The history of the vaccine Ruti against the latent tuberculosis infection would be enough to write a book. While Pere Joan Cardona was doing his phD, he made a revolutionary observation about how the tuberculosis bacilli can remain dormant in the lungs of people. At that time, he didn’t dare to make much noise with his discovery, which contravened the established thoughts, but he couldn’t take this idea away and it became the focus of his research since then. The result of the research has been Ruti, a therapeutic vaccine that might be able to reduce the treatment of latent tuberculosis infection from six months to just one. In the history of Ruti, it is also involved a sponsor, the wife and the brother in law of the researcher and a host of mysterious characters from the “dark side”. Cardona explained his adventure on 16 March at the Bellvitge University Hospital, in the cycle of IDIBELL seminars.

Pere Joan Cardona is a microbiologist at the Germans Trias i Pujol University Hospital in Badalona in Northern Barcelona -known popularly with the name of Can Ruti-, head of the Experimental Tuberculosis Unit of the Institute for Research in Health Sciences Germans Trias i Pujol and Associate Professor at the Autonomous University of Barcelona. In 2005 he founded Archivel Pharma, a company of which he is the scientific and medical chief, where the vaccine is produced industrially at its facilities in Badalona. This drug will begin the Phase 3 of its clinical development, after the same company has completed the previous stages. This is an unusual case in our country.

The story began in the late nineties, when Pere Joan Cardona found that in latent tuberculosis infection, the bacilli that cause the disease (Mycobacterium tuberculosis) are not asleep, locked inside granulomas, as was previously thought and as medical books continue explaining, but carry out an ongoing battle against the host. Then, the dynamic hypothesis of latent infection appeared. This hypothesis integrated physiological and clinical aspects of the disease with pathological and microbiological aspects of the bacillus.

Under this scenario, after the occurrence of infection, the bacilli are able to get out of the granulomas where they are confined under a stressful situation. The foamy macrophages sweep the bacilli, which re-infect the individual through aerosols reaching the lungs through the airways. Thus, the patient is continuously reinfecting himself. In some cases, for reasons not entirely known, the infection becomes active and causes the disease, in the ten percent of those infected.

From the dynamic hypothesis, Cardona developed a therapeutic vaccine made from inactivated fragments of the bacillus, which can recognize antigens of bacilli in replication or non-replication, which increases the effectiveness of control of reinfection. The vaccine is complemented with standard antibiotic therapy (isoniazid), but it can be shortened to one month treatment, which now lasts six or even nine months. This is important because a high percentage of people with latent infection do not complete the treatment, which, apart from keeping the infection, causes antibiotic resistance. In addition, isoniazid has many side effects that advise against its administration for so long to elderly or to people with other health problems. The researcher named the vaccine Ruti, in honour of the hospital where he works.

The venture began in 2000 in a Chinese restaurant. Among noodles and spring rolls, the researcher and his wife, Isabel Amat, which is chemical, convinced Pepe Martinez that the idea could be profitable. Martinez was a businessman in the field of perfumery who had lived many years in the USA, where the culture of patronage is widespread. The businessman provided funding that allowed the drug patent and the creation of the spin off Archivel Technologies, which later became the biotechnology company Archivel Farma. Then, the researcher began his venture. “I got in touch with the ‘dark side’, the business world, and I realized that I had to learn everything”, Cardona told at the seminar. The researcher found that the research and business are poles apart –“money and research do not fit”- and began to become familiar with concepts that until then he fell far short, like “risk analysis, optimization of capital, board of directors … even criminal liability”.

At first the company was formed by the sponsor, the researcher, his wife and his brother in law. It was, as the investigator defined, a “family office”. Today the Badalona facilities have eighteen workers. Archivel is authorized by the Spanish Agency of Medicines and Health Products to manufacture medicines for human use in research and manufacturing facilities allowing the production of sterile biological medicines.

It was the inflow of funds from a venture capital firm which allowed the project move forward. In 2007 the vaccine was first tested in humans. The test was conducted in the Germans Trias Hospital with 24 healthy volunteers. It was a success. The second phase was conducted in South Africa with people with latent TB infection, some of which were also infected with HIV. The trial concluded late last year. It was also a success. Now, Archivel is about to begin the Phase 3 clinical development and Cardona expects that the vaccine may be ready for release in 2014. But for having a happy ending, the story needs more funding. “So far we have spent ten million euros, but we need ten more, probably now we are in the moment of greatest financial risk”. The researcher explains that the way to get resources is through the establishment of a network of collaborators, with a win-win strategy in which all parties end up winning.

Profitable business

Pere Joan Cardona is sure that the product should be attractive to investors. Latent tuberculosis infection affects more than two billion people worldwide, one third of humanity. Every year one hundred million people are infected and two and a half million die from the disease. Every second a person dies of tuberculosis. Although the infection is more widespread in developing countries, there are neighbourhoods of major European cities where the number of infected is very high. In the Raval, in Barcelona, for example, there is an incidence of 150 cases per hundred thousand inhabitants, a figure similar to that of cities like Bombay. AIDS and immigration have significantly increased the number of people living in Western countries. Seen through the eyes of the “dark side”, the Ruti seems a very profitable business.

The history of Ruti is an example of how “scientists can go hand in hand with business to generate projects in which knowledge has a practical impact on society”, explained Cardona. And finally, the researchers cautioned, “It’s nice to have good ideas, demonstrate mechanisms of action, publish in major journals, but it is still better be able to transfer the results to a company that can revert to the patients and create wealth”. This reminds IDIBELL mission, right?