In 2012, four Brazilian laboratories—Biolab, Eurofarma, Cristália, and Libbs—joined forces to create a joint venture focused on the production of biologically engineered drugs for treating complex diseases. To lead Orygen Biotecnologia they hired British biochemist and naturalized Brazilian citizen Andrew Simpson, then scientific director of the Ludwig Institute for Cancer Research in New York. “It was a fantastic opportunity,” he recalls.
Having already led both the genome sequencing of the Xylella fastidiosa bacterium in Brazil and the Brazilian team that participated in the international program to sequence the human cancer genome, Simpson believes one of Orygen’s main innovations is its organizational structure. “The company is organized like a startup, but it’s linked to the well-established pharmaceutical corporations who are supporting it. We’re looking for a way to establish ourselves as a Brazilian biotechnology company. There isn’t a model which we can copy,” he adds.
In this interview, he discusses the challenges of running a company focused on developing highly complex drugs, such as monoclonal antibodies (laboratory-produced proteins for combatting diseases such as cancer and autoimmune disorders) and recombinant vaccines (vaccines made from illness-causing components of viruses or bacteria—not from the attenuated or inactivated microorganism itself, as with conventional vaccines.) If all goes well, Simpson says Orygen’s first drugs—a flu vaccine and a rheumatoid arthritis drug—will hit the market next year.
Orygen was created with the purpose of manufacturing innovative pharmaceutical products that use biotechnology. Has this goal been met?
Actually, our initial goal was more focused. Orygen was created to work on the development of biosimilar monoclonal antibodies, a type of biologic medicine, within the federal government’s Production Development Partnerships (PDPs) program. This project is taking a long time to develop, not only at Orygen, but also with Brazilian pharmaceuticals in general, for one simple reason: the patents for the originator antibodies are only now expiring.
What are Production Development Partnerships?
The PDPs were implemented by the government to enable publicly funded labs to produce strategic drugs for the Unified Health System (SUS). To participate in the program, a Brazilian private company must sign an agreement with a multinational that already owns a certain technology, and form a partnership with a publicly funded laboratory to which this technology will be transferred. We’re in the middle of the process. We’ve already established PDPs for the manufacture of biosimilars with the multinational Pfizer and a publicly funded lab, the Institute of Technology of Paraná [TECPAR], and we’re analyzing other opportunities.
What are the characteristics of a biosimilar drug?
Biosimilars are copies of biologic medicines whose patents have expired, such as hormones, and primarily, monoclonal antibodies. Because they are large, complex, and heterogeneous molecules, batches of biologic products are never identical to others, and their production is complex. For this reason extensive molecular comparability studies and comparative clinical trials are needed to demonstrate their safety and efficacy. This isn’t the case with generics, which are exact copies of a synthetic product, are less complex, and require only bioequivalence studies, among others.
Which biosimilars do you work with?
We are licensed to produce four, all from Pfizer. Two of them, rituximab and bevacizumab, are for treating cancer; the other two, infliximab and adalimumab, are for autoimmune diseases such as rheumatoid arthritis. Pfizer’s biosimilar infliximab was approved a few months ago by the FDA (the Food and Drug Administration, the US agency responsible for drug safety), and it has already been submitted for registration with the Brazilian Health Regulatory Agency (ANVISA). If all goes well, we’ll start selling it in 2019. Initially, we’ll import it from the United States. Later, we’ll begin production in Brazil and eventually we’ll transfer technology to a publicly funded lab. This is the route for PDPs.
Do you also have plans to create innovative medicines?
Yes. We’re already working on two products in the area of immunology: vaccines against parasitic diseases, more specifically against schistosomiasis, and against some of the most common forms of cancer, such as breast, lung, prostate, melanoma, and throat. Existing vaccines essentially fight viruses and bacteria, and work primarily through the stimulation of antibodies. To work against parasites and cancer a more complex immune response is necessary. The most important component that needs to be stimulated is lymphocytes, especially T-cells, which attack tumors or complex organisms. It takes more than one antibody to destroy cancer cells or parasites. In addition to the antigen—the molecule that drives the adaptive immune system—an adjuvant is needed, a substance that stimulates the immune response in a generalized way and provides for a more complete response from the body.
Are these products being made only by Orygen or through a partnership?
The vaccine project against schistosomiasis is funded by Orygen, but we do have partnerships with the Oswaldo Cruz Foundation [FIOCRUZ] here in Brazil, and other entities outside the country. The cell line that produces the recombinant protein was generated by FIOCRUZ and the adjuvant was developed by the Infectious Disease Research Institute in the United States. Clinical trials take place in Senegal, where both of the two main species of Schistosoma that infect humans exist—only one of them is found in Brazil. In the case of the cancer vaccine, the peptide [protein fragment] was created by the Ludwig Institute for Cancer Research in New York and the adjuvant by the American company Oncovir. Clinical trials will occur outside Brazil—we don’t know where yet.
Besides the biosimilars and the two vaccines, what else is on Orygen’s radar?
We’re always on the alert for new biologic products that could make an important contribution to the health of Brazilians. We have an agreement with the US company Protein Sciences Corporation, which developed the first recombinant influenza vaccine, named Flublok, and has registered it in the United States. It was an important breakthrough. The product registration process in Brazil is proceeding well and we hope to put it on the market in 2019 or 2020.
With its partners, the company is developing vaccines against parasitic diseases and cancer, in addition to biosimilar monoclonal antibodies
How do recombinant vaccines like Flublok differ from conventional vaccines?
Conventional vaccines are manufactured using the viruses or bacteria that cause the disease, in their attenuated or inactivated form. In recombinant vaccines, we use only one part—most often a protein—of the microorganism, and we produce the protein in other organisms in a recombinant form. The fact is that conventional vaccines may carry a risk of developing a mild form of the disease when made using the attenuated virus (see article on page 18). Recombinants don’t have this problem, since they use only a piece of the pathogen. Another advantage in the case of influenza is that the production of recombinant vaccines is more appropriate in the event of a pandemic. It’s much faster to produce a vaccine by recombination than by the conventional method, in which the virus is reproduced in eggs.
Does Orygen have the resources, know-how, and staff to face these challenges?
Today, our team is small. In the technoscientific area, we have three people. We don’t yet have any established R&D activity, but when we need it, we’ll have help from professionals from partner companies Biolab and Eurofarma [Cristália and Libbs left the Orygen deal in 2013]. In addition to R&D structure, they have commercial, production, and regulatory expertise. We also hire consultants, and we can draw on the established Brazilian scientific community, such as FIOCRUZ. This is a structure that makes sense. At Orygen we have people with broad knowledge and we associate ourselves with professionals and companies that complement our needs. We’re going to build the company based on the projects, not the other way around.
What are the most innovative things about Orygen?
I would say that the cancer and schistosomiasis projects are the most innovative, but I’d also draw attention to the company’s structure. The company is organized like a startup, but it’s linked to two established pharmaceutical companies who support it. Since its inception, Orygen has been looking for innovative ways to establish itself as a Brazilian biotechnology pharmaceutical company. There isn’t a model that we can copy. We are continuously inventing, exploring, and discussing the company’s direction.
Is the innovative business model adopted by the company similar to that adopted by Recepta Biopharma, a Brazilian biotechnology company that’s also dedicated to the production of monoclonal antibodies?
There are both similarities and big differences. We’re working with a significant variety of products at different stages of development, and we’re building a production and marketing structure, in addition to the development sector. The support of two large pharmaceutical companies gives the work a certain robustness. In addition, the projects under development are completely innovative in areas where no similar products exist on the market.
How much was invested in the company so far?
A lot of money. Almost all of the investment was made with funds from Biolab and Eurofarma, but we also had a loan from FINEP [the Brazilian Funding Authority for Studies and Projects] and we should receive another loan from the BNDES [Brazilian Development Bank]. These aren’t nonrepayable grants. We still don’t have a factory of our own, but we’ve already bought property in São Carlos, in the state of São Paulo, and designed the production plant. We will begin production at the Eurofarma Industrial Complex in Itapevi [in the São Paulo metropolitan region], in a sector dedicated to biotechnology. When demand grows, we’ll begin production in São Carlos. We will proceed cautiously because of the high investment.
