toxicities and that when they’re used, some patients experience very severe side effects, including cardiovascular conduction abnormalities and agranulocytosis, which is kind of like wiping out your immune system” Klepser said.

People who hoarded these drugs or took them unsupervised became a problem too, said Akselrod. “This is in the context of an unprecedented global emergency and it’s quite understandable if people are scared and trying to reach for anything that’s available that we think might help. But people who depend on these drugs to control their lupus or rheumatoid arthritis find themselves unable to refill their prescriptions. They’re at risk of having their disease flare up and force them to go to the hospital at a time when it’s very unsafe for them to be doing that and when they should be isolating at home and trying to avoid infection at all costs.”

Ivermectin

What it’s currently used for: Ivermectin is used to treat parasitic worms. It comes as pills or as topical creams to treat headlice and other skin conditions. One formulation is commonly used in dogs to prevent heartworm. The FDA has warned consumers not to self-treat with ivermectin, especially with formulations meant for animals.

Clinical trials: In June 2020, researchers published a study showing that the drug could prevent the virus that causes COVID-19 from replicating in petri dishes. If it worked the same way in humans, this would be likely to significantly reduce symptom severity. Some doctors started prescribing it to COVID-19 patients, especially in Latin America, but the NIH said there was is not enough evidence to recommend for or against its use. The group also noted that in order to be effective, it may be required to use incredibly high doses (up to 100 times the usual anti-parasitic dose) which would create new safety concerns. Several clinical trials have tested the drug in COVID-19 patients, but results have been inconsistent.

Known serious side effects: It can cause headaches, dizziness, muscle pain, rapid heart rate, chest discomfort, shaking, nausea and diarrhea. Rarely, patients can have severe allergic reactions.

Convalescent Plasma

What it’s currently used for: In August, the FDA announced an emergency use authorization for convalescent plasma. It’s thought that since the blood of patients who have recovered from COVID-19 should be filled with antibodies, giving a portion of it to current patients should help them recover. It’s the same idea behind the monoclonal antibodies, which are mixtures of antibodies made in a lab rather than taken from a recovered person’s blood.

“This approach predates a lot of the current science on vaccines in immunology and the antibody response,” Akselrod said. “For more than 100 years people have tried this approach in trying to use the blood of people recovered from an infectious disease to cure those still suffering from it. The promise is that there is historic experience with it. The downside is, of course, we don’t know how effective it will be for this virus, in part because there might be slight variations in the virus that circulates across the big population. Viruses do mutate and change their surface appearance in ways that try to evade the immune system.”

Clinical Trials: Studies have been mixed. In October, the NIH wrote that there was insufficient evidence to recommend the use of convalescent plasma. However, a study published on January 6, 2021 in the New England Journal of Medicine showed that the treatment can reduce the risk of severe illness when given to older patients within 72 hours of COVID-19 symptoms starting.

Potential risks for COVID-19 patients: “I think the major limitation of using immunoglobulin from recovered patients is that the supply is not going to be very high,” said Akselrod. “Transfusion reactions are possible with any blood product because you’re giving someone else’s biological product. The recipient’s immune system might not like it and they might have a severe reaction to the transfusion, which is why it has to occur under supervision. The limitation will be both in the supply and in the distribution, administration, and safety.”


Sarah Ludwig Rausch

Sarah Ludwig Rausch

Sarah Ludwig Rausch is a freelance writer and copyeditor based in South Dakota. Find her at BlueZebraMedia.com.


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