Issue Date: April 20, 2009
Paying Attention To Neglected Diseases
IN FEBRUARY, when Andrew Witty, chief executive officer of GlaxoSmithKline, announced measures his company would take to develop and offer drugs for neglected diseases in the poorest countries, he received a lukewarm response from Médecins sans Frontières (Doctors Without Borders). The Nobel Prize-winning activist group criticized what it called a lack of details, adding that the patent pool Witty proposed should also include intellectual property (IP) related to HIV/AIDS.
Although the exchange was a familiar one, GSK and MSF are not entirely at odds. In fact, Witty mentioned work the firm is doing with the Drugs for Neglected Diseases Initiative (DNDi), a Geneva-based organization created by MSF and other partners six years ago to coordinate research among disparate public and private entities.
Rooted in a prominent activist group, DNDi finds itself straddling two worlds to carry out its mandate. It balances traditional activist pressure on businesses and governments with a hands-on, practical approach to research management.
DNDi's collaboration with GSK focuses on developing compounds from existing GSK research programs to fight three parasite-borne diseases: leishmaniasis, a skin infection; human African trypanosomiasis (HAT), or sleeping sickness; and Chagas disease, also known as American trypanosomiasis. Work will be done at GSK's Tres Cantos, Spain, research facility, which is dedicated to diseases of the developing world.
Among its other projects, DNDi hopes to soon begin Phase I clinical trials on a sleeping sickness drug called fexinidazole with a roster of partners including the Swiss Tropical Institute; Accelera, an Italian biotech firm; and Axyntis, a French pilot production company. DNDi has already delivered two fixed-dose combination drugs for malaria—artesunate/amodiaquine (ASAQ), developed with Sanofi-Aventis, and artesunate/meloquine (ASMQ).
According to Jana Armstrong, executive director of the initiative's North American operations, based in New York City, DNDi's purview is the rarest of debilitating and deadly diseases that affect the poorