Coronavirus continues to affect our lives. Our movements have been restricted to minimize their probability of contagion, while health centers and hospitals are overloaded fighting against the disease. In these critical circumstances, what we can best do is talk about the possibilities of obtaining some type of treatment or vaccine against coronavirus. And knowing how to correctly interpret the information that comes to us about it.
The clinical trial obstacle course
Even if it is an emergency situation, any treatment that we want to experience in human beings cannot be tested without further ado. Every possible new drug is, by definition, a substance capable of affecting our body, and there is always the possibility of causing some unpredictable side effect. For this reason, a drug candidate must go through different phases of a clinical trial until it can be used in patients with complete safety.
Before starting to be tested in humans, candidates must pass phase 0. In this initial phase, the possible drug must be tested in experimental animals to demonstrate that it has some beneficial effect against the disease and that it is not especially toxic. The problem is that coronaviruses like SARS-CoV-2 do not have to be able to infect other animals just like humans. For this reason, the results of success in animals can lead to surprises when passing to humans. To improve the chances of success, animals that look as human as possible are investigated, such as primates or genetically modified mice that present human proteins capable of deceiving the coronavirus.
If the possible treatment works in the experimental animals, we can move on to phase 1. Now, yes, with humans. In this phase 1, treatment is tested with approximately a dozen healthy volunteers, who are given a small, controlled dose that is gradually increasing. The objective of this phase is to check the possible side effects of the medicine and calculate the maximum dose of the treatment that we can admit without having any undesirable side effect.
This maximum dose is key for the next phase of the clinical trial, phase 2. At this point, the first tests are already beginning with a hundred patients. Each of them receives an adjusted dose of the drug and is checked for improvement in their disease. In case of not seeing any improvement, the dose is increased little by little until reaching the maximum dose calculated in the previous phase. If this maximum dose has been reached and there is no effect, then the medicine is automatically discarded and it will not be possible to use it.
A new treatment may be shown to have a positive effect in phase 2, but still not be a good medicine because it is too mild. To demonstrate whether this medication is worthwhile, there is phase 3. In this phase, the candidate treatment is compared to the best available treatment for the disease. If the best available treatment is better than the new one, it does not pass the test since it is considered unethical to get a worse treatment than what already exists. However, there are several exceptions to this rule. For example, the new treatment may be slightly less effective but have far fewer side effects. Or it can be used in a part of the population where other treatments cannot, such as children or pregnant women. The idea of phase 3 is to demonstrate that the new treatment is important for its normal sanitary use, and it is an increasingly strict phase as the medicines for a given disease improve.
In the search for treatment against coronavirus, it is the circumstance of having no known treatment to compete against, so the candidate treatment is compared against a placebo, a fake drug that has no effect but has the same appearance as the treatment to try. Certain symptoms such as pain can be altered by our own expectations of being treated, under a phenomenon called the placebo effect. In order for phase 3 to be overcome, the new drugs must be better than the placebo effect and demonstrate a greater effect than we achieved by suggestion ourselves.
If a candidate manages to pass phase 3, we can already say that we have an appropriate drug to be used in patients. However, there is a final phase 4, in which the drug remains under surveillance while being used in different patients, controlling for possible rare side effects, which appear in less than one in a thousand patients and which were invisible in the previous phases. for the low initial numbers.
As we can imagine, these very restrictive conditions make the majority of treatment candidates to be ruled out in one of these phases. Pharmaceutical industries typically take between ten and fifteen years to generate a new drug, through an intensive process of trial and error.
But this decade of trying is necessary for medicines for known diseases, since we have good treatments that we have to overcome in phase 3. In the case of coronavirus, we only have to achieve something that works better than placebo, even slightly , and grow slowly from that point. This increases the chances of getting viable treatments as long as there are many different treatments to try.
The best vaccine
Since its official discovery in December 2019, more than 35 pharmaceutical companies and scientific institutions have turned to finding a treatment or vaccine for coronavirus. Most centers are still in an experimentation phase, trying to understand the nature of the virus, knowing its operation, their ability to mutate over time or their weak points that they have to attack the drugs.
With this increased knowledge of the virus, we can begin to develop strategies to combat it, but we must follow all phases of the clinical trial to guarantee the safety and efficacy of the drug we generate. There are some more advanced companies that have already started the first human trials, but remember that any drug can fall off this list if it fails to pass the tests. What should give us hope is not so much to see if these first candidates succeed (which we hope they do), but rather that there are many other drugs in development simultaneously, which ensures the possibilities of obtaining some treatment in the future.
