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Medical drugs

Creative copies

Preparing molecules that simulate others could facilitate the search for truly original pharmaceutical products

MIGUEL BOYAYANTen years ago, Pfizer, a multinational pharmaceutical company, began to sell Viagra, a drug for sexual impotence. The drug had been discovered by British researchers and had initially been meant for use as an alternative to treat heart diseases. Expectations related to the blue pills included a quick profit and a mode of action that had already been clarified. This allowed two other major pharmaceutical companies, Bayer and Lilly Icos, to launch similar molecules with the same effect in the following years. Now, a Brazilian company – São Paulo’s Cristália – has entered the race with a molecule with the same mode of action as the other three. The story of this drug might have a lesson to teach those involved in research and development or those who take pharmaceutical drugs in Brazil.

Even though there is nothing original about the Brazilian drug, as it reproduces the same kind of action mechanism in another molecule – that of Viagra -, this is the first time that a new drug has been fully developed in Brazil – having gone though all the necessary steps to do so – the conception, testing on animals and human beings and the approval of the regulatory authorities. Molecules  of this kind, referred to as me-toos because they contain less significant or incremental innovations that stem from a medical drug with radical innovations, suggest that following previously explored paths could be a way of gaining breathing space and experience that might lead to longer, more expensive and truly original projects. These molecules might also represent a new action strategy for the Brazilian pharmaceutical industry, which survived the free copying of medical drugs until 1997, when the patent law in effect began to include pharmaceutical products, and since 1999 has emphasized the production of generic drugs.

The me-toos represent a quick and relatively low-cost way.  Viagra’s creative copy, the commercial name of which is Helleva, took seven years of work and investments in reais, the amount of which has not been disclosed. But this was certainly less than the 15 to 20 years and the US$ 800 million that the pharmaceutical companies claim are the minimum period and investments currently necessary to discover, test and approve a new medical drug. The production of molecules that are not identical yet have similar structures to other existing molecules is not that simple, especially for beginners. This production implies planning capacity, the skill to find  loopholes in the patents of the original molecules, and a lot of perspiration to identify and bring together researchers, physicians and statisticians prepared to conduct all the tests that the Agência Nacional de Vigilância Sanitária/ Anvisa, Brazil’s regulatory authority, demands before the drug can be marketed.

“Some companies and research groups would like to produce revolutionary molecules, but this is not possible,” says pharmacologist Gilberto De Nucci, a professor of the University of São Paulo/USP) and of the State University of Campinas/Unicamp), who selected the Brazilian molecule that most closely resembled Viagra. “We have to learn to produce the me-toos before we produce truly new compounds,” he states. The me-toos have a low possibility of failure as they are based on an action mechanism that has already been tested and is available in existing markets. “The me-toos come with a pedigree, because they have already been selected.” The expression “me-too” has a negative connotation, even though these kinds of molecules can also foster competition and motivate prices to drop, as was the case with Ciallis, manufactured by Lilly, and Levitra, manufactured by Bayer. These two brands undermined Viagra’s sales by fifty percent, after these sales had totaled US$ 1 billion in the period from 1999 to 2001.

Ogari Pacheco, chairman of the board of directors of Cristália, who disagrees with the concept of the me-toos, says that he would not call Ciallis and Levitra me-toos, because they are original molecules.  But he agrees that mimicking the structure of a better known compound is the “easiest, quickest and most logical way” for the Brazilian pharmaceutical industry to create financial reserves and invest in things that are really new: “It is impossible for a pharmaceutical lab to produce only innovative products,” he states. He knew that not everything would be that easy and quick when he decided in 2001 “to mimic the effect of the mother drug,” as he refers to it. This was the first time in the company’s history – a company which he helped establish in 1974 – that he was willing to follow all the steps in the development of a pharmaceutical product ? conception, pre-clinical and clinical trials, patenting and approval by regulatory authorities. Pacheco and his development team had to learn the rules of the game and find experts to conduct the trials that would prove that the molecule synthesized by the company was safe and efficient for use in cases of erectile dysfunction.

Survival
Antonio Carlos Martins de Camargo, director of the Applied Toxicology Center/ CAT, located at the Instituto Butantan, classifies pharmaceutical companies into two categories:  the companies that innovate and the companies that copy. The team he heads discovered and patented 12 molecules to treat cardiovascular diseases, lung hypertension, pre-eclampsia and Alzheimer’s, provided that they pass all the tests on animals and human beings. However, Camargo acknowledges that the creative copies are valuable from a practical point of view, because they help the companies survive.

“We face a lot of prejudice,” says Jorge Afiune, medical director of Cristália. “During most of the development work, we were viewed as a backward version of a laboratory that was confident it could produce something new.” Alba Brito, a pharmacologist at Unicamp, and who has participated in the initial stages of the development of new medical drugs for nearly 30 years, mentions four dogmas: the manufacturing of medical drugs is the exclusive prerogative of multinational companies; it is expensive; it is not for amateurs; we don’t have the experience. “The dogmas hinder any initiative and nobody in Brazilian industry is willing to back this battle, because it might not result in anything,” she says.

Rahim Rezaie and Sarah Frew, researchers from Canada’s University of Toronto, who visited Brazil to explore the possibilities of interaction between companies and public research centers, wrote an article that was published in June in Nature Biotechnology journal. In the article, they stated that the businessmen themselves attributed the lack of joint projects to the fact that everything worthwhile was being done abroad. Rezaie considers this prejudice to be understandable, “due to the increasingly global nature of biotechnology and the required specializations,” but he also found this attitude to be strange because, in his opinion, entrepreneurs could look for solutions first in their own back yards.  Paying more attention to the global rather than to the local is one of the characteristics of which US historian George Basalla referred to as “colonial scientist,” in an article published in Science magazine on the production of scientific knowledge.

Rezaie believes that these ideas linger on because of differences between the public and private sectors: “There are centers of excellence that remain unknown, especially to the business community.”

In 2001, the same year that the pharmacologists from Cristália and from USP selected lodenafil carbonate as the molecule that most closely resembled Viagra’s sidenafil, tests began to be conducted on mice, rats and dogs. The tests showed that the new compound had acceptable toxicity levels and the desired pharmacological properties. One of the lessons learned from this initial phase was that: “Not everything has to be made in Brazil,” says De Nucci, who coordinated part of these tests, partially conducted in France.

The most difficult stage – the clinical trials on human beings – began in October 2004; they were difficult because of the lack of experienced professionals. Marco Antonio Zago, a professor at USP and president of Brazil’s National Scientific and Technological Council (CNPq), had already advocated in 2004, the strengthening of clinical research in Brazil, in an article published in Ciência & Saúde Coletiva magazine; in the article, he wrote that this could be achieved through the strengthening, expansion or recovery of medical research centers. “Medical and university institutions must re-evaluate their relationship with industry, in the sense of meeting public interests,” he wrote.

De Nucci coordinated the first stage of the tests with the Brazilian copy of Viagra on 33 healthy volunteers. The next step, which evaluated the efficiency of the compound on 72 men with erectile dysfunction, was conducted at three public hospitals, under the coordination of the team from Cristália. To convince the physicians who had evaluated drugs created in other countries, and were qualified to participate in this new test, Afiune – instead of only requesting or contracting their services – showed them the findings of tests that had already been conducted with the molecule that inhibited the same enzyme, phosphodiesterase-5, which is blocked by Viagra. The Brazilian equivalent began to gain scientific credibility. The tests in the second stage, involving 350 men with erectile dysfunction who were being treated at 12 medical centers, were conducted under the coordination of a Brazilian company specialized in clinical tests. The trials, which produced positive results, were concluded in December 2006. They proved that the Brazilian molecule had the same side effects as Viagra and the equivalent drugs, which include facial flushing and slight nasal congestion.

Competencies
The clinical trials also taught some lessons. The first and most obvious lesson is that competencies are dispersed at national research centers, and it is necessary to have “stronger documental accuracy,” suggests Afiune. “Unlike purely academic research, clinical research has to be very well documented, and has to have total traceability.” Another lesson learned was that planning the trials together with the professionals involved in them helps avoid mistakes. And the third lesson learned was to avoid collecting too much or too little data; as for conducting analyses, “it’s very important to have a statistician by your side right from the start, when the protocol is being devised”.

During the final stage, the analysis and approval of the new medical drug by Anvisa, Pacheco reported that he noticed “a lack of alignment between the demand and the problem resolving capacity” in the course of the process which obliged the company to send 70 kilos of documents to the regulatory agency. “I believe this is due to the regulatory agency’s lack of preparedness to analyze this kind of process; it’s not bad faith,” says De Nucci. “There are very few people in Brazil who are qualified to evaluate a new medical drug.” In 2006, Pacheco was granted the patent for the new pharmaceutical product in the United States; in 2007 he was granted the patent in Europe and he is still waiting for the Brazilian patent, requested in 2003, the same year as in the United States.

The São Paulo laboratory is now planning to attract the preference of 1.7 million men who take medicine for erectile dysfunction by offering a Brazilian-made product that is expected to be 30% less expensive (the Indian version of Viagra costs 10% less than the original one). However, there is no guarantee that profits will be easy. In a study published in 2001 in Research Policy, Basil Achilladelis and Nicholas Antonakis, from Greece’s University of Athens, studied the origin and commercial results of 1,736 new medical drugs launched in the period from 1800 to 1990. They noticed that 65% of the radical innovations were a commercial success; the intermediary innovations (the so-called “me-betters”) were a moderate commercial success and most of the incremental innovations (the me-toos) were a commercial failure because they were unable to get any elbow room in competitive markets. The real innovations analyzed in the referred study were concentrated in five countries (the United States, Germany, Switzerland, Great Britain and France) which account for 80% of those making a difference.

A benefit gained by the company that manufactures Helleva is the fact that now the drug has become its own me-too. “What we learned can be used in other projects,” says Afiune. He added that the company is working on the development of 26 new molecules, 14 of which are incremental, or me-better, with improvements in relation to the original version, and 12 are radicals, including one for heart attacks. “The research team at Cristália likes challenges, because all the members came from universities,” says pharmacologist Regina Scivoletto, a retired USP professor and chair of the company’s scientific board. At the beginning of this year, the company whose head office is in the city of Itapira, State of São Paulo, was one of the winners of the Prêmio Finep Technological Innovation award.

The lessons can also help other companies produce me-toos and gain some breathing space to attempt to create original molecules, says Henry Suzuki, technical director of Incrementha, a laboratory that congregates the research and development efforts of two Brazilian companies, Biolab and Eurofarma. “We are making an effort to develop our own portfolio, with more consistent research and development and the ownership of intellectual property,” he says. This could also be a strategy to develop drugs for neglected diseases, such as malaria, tuberculosis, leishmaniasis and leprosy, which are still rampant in Brazil. “If I am guaranteed that the products will be marketed,” says Pacheco, “I can easily produce them.”

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