bioBr 2019 - 3rd edition

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Gold partners

Silver partners

Exhibitors

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Promoted by

SUMMARY 16 22

SIRIUS Shine a new light on Nature’s treasures

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VACCINE Instituto Butantan: searching for partnerships BIODIVERSITY A Systematic and Exclusive Platform to Discover and Develop Innovative Medicines from the Brazilian Biodiversity INNOVATION Biolab Pharma: synonymous of innovation CANNABINOIDS Therapeutic and commercial potentials of cannabinoids FUNDING Brazil, ready to play in the Big Leagues?

ACCENTURE Health in Brazil: scenario and investment opportunities BIOSIMILARS Status of the registration of biological drugs in Brazil DEVELOPMENT Actions and initiatives of the Ministry of Health to foster innovation ecosystems in Brazil BIOTECH SECTOR Brazilian biotech sector overview

BIO Br Project Management by: Reporter: BIOMINAS Brasil / Business Executive: Norberto Prestes / Planning, Control and Operation: Carolina Sellani, Marcela Domingues and Natalia Araújo Art Editor: Daniel Guedes / Contact us at: comunicacao@abiquifi.org.br / Visit our site: bph.org.br

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SIRIUS

Shine a new light on Nature’s treasures:

unlocking the power of the Brazilian biodiversity assisted by SIRIUS, the Brazilian 4th Generation Synchrotron Light Source

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razil hosts around 55,000 angiosperm species from the 250,000 already described in the scientific literature. It is over onefifth of the planet’s botanical biodiversity, with many species endemic to Brazil.

The Brazilian Center for Research in Energy and Materials (CNPEM) is a private nonprofit Brazilian research institution working under contract with the Brazilian Ministry of Science, Technology, Innovation and Communications (MCTIC). CNPEM operates the only synchrotron light source in Latin America and is constructing Sirius, a 4th generation synchrotron light source. This and other world-class CNPEM’s facilities are open for academic and industrial research.

PHYTOBIOS is the R&D radical division of Centroflora Group, with robust logistics and over ten years of experience in bioprospection. The company works in compliance with the Brazilian regulations and the Convention on Biological Diversity (CBD – Nagoya Protocol) and is responsible for the expeditions and herbal extract preparation.

CNPEM joined forces with PHYTOBIOS to create the Brazilian Biodiversity Molecular PowerHouse (MPH), a platform that uses high technology and the Brazilian biodiversity to discover new therapeutic agents for unmet medical needs. MPH promotes the use of synchrotron light and other state-of-the-art analytical tools to screen the vast Brazilian botanical diversity organized in a highly curated, totally novel, and very well-maintained

collection of plant extracts and fractions. Putting the largest vegetable biodiversity in the world “under the microscope” of the most advanced synchrotron light techniques can result in a significant reduction in time and risk compared to the traditional bioguided natural product-based Drug Discovery Process.

THE PLANT COLLECTION The MPH collection currently holds over 600 species and continuously grows, like a living organism. The main goal of the platform is the broad coverage of the chemical possibilities of plants’ metabolites. Since 2015, 3 to 5 expeditions per year have collected samples from the four richest Brazilian biomes. Mass Spectrometry analysis produced spectral fingerprints to access chemical diversity. Plant families known to produce chemical structures underrepresented within the MPH’s library are prioritized for next expeditions, thus increasing chemical space coverage and avoiding redundancies.

Besides regulatory compliance and chemical diversity, other essential characteristics of the MPH collection are: storage and management under quality concepts; state-of-the-art processing, allowing detection of substances at low concentrations; full traceability, including the precise collecting location by GPS; plant identification by a qualified botanical taxonomist; testimony samples stored in a plant bank; and replacement assurance for further investigations.

The library is made of plant extracts

COLLECTING PLACES

THE AMAZON FOREST: the world’s largest rainforest (green pins on the map).

THE ATLANTIC FOREST: a rainforest smaller than the Amazon, but with approximately seven times more different species per area (blue pins).

CERRADO: A predominantly dry biome like the African savannas, considered a “hot spot,” with a high chance to find active metabolites (brown dots).

CAATINGA: in indigenous language: “white forest.” It is wet three months per year when all life thrives. The remaining nine months are arid, with temperatures over 35oC. The leaves fall, the soil gets dry and white. The leafless trees trunks become white, exposed to the sun, unshielded by any clouds. It is also a “hot spot,” with a higher chance to find active metabolites (yellow dots).

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and chromatographic fractions. The dry ethanolic extracts are produced by PHYTOBIOS and fractionated and stored at the CNPEM for use in bioassays and analytical processes.

TARGETING NATURAL PRODUCTS WITH STATE-OF-THE-ART TECHNOLOGIES Natural products (NP) display tri-dimensional features, ideal for interacting with putative protein drug targets. As probes, the NP disclose new binding sites and mechanisms of action (MoA), providing insights over innovative chemical scaffolds.

Despite the NP enormous potentialities for drug discovery, some bottlenecks have prevented their broader use in drug discovery. The main technical limitations are the time and resources consuming NP isolation and structural elucidation, steps so far essential for further drug development.

The MPH’s natural product drug discovery workflow uses the CNPEM’s state-of-the-art technologies to maximize the impact of the Brazilian biodiversity on pharmaceutical innovation.

Synchrotrons are particle accelerators that produce intense electromagnetic radiation beams with wavelengths ranging from the infrared to the hard X-rays. This allows studying the atomic and molecular structure of several kinds

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of materials, including pharmacological targets.

SIRIUS is a 4th generation synchrotron, the largest and most complex research infrastructure ever built in Brazil, and the second 4th generation synchrotron of the world. The first x-ray beam is expected to shine by the end of 2019, providing experimental tools with unprecedented time and spatial resolutions. This state-of-the-art infrastructure will soon place Brazil among the world`s leading nations in synchrotron light science.

Protein crystallography is one of the most important applications of synchrotron science. This technique allows the determination of the atomic structure of proteins, aiding the design of novel therapeutic agents. The target protein binding site 3D structures aid the rational design of new compounds with better putative interaction with the target protein (higher affinity).

MANACA (MAcromolecular micro and NAno serial CrystAllography) is among the first SIRIUS beamlines to start operating for the scientific community and is dedicated to protein crystallography. This experimental station is envisaged to be user-friendly and support remote data collection and automated processing at high speeds.

The MPH’s NP drug discovery process starts with high throughput screening of the MPH library. The most active extract fractions are directly submitted to protein crystallography. The target protein crystal is soaked into the active extract fraction (a mixture with tens of compounds) capturing the bioactive compound to disclose its binding site and 3D structure. Further, MS-metabolomics detects and relatively quantifies the compounds in the mixture. The bioactive compound is computationally sorted from the mixture, and its chemical structure

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(chemical formula and spatial arrangement) is proposed from its MS/MS spectra fingerprint.

The whole process runs on a miniaturized scale.

This innovative workflow significantly improves the NP libraries usability for drug discovery purposes. In a few and automated steps, it quickly identifies the bioactive compounds and their binding sites in the target protein, providing the information for structure-based drug design (SBDD). This Brazilian initiative is unraveling innovatively and compellingly the hidden treasure of Brazil’s Biodiversity. Multiple targets can be screened against this unique chemical collection.

