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Interview

João Batista Calixto: The voice of Brazilian pharmaceuticals

The pharmacologist from Minas Gerais has dedicated his life to developing new drugs

Calixto: the Brazilian pharmaceutical industry emerged through producing generic drugs, and doesn't prioritize innovation

Léo Ramos Chaves

Born 70 years ago in the small town of Coromandel in western Minas Gerais, and a resident of the state of Santa Catarina since the 1970s, João Batista Calixto is one of the few Brazilian researchers whose résumé includes the development of two innovative medicines. One of them, the anti-inflammatory Acheflan, was the first drug fully produced in Brazil through every stage, from basic research to commercialization. The other is a cosmetic product launched by Natura. An advocate for innovation in the health sector, Calixto has dedicated his life to the study and creation of new pharmaceuticals.

“Developing medicines is a passion,” says the pharmacologist, who retired from the Federal University of Santa Catarina (UFSC) six years ago to establish and direct the Center for Innovation and Pre-Clinical Studies (CIEnP) in Florianópolis. Funded by the federal government, the Center conducts studies on the efficacy and safety of molecules with medicinal potential, using in vitro testing and animal models, which are fundamental stages in developing new drugs.

An authority in the study of active ingredients in plants, Calixto is the author of more than 300 scientific articles, which have been cited around 16,000 times. He taught at UFSC for 37 years, where he coordinated a lab that specialized in preclinical trials, and where he still works as a visiting professor. In the following interview, given at CIEnP’s modern facilities, the researcher spoke about the difficulties of innovating in the pharmaceutical sector and about the state of Brazilian science today, going into detail regarding the products he has created.

What are the current challenges in the pharmaceutical field?
The main challenge is creating medicines for what are called multigene diseases—chronic and complex diseases—such as Alzheimer’s, Parkinson’s, and cancer. They result from the natural aging process and involve multiple pharmacological targets, in other words there are many biological processes to be controlled. Other diseases have only one target and can be treated by just one drug, which is generally simpler and easier to produce. Medicines for multigenic diseases were created during the final decades of the last century. The investment needed to make more complex drugs goes up exponentially, as does the final cost—there are now treatments based on gene therapy that cost US$2.3 million. Innovation in healthcare is the most expensive in the world, and the most difficult to do because it’s very complex and extremely regulated. Developing a new drug can take 10 to 15 years and cost more than US$1 billion, with a 1% probability of success. The vast majority of these molecules die along the way. Only a few countries, including the United States, England, Germany, France, Switzerland, and Japan, have mastered the process from discovery to commercialization.

Could Brazil join this group?
It’s very difficult for Brazil to develop such expensive and complex drugs. We’re at a different stage. We have to treat the diseases resulting from aging while at the same time, the old ones, including neglected and endemic diseases such as malaria, Chagas, and schistosomiasis. We continue to pay royalties on simpler medicines, created over the past decades. What we managed to do well was generic drugs, even though we import the raw materials. The deficit in the pharmaceutical trade balance, including old medicines, raw materials, and new drugs, exceeds US$10 billion per year. That’s more than the income generated by agriculture in the state of Mato Grosso, one of the largest producers in the country.

What should the country invest in?
We should invest in developing vaccines and traditional medicines that originate from our biodiversity, and in incremental innovation. We need to invest in an industry that will become minimally competent and be able to reduce the trade deficit, and contribute to sustaining SUS [the Unified Health System]. We spend a lot of money importing every kind of medicine, while at the same time we’re struggling to cope with new medical problems. At our current level of coordination between research centers, the government, and companies, trying to create drugs for more complex diseases is a losing battle. While the pharmaceutical industry in Europe and the United States values innovation and takes risks, ours emerged out of copying, and therefore we don’t prioritize innovation.

How so?
Many owners of large national labs sold medicines and then became business owners. Today, they earn big with generics and biosimilars. We’re the world’s seventh-largest pharmaceutical market, and since the Brazilian income is still low, there’s room for growth. Most of the multinational pharmaceutical companies are here, and the government, through SUS, is the biggest buyer. Brazilian businesses don’t feel the need to innovate and hence are limited to the local market. This scenario will only change when young innovators emerge. It would be nice to have a unicorn [a startup worth US$1 billion or more] in the pharmaceutical field.

