As the number of cases of COVID-19 continues to mount, so do entries at clinicaltrials.gov for potential treatments, reaching into the existing pharmacopeia for repurposing candidates.
Clinical trials for COVID-19 treatments range from 10 people to nearly 600, and most are happening in China. But a caveat: ClinicalTrials.gov is a clearinghouse of proposals, not requiring approval. The entries are from all over the world.
Normally – and these are far from normal times – a clinical trial is optimally designed to assess the safety and efficacy of a new treatment on two groups of people, one taking the drug, the other a placebo. Or, in a crossover design, participants take courses of both treatment and placebo at different times but don’t know which is when.
The standard, scientific approach to evaluating drugs takes time. Lots of it. And right now, people are hesitant to sign up for a clinical trial knowing that they face a 50:50 chance of being assigned to a placebo group.
The world can’t wait for clinical trial results, and so information is getting out in other ways. Although the medical and scientific journals have been terrific at getting new information out ASAP, social media has at the same time provided a conduit for what may become a tidal wave of misinformation. Just yesterday, for example, a meme circulated claiming that a gargle with salt water and vinegar would simply wash away the hardy SARS-CoV-2 coronavirus.
Dr. Anthony Fauci weighs in on treatments using existing drugs
When Dr. Fauci, director of the National Institute of Allergy and Infectious Disease and unofficial guru of the pandemic in the US, spoke to the media via webinar on March 18 about the challenges of finding treatments, he began with a warning for people not to resort to do-it-yourself remedies, especially repurposing drugs on their own. He used the anti-malarial drug chloroquin as an example because several clinical trials are evaluating it. “I think so much is out there on social media and in medical letters and reports that are not reviewed that people are going to start using it anyhow. Hopefully a program will make it accessible at the same time that it is being studied.”
Misinformation propagates about more commonly used drugs too. Consider ibuprofen.
Dr. Fauci and others say there isn’t definitive data on the value or danger of ibuprofen, yet it made headlines despite the uncertainty. “I suspect there was discussion off-the-cuff that turned into letters that turned into social media and there is no idea where the information comes from,” he said. Dr. Fauci suspects that people were thinking about the link between influenza and taking aspirin causing the neurological Reye’s syndrome in kids, and someone somehow made the leap to NSAIDs like ibuprofen. “To bring down temperature, use Tylenol,” he advises until firm data point one way or the other.
A possible role of ACE inhibitors is especially confusing. These widely-used hypertension drugs block receptors on lung cells that are similar to the receptors where SARS-CoV-2 binds and enters. Do they help, serving as decoys for the virus? Dr. Fauci said that it could be just the opposite, pointing to data from Italy. There, he noted, 99% of people who died from the virus had an underlying condition, and 75% of them had hypertension.
“Putting the dots together,” Dr. Fauci said, given the high quality of health care in Italy, “why should someone who has hypertension well controlled have a much greater chance of dying than someone with any other type of underlying condition?” He ventures an hypothesis: perhaps ACE inhibitors boost the number of receptors for the virus. Ongoing natural history studies from Italy will help to figure this out, he added. Meanwhile, people with hypertension should ask their cardiologists for advice.
Perusing ClinicalTrials.gov
For a snapshot of efforts to find pre-existing approaches for COVID-19, I went through all 100+ entries and grouped the treatments. Most are festooned with a blue rectangle around the word “NEW.” The proposals were obviously filed quickly, because most of them haven’t filled in the field for rationale. So I’ve guessed on the logic for a few.
I’ve roughly organized the entries by technology: Chinese herbs, recombinant DNA, monoclonal antibodies, nucleotide/side inhibitors, immune modulators, and several interesting others.
Chinese herbs
Huaier granule is an elixir from a mushroom, Trametes robiniophila murr, that grows on hardwood tree trunks. It purportedly stops cancer cells and blood vessel lining cells from dividing, and has been part of Chinese medicine for 1600 years. The clinical trial, set to end in September, has enrolled 550 people diagnosed with mild COVID-19 and otherwise healthy. They’ll take a granular preparation by mouth 3 times a day for 2 weeks. The trial is randomized and the researchers will assess mortality.
Tetrandrine is an alkaloid isolated from the root of Stephania tetrandra, a vine that grows in China and Taiwan. It treats silicosis, autoimmune disorders, inflammatory lung diseases, cardiovascular diseases, hypertension, and cancer. For COVID-19, tetrandrine decreases proliferation of fibroblasts, which might alleviate or slow lung damage (fibrosis). It’s given in tablets.
Recombinant DNA
The first modern biotechnology, recombinant DNA isolates and mass-produces the gene encoding a human protein in single cells growing in culture, such as bacterial cells or white blood cells. The first recombinant drug was human insulin. Herbert Boyer and Stanley Cohen pioneered the technology in 1973, and today it is the source of several dozen drugs.
