Although Cuba has not completely defeated COVID-19, as evidenced by the outbreaks and positive cases detected in recent days, the island has undoubtedly successfully managed to cope with a disease that has become a pandemic, which has already spread to some 8 million people and killed more than 430,000 worldwide.
The island’s figures, although they have maintained a progression since the first cases were reported on March 11, have not suffered an exponential jump, as has happened in many nations, and have managed to remain within a favorable scenario. This has prevented hospitals from overloading, victims from multiplying—to date, just over 2,260 infected have been confirmed and 84 patients have died—and for the country to carry on its shoulders the weight that an uncontrolled epidemic would represent for its already hit economy.
The key to this achievement, the Cuban authorities assure, has been the implementation of a comprehensive strategy that combines active epidemiological surveillance, isolation measures for the population—although without decreeing quarantine, except where there have been localized transmission events—, the compulsory hospitalization of positive cases, contacts and suspects—even asymptomatic—, and medical attention that has not spared all the resources at its disposal for the treatment of the sick. And within these resources, Cuban biotech products have been undisputed protagonists.
Cuban protocol to confront COVID-19
As part of the protocol established by the Ministry of Public Health (MINSAP) to combat the disease, several drugs produced in Cuba have attracted headlines. Their effectiveness in preventing progression toward the most severe stages and in reducing the fatality of COVID-19, has benefited numerous patients treated on the island and has generated interest beyond its borders. This, however, was not been by chance. Nor is it an exclusive result of the intense work of Cuban scientists in the last two months. Its reason must be traced back much earlier; it must be sought in the integration of the island’s renowned biotechnology industry.
“What we have done during the pandemic is the consequence of many years of work,” Eulogio Pimentel, general director of Havana’s Center for Genetic Engineering and Biotechnology (CIGB), explained to OnCuba. “It is the result of a macro design, not of a scientist or of a single entity, but of how to build an industry that was supposedly closed to countries like Cuba, which, precisely because of the cost of researching and maintaining the standards required in the production systems of the biotech industry, are excluded from it. However, in Cuba a whole process was masterfully designed since the 1980s, which includes an important group of scientific institutions and that has allowed us to get to where we are today.”
“We are institutions that in some cases even work in common diseases, but using different strategies from the scientific dimension and from the productive technological dimension. And although we don’t compete with each other, because a poor country like ours doesn’t have the resources for several centers to be working on the same thing, we do complement each other a great deal, and an example of this complementation has been precisely this pandemic. In the fight against COVID-19, the Center for Molecular Immunology, the National Center for Biopreparations, the Center for Immunoassay, the National Center for Scientific Research, the CIGB itself, we have tensed our muscles and the research and manufacturing activity has become tense to the fullest. And to the same extent we feel, not pleased, but comforted that the effort of the institutions of the Cuban pharmaceutical and biotechnological industry, together with that of our health system, that of the doctors, specialists, nurses, who are the direct protagonists in this struggle, has made it possible for Cuba to show today a practically controlled pandemic, which has even superimposed the most optimistic models that were had of how the coronavirus would evolve here.”
Interferon’s path
Days ago, Cuba commemorated the 39th anniversary of the first production of human interferon not obtained by genetic engineering, achieved by six professors from the island who were in Helsinki, Finland, learning the technology to obtain it from human blood. Those years would mark the beginning of a path that has consolidated the prestige of Cuban biotechnology at a global level and that has one of its emblematic products in interferon; a banner that, decades later, has again proven its worth in the unexpected scene of the pandemic.
“Interferon has traveled throughout the history of Cuban biotechnology, from being the founding pillar in terms of being the first genetically engineered molecule that had a clinical impact, to becoming today a medicine of cardinal therapeutic importance in achieving the clearance of the viral load in patients suffering from COVID-19,” says Pimentel, who recalls that thanks to a joint venture between Cuba and China, this drug had its first test against SARS-CoV-2 in that Asian country, the origin of the pandemic. The success achieved there, he affirms, “gave us great satisfaction and also helped us to have more confidence in the use of recombinant interferon alpha 2b against this disease.”
According to the general director of the CIGB, this product “has played a key role in dramatically reducing the number of patients who reach the condition of serious or critical,” as part of the Cuban treatment protocol. This, in turn, has a positive impact on low mortality. A scientific report of the first 30 days of its use in Cuba during the pandemic, sent to a prestigious scientific journal, confirms that, until the date of the end of that study, patients treated with Heberon―trade name for Cuban interferon―had a case fatality rate of just 0.9%, something that Pimentel does not hesitate to describe as “impressive.”
To this is added another very illustrative piece of information, the result of the accumulation of evidence collected on the island on the clearance of the coronavirus in samples taken by real-time PCR. “Right now,” says the expert, “from the accumulated number of patients we have studied, after four days more than 70% have already cleared their viral load. This is really a symbol of where we started and where we are now.”