One of the most celebrated treatments is the development of a vaccine for SARS-CoV-2. The first advance in this regard came from the hand of the Modern biotech company. By knowing the genetic information contained in the coronavirus, they managed to create a similar but benign RNA sequence, allowing the proteins that make up the virus to be generated but without contagious capacity. If this unarmed virus is successfully introduced, we will have an ideal training for our defenses and we can immunize ourselves when the real virus arrives.
It is this modified RNA that has served as the basis for different companies and countries to start prototyping vaccines. Currently, one of the most advanced vaccines is the one developed in China, which this week has obtained permits to start phase 1 in humans in the coming weeks after successfully passing phase 0 in spider monkeys.
In parallel, the American company Kaiser Permanente has already started testing in phase 1 of humans their own version of vaccine using the modified RNA, with the peculiarity of skipping phase 0 of animal testing. To do so, it required the permission of the American Drug Agency, which has been granted on an exceptional basis due to the current emergency. In exchange for skipping phase 0, phase 1 will be slower and more controlled, with one volunteer each time and with more precise doses to avoid unpredictable side effects.
The rest of the international companies that are working on a vaccine are still in phase 0, testing viability with animals before moving on to humans. It is not surprising that in the coming weeks we will receive news of more possible vaccines starting their own phase 1, companies such as the German CureVac, which despite being in phase 0 recently received US offers to transfer their research to this country.
We must understand that creating a safe and effective vaccine is going to be a slow process. Going through all these testing phases will require several months of testing and permits. In addition, once a vaccine is accepted, it is necessary to start the industrial production of said vaccine in order to immunize the entire population, something that we cannot start at this time either because we do not know what the winning vaccine will be.
But there is a shortcut, another method that some companies are using to combat the coronavirus in the short and medium term: recycling the medicines that we already know.
Take advantage of what we have
Each pharmaceutical company has different drug patents at their disposal that they can take advantage of to conduct clinical trials with the coronavirus and see if they are of any use.
The advantage of this method is that, if tested in phase 0, there is no need to go through phase 1, and we can start directly in phase 2. We already know the maximum dose that we can use in humans and the possible side effects, so we can fully focus on phases 2 and 3 to see if the drug has a real effect against the coronavirus, saving valuable time in this alert situation.
With this system, there are currently three drugs that are standing out as possible treatments for SARS-CoV-2, whose phase 2 and 3 tests are already being carried out in hospitals in several affected countries, including Spain. It should be noted that in these phases of the clinical trial it is still possible that the drug will be discarded if no effect is seen in patients when compared to placebo. But just as some treatments will be discarded, other recycled drugs will appear.
One of these drugs is remdesivir, which has started its phase 3 trials in various hospitals in Spain. This drug created by Gilead Science has already passed phase 1 previously as an experimental treatment against the Ebola virus. It has an effect on the replication of different viruses, slowing their ability to multiply, and it is expected to be effective against the coronavirus in the same way that it has been for Ebola.
Another phase 3 candidate is the combination of darunavir and lopinavir. The first is a drug used to treat HIV, and the second is an antiviral that works against the SARS virus, much like today’s coronavirus. Currently, they are included in the protocol recommended by Health and the WHO for the primary treatment of coronavirus, waiting to see if there is any better drug.
The latest candidate is a surprisingly old drug: chloroquine. This medicine has been used widely as a treatment against malaria and it was currently in disuse due to the substitution of better drugs and its drop in efficacy. This drug is so old that it no longer has an active patent, so there are several pharmaceutical companies that can manufacture it and several phase 3 clinical trials have started. For now, it has been proven to have a symptomatic effect, improving pneumonia caused by the coronavirus and improving patient survival. Most of the trials have been conducted in China and are expected to appear in the next WHO guide on coronavirus treatment.
In summary, the discovery of new coronavirus treatments will be a dynamic process, and it is a matter of time before any of the phase 0 drug candidates end up being reliable enough to pass on to humans. In the coming weeks and months we will have good news from some candidates, and unfortunately worse news from discarded candidates. The important thing is that this race to obtain a cure continues. It doesn’t matter who wins, because we all end up winning.
DON’T NECK IT:
- Although these drugs already exist for other diseases and are candidates to be useful in the fight against the coronavirus, this does not imply that they can be used directly. Current trials are there to demonstrate their true effectiveness and to avoid any side effects that may worsen the disease. Also, the effective dose does not have to be the same for different diseases.
- For each treatment discussed, there are ten that are still in development and will appear shortly if they manage to go to phase 1. The important thing is to advance in parallel as much as possible to get the best possible treatment before.
- Liu, Cynthia, et al. “Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases.” ACS Central Science, American Chemical Society, 2020
- Cascella, Marco, et al. “Features, Evaluation and Treatment Coronavirus (COVID-19).” StatPearls, StatPearls Publishing, 2020