Creative public-private partnerships help developing nations combat life-threatening infectious diseases
The bug has outwitted us, says Maria Freire, PhD, CEO of the Global Alliance for Tuberculosis Drug Development (known as the TB Alliance), referring to the growing incidence of multiple-drug resistant (MDR) tuberculosis (TB) and the 2 million people who fall prey to the disease each year. MDR-TB is a result of the resistance that Mycobacterium tuberculosis (the causative agent of TB) has developed to isoniazid and rifampicin, two of the most commonly used drugs used for treating TB.
While celebrating World Tuberculosis Day on March 24, researchers and clinicians were lamenting the fact that there have been no new TB drugs on the market since 1964. "When we think of illnesses of today and those which affect us here in the United States, such as cancer or diabetes, it would be incomprehensible for us to accept that we will be treated with drugs that are 30 or 40 years old," says Freire. "And yet for TB, we seem to believe that this is an acceptable state of affairs."
The rising costs of getting a new drug to market is one of several reasons forcing large pharmaceutical companies to divert all their resources to blockbuster drugs (defined as drugs that bring in more than $1 billion in revenue). "TB is not an attractive market in terms of monetary rewards, so it does not have the attention from big pharma that it deserves," says Aileen Allsop, PhD, vice president and coordinator of project evaluation, who oversees TB research at the AstraZeneca (AZ) site in Bangalore, India. Besides TB, other ailments like malaria, dengue fever, and Chagas disease that affect millions in the developing countries are referred to as "neglected diseases."
Over the last few years, however, the big pharmas have faced intense pressure from public organizations such as the World Health Organization (WHO) and patient and physician groups to address the needs of patient health in developing nations. Some companies have responded to the pressure by dedicating resources to these neglected diseases. GlaxoSmithKline, Brentford, UK, established Diseases of the Developing World Initiative, which includes drug discovery labs in Madrid. AstraZeneca dedicated its research site in Bangalore, India, for the discovery and development of drugs against TB. Eli Lilly, who makes two of the second-line drugs for TB, recently announced that it is looking to transfer the technology and know-how to manufacture their drugs, "with no strings attached," to companies situated in areas where these medications are most needed.
In an effort to minimize their costs and risks, some pharmaceutical companies are also partnering with public and private organizations to co-develop drugs for these diseases. This has led to creative public-private partnerships like the TB Alliance, Medicines for Malaria Venture, Drugs for Neglected Diseases Initiative, and many others. The most recent is the establishment of the Novartis Institute for Tropical Diseases (NITD), Singapore, which is devoted to research on MDR-TB and dengue fever.
"NITD is a public-private partnership between Novartis and the Singapore government," says Alexander Matter, PhD, who became the institute's inaugural director in August 2003. NITD is set up as a not-for-profit venture and its mission is to find small molecule drugs for dengue fever and MDR-TB, one viral and the other a bacterial disease. Compounds originating from the research at NITD will be patented and then licensed out to companies, including Novartis, who will then produce and market the drugs. "Our aim is to make these compounds available at cost," says Matter.
Drawing on complementarities
The NITD, established in 2001, will have about 100 scientists by the time it moves into its new premises in the Biopolis in July this year. The creation of this $122 million research institute marks the re-entry of the company into the anti-infectives market. Before its merger with Sandoz to form Novartis, Ciba-Geigy had programs in anti-bacterial and AIDS research. At Ciba, Matter had been the head of infectious diseases and led a successful AIDS research unit for about 10 years. He was until recently the head of oncology at Novartis and led the discovery of Gleevec, currently one of the most successful targeted therapies for cancer.
"Oncology and infectious diseases are not so far apart classically in research," says Matter. "Both were treated using chemotherapy. Its interesting to see that oncology has switched from a purely cytotoxic approach to pharmacology [with targeted therapeutics] and so has infectious disease research." Certain targets such as protease inhibitors, for example, are common to both therapeutic areas.
"With NITD, we wanted to leverage what was already on-going [in terms of research] at Novartis because this enhances our critical mass in our effectiveness," says Paul Herrling, PhD, head of corporate research at Novartis and the man who led the creation of NITD. While there were many tropical diseases that NITD could focus on he was looking for ones that were unique and yet complementary to the activities at the company. A tour of several tropical disease institutes, schools of public health, and meetings with government health officials convinced him that MDR-TB and dengue fever would be the right choice.
Novartis had expertise in working with targets for the hepatitis C virus (HCV), which shares commonalities with the virus that causes dengue fever. "A polymerase in HCV is closely related to the polymerase in the dengue virus, which includes a family of viruses such as West Nile virus, encephalitis, tick form encephalitis, and human yellow fever," says Matter. With TB, the patient need was found to be extremely well-defined. "The cost of the treatment has to be in the range of $1 a day," says Matter. "The stability of the drug has to be such that it does not need any refrigeration, is orally available, and cheap to produce. But what that also means is that the benchmark is relatively higher than for other areas like oncology where it is possible to work with expensive compounds that can be injected."