It’s not surprising then that, according to Pimentel, some 82 countries have taken an interest in Cuban interferon for its use against COVID-19, of which “some have signed agreements with us,” while “others are already using it in their therapeutic action protocols.” It’s also not surprising that, despite the fact that “like most drugs of biological origin, it is very expensive,” Heberon is available to all COVID-19 patients in Cuba and that the Cuban biotechnology industry guarantee the necessary inventory for the coming months, even for a scenario not as favorable as the one the island is going through today.
“Our interferon is supplied to all infected, and even before, to suspects and medical personnel as a preventive element. It is an expensive molecule, perhaps many countries cannot afford to use it as we are using it today in Cuba, but that use has led to the impact it has had during the pandemic,” he affirms.
But it doesn’t end there. A combination of alpha interferon with gamma, still under study, makes the CIGB researchers feel very optimistic.
“The clinical trial is having a magnificent result,” said to OnCuba Dr. Gerardo Guillén, director of biomedical research at CIGB. “These days, the first publications of the results came out about remdesivir, a drug that is approved by the United States Food and Drug Administration (FDA) for emergency treatment in the pandemic and that decreases from 15 to 11 the average days in which patients remain hospitalized with viremia, that is, with the virus still detectable by PCR,” he explains. “Well, interferons are reducing viremia by more than 50% and even in 70 and 80% of patients in just 3 and 4 days of administration. That is, they reduce by 11 or 12 days the time patients need to negativize the virus. And these results undoubtedly have an impact on the initial stages, to prevent the advance toward a serious condition.”
Against the “cytokine storm”
Although less publicized than interferon, two other Cuban biotechnological products have proven effective against COVID-19, particularly in the more severe stages of the disease. The humanized monoclonal antibody, Itolizumab, from the Center for Molecular Immunology (CIM) and the CIGB 258 peptide, from the Center for Genetic Engineering and Biotechnology and whose commercial name is Jusvinza, have contributed to saving quite a few of those who, unfortunately, have reached the intensive therapy units. And they have done so thanks to their power to control the so-called “cytokine storm,” a defensive immune reaction that is triggered in advanced stages and is potentially fatal.
“In Cuba we are used to dealing with storms, hurricanes, tornadoes, and in this case we are talking about cytokine storms,” reflects Pimentel. “And it has been unusual and unexpected to verify that the cytokines that are part of all the links that cause inflammation in the body, were very high in these patients. So, although there is still a lot to study about both drugs, that we have two therapeutic alternatives, two tools based on different mechanisms of action, but with a common effect that contributes to stopping the pro-inflammatory process, it is something very satisfactory and desired, which occurred as a result of previous investigations.”
In both cases, these are already existing products for the treatment of other diseases, redirected in the face of the pandemic emergency. Itolizumab was initially created for use in cancer, the specialty of the CIM, and was extended to chronic autoimmune diseases such as severe psoriasis and rheumatoid arthritis, while the CIGB 258 was also originally developed to treat the latter type of diseases. However, after the publication of the first articles explaining the pathogenesis of COVID-19, both emerged as promising alternatives.
Then, the studies carried out along the way―the one of the CIM began on March 28 and the one of the CIGB, about a month later―have confirmed their value for patients in severe stages, which, moreover, are usually aging patients, with a physiological deficit of the immune system and with various comorbidities―including high blood pressure, diabetes, heart failure and kidney failure—, which further complicates their medical care. Therefore, after validation by the island’s regulatory authorities, the MINSAP authorized their generalization throughout the country and their inclusion in the Cuban treatment protocol.
“In Cuba, we deliberately didn’t want to do a controlled trial in which there were patients without access to one of the two medications,” explains Dr. Tania Crombet, director of clinical research at the CIM. “In other countries, drug trials have been carried out in which there is a placebo group, but the intention of the Ministry of Public Health and our scientific advisory group has been not to leave any Cuban untreated, and once we learned that the two molecules could play a role in the stage of systemic inflammation, what we proposed was that all patients who reached these stages receive some of the medications. Then we will try to make some comparison with the group of patients who worsened when we did not yet have the approval of the regulatory authority to introduce the two drugs into the protocol.”
“Currently,” explains Dr. Guillen, “their application is a decision-making problem. Both CIGB 258 and Itolizumab are included in the therapeutic protocol, but are not applied together. It is decided between one and the other at medical discretion, depending on the patient’s condition and the clinical experience of the specialists. Both contribute to control the elevation of markers that lead to the aggravation of patients and reduce their levels, which correlates with clinical improvement. That is why they can be used interchangeably and, as they are redirected products for their use, because this disease is something new, the treatment with both products has been adjusted and optimized, to the extent that intensive care physicians who use them have acquired experience and interacting with the latter.”