What are the main challenges facing the company?
The largest is to identify and develop unique products with sufficient commercial robustness that justify the investment of hundreds of millions of reais in the construction of a factory and hiring personnel. The basis of all this relies on choosing products with the greatest potential for success. It is not a trivial choice. In the area of biosimilar antibodies, we’re considering developing everything internally. We did evaluate possible collaborations with small companies, but soon realized that given the complexity involved in the development and manufacture of these drugs, besides the stiff competition, it would be better to have an experienced partner. So we opted to work with Pfizer. Our Brazilian competitors in this area, such as Bionovis and Libbs, did the same thing: they sought support from large multinationals.
What is the importance of your participation in the genome sequencing projects you coordinated 20 years ago in São Paulo?
It was a crucial moment in my career. Coordinating the Xylella fastidiosa gene sequencing, and managing the national research bureau responsible for sequencing the human cancer genome—an international program funded by the Ludwig Institute of New York—were bold projects in which I had the opportunity to play a central role. They gave me visibility. I was successful at my job, which allowed me to progress within the Ludwig Institute during my time there.
At the time it seemed that thanks to genomics we were about to see rapid improvements in areas of human health, and shortly in agriculture as well. How do you see those promises playing out today?
Everything that was promised by the genome project is gradually being realized. Acquiring knowledge may come relatively quickly at times, but translating that knowledge into useful tools always takes more time. This is partly due to the regulatory structure, especially in the pharmaceuticals industry. A lot of the medicines on the market today wouldn’t have been developed without our knowledge of the human genome.
Léo Ramos Chaves
The production line at Biolab, one of Orygen’s parent companies, along with EurofarmaLéo Ramos ChavesWhat was it like to leave the Ludwig Institute’s robust research environment and assume your role as director of a Brazilian pharmaceutical startup?
It was a fantastic opportunity. Orygen’s founding companies needed someone to run it. A headhunter interviewed me and chose me as the appropriate person. I took the job with great satisfaction. For me, it’s a pleasure to live in Brazil. My life here is much more agreeable than it was in New York, when I was working at the Ludwig Institute, or in London, where I started my career. Brazil is a country of great opportunities and challenges. I have the privilege of running a Brazilian biotech startup. I feel very proud to have reached this point.
You were originally hired as Orygen’s president, but today you’re its scientific director. Was there a demotion involved?
No. Actually, I consider it almost a promotion because I was freed from some functions. When Orygen was created it needed only one person; so a president was hired. But my expertise is in the scientific area. After a time, we transferred the president position to one of the partners, and we just recently hired an executive to become the company’s new CEO.
Why did you move from England to Brazil in the 1990s?
At the beginning of my career, I worked at the National Institute of Medical Research in London. I was already active in parasitology, and I’ve always had a broader interest in medicine than in just regional English diseases. For years, I’d done projects in Africa. It was an interesting period, but frustrating. There aren’t good working conditions there, or a structured scientific community. One day, at age 30, I was arriving at work and I thought, “Am I going to spend the next 30 years of my life dealing with the rain, the darkness, and the gray skies of London?” I decided to try something else. That’s when I got a chance to work in Brazil. The country not only had the diseases that I was interested in, but quality scientists as well. I resigned and settled in Brazil.
Where was your first professional opportunity in Brazil?
I started at the René Rachou Research Center, at FIOCRUZ, in Belo Horizonte. I also worked at UFMG [Federal University of Minas Gerais]. At the time, I was already a molecular biologist working with DNA, RNA, genes, cloning, and PCR [polymerase chain reaction, a technique used to make copies of a specific segment of DNA], which was relatively new to Brazil. Coming to Brazil allowed me to expand my area of interest, focused on schistosomiasis, to other types of organisms, including humans. That was what attracted the attention of the Ludwig Institute, which had a branch in São Paulo, and they ended up hiring me in 1995. In Belo Horizonte, I married Catarina, who is from Minas Gerais, and we had children. I joined Brazilian society and ended up becoming a naturalized citizen. I’m very happy here.