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MPH IS PARTNERING WITH ACHÉ TO TRANSLATE DISCOVERIES FROM NATURE TO THE CLINIC Aché is considered one of the most innovative pharmaceutical companies in Brazil and joined forces in 2017 with CNPEM and Phytobios. The MPH platform is an essential component of Bioprospera®, one of the five Innovation Platforms of Aché. The Bioprospera® platform aims at discovering and developing innovative medicines from natural sources. The company has been ramping up the investments in innovation since the ‘90s.

Those efforts were crucial in the development of Acheflan®, the first innovative pharmaceutical product 100% Brazilian, originated from the local biodiversity.

Upon the legacy of Acheflan®, the company inaugurated in 2015 its Design & Synthesis Laboratory, first of its kind in Brazil, which internalized a strategic activity in the discovery of innovative small molecules. When applicable, this expertise will be essential in the optimization of library hits into clinical candidates.

It is a unique moment to launch such an initiative, as it combines cutting-edge technologies, technical excellence, the largest vegetable biodiversity in the planet, and a favorable legal framework, with the potential for developing breakthrough therapies from natural sources to treat global unmet medical needs. ●

SOME SUCCESSES of structure-based drug design (SBDD) aided by protein crystallography, include captopril (Capoten) for the treatment of hypertension through the inhibition of the angiotensin-converting enzyme; dorzolamide (Trusopt) for the treatment of glaucoma through inhibition of carbonic anhydrase; several drugs for the treatment of AIDS that inhibit the HIV protease and reverse transcriptase; the anti-influenza drugs Relenza and Tamiflu that inhibit the flu virus surface protein neuraminidase and countless others.

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VACCINE

Instituto Butantan: searching for

partnerships

The Brazilian institution takes aim at securing a share of immunobiological global market

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he hematologist and researcher Dimas Tadeu Covas became Instituto Butantan CEO in 2017. From now on, Covas has been committed to solve a number of bottlenecks – in areas such as research, development and manufacture of immunobiologicals. First and foremost, priority was given to modernize and expand industrial plants – by completing the one dedicated to tetravalent dengue vaccine and remodeling and modernization of the influenza vaccine area, which brought Butantan overall capacity for flu vaccine from 60 million to 140 million doses. This places the institute as the largest producer of flu vaccines in the Southern Hemisphere. In this interview, Covas talks about the past, present and future of institute he directs. “We already are the largest producer of vaccines in Brazil. Now, we in-

tend to conquer other markets. We want to internationalize this amazing institution. That’s why we are looking for partners.”

How would you present Instituto Butantan? There are at least three ways to explain what kind of institution Butantan has been since 1901. Presently, Butantan is the largest producer of vaccines in Brazil. Out of more than 170 million doses of vaccines that annually supply the Brazilian Immunization Program, 100 million are provided by its production. We manufacture 100% of the influenza vaccine used in the program, which allows the country to protect 60 million people from the disease annually. We are also proud to produce 90% of the hyperimmune sera against toxins used in the health system. This way, Butantan gives robustness to our future goals, which is, in the words of the governor of the State of São Paulo, to become the largest producer of vaccines in the world. There

is one aspect of Butantan that explains the position we reached today: in 2021, the institute completes vigorous 120 years - a testament to its institutional resilience.

Word about Instituto Butantan began reaching foreign countries already in the first decades of the twentieth century. Its international reputation came especially from research on snakes and serums to combat the poisoning effects. The first director of the Institute, Vital Brazil, discovered the specificity of the sera against snake poison. Afrânio do Amaral, who directed the Institute later in the 1930s, was at the cover of Time magazine, photographed with a snake in his hand. Important international personalities visited Butantan to watch the extraction of poisons and to know in detail the production of sera. A final example of an illustrious visitor: Theodore Roosevelt, who wanted to meet Butantan and was in the Institute shortly after leaving the US presidency.

What led the São Paulo government to the

decision to create Butantan in 1899, following the Pasteur Institute in Paris, was the need to produce here the anti-pest serum, then missing in the world. An epidemic of plague occurred in the north of Portugal and soon there were cases in the two main Brazilian ports, Santos and Rio de Janeiro. Thus Butantan, from the beginning, had the mission to assure safety in serums and vaccines for the population of São Paulo first, and then all Brazil. The commitment to people’s safety will be the same in this new stage of taking Butantan’s products to the world, especially to the less developed countries that need immunobiologicals at more affordable prices. Butantan is a non profit public institute, which puts us in an advantageous position.

You have mentioned that Instituto Butantan headquarters is in São Paulo’s state.

What is the importance of this location?

For any company interested in building a

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partnership with Butantan, the fact that we are in São Paulo presents its advantages. The economy of São Paulo is the second largest in South America: it only loses in size for overall Brazilian economy. The state’s GDP is close to US $650 billion and represents a third of Brazil’s GDP and 30% of industrial production. In what concerns us more closely, São Paulo holds 77% of the national pharmaceutical market. Of the São Paulo’s GDP, 2.5% comes from the pharmaceutical market: the largest industries in the sector, multinational and national, are headquartered here. That is to say: the so-called Industrial Health Complex resides or depends mainly on the State.

Of the investment in Brazilian Research and Development, 74% happens here. More: the state has the most qualified workforce, the lowest crime rates, the highest per capita income, the best index of human development.

Of the 20 best highways, 18 are in São Paulo.

The largest port in Brazil, Santos, is in São Paulo. As the state governor says, São Paulo is a nation, already has the best business environment in Brazil, and is willing to work to improve it even more.

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Instituto Butantan cooperates with the National Health Organization on the preparation for an eventual pandemics of the H7N9 flu. How can the institute contribute in case of need? Our H7N9 influenza vaccine is already in phase II clinical trials, to demonstrate the quality of our product. In 2018, we invested in the industrial plant with two objectives: to expand it and prepare it for pre-certification by WHO, which we are predicting will happen this year. The factory was practically fully refurbished, from the viral banks to the packaging and the new quality control. With the expansion, our seasonal influenza vaccine production capacity is already at 80 million doses in the period between September - when WHO sends the strains - and March, when the vaccination

campaign begins in Brazil. So we are ready to respond quickly in case of a pandemic; we estimate we will be able to deliver at least 120 million doses to Brazil and the world. This will not be the first time that Butantan has participated in a global effort to combat an influenza pandemic: in 2009 the Institute provided 33 million doses of H1N1 vaccine to the WHO. It is our interest to put this new capacity at the service of the international vaccine market.

We can start supplying vaccines to the northern hemisphere at any time, taking advantage of the different seasonalities. As public producers, we can provide vaccines to poorer countries as well, which need to establish more robust vaccination coverage. We are also working to increase the yield and immunogenicity of our product by the development and use of our own adjuvants to better serve the elderly population. At the same time, we developed the tetravalent vaccine, which is already ready for clinical trials. Vaccines against influenza virus are currently the main product of Butantan and receive our full attention.

The technology used by Butantan on the manufacturing of the flu vaccine results of a transfer process with Sanofi. How do you evaluate this experience? It is possible to describe the technology transfer experience between Sanofi and Instituto Butantan as successful, with it even becoming a model for other Butantan productive development partnerships. The contract was signed in 1999, exactly 20 years ago, and was only concluded in 2011. In exchange for the technology, Butantan offered Sanofi guaranteed access to government procurement of the vaccine for the National Immunization Program.

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The cost of the technology was embedded in the guarantee of sale to the federal government. When Butantan began to produce, the Sanofi product (packaged in the institute) was being replaced by our product, until we reached self-sufficiency. Today, we have ongoing transfer processes with GSK for the acellular pertussis vaccine and with Merck for HPV and Hepatitis A. In part, we have already produced these vaccines here, and in part they are provided by companies.

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At the end of 2018, Butantan signed a deal with MSD on the potential candidate for Butantan’s dengue vaccine. This is an unprecedented agreement for Butantan and Brazil. In this case, concerning this candidate for the dengue vaccine, Butantan started out ahead of Merck. From the recombinant strains for the four serotypes of dengue viruses licensed to us by the National Institutes of Health, Butantan has developed a cell culture process, for which we have a granted patent by the United States Patent and Trademark Office (USPTO). Based on the process, we started producing the candidate looking forward to the execution of clinical trials. Our protocol was to test the vaccine in seventeen thousand people, in different age groups, and we have already concluded the engagement of volunteers. MSD licensed the same NIH candidate, and was interested in accessing the proprietary technology we developed and the data from our clinical trial. The agreement thus puts Butantan in the position of being the partner that transfers technology and information to MSD. This is what is unique: the transfer of knowledge is from the South to the North, and not the opposite, which is the norm for countries like Brazil. During the clinical trials, we built our new dengue factory with a production capacity of 30 million doses per year. Our priority will be the mass vaccination of the Brazilian population. In a few years, everyone will have been vaccinat-

ed. Then it will be time to address the Asian countries, for example, where the epidemics of the disease reach millions of people.

You claim to be searching for new partners for the production of immunobiologics. What kind of partnership draws Butantan interest? We are open to proposals, mainly the ones which combine our strengths with the strengths of our partners.

Our interest is to collaborate to complement the productive chain, co-develop innovative products, transfer technology, agreements of mutual access to technical information. We see these partnerships as essential for the improvement of the Butantan factory park, in order to increase the population’s vaccination security. The internationalization of the Institute, in our view, will advance more rapidly through partnerships. We want to use our experience in the public market of organic products purchases in Brazil to participate in the improvement of health conditions in the public market of other countries.

It is our mission: we are at the service of life in Brazil, and we want to do more for other countries that need our 120 year expertise.

What is ahead for Instituto Butantan on the coming years? We have already started the construction of the monoclonal antibody plant, in which we will produce six different products. We will also increase and improve our packaging line, expand our storage areas and the ability of pilot and scale up labs.

Now our most ambitious project is the construction of a production center for vaccines against HPV, Hepatitis A and B, diphtheria, tetanus, pertussis and acellular pertussis.

The CPV design innovation is its vertical structure, unprecedented in the world. It will be the icing on the cake of our planning, which will require investment of around $750 million. Fundraising has already started and we are optimistic. â—?

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BIODIVERSITY

Bioprospera : A Systematic and Exclusive ®

Platform to Discover and Develop Innovative Medicines from the Brazilian Biodiversity Brazil’s greatest biological diversity, advanced science and legal framework offer a unique opportunity for the development of breakthrough therapies to treat global unmet medical needs

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fter the regulation of the generics market, Brazilian pharmaceutical companies have demonstrated significant growth rates.

The current scenario is one of great competition for market share and price reductions among generics.

In order to gain market differentiation and internationalize the company, Aché has been ramping up the investments in innovation. It has been recognized as the most innovative pharma in Brazil for the last 5 years and is now among the top 10 most innovative companies in Brazil, when all industry sectors are considered (Ranking “Valor Inovação Brasil”).

Bioprospera®, one of the five Innovation Platforms of Aché, aims to discover and develop innovative medicines from natural sources, the Brazilian Biodiversity in particular, which is the largest and most diverse in

the world. The platform is structured to be sustainable in the broad sense of the term.

For example, it relies on both in-house capabilities as well as strategic partners, existing ones, such as Phytobios and CNPEM, and future partners with complementary expertise along the R&D odyssey of an innovative drug derived from or inspired by the Biodiversity.

Bioprospera® is based on two research approaches to discover active molecules and extracts from nature: (i) Ethnopharmacology and (ii) Bioprospection. Using scientific rigor, the former unravels the pharmacological and toxicological effects described for medicinal plants. In other words, differently from the millenary accounts on the use of medicinal plants to cure and prevent

diseases, Ethnopharmacology makes use of systematic bio-analytical techniques and methodologies. When building a pipeline of preclinical programs based on Ethnopharmacology, it is equally important to leverage the available sociocultural knowledge of medicinal plants using secondary data sources and big data analytics.

Bioprospection starts with expeditions and sample collections from different biomes. Aspects like regulatory compliance, traceability, processing, reproducibility, and quality control are very important when building libraries of plant extracts. Nonetheless, the main driver for the renaissance of this approach were the recent advances in analytical instrumentation for both separation and structure elucidation, coupled with the increasing sophistication of bioassays. In other words, it is now possible to obtain bioassay information on much smaller amounts of crude extract as well as isolate and identify the active compound(s) in a complex mixture. High resolution x-ray crystallography using fourth-generation synchrotron light sources, such as Sirius, is playing a major role too in fishing out the active compound from the extract and identifying its structure when bound to the target of interest.

It is important to stress that none of the two approaches, Ethnopharmacology or Bioprospection, lead to extractivism practices of plants that contain active compounds or extracts. As a matter of fact, to manufacture the innovative drug at an industrial scale, the plant is cultivated and harvested following good and sustainable agricultural practices.

Here, it is important to recognize the work of Centroflora, Aché’s long-time partner.

Building upon the legacy of Acheflan®, in a relatively short period of time, Bioprospera® already delivered a success case based on Ethnopharmacology. A first-in-class oral therapy for the treatment of vitiligo, is in clinical trials in Europe. This program is a perfect example of how secondary informa-

tion of sociocultural knowledge of medicinal plants can be turned into a worldwide patented innovative clinical candidate that demonstrates unprecedented efficacy, with the potential to become a blockbuster.

Finally, it should be highlighted that Bioprospera®, a platform that generates (and shares) value from the most biologically diverse country in the world, home of 20% of the global diversity, can only exist in Brazil.

Besides natural resources, the country’s ecosystem also contains scientific know-how and advanced legislation, and Aché, a Brazilian pharma that made a strong commitment to innovation, with significant investments in infrastructure, organizational structure, culture, processes, and technologies over the years. ●

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INNOVATION

Biolab Pharma: synonymous of innovation

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eing among the 5 largest and best pharmaceutical companies in the country and being the national company with the largest share of innovative products in the portfolio”. This is Biolab’s main goal and position that we will achieve with much work and the dedication of a team of professionals who are passionate about innovating.

Thus, we remain more focused than ever and see challenges as opportunities. Our confidence in the country and the advancement of health have not waned.

Do not get me wrong, this optimistic look has solid foundations, as we believe in the work we do, the products we bring to the market and the team that works together so that the results are achieved.

All of us at Biolab work so that we can make the search for innovation in a reality, through new technologies, molecules, medicines, dermo cosmetics, food supplements and health products that help transform lives.

Today, we have two units dedicated to research, development and innovation. One of them is in Itapecerica da Serra (SP), which has more than 100 researchers dedicat-

Dante Alario Junior, CSO - Technical and Scientific President of Biolab

ed to incremental innovations, such as mechanisms for programmed drug release, oral dissolution systems and new formulations and encapsulations, based on technologies such as nanotechnology.

As for the second unit, pioneering is so present in our culture that we are the first Brazilian pharmaceutical industry to have a research center outside the country. The place chosen was Mississauga, in Toronto, Canada.

Having a unit abroad enables us to have more agility in research, in addition to exposing our products in the most demanding regulations of the world certifying our excellence.

But it is not just international challenges that Biolab feeds on. The purchase of Actavis Brasil enabled our company to enter into two new and competitive markets in the country: drugs for the Central Nervous System and Generics.

We are also making efforts to expand our production base. The works of the new industrial complex of Pouso Alegre (MG) are in progress. When the project is completed in 2021, our production capacity will be three times the size it is now, and will reach the regulato-

ry demands for export to the strictest countries in the world.

Today, with its 22 years of history, Biolab already has many important achievements which certify that the right path for our company is to focus on innovative solutions. Photoprot ® and Vonau Flash products are two examples of this successful strategy. Photoprot ® is the first photoprotector with factor 99, made with Nanocapsules. Vonau Flash ® uses new technology for immediate oral Dissolution (Flash), which enables it to be absorbed faster by the body.

Both products were developed with the partnership of universities: Photoprot with the Universidade Federal do Rio Grande do Sul and Vonau Flash® with the Faculdade de Ciências Farmacêuticas of Universidade de São Paulo.

With all these news, our expectations for the future could not be better. For us, it is a great achievement, despite the normal challenges of the market, to be a strong company, which grows year after year.

Over two decades of work, the company has planted seeds that bear fruit to this day. Our expectation is to reap even more and plant good seeds for the next generations. ●

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CANNABINOIDS

Therapeutic and commercial potentials of

cannabinoids

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ne of the oldest plants known to man is Cannabis. The earliest citations for its use appear around 2723BC in the oldest known medicinal text, the Shen Nung Pen-Ts’ao King (in Chinese), which classifies drugs as tonic, effective and toxic. It was used for menstrual cramps, asthma and skin inflammation. Also, from very early on (according to millennial documentation of Chinese, Persian, Hindu and Greek), marijuana and hashish obtained from hemp - a species of the Cannabis plant - were used to ameliorate physical and spiritual ills.

Cannabis is commonly divided into three species: C. sativa, C. indica and C. ruderalis.

However, this classification does not follow a consensus among taxonomists, for whom the prefered classification is in a single species, Cannabis sativa L. (Linneaus) with subspecies sativa, indica and ruderalis1.

Whether they are different species or subspecies, these three varieties of Cannabis present differences, mainly in relation to the composition of their chemical constituents, called phytocannabinoids - a collection of more than 100 chemical compounds found in the plant.

The primary targets of these phytocannabinoids are receptors in our body, called endocannabinoid receptors CB1 and CB2. After the discovery of these receptors, a therapeutic strategy of direct inhibition of the receptors was adopted. One of the first drugs that directly blocked these receptors unfortunately resulted in a troubling failure. In 2006, the European Medicines Agency approved an anti-obesity drug, called rimonabant, which suppressed hunger by direct inhibition of the CB1 receptor. Two years later this drug was taken off the market because of the risk of developing psychiatric disorders, including depression with suicidal tendencies 2.

However, another approach strategy to

HGSM Consulting (Eder de Carvalho Pincinato; Margarete Akemi Kishi; Heitor Pineda and Sthefan Ferrari)

use these compounds is based on the derivation of CB1 and CB2 inhibitory drugs (among others), starting from the plant. This strategy opens up a huge range of therapeutic possibilities.

CANNABIS SATIVA HERBAL MEDICINE - THE TREASURE KEY At present, we are experiencing a particular global moment of rediscovery of the therapeutic properties of Cannabis, as well as the recognition of some countries regarding the right to autonomy of the medicinal and recreational use of the plant. Brazil, for its part, experiences a significant variety of claims, especially from some social, political and scientific movements. These movements signal the current need for regulation of marijuana for medical purposes, mainly motivated by high import costs, bureaucracy and urgency for the treatment of diseases by the administration of cannabinoids (epilepsy, sclerosis, anorexia, neuropathic pain, fibromyalgia, etc.).

One of the first medicinal products derived from Cannabis extract approved for therapeutic use was nabiximol (Sativex, GWPharma) in the form of spray for oral absorption. This medication has been used in the treatment of spasticity derived from multiple sclerosis, neuropathic pain, among others. Subsequently, two other synthetic cannabinoid drugs mimicking the effect of tetrahydrocannabinol (THC) were also ap-

proved. Nabilone (Cesamet, MEDA Pharmaceuticals) and dronabinol (Marinol, AbbVie)3. Among the cannabinoids currently studied, cannabidium (CDB), which according to the European Pain Federation, has scientifically proven indication for use in cancer pain, chronic neuropathic pain, rheumatic pain, refractory epilepsy, among other conditions, however, should always be used when conventional treatments have failed in their expected control.

Nonetheless these are just a few examples of the enormous therapeutic potential and the varied products being researched around the world. As one very bold example of the applicability of their compounds, executives from companies like AB InBev, Heineken, Coca-Cola and Diageo left their traditional drinks aside and went to understand how this universe works. According to the Canadian newspaper The Globe and Mail, the companies have begun a rapprochement with some of Canada’s leading producers of Cannabis 4.

According to experts, the worldwide market for the therapeutic use of Cannabis is estimated at $ 19 billion, and if the US legalizes the market, sales in this country alone could reach $ 80 billion by 2030⁵. Although controverse, the use of cannabinoids is becoming a reality.

The market trend is huge and we expect to see some regulation unfolding coming from several countries in the next year or so 6. ●

1. Small E, Cronquist A. A practical and natural taxonomy for cannabis. Taxon. 1976;25:405–435.

2. Nature, volume 525, pages S6–S8, 2015.

3. Neurotherapeutics. Oct;12(4):731-4, 2015.

4. https://www.em.com.br/ 5. Owusu, T. Cowen’s Cannabis Analyst Raises 2030 U.S. Market Forecast to $80 Billion. The Street.In:https://www.thestreet.com/investing/ cowen-cannabis-analyst-raises-2030-us-market-forecast-to-80-billion-14828252. Ao em 03/03/2019 6. Umpieres, RT. InfoMoney. In: https://www.infomoney.com.br/mercados/acoes-eindices/noticia/7623857/investidores-ganham-2.000-com-maconha.-e-tudo-dentro-da-lei

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FUNDING

Brazil, ready to play in the Big Leagues?

Marcel Frenkel Co-founder, Gavilán Biodesign

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razil will become the 5th largest pharma market by 2021, but is it ready to develop its own novel therapeutics?

It is no mystery that Brazil is rich in natural products and unexplored chemistry. The biologic diversity of the Amazonian rainforest may very well be unrivaled anywhere else in the world.

Currently most FDA approved drugs are either variants of or natural products themselves. Therefore, fast and privileged access to unexplored natural products can be a major advantage to Brazilian companies, and help them develop effective, novel, IP-unrestricted, chemical matter. Even so, only access to raw materials is not enough to warrant enthusiasm about Brazil’s national drug development, as other factors must be ready to accommodate the development efforts.

Manufacturing is key, and for years Brazil has excelled in developing and distributing generics.

Brazil’s pharmaceutical companies have developed state-of-the-art synthesis and purification facilities that are effective and highly regulated.

The widely successful national production of generics and their mass distribution to what is the largest socialized healthcare system in the world has proved that Brazil owns

the production capabilities to develop novel therapeutics nationally.

One important characteristic that should not be overlooked is Brazil’s rich ethnic diversity, which few other countries in the world possess. This rich ethnic composition allows clinical trials in Brazil to sample multiple genetic backgrounds and to understand the effects these differences may have on efficacy and side effects of a given therapeutic will hopefully help reduce population bias in drug development. This also allows therapies developed in Brazil to understand what markets they should or should not seek regulatory approval.

Moreover, ANVISA, Brazil’s regulatory agency, has achieved important milestones in its modernization, culminating in 2016 when Brazil became a member of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Being a member of ICH guarantees that Brazil’s drug approval process is world class. This combined with the diverse genetic backgrounds found in the Brazilian population, make Brazil an ideal place for clinical trials.

With both the regulatory and technical sides suggesting that Bra-

zil was ready to develop its own therapeutic pipeline, Brazil’s R&D remained in question. Brazil answered that question in style by opening Sirius, a R$1.8B state-ofthe-art synchrotron poised to revolutionize Brazil’s rational drug design efforts. Sirius makes Brazilian companies attractive partners for startups like Gavilán Biodesign.

Gavilan’s platform uses structural data, like the one produced by Sirius, as input. Gavilan’s in silico drug design platform simultaneously optimize for dozens of drug-like properties, including a unique feature: designing for resilience to drug resistance. This decreases development cost while maximizing revenues and tackling a major source of therapeutic failure.

Gavilan is willing to invest in Brazil by partnering with Brazilian companies and leveraging its discovery platform to help Brazilian companies fast track new therapeutic assets.

With preferred access to a wide variety of novel chemical matter, a strong manufacturing and distribution history, a rich multicultural population, a modernized regulatory agency, and a demonstrated commitment to R&D, Brazil has emerged as an exciting market for investment in the drug discovery space. ●

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Health in Brazil:

scenario and investment opportunities

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or most countries in the world, health currently represents one of the main industries in terms of expenditure. According to the World Bank, in 2015 the total spending on health globally amounted to USD 7.40 trillion, with an average annual growth of 3.3% from 2010 to 2014, above the global GDP growth in the same period, which was 2.5%. In Latin America, spending on healthcare totaled USD 404 billion. Brazil is the largest health market in the region, representing 39% of the total amount, with US$ 160 billion spent in 2015, followed by Mexico and Colombia as the main health markets in the region.

With a per capita spending on health 75% above the average of the 20 largest emerging economies, Brazil is the 8th largest health market in the world. In Brazil, health services

can be accessed in two ways: through the public health system, in the form of the Brazilian National Health System (SUS), or through the supplementary health system. SUS is a public health program that allows universal access to providers of health services by part of the population. Supplementary health, regulated by the National Regulatory Agency for Private Health Insurance and Plans (ANS), ensures the population’s access to service providers that have no agreement with SUS, by means of private health plans. Unlike other countries, the access to the private system in Brazil does not prevent one from accessing the public health system. Therefore, it is a supplementary health system to that offered by SUS. SUS is the world’s largest public health system with universal coverage, and the only one with legal provision for the supply of pre-

scription drugs. SUS was fully responsible for providing health services to 75% of the Brazilian population in 2017. Other indicators reinforce the importance of SUS: it is responsible for 43% of health expenditures in Brazil (2015), 59% of hospitalizations (2016), 53% of medical exams (2016) and 98% of vaccines (2016). From the industry’s point of view, the main advantage of SUS is that it is only a source of payment, which negotiates centrally with the medicine and health products industry, unlike the supplementary health operators, which totaled 766 companies in 2017.

In general, three main factors increase Brazil’s competitive advantage as a destination for foreign investment: the size of its health market, the relevance of SUS as a centralized decision maker that affects 75% of the population, and the high rate of local competitiveness, fragmenting the market between local and global players. The growth of the health industry in Brazil should continue in the coming years due to six main trends: the aging of the population, the increase in average income, the increase in chronic diseases, the incorporation of new technologies, the transformation of the patient into a consumer of services, and the judicialization of health.

The growth trend of biotechnology-based drugs is also very strong in Brazil. In 2016,

they already accounted for 19% of total market revenue, while globally this figure was 25%. In terms of sales, biological drugs grew 45% between 2015 and 2016, well above the 19% growth in generic drugs and 15% in new prescription drugs. In recent years, there has been a growing share of imports to supply the Brazilian market. Regarding pharmo-chemicals, for example, imports increased from 71.2% in 2010 to 77.4% in 2015. The same occurred with prescription drugs: 21.9% to 26.3%. The growth in the pharmaceutical preparations industry was even higher, with an increase of almost 15%: from 16.3% in 2010 to 30.3% in 2015. In 2017, Brazil imported a total of US$ 6.1 billion in pharmaceutical products.

All these trends, summed up, have the potential to boost two sub-sectors in particular: pharmaceutical and health products. This is the main object of the strategy for FDI attraction (FDI) by the Brazilian Trade and Investment Promotion Agency (Apex-Brasil). Brazil is the second largest pharmaceutical market among emerging countries – only behind China – with a total volume of BRL 73.7 billion in 2016. In the coming years, the sub-sector is expected to grow 7.9% per year and reach the amount of BRL 107.7 billion in 2021. On the other hand, the health products sub-sector handled a smaller volume, BRL 14.9 billion

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in 2016, which still ranks Brazil as the 3rd largest emerging market. Projections indicate that the trade sector should grow 5.8% in the coming years, reaching BRL 19.7 billion in 2021.

When it comes to FDI attraction to the health industry, one of the frontline players is indeed Apex-Brasil. With a series of free services, the Agency seeks to help foreign companies and investors find their way to prosper in Brazil through investment opportunities.

Apex-Brasil’s efforts are focused on attracting two types of investment: foreign companies that wish to establish production facilities in one of the largest and most dynamic markets in the world, and venture capital aimed at supporting foreign investors to find good results through investment opportunities in creative and innovative companies in Brazil.

In 2018, a study on the health industry was carried out by Accenture for Apex-Brasil, in order to define the strategy for foreign direct investment attraction in the Brazilian health industrial complex. From the data cross-checking, 10 segments were prioritized for FDI attraction, 5 in each of the sub-sectors. All of them present good market prospects, are relevant to SUS, and have competitive advantages for manufacturing in Brazil.

In the Pharmaceutical sub-sector: Oncology and Immunomodulators; Digestive System and Hormones; Neurology; Respiratory System; and Cardiovascular System.

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In the Health Products sub-sector: In Vitro Laboratory/Diagnosis; Consumer Materials; Radiology; Patient Care; and Orthotics & Prosthetics. For each sub-sector and its prioritized segments, a value proposition was prepared seeking to highlight the Brazilian characteristics, whether demographic or governmental, that make Brazil a better, superior FDI target market.

Thus, Apex-Brasil has the tools to show foreign investors the most attractive and competitive segments for their business in Brazil.

Apex-Brasil is ready to help in all stages of the investment process. Its service portfolio includes identification and contact with potential partners in a specific segment of the Brazilian industry, and the provision of information on more specific aspects, which will help future investors to better understand Brazil. Apex-Brasil prepares reports covering market industry and sectors, economic trends, general guidance on legal and fiscal issues, mapping and scheduling of meetings with key stakeholders, such as government and private institutions, as well as information on entry costs, appropriate site location and availability of talent/workforce. It also supports foreign investors willing to identify local companies, universities and research centers to establish partnerships, joint ventures or other types of collaboration. Additionally, Apex-Brasil can assist capital investors in the process of identifying venture capital opportunities, projects and companies, and also private equity investments in the country. ●

References: Fitch solutions. 2019. Brazil Pharmaceuticals & Healthcare Report.

Available in: https://store.fitchsolutions.com/all-products/brazil-pharmaceuticals-healthcare-report Fitch solutions. 2019. Brazil Medical Devices Report.

Available in: https://store.fitchsolutions.com/all-products/brazil-medical-devices-report Apex-Brasil. 2018. Estratégia de atração de investimentos estrangeiros diretos no complexo industrial de saúde no Brasil.

IBGE. 2017. Conta-satélite de saúde: Brasil : 2010-2015 Rio de Janeiro. IBGE, 2017. Available in: https://biblioteca.ibge.gov.br/visualizacao/livros/liv101437.pdf

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Status of the registration of biological drugs in Brazil

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“NVISA’s goal is to stay up to date to the policies of the world’s top regulatory agencies when concerning biosimilars. We welcome companies to discuss how those products will reach the market with the adequate quality, safety and efficacy levels, possibly allowing a larger share of the population to have access to this class of therapies, due to their lower prices.” This statement by Daniela Marreco Cerqueira, deputy director of the Second Direction of Anvisa, is a good overall picture of nowadays Brazil’s regulatory framework, critical to the development of the market for biological and biosimilar products in the country.

There is considerable expectation worldwide for biosimilars to amplify the access to therapies which carry a heavy financial burden on patients and public health system.

Specially in Brazil, the Ministry of Health reports in late 2016 that although only 4% of the drugs SUS (Brazil’s public health system) purchases are biotherapeutics, and this small share represents 51% of the system’s expenditures¹. The shift to biosimi-

lars could help ease the costs of treatment to a tight budget health system.

According to Daniela, who was until recently manager of the GPBIO, the agency’s department for biological products, the main regulatory legislation for biotherapeutics and biosimilars in Brazil is the “Resolução da Diretoria Colegiada (RDC) nº 55”, released in 2010. It allows registration in three different paths: the full complete dossier, applied to new biological products; the individual path, in which non-new and non-comparable products are registered, such as vaccines and blood products; and the comparison path, used to register biosimilar products, which asks for full set of data on quality, safety and efficacy of the referred product, referencing the previous, already registered product. All of the three paths are analyzed with an equal timeframe by the agency, except prioritized

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products covered by the 204 and 205 resolutions published in 2017. The speed of the analysis process is also linked to how fast applicant companies respond to the demands made after the original due evaluation of the agency, which depends on the quality of the presented documents and dossier.

“The standards that ANVISA requires for the registration of biosimilars are in line with requirements made by other regulatory agencies in the world”, says Daniela. “There is no prospect or need of changing legislation for this year”, she follows, concerning the outlook of ANVISAs actions for 2019. A review of the RDC nº55 is scheduled to start in 2020. Regarding interchangeability, a subject which inspired many doubts on applicants in the near past, the agency published a clarification note in 2017, explaining it will not consider biosimilar products as interchangeable, a position also taken by other foreign regulatory agencies. ANVISA’s Biologics department will focus 2019 on producing clarifying content for the community interested in biologics, such as a hotsite with information for the general public and a brochure for health professionals. The main challenges faced by the agency for registering biological and biosimilars were overcome back in 2010, when the RDC nº55 was first published. The analysis team nowadays is as qualified and effective as other agencies, Daniela explained, and the goal is to stay up to date with the latest developments in the field. Discussing with the Ministry of Health how those medicines will gain access to a larger public will be necessary, but usually biosimilars can reduce the cost of a therapeutics in up to 70% of the original drug’s price.

According to Daniela, there is no clear pattern on the main errors committed by applicants when trying to register products.

Some attention points are the comparability

in terms of pharmaceutical technology, when the applicant fails to demonstrate that the molecule of the biosimilar product is dissimilar to the product already registered and when the clinical trial is unable to prove that the existing differences between products have no impact on the safety and efficacy of the product. Applications were also received without complete clinical studies and lack of presentation of comparative immunogenicity between the two products, which prevents the granting of registration. ANVISA publishes the reports of its every analysis and this can be helpful for requesting new products registration in a complete way, streamlining the licensing process.

Daniela believes that the new law of biodiversity access, published in 2015, will help boost new entrants of a forthcoming path of registry (which is currently in the public consultation stage) for diminished complexity biological products. It is expected that within this modality there will be an increase in the entrance of registry applications and some products derived from Brazilian biodiversity may fit into this category.

The use of biosimilars can greatly impact the overall cost of treatment for diseases such as cancer. Furthermore, it can ease the high volume of resources dispensed in high value medicines, and with a good and agile regulation maintain and expand the quality and effectiveness of treatments for the country.

Daniela’s and ANVISA’s view put Brazil on the same page as the benchmark regulation in the world, placing the county in a premier position for the growth of this market. ●

1. http://portalms.saude.gov.br/noticias/agencia-saude/26775-saude-investe-r-443-mi-para-producao-de-medicamentos-biologicos

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Actions and initiatives of the Ministry of Health to foster innovation ecosystems in Brazil

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018 was a blooming year for Brazil’s innovation and startups ecosystem. Early in January, “99”, a brazilian car share startup, was acquired by Didi, becoming the first Brazilian unicorn. After that, six others followed suit (Movile/iFood, PagSeguro, NuBank, Stone, Arco Educação and more recently, GymPass), by way of acquisition, IPO or growth in value, in areas such as fintech, logistics and education. This fertile period for high flying startups has placed the country among other technology powerhouses.

With recent changes to legislation regarding Science and Technology (the new regulation mark is active for almost three years) and venture capital, 2019 holds both the challenge of living up to the expectations created after

such a prolific year as 2018, and the potential to be even better, with the further maturing of the ecosystem¹. According to ABStartups, the Brazilians Startup Association², the country is home to 10.200 startups, 20% more than in 2017, and a galloping investment scenario.

One of the areas showing promising signs of growth and which will be buzzing is healthtech. Health related expenditures represented 9,1% of the Brazilian GDP in 2015, a number which is projected to climb to 11% by 2040.

Moreover, Brazilian public health system, Sistema Único de Saúde (SUS), is responsible for 43% of pharmaceutical sales in South America, leading the region with a large margin over Mexico, which is responsible for 17%. In a global perspective, Brazil is expected to become the world’s fifth largest pharmaceutical market

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by 2020³. Those two pieces of information are a good measurement of just how relevant Brazil’s health market is and its upward trend.

Leading the way on health innovation, prominent private players in Brazil’s ecosystem have already been nurturing ways of establishing their policies. In the past decade, in addition to already active solid research and development departments, capable of improving products and services, it is becoming more and more trendy to open a direct line to the innovation ecosystems, specially startups and universities. Being via open innovation, corporate venture or other strategies, companies are increasingly adding innovations to their structures, products and services.

But what about the role of the public sector in this process? As one of the main financial driving forces in the region, the government must take action to join and facilitate this innovation revolution. More than so, it is its constitutional duty, says Thiago Rodrigues dos Santos, Director of the Department of the Industrial Complex and Innovation in Health - DECIIS, within the Secretariat of Science, Technology and Strategic Inputs (SCTIE) of the Ministry of Health (MS). He cites the articles 218 and 219 of the 1988 federal constitution as the legal framework for health innovation in Brazil, which enforces to the State an obligation to promote and encourage scientific development, research and technological training. Furthermore, the Constitutional Amendment No. 85 of 2015 amends and adds provisions in the Federal Constitution to update the treatment of Science, Technology and Innovation activities.

Apart from what is stated in the law, what has the Ministry of Health been doing to promote health innovation and entrepreneurship in Brazil? Thiago highlights the Programa para o Desenvolvimento do Complexo Industrial da Saúde (PROCIS) or Industrial Health Complex Development Program, created back in 2012. Its goal is to strengthen the technological infrastructure of Public Laboratories

and Science and Technology Institutions, using an legal instrument called Partnerships for Productive Development (PDP) that aim to increase the participation of public laboratories in the production of medicines for SUS, employing the use of the State’s purchasing power.

Another important development was the inclusion, in March 2018, of the Ministry of Health as an intervener and member of the Board of Directors of EMBRAPII (Brazilian Association of Research and Industrial Innovation), which is, since 2013, one of the main programs established to support technological research institutions fostering innovation in Brazilian industry. MS sees this role as a part of the management of EMBRAPII as a key strategy to overcome one of its perceived challenges regarding innovation in Brazil, the technological risk centralization. The most usual ways of promoting innovation focus on credit and repayable financing, and are able to reduce the cost of projects, but not the technological risk inherent in the process.

The absence of risk sharing mechanisms has been the main bottleneck for companies’ participation in projects linked to SUS demands, that is, the participation of companies in innovative processes linked to the public demand for new technologies and not the technological supply. The institution of Embrapii and the participation of the Ministry of Health in the management contract signed with Ministry of Science, Technology and Communications (MCTIC) aims to overcome this challenge and to reverse the logic of technological supply to the logic of technological demand. The strategic goals which should guide

DEVELOPMENT

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this partnership are, namely: (i) overcoming economic bottlenecks and the technological lag of SUS; (ii) to improve the performance of research institutions in the development of technological innovation projects with companies operating in the field of (CIS); (iii) to establish new models of operationalization, improved to the health area.

Thiago believes that regarding the new access to biodiversity law, MS participation in committees will assure correct development of the country. The participation in the committees is aimed to strengthen its representation on the agenda as well as assist in meeting the frequent demands of the Federal Public Ministry related to the attributions of Public Health. MS is a part of the Conselho de Gestão do Patrimônio Genético or Genetic Patrimony Management Council (CGEN) board, which is responsible for coordinating the elaboration and implementation of policies for the management of access to genetic heritage and associated traditional knowledge and benefit-sharing. Another MS concern that deserves attention is marine life. By being a member of both the Comissão Interministerial para os Recursos do Mar or Interministerial Commission for the Resources of the Sea (Cirm), which counts with the participation of several representatives of the executive branch for the definition of execution of the National Policy for Marine Resources (PNRM), and the committee of Marine Biotechnology or Comitê de Biotecnologia Marinha (Biomar), with the objective of promoting the study and sustainable exploitation of the biotechnological potential of marine biodiversity, aiming at the scientific, technological and economic development of the country, also linked to the attainment of the United Nations Sustainable Development Objectives, ODS 14 - Conservation and sustainable use of the oceans, seas and marine resources, by developing marine technology research and transfer capabilities.

To strengthen SUS is a very pressing matter for the MS. One way of doing that is to en-

hance Brazil’s national scientific and technological infrastructure. Thiago points out that among the ten largest companies active in the Brazilian market, four were born in the country and are first, third, fourth and fifth in market share. He emphasizes the actions of MS in investments for the implementation of Multi User Health Research, Development and Innovation Centers in ICT, with plants for the production of pilot lots of pharmacotechnical units (synthetic and biological) under Good Manufacturing Practices (GMP) conditions. Other than that, one can notice the efforts used with Technical Cooperation Terms to promote an environment favorable to innovation in Health with the following main purposes: i) to implement the processes of innovation and development of priority technologies; ii) to support improved regulatory strategies with transversal actions conducive to development and innovation; iii) to promote international cooperation in the production and innovation system; and iv) enable actions related to technology transfer, technological ordering and technology compensation in health. Finally, it is worth mentioning the Plan of Action of Clinical Research composed of a series of strategic actions distributed in 6 axes that aim to: (a) improve the system of ethical analysis in research involving human beings; (b) support Anvisa in improving the regulatory system for clinical research; (c) improve the country’s installed scientific capacity in clinical research; (d) promote the continuing training of human resources in clinical research; (e) improve the governance of the National Clinical Research Network (RNPC); and (f) support the translation and dissemination of knowledge in clinical research.

For 2019, strategic partnerships are an important part of the national strategy for development, strengthening and innovation within the Industrial Health Complex (CIS). The Partnerships for Productive Development (PDP) modality is one of the most effective

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tools aimed at consolidating the national production of strategic technologies to meet the demands of SUS, optimizing the public procurement processes of the Ministry of Health, since the internalisation of strategic product technology for SUS, the national public producers become holders of the technology, reducing the productive and technological dependencies and rationalizing the purchasing power of the State. The PDPs involves cooperation through agreement between public institutions and private entities for the development, transfer and absorption of technology, production, productive and technological capacity of the country. Currently, of the Partnerships for Productive Development (PDP) there are 93 in force, of which 81 are Synthetic and Biotechnological, 05 of Vaccines, 01 of Hemoderivative and 06 of products for health.

The regulatory framework on PDPs is under review and seeks to fill some regulatory gaps, especially regarding procedural rite and price issues. But above all, it is intended to provide more sustainability conditions for strategic projects for SUS, such as PDPs for biological products, vaccines and blood products. Regarding synthetic products, aspects related to the national production of active pharmaceutical ingredients (IFA) gain more attention and detail. Thus, the new management is in the process of evaluating the current partnerships and definition of new guidelines for maintaining those that are more strategic for SUS. In a recent report published a year ago, Liga Ventures mapped the Brazilian Healthtech sector. They identified 263 startups which had products or services related to any of the following areas: Autism, physical and mental well-being, Business Intelligence/ Artificial Intelligence/Big Data/Analytics, Search and Schedule engines, physical spaces, blood glucose, hard sciences, Information/Training/Learning, Internet of Things, drugs and equipment marketplaces, nutrition, health insurance plans, medical records and prescriptions, prostheses, health on demand, health management systems, systems of images, reports and exams and telemedicine. The categories with the most abundant startups were Health Management Systems and Hard Sciences. SĂŁo Paulo is by far the city with the most startups, followed by Belo Horizonte. The growth of this sector is clear from 2015 and 2016, the years when most startups were founded. The hope is that from now on, with the incentives from the MS, the new biodiversity access law, the new science and technology legal framework and the maturing and development of the venture capital market, this number will grow substantially.â ´ â—?

1.https://www.forbes.com/sites/angelicamarideoliveira/2019/01/23/2019-the-year-of-tech-startup-exits-in-brazil/#7a3b209875a3 2. https://abstartups.com.br/PDF/radiografia-startups-brasileiras.pdf 3. http://portalms.saude.gov.br/noticias/agencia-saude/43402-autoridades-debatem-investimentos-no-setor-saude 4. https://insights.liga.ventures/healthtechs/

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Brazilian biotech sector

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he Convention on Biological Diversity defines biotechnology as “any technological application that uses biological systems, living organisms, or derivatives thereof, to make or modify.”.