What’s missing for that to happen?
The environment for innovation in this sector isn’t yet established in Brazil. Those few who do invest in startup companies in this country aren’t always aware of the difficulties of getting a new drug on the market. There are also problems with the regulatory system, although it has been improving. And researchers don’t generally know the legal requirements necessary to launch a new product onto the market. As a result they waste time and money on unnecessary testing. Even so, we have good ongoing projects, although most of them represent incremental innovation—which means they’re improving on an existing product.

Some pharmaceutical companies are opening R&D units outside the country, where the environment for innovation is friendlier

What does CIEnP do?
CIEnP was opened in 2014 to carry out in vitro tests [on cells] and preclinical studies [on animal models] of new molecules, two of the phases in developing drugs and cosmetics. Funded by the Ministry of Health together with the Ministry of Science, Technology, Innovation, and Communications, as well as by the state government of Santa Catarina, the Center partners with universities, research institutes, startups, and companies. We have several collaborations focused on incremental innovation, but radical innovation, the kind that costs a billion dollars, is difficult to do. We don’t do academic research here, only innovation. We have a rodent vivarium that meets international standards, and 35 employees, 12 with doctorates and 5 with master’s degrees. The cost for creating CIEnP was around R$30 million. The federal government has funded us since the beginning because we’re not yet self-sustaining—at our best, we billed 28% of our budget. Our annual costs are approximately R$6 million. Due to the country’s economic difficulties, there was a serious reduction in demand for our services in 2019.

What strategy did you adopt when orders fell?
When demand for our services fell, which is basically pharmacokinetic trials [tests to determine how drugs are absorbed and metabolized by the body], on the safety and efficacy of new drugs and compounds, we reviewed the scope of our operations, and decided to take a step back. We started to develop our own products, to later be transferred to a pharmaceutical company in Brazil or abroad. We are currently negotiating over two products, an herbal medicine and a cosmetic. If we close the deal, we’ll receive royalties for the first time. We also work for DNDi [Medicines for Neglected Diseases Initiative], an NGO. We’ve been doing preclinical studies on several molecules for the last two years. There is also an innovative product obtained from catuaba bark [Trichilia catigua], studied by our group at UFSC for over 15 years. It’s a project with Catarinense Pharma, formerly Laboratório Catarinense, a long-standing partner. It’s intended for treating mild and moderate depression, and is in the final phase of clinical study. If the trials go well, the drug should be launched in the next few years.

How did you participate in developing the herbal medicine Acheflan?
When I came to Santa Catarina in 1976, there was practically no vision for science in the state much less a foundation to support research. So, I decided to create partnerships with the private sector. The first was with Laboratório Catarinense, as it was called then, which specialized in plant-based medicines that had yielded results and patents. At the end of the 1990s, the wave of generics began in Brazil. The Aché lab decided that it was not going to make generics, but rather an innovative project based on plants from Brazilian biodiversity. Because of my experience with Catarinense Pharma, I was invited to be part of the group. We started working with ten Brazilian plants, among them Cordia verbenacea, popularly known as erva-baleeira [whaling herb], from which are extracted the active ingredients that give Acheflan its analgesic and anti-inflammatory properties. It was the plant the company placed the most hope in, and it was the first to deliver results. We did the preclinical studies. In 2005, after seven and a half years of work, US$7.5 million in investments, and getting approval by ANVISA [the Brazilian Health Regulatory Agency], the product was launched. It was the first drug made entirely in Brazil, through every stage of development. Since it was launched, Acheflan has become the country’s best-selling drug in its category of topical analgesics and anti-inflammatories. In two and a half years, the revenue generated by its sales paid for the investment made in all ten plants we studied.

How do you explain these results?
It only happened because of the passion for innovation of one of Aché’s owners, Victor Siaulys. He said openly that he didn’t want to die without creating an innovative medicine. He used to say that, despite having created a large lab, one of the products he sold the most of, the nasal decongestant Sorine, was very simple. Its active ingredient is sodium chloride [salt].