"Originally, we thought also of working on a parasitic disease but then decided to focus on just these two for reasons of critical mass," says Herrling. Also, the goal was to concentrate all efforts on developing drugs that were small molecules. "We decided not to pursue vaccines because we lacked the know-how and also felt that the technical difficulties for vaccine research were very high," says Matter. Currently, a vaccine exists for TB, but it is not quite effective, and there are a few vaccine candidates in development for dengue fever. "It is not clear if it is possible and feasible to develop effective vaccines for these diseases. Although there are several clinical trials that are ongoing, the outcome is still unsure," says Matter.
Location, location, location
The choice of Singapore as the location for NITD was driven by several factors. "One had to do with attracting the best talent; hence, we had to put it in an environment that is attractive to good scientists," says Herrling. "The other is that if you are serious about drug discovery, you have to be close to the patients, physicians, and where the disease occurs, especially with diseases that we are not familiar with."
Since these diseases did not occur anywhere close to its existing research centers, Novartis had to consider building a brand-new facility. "Although these diseases occur in several countries in the Asia-Pacific region, when considering the research infrastructure, available the options are very few," says Herrling. "It would be tragic to spend five years working on a drug only to find that you chose the wrong strategy." Singapore definitely offered a promising setting since it offered a leading research and technical infrastructure, attracted leading researchers and was surrounded by countries that offered easy access to patient population. (See sidebar "Why Singapore?" for more details). "The goal was to mix the drug discovery experts from our organization with the specialists for those diseases, most of which are mostly academics," says Herrling.
However, the help that the Singapore government offered Novartis was a critical factor in the decision to house NITD in Singapore. "The Singapore government has not only invested in a serious manner over the next 10 years but is providing daily substantial help," says Matter. For instance, says Herrling, the Economic Development Board (EDB) is helping Novartis pay the costs of the relocation from their preliminary labs that were set up in 2001 in the Capricorn Building in Singapore's Science Park to their new laboratories in the Biopolis. "All this makes for a package that is extremely attractive," says Matter.
The Biopolis is a 2-million-square-foot complex consisting of seven buildings dedicated for biomedical research. Five of the buildings are occupied by local government agencies and publicly funded research institutes, whereas two buildings are allocated to pharmaceutical and biotechnology companies.
"The whole idea of the Biopolis is to have an integrated R&D infrastructure where we can co-locate the public research activities as well as [drug] industries," says Chu Swee Yeok, first director, Biomedical Sciences at the EDB, Singapore. "We feel that this is important for ideas to cross-fertilize and to facilitate interaction among the researchers and access to shared facilities." While providing separate laboratory space, there are also shared facilities available for electron microscopy, proteomics, NMR, histology, x-ray crystallography, DNA sequencing and analysis, flow cytometry, and animal work.
Collaborating for success
"We don't start from scratch," says Matter. "We have access to Novartis' compound library collection and we also have compounds that have been donated to us for TB, by companies like Chiron." NITD researchers have complete access to the expertise and technologies available throughout the company. "One of the scientists from Singapore is currently working with the high-throughput genomic technologies at the Novartis Institute for Genomics [La Jolla, Calif.] to screen for one of the protease targets for dengue, the NF3 protein," says Herrling.
NITD is also working in close collaboration with the Novartis anti-infectives group in Cambridge, Mass., to exchange assays and compound libraries and with another group that specializes in protease research. There is a tremendous know-how in protease research accumulated over the decades at Novartis, says Matter, that NITD can draw on. "In this way, we are leveraging the rest of the organization," says Herrling.
Researchers at NITD plan to use compounds previously developed for hepatitis C to screen leads for targets for dengue fever. "At the same time, the libraries created for dengue research at the institute will also be looked at for hepatitis C," says Herrling. "If a compound from the dengue library works for hepatitis C, it would go through the normal pharmaceutical pipeline. Once it reaches the market, a royalty from the sales would be paid to the NITD."
"With funds from Novartis and the Singapore government, we have currently financed the research at the institute for 10 years," says Matter. However, the institute will have to depend on partnerships with non-governmental organizations (NGOs) and others for the development, production, and marketing of any drugs that emerge from the research.
While collaborating internally with groups at Novartis the institute is also working closely with other external organizations and academic factions in Singapore. NITD is a part of the Singapore Dengue Consortium, an alliance with six Singapore research organizations whose goal is to leverage the assets to understand and manage the incidence of dengue fever.
What is further unique is that the institute will be a training ground for graduate and postgraduate students and senior scientists on sabbaticals to learn how to do drug discovery. "While we will patent all the compounds, we will be able to share scientific data much earlier than in a commercial organization," says Herrling.
"NITD is already discussing targets and compound structures with the scientific and academic community, which speeds up the research process quite significantly. We need to then build a firewall to protect the libraries that come from the commercial organization, but that's [possible]."
"I call this institute an experiment where we are learning how to do this type of drug discovery," says Herrling.