Recombinant interferon is a candidate in several clinical trials for COVID-19. It is a type of immune system biochemical called a cytokine that takes part in cell-to-cell signaling. Interferon puts the brakes on other coronaviruses growing in cell culture.
Another recombinant DNA strategy was to supply copies of the receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (rhACE2), but a ClinicalTrials.gov listing was taken down a few days ago. So stay tuned.
Monoclonal antibodies
The generic name for a drug derived using monoclonal antibody technology ends in “mab.”
A “MAb” is a single antibody type that targets a specific molecule on a pathogen or cancer cell’s surface, possibly shuttling in a toxin to kill it. MAb technology debuted in 1975, invented by Georges J.F. Köhler and César Milstein. A few existing MAb-base drugs are being tried against the novel coronavirus:
- Actemra (tocilizumab) dampens the immune response in people with rheumatoid arthritis. Will it help to quell the out-of-control outpouring of immune system biochemicals, called a “cytokine storm,” that ends most battles against COVID-19?
- Soliris (Eculizumab) controls the immune response in two rare conditions. It lowers outpouring of complement, another class of immune system biochemical that promotes inflammation.
- Bevacizumab is a cancer drug that inhibits blood vessel extension (an angiogenesis inhibitor). It’s being tested to see if it has an effect on shortness of breath (dyspnea), severe pneumonia, and pulmonary lesions in COVID-19.
Antivirals
A drug that ends in “vir” is a nucleotide or nucleoside analog, which means that it mimics a DNA or RNA “letter” and interferes with viral replication. (A nucleotide is a base, sugar, and phosphate; a nucleoside is just a base and a sugar.) A few existing antivirals, some on the market for other indications, one in development, have emerged as COVID-19 candidates:
- Lopinavir/Ritonavir treat HIV infection. But a study from China published in yesterday’s New England Journal of Medicine that treated 99 patients with 100 controls found “no benefit.”
- Remdesivir treats Ebola and Marburg hemorrhagic fevers.
- Favipiravir, aka Avigan and T-705, has been in development at Fujifilm Toyama Chemical in Japan since 2014 to treat several RNA viruses, including influenza. Tested on 340 COVID-19 non-severe patients, half receiving the drug and half not, favipiravir shortened the time for viral clearance from 11 days to 4, and improved lung function in 91% of participants compared to 62% not given the drug.
Stem cells
Several clinical trials are testing mesenchymal stem cells, which are multi-potential and multi-purpose. They usually come from bone marrow, but one trial is getting them from dental pulp and two others from umbilical cord blood. The stem cells are being sent in to coronavirus-ravaged lungs to try to heal damage.
Immunomodulators
The role of the immune defense in COVID-19 is a complex, ever-changing matter of balance. Immunosuppressed individuals are at elevated risk of infection, yet people who die from it often undergo cytokine storms, succumbing to an overzealous immune response that can rapidly lead to sepsis.
Existing drugs that alter immune function in clinical trials include the multiple sclerosis drug Fingolimod to tackle COVID-19 pneumonia and PD-1 blockers used to treat cancer to treat cytokine storms.
Traditional infection treatments
Corticosteroids (methylprednisolone in particular) are being tested to treat COVID-19 pneumonia, as well as vitamin C infusions to quell inflammation and cytokine storms, which it has done in severe influenza. One trial is looking at the tuberculosis drug carrimycin and several at chloroquin.
Drug combos
One clinical trial is comparing four drugs:
- Bromhexine hydrochloride, the main ingredient in Robitussin
- Arbidol, an influenza drug
- Recombinant human interferon in a nasal spray
- Favipiravir tablets
Another clinical trial, in Thailand, is testing “various combinations of” two anti-virals, the malaria treatment chloroquin, and a protease inhibitor.
Interesting others
Viagra (sildenafil) is being tested on 10 people of both sexes for likelihood of remission or progression. The drug’s ability to dilate blood vessels may help fight lung inflammation in COVID-19.
Thalidomide is famous for stunting limbs in children of women who took it during pregnancy in the 1960s, to combat morning sickness. It has been redeemed as a treatment for multiple myeloma and interstitial pulmonary fibrosis, as an antidote for poisoning with the herbicide paraquat, and in treating the 2009 H1N1 influenza.
Thalidomide has anti-inflammatory, anti-fibrotic, anti-angiogenesis, and immune regulation effects, and in COVID-19, may help to control lung inflammation and slow or halt lung damage. In the new clinical trials, researchers are tracking fever, respiratory rate, oxygen saturation, alleviation of cough, and duration of illness.
“Washed” fecal transplant is being tested to treat diarrhea from antibiotics used to treat secondary bacterial infections.
Nitric oxide gas is in a clinical trial on 240 people with COVID-19. In the SARS and MERS epidemics, it shortened time on ventilators.
And finally, antibodies from survivors might provide protection. Next I’ll tackle vaccines.
A version of this article originally appeared at PLOS and has been republished here with permission.
Ricki Lewis is the GLP’s senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis
