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(CNN) -
The practice of finding new uses for existing drugs, called drug repurposing or repositioning, is not new.
The most famous example is sildenafil, also known as viagra.
The little blue pill, which was originally developed to treat high blood pressure, received approval from the US Food and Drug Administration (FDA) in 1998 to treat erectile dysfunction and quickly became a highly successful drug.
Another notable example is thalidomide.
In the late 1950s it was given to women to prevent morning sickness, and it was soon found to cause serious birth defects.
It got a second life in 1998 as a treatment for leprosy (now called Hansen's disease), and then a third life in 2006, when it was approved to treat multiple myeloma, cancer of the bone marrow.
When covid-19 became a pandemic last year, a race was launched to find any treatment that could help against the new virus that has made it seriously ill and killed millions, while leaving others completely unharmed.
One option was to develop new drugs that would specifically target SARS-CoV-2, the virus that causes Covid-19, from scratch.
New treatments such as monoclonal antibodies are the result of these efforts.
But developing, testing, and then getting FDA approval, not to mention creating the infrastructure for the production and distribution of a new drug, all takes time.
And the world did not have, and still does not have, time.
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Other researchers quickly began looking for what was already on hand, in hospitals and pharmacies, and on drug store shelves.
“The advantage of drug re-adaptation is that this drug is already approved.
It has already gone through the regulatory process to prove that it is safe and effective for something.
So if you can find additional uses for that drug, you already know it has a good safety profile, "explained Dr. David Fajgenbaum, an immunologist at the University of Pennsylvania and director of the Center for Cytokine Storm Treatment and Laboratory.
This is not to mention that there are cheap, generic versions of many older drugs because their patents have expired.
"It's just a matter of matching the right drug to the right disease," Fajgenbaum said.
"Fortunately, there are more than 2,000 drugs that are already approved by the FDA for at least one disease, and we have learned that there are many other diseases for which those drugs can also be retrofitted."
READ: Glossary of drugs and substances that have been linked to the coronavirus
In fact, Fajgenbaum said he has "dedicated (his) life to promoting drug re-adaptation" for diseases without specific treatments.
His passion is driven in part by his own experience.
In 2010, while in medical school, he first became ill with Castleman's disease, a rare autoimmune disorder that, like Covid-19, can cause the immune system to suddenly flood the body with inflammatory chemicals in the body. a so-called cytokine storm.
The result can be organ and tissue damage and sometimes death.
Castleman's disease left Fajgenbaum near death five times, until he found his own treatment with a repurposed drug.
"In fact, I am alive today because of a drug that was developed 30 years ago for another condition that we identified through a very systematic process and we think it could help save my life," he said.
Here I am, more than seven years later.
During the time he was ill, he founded the Castleman Disease Collaborative Network, a global initiative dedicated to fighting Castleman disease.
CDCN's collaborative method of organizing medical research later became a model for other untreated diseases.
A plan to save lives
When covid-19 appeared, Fajgenbaum realized that he was perfectly positioned to search for repositioned drugs to combat it.
On March 13, 2020, the day that much of the country began to shut down, “I found myself that night sitting next to my wife, hoping and praying that some researchers somewhere would follow the plan we are following to identify this drug that It saved my life, ”he said.
About a minute later, he said, he realized "that investigator somewhere" would be him.
He contacted his team at the Cytokine Storm Laboratory and Treatment Center.
“I turned to my team and said, 'This is a disease that has many similarities to Castleman's disease.
They have experience with routine drug re-adaptation and frankly I'm alive today because of it.
Let's apply this approach to covid, "he said.
They then launched the CORONA project (Fajgenbaum is its director and principal investigator), one of many global efforts (both private and governmental) trying to identify, test and / or track promising treatments among existing drugs to combat COVID-19.
His laboratory assembled a team of volunteers to systematically review "all reported cases of any drug administered to any human with COVID-19" and gather all the information into a database.
“Initially we thought there might be a couple dozen drugs that would be tried.
It's amazing, so far more than 400 different drugs have been administered to patients with COVID-19, "he said, noting that the number of patients involved is approximately 270,000.
Fajgenbaum explained that several approaches can be used to match a disease to a potential treatment.
These include translational research, which involves finding out what goes wrong at the cellular level with a given disease and seeing if there is a drug that fixes the problem.
There is also a high throughput drug screening test, which basically consists of testing different drugs in a Petri dish with the cells of the patients and seeing what happens.
Artificial intelligence can also be used to find previously unknown connections between disease processes and drugs.
"But at the end of the day, the only way to know if one of these drugs that looks promising in the lab really works in humans is to give it to humans and see how those patients fare," he said.
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Testing drugs to treat COVID-19 in a trial is critical and complicated.
Since people can get better without medication (unlike, for example, Castleman's disease or pancreatic cancer), it is important to conduct randomized controlled trials, in which patients are randomly selected to receive the active drug or a placebo.
Otherwise, it is difficult to know if the patients would have improved on their own anyway.
This country's experience with hydroxychloroquine is a case study of what happens when advertising is ahead of science.
Based on early, often observational studies, many believed that the antimalarial drug (repositioned as a treatment for rheumatoid arthritis) would help treat people with COVID-19, or perhaps prevent them from getting infected or sick.