Besides Acheflan, have you made other products that arrived on the market?
Yes, two others. One of them was a cosmetic for Natura. In 2005, FINEP [the Brazilian Funding Authority for Studies and Projects] launched a competitive grant fund for innovative medicines. Natura had just bought Flora Medicinal, an herbal medicine manufacturer, and called our group from UFSC to better study a tranquilizer whose ANVISA license had expired. The product was a mixture of two plants, one of them from the passion fruit family. We tried for a while, but we didn’t find the hoped-for tranquilizing effect. During the study, however, we saw important effects in one of these plants and suggested that we try to create a cosmetic, rather than a medicine. The work resulted in a cream in their Chronos line, Flavonoides de Passiflora. This cosmetic earned a patent in Europe and sold quite well in Brazil. It was the first time that UFSC received royalties from a technology transfer project.

And the other?
It was a tranquilizer created by Aché from that list of ten plants that we’d started working with in the 1990s. This herbal medicine, called Sintocalmy, was made from another passion fruit species, Passiflora incarnata. We studied the plant, developed the product, and presented it in the form of a tablet. Aché carried out a comparative clinical study with the tranquilizer and the anxiolytic Diazepam and the results were good. The herbal medicine was registered with ANVISA in 2010 and today it sells as much as Acheflan. Since they were launched, the two have grossed more than US$500 million. Again, with my team at the UFSC Experimental Pharmacology Lab, I coordinated the preclinical studies.

Eduardo Cesar Cordia verbenacea, the plant that was the basis for developing Acheflan, the first medicine produced entirely in BrazilEduardo Cesar

How did you conduct the preclinical trials of these drugs?
With a lot of difficulty. The university did not have adequate labs, fully qualified professionals, or quality test animals. This experience led the federal government to invite me to set up CIEnP. But it must be made clear that we only accomplished these innovations because we’d done a lot of basic science, published numerous scientific articles, and mastered the frontier technologies in our field.

Are the tests for the approval of herbal medicines simpler than those required for registering synthetic molecules?
The development stages are basically the same, but the process of creating an herbal medicine is simpler, yes—and the success rate is higher. In most cases, the plant the medicine originates from has already been in use by people for a long time. You don’t start at random, but based on accumulated knowledge. However, new synthetic molecules have never been tested. The chances of a product made from plants being safer are also higher. Many chemical molecules don’t result in new drugs because they’re toxic, not because they are ineffective. Plants can also be toxic, but it’s less frequent.

What is the role of natural products in drug development strategies?
They are very important. Approximately 35% of the global drug market, estimated at more than US$1.2 trillion per year, results directly or indirectly from natural products—plants, animals, and microorganisms. All antibiotics were initially produced from fungi and other microorganisms. About 60% of drugs for treating cancer are derived from natural products. Hence their importance. Much is said about the potential of biodiversity in the Amazon, but we can’t forget the Atlantic Rainforest and the Cerrado [wooded savanna]. Biodiversity is one of the few areas in which Brazil has an advantage over the rest of the world. We have rich biodiversity, abundant water, and space to plant.

What are the advantages and difficulties of working with companies in developing new molecules with therapeutic potential?
Companies in this field rarely hire PhDs, or hire very few of them. And most don’t have a robust research and development [R&D] division. Thus, during the development of a new drug, it’s necessary to negotiate with the owner of the company, or possibly, with the clinical director. Most of the decisions about the project are made by the owner of the laboratory. In addition to delaying the process, at any time he may decide to suspend the study. In addition, Brazilian labs don’t have an ongoing innovation portfolio. This isn’t a priority for them—nor do I blame them, as there are few incentives to innovate in Brazil, and the difficulties are many. Some pharmaceutical companies are opening R&D units outside the country, where the innovation environment is friendlier.

How would you evaluate your professional life, on balance?
In 2013, when I was at the height of my academic career, I retired from UFSC—where I’m still working as a visiting professor—to set up CIEnP. I keep fighting to help our country develop. That is my goal. I had already received invitations to work in the industry, but I turned them down because establishing a place like CIEnP has always been my dream. Developing medicines and helping companies to innovate is a passion. I know it’s possible. We’ve already proven that.

How do you view the current difficulties of Brazilian science?
The budget cuts were large and unprecedented, but I’m optimistic. At times like this we must focus on what really matters. The current times will certainly change our way of thinking about and doing science. Technological innovation often occurs in times of great social and economic difficulty. We will emerge from this crisis more humble, with more capacity to collaborate, and investing in quality over quantity.

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