Itolizumab
With more than 20 years of research and produced in Cuba since 2014, this monoclonal has been the CIM’s successful bet for the treatment of patients in severe stages of COVID-19.
“Itolizumab is a humanized monoclonal with genetic techniques based on a murine monoclonal (sub-family of rodents that includes rats and mice), in such a way that we now have an engineered molecule with a low proportion of murine residues―less than 5%―which interact with the target, and the rest of the support is human, which makes it a not too immunogenic molecule for the patient, that is, it does not trigger a response against what one is injecting, and that, in addition, it reduces pro-inflammatory cytokines,” Dr. Crombet explained.
“At the same time, it is a fairly safe molecule that does not exacerbate lymphopenia, that is, despite being a monoclonal that recognizes a target that is in the T lymphocyte, it is known that it does not destroy this lymphocyte,” she adds. “That is one of the conditions that allowed us to propose its use for COVID-19. It is known that there is a correlation between lymphopenia and the severity of the patient, including the progression of this disease, and if because of 20 years of experience we knew that our monoclonal does not destroy the T lymphocyte, it was a very good thing because it allowed us to predict that it would not exacerbate other secondary infections that are greatly feared in this type of patient.”
“We are introducing it in the hyper-inflammatory stage of the disease, not only in the seriously or critically ill patient; we have also had an experience in people with moderate disease, who have not yet been in therapy, but with a high propensity to worsening, aged patients, with many comorbidities, and according to preliminary data, we know that the molecule does do what we want it to do,” she adds. “We have more than 20 characterized, seriously, critically, or even moderately ill patients, and we know that in virtually all of them pro-inflammatory cytokine concentrations are reduced. And we also know that our molecule also improves respiratory and oxygenation parameters, which practically improves in 80% of critically and seriously ill patients in intensive care. And the oxygen requirements of these patients in therapies have been reduced.”
However, the director of clinical research at the CIM recalls that this is an ongoing investigation. So far, of the more than 80 patients treated with Itolizumab, she specifies, cytokines have been measured in 26, while more samples are being processed. This is why, she affirms, “any numbers we manage are still preliminary, because we are still involved in the great challenge of gathering all the information in order to be able to offer definitive data in the end.”
Regarding this, she confirms that the study carried out in Cuba will be joined by the results of a clinical trial in India, where it is being investigated as a result of agreements between both countries and where the drug was already registered for the treatment of psoriasis.
“A controlled trial is taking place there in the case of COVID-19, which started shortly after ours, and the preliminary news we have is very good,” says Dr. Crombet. “The trial has 12 patients at the moment and is preliminarily confirming the data obtained in the series of Cuban patients. I think that when we have conclusive data from the research in Cuba and India, we will be able to hold meetings with the U.S. company that has the commercial rights in the United States, with which we have already had the first online contacts, to assess in that country the relevance of a clinical trial with this molecule for COVID-19.”
CIGB 258
Parallel to Itolizumab, the CIGB 258 or Jusvinza has carved out its own path in the face of the pandemic. It is “a peptide that we had been developing as a drug against rheumatoid arthritis,” explains Dr. Guillén. “A phase II clinical trial including 187 patients was underway and a phase I clinical trial with 18 patients had been done before, which had demonstrated a broad safety profile and, in addition, we had already been able to obtain a lot of information on how this peptide works. This allowed us to formulate the hypothesis that it could help in the cytokine storm phenomenon, which is what leads to the worsening of the disease and respiratory distress characteristic of COVID-19 patients who go on to severe and critical stages.”
“It also has the advantage that it does not immunosuppress,” he adds. “It manages to control the cytokine storm by impacting the cells that are contributing to the exacerbation of this phenomenon in the body and through the cells that regulate and balance this response of the immune system, but does not affect the rest of the body’s defense, which in this case is relevant because it is an infectious disease, so as long as the patient is positive he needs these defenses to be able to fight the virus.”
“We initially had a compassionate use permit,” Pimentel says, “for use in those patients with whom there was no other alternative and the challenge of possible therapeutic efficacy was greater, because they were patients with many comorbidities, even with oncological diseases, in critical or severe stages. Ever since we started until today we have achieved a casuistry of more than 50 patients and we report in the case of critically ill patients a survival rate of more than 70%, while in the seriously ill it is more than 90%. And among the deceased there have been patients who were already negative for the virus, with x-rays showing that they came out of respiratory distress, but we still report them because they were treated with our medication during the illness.”
“In order to understand the importance of these data,” concludes the director general of the CIGB, “in a robust health system such as that of the United Kingdom, it was reported a few weeks ago that the case fatality rate in critically ill patients was 65%, while in the United States it was over 80%, and to speak of the fact that in Cuba the survival of this type of patients treated with our peptide is above 70% (that is, a lethality of less than 30%), is a figure that draws a lot of attention. And for us as scientists it is very encouraging.”
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