But when the results of the randomized controlled trials came back, the drug was shown to be ineffective.
It is also important to determine the right time to administer medications.
A great example, Fajgenbaum said, is dexamethasone, an inexpensive steroid that has been around for decades and is used to treat many conditions, from inflammatory arthritis to skin, eye and breathing problems.
“Surprisingly, a third of the patients hooked up to ventilators are saved if they are given dexamethasone.
It is a great benefit.
It is also useful in patients who are not yet connected to ventilators, avoiding that they have to be connected.
Interestingly, dexamethasone is actually harmful if administered too early in the course of the disease.
So taking it when you have a recent diagnosis will actually be detrimental to you, underscoring how complicated Covid-19 is, "he said.
If researchers miss the right time, the study results can also be inconclusive or contradictory, which can be confusing and frustrating.
An example is tocilizumab.
Several studies have shown that it helps patients survive and several others show that it does not.
The key seems to be the moment of application.
In order for it to work, it appears that it must be administered within 24 hours of a patient's admission to the intensive care unit.
“This is not a disease where there is going to be a single solution, a drug that is consistently effective.
In fact, different drugs could be given during different stages of the disease course, ”he said.
Other drugs that Fajgenbaum says look promising include baricitinib, which like dexamethasone and tocilizumab also suppresses the immune response and is approved for rheumatoid arthritis, the gout drug colchicine, the anticoagulant heparin, and intravenous immunoglobulin.
Helping critically ill patients survive is an important part of the puzzle.
Another is to prevent infected patients from getting so sick in the first place.
That's where one of the real needs lies, Fajgenbaum said.
“I think we really need to focus on (…) patients who are diagnosed and avoid needing to be hospitalized in the first place.
It is a difficult population in which to conduct trials (…) because in these patients, although they do not show symptoms, all were infected for the first 5 to 14 days before, ”he said, noting that antivirals are unlikely to be effective at such an advanced stage of the disease.
One drug that he says shows promise in helping patients avoid hospitalization is fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) used to treat depression.
Decreases inflammation in the brain.
A couple of preliminary studies have found that it helps keep newly infected people out of the hospital.
One benefit of fluvoxamine is that, unlike monoclonal antibodies that need to be infused, it is a pill.
No 'home runs' yet
Dr. David Boulware, a professor of medicine at the University of Minnesota, has been involved in several different trials looking for repositioned drugs for COVID-19, including a series of trials on hydroxychloroquine.
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"These are really cheap available drugs, which is exactly why we should look at them, because they are really cheap and available," he said.
Now Boulware is involved in a multi-center trial on fluvoxamine.
But it has been challenging, he says, because the trial has to recruit patients with recent infections as soon as possible.
So far, he says they have about 300 people signed up out of the 1,000 needed.
"So it has been relatively slow (...) If we had 500 people registered during the next week, we would finish in two or three weeks and we would have a definitive answer," he said.
Both Boulware and Fajgenbaum said another challenge is financing.
Fluvoxamine, Boulware said, costs about $ 12 per course of treatment.
"They are generic drugs, so they do not have a patent (...) There is not a large pharmaceutical company behind to promote it," he said.
He says that it is really up to private donors or the federal government to support the research, as there is no profit incentive for drug companies to do so.
“To date, most of the trials really focused on early treatment had been done by (supported by) private donors, philanthropic groups.
But I think there is now an emerging interest at the federal level to look at some of these repurposed drugs, "Boulware said.
Dr. Francis Collins, director of the National Institutes of Health, said the government has supported the repurposed drugs.
“We have invested a lot.
And that has been an obsession for me for the last 10 or 11 months.
"When I looked at where we were in March 2020, the effort to find therapeutic agents was pretty scattered at the time," he said.
"Much of it was focused on hydroxychloroquine, which we all know did not turn out well ... But in terms of other possibilities, there were about 600 candidate ideas that could be potentially valuable, but there was no really organized way to prioritize them."
Collins said he worked with industry to establish a public-private partnership, called ACTIV: Accelerating Covid-19 Vaccines and Therapeutic Interventions.
A working group of experts reviewed the 600 options and helped prioritize the ones worth investigating.
So far about 20 have been tested.
The project has had some successes.
"That was remdesivir, and that is dexamethasone, and that is a drug called baricitinib (...) but most of the readjustments have not worked (...) and that is not unusual," he said, explaining the lack of what called "home runs."
As for fluvoxamine, Collins said the jury is still out.
'Fluvoxamine looks promising at the moment, but it could be where hydroxychloroquine was a year ago and not work.
So I don't want to open the door for everyone to start using it.
I mean, 'Let's try that.
Let's find out the answer. '
And then the search continues.
Fajgenbaum is obsessed and motivated by the prospect that other medications are there, in plain sight, and can help someone fight something.
“So what keeps me awake at night is to say, 'These drugs are there.
What can we do to find out how these drugs that are approved for something can be used in a new way that can save a patient's life?
'", He said.
"There are medications at the neighborhood pharmacy that you could potentially [use as] treatment for yourself or someone you love," he said.