Therefore, to be considered a biotech company it is necessary to have a product or service that can be applied in the market. A study done by CEBRAP (The Brazilian Center of Analysis and Planning) mapped 237 biotechnology companies in Brazil, and according to SINDUSFARMA (The Syndicate of the Pharmaceutical Products Industry in the State of São Paulo) in 2017 the Brazilian biopharmaceutical and biotechnology market was worth about US$ 18 billion.

Most businesses are working with human health (39,7%), followed by two critical sectors: animal health and reagents. Biotech companies that work with agriculture represent 9,7% and can grow even more since it is a vital area for Brazilian GDP. It is important to consider that many biotechnology companies can apply their products and services in several fields and the search done by CEBRAP considers only each companies main acting area.

The graphic above shows the distribution of biotech businesses around Brazil. The Southeastern region has the highest concentration of companies (78,1%) represented by São Paulo (SP), Minas Gerais (MG), and Rio de Janeiro (RJ) States.

The south region holds 13,9% being Paraná (PR) and Rio Grande do Sul (RS) the States with the

THE 237 COMPANIES MAPPED ARE DIVIDED INTO THE FOLLOWING AREAS GRAPH 1 - DISTRIBUTION BY AREA

OTHER SECTORS 8,4% ENVIRONMENT 9,7%

BIOENERGY 5,1% HUMAN HEALTH 39,7%

AGRICULTURE 9,7% REAGENTS 13,1%

ANIMAL HEALTH 14,3%

GRAPH 2 - DISTRIBUTION OF BIOTECH COMPANIES PER STATES CE 1,7% PE 4,2%

MG 24,5%

PR 4,6% RS 8,0% RJ 13,1%

SP 40,5%

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biggest contribution, and the Northeastern accounting for 6,3%.

São Paulo (SP) has a vast amount of those companies. The city represents 18% of all Brazilian biotech companies , while Belo Horizonte (MG) follows at 13%. These two cities are biotechnology hubs, with an ecosystem of companies, startups, business incubators and accelerators, research centers, universities, and government institutions.As a result of the actions of this innovation ecosystem participants, a high number of companies are also nearby those cities.

Providing the right environment is key to developing innovative companies and startups. The study showed that 50,3% of biotech companies are, or have been, in a business incubator.

A research done by Biominas Brasil show that Brazil has a total of 140 business incubators, but not all of them have the infrastructure to really help biotech companies in their early stages. That same logic also applies for the 50 businesses accelerators. Most of those incubators are linked to universities and technology parks, creating a connection between the academy, entrepreneurship and the market.

The accelerators are often close to major universities and relevant cities of the innovation ecosystem such as São Paulo and Belo Horizonte.

That same research mapped 222 startups and research projects in Brazil that focus on biotechnology for human and animal health. Those numbers show that Brazil has the potential to grow and develop new biotech companies, but it is necessary to invest in the alignment between all players, such as investors, startups, researchers, consumers, etc. That alignment is being done by government agencies,

innovation centers within universities and private institutions, such as Biominas Brasil, that are dedicated to fomenting the biotech ecosystem.

Biominas is a private institution with 29 years of national and international experience. Its core business is innovation and entrepreneurship in Life Science.

Biominas creates and develops innovative businesses from promising ideas and projects originated from universities and research centers. Biominas helps large and medium-sized companies that want to innovate and improve their connections with startups and researchers.

Government agencies, universities and institutions like Biominas need to provide guidance to startups and companies so they can understand the market and provide their solutions efficiently. They also need to provide

initial low-cost infrastructure, since biotech requires high investments, and new companies need a place such as incubators to start their businesses.

As most startups and projects mapped are in the health sector, they too need access to information. They need to be aware of intellectual property and regulations, so it’s possible to innovate according to government rules.

The biotechnology industry is known for its complexity and investments in R&D. To succeed it is fundamental to invest in innovation and research. One way to measure a country’s investments in R&D is to analyze the intellectual property system: The National Institute of Industrial Property (INPI) is the official government body responsible for Industrial Property rights in Brazil, a federal au-

GRAPH 3 - NUMBERS OF PATENTS FIELDED BY AREAS FROM 2012 TO 2016 Microorganisms, enzymes and their compositions

860

Medicines

586

Fermentation and recovery of by-products

448

Peptides

367

Measure and test involving microorganisms or enzymes

253

Analysis of biological material

218

Agriculture

169

Environment

167

Devices for enzymology and microbiology Food and drinks

130 77

Nanobiotechnology

38

Genomic and proteomic libraries

28

tarchy of the Ministry of Industry, Foreign Trade and Services. Its mission is to stimulate innovation in technology services in Brazil, through the efficient protection of industrial property.

INPI released a study about overall status of the biotech sector in Brazil, showing the number of patents filed, the technologies’ origin, and the main depositors from 2012 to 2016.

For this study, INPI classified biotechnology in 12 areas. As presented in graph 3, those 12 areas have 35 categories to better represent the patents. Following that classification, “Microorganisms, Enzymes, and their Compositions” represent 25,7% of all patents filed in that period, followed by “Medicines” with 17,5%. The area with less representation is “Genomic and Proteomic Libraries” with 0,8%.

Agriculture and environment are fundamental fields for Brazil’s economy and hold 10,1% of patents filed.

55% of the main patents depositors in Brazil are universities, representing 10% of all patents filed in the period. Those numbers prove how relevant it is for companies to connect with universities and create relationships with researchers. That also shows Brazil’s potential to foster new businesses, startups and create innovation clusters. It is significant to highlight the universities from Minas Gerais and São Paulo, the ones with most patents filed, proving their status as biotech hubs.

Brazil is the birthplace of 28,6% of technologies whose patents were filed between 2012 and 2016. It is safe to presume that most of those technologies are from universities since they are responsible for most of the patents deposited in the coun-

GRAPH 4 - MAIN DEPOSITORS FROM 2012 TO 2016 UFMG (Brazil)

79

Dow Global Technologies (USA)

63

USP (Brazil)

63

UNICAMP (Brazil)

46

Nestec (Switzerland)

39

Embrapa (Brazil)

29

Hoffmann La Roche

27

UFPR (Brazil)

26

UNESP (Brazil)

25

UFRJ (Brazil)

24

UFRGS (Brazil)

23

UFPEL (Brazil)

19

UnB (Brazil)

19

BASF (Germany)

17

Novatis (Switzerland)

16

UFV (Brazil)

16

Du Pont (USA)

14

Petrobras (Brazil)

14

UFU (Brazil)

13

DMS (Netherlands)

12

GRAPH 5 - MAIN BIOTECH TECHNOLOGIES ORIGIN FROM 2012 TO 2016 Brazil

955 649

Canada

602

USA 435

South Korea EU

213

Australia China Japan

133 99 71

try. Furthermore, it is relevant to recognize the influence of foreign companies in Brazil, since a number of them invest in innovation in the country and create positive relations with local startups and researchers.

This Brazilian biotech sector overview shows the investments that are being done in recent years to improve and grow biotechnology in Brazil. To innovate and generate

new business opportunities is crucial to continue to invest in R&D, patents and create ways to nurture startups, researchers, and entrepreneurs. The number of startups and research projects in biotech is growing in Brazil, presenting a positive panorama for companies that aim to expand investments, market share and develop more products and services in the country. ●

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