Startup produces cholesterol-lowering molecule in tomatoes

By Elton Alisson  |  FAPESP Innovative R&D – Researchers at the startup Crop Biotecnologia in Botucatu (state of São Paulo, Brazil) have developed a platform to express peptides (short chains of amino acids, the building blocks of proteins) in tomatoes for use in treating chronic diseases such as dyslipidemia (high cholesterol). One such peptide can lower bad cholesterol (LDL) when taken by mouth, inhibiting the pro-protein convertase subtilisin/kexin type 9 (PCSK9).

The PCSK9 protein breaks down the LDL receptors in the liver so that we have less of them and our bad cholesterol goes up. PCSK9 inhibitors allow the number of bad cholesterol receptors in the liver to increase by blocking the activity of the gene responsible for creating the pro-protein.

Developed as part of a project supported by the FAPESP Innovative Research in Small Business program (PIPE), the platform and peptide are being patented. Two pharmaceutical companies are interested in a licensing agreement, and a venture capital fund is thinking about investing in the startup.

“Through interviews we conducted in the final stage of our participation in the PIPE High Tech Entrepreneurial Training program, we were able to obtain two letters of interest from pharmaceutical companies and sign a term sheet [outlining an anticipated investment deal] with a fund,” Lucas Ribeiro, co-founder and scientific director of Crop Biotecnologia, said in a talk closing the 18th edition of the program.

Before they took part in the training program, the startup’s founders intended to grow tomatoes that expressed PCSK9, lyophilize them, and supply the product as a powder extract to manufacturers of nutraceuticals and functional foods. The additive can be encapsulated in a plant matrix also developed by the startup and available from the platform, making the peptide more stable in stomach pH, capable of being administered orally, and more easily absorbed by the intestine.

In conversations during the program with representatives of 47 companies, however, they realized that the market for nutraceuticals is 30 times smaller than the market for pharmaceuticals. They also became aware of the regulatory barriers to be faced, since the product is obtained from a genetically modified fruit.

“We, therefore, decided to focus on the pharmaceutical market, where the peptide has significant sales potential,” Ribeiro says.

According to market research, demand for cholesterol-lowering drugs is growing 3% per year and is expected to reach USD 37.7 billion in 2027. The main medications available for this purpose are statins and monoclonal antibodies.

After talking to representatives of the pharmaceutical industry and potential investors, the entrepreneurs concluded that the platform for orally administered therapeutic peptides was more valuable than the cholesterol-lowering molecule on its own. “The investors believed our platform should be extended to include other therapeutic peptides,” Ribeiro says.

The entrepreneurs took this as a tip to search for therapeutic peptides that could be developed via the platform and came up with 95, most of which have to be injected and could create complications. In addition, the production cost is very high. For example, it costs about BRL 70,000 (now about USD 13,500) to perform chemical synthesis of 100 milligrams of PCSK9.

“The interviews we conducted during the PIPE High Tech Entrepreneurial Training Program gave us new ideas about how to get proofs of concept faster and express other molecules that had already been validated via our platform,” Ribeiro says.

The strategy of licensing the platform will also allow more time and scope for other projects, adds Aruã Prudenciatti, the firm’s CEO and a co-founder.

“It was an alternative we saw to avoid the ‘death valley curve’: many biotech startups take years to start generating revenue, and meanwhile need to attract capital for reinvestment in other ideas. Licensing of technologies is a way to do that,” he says.

Interaction with the market

Helping startups pivot – shift business strategy to accommodate changes in the industry or market, among other factors – is one of the main aims of the course offered by PIPE-FAPESP since 2016. Almost 400 high growth potential startups supported by PIPE-FAPESP in different sectors have taken the course in the past five years.

The latest edition assembled researchers who founded 21 startups in manufacturing, logistics, agritech, construtech, healthtech and biotech.

“The training provided by the program helps entrepreneurs access and interact with the market by networking and building business relationships,” says Marcelo Nakagawa, a member of FAPESP’s Research for Innovation Area Panel and one of the coordinators of the program.

Participants are encouraged to interview 100 prospective customers, partners and users of the technology they are developing in order to refine their business models.

A recording of the event can be watched at: fapesp.br/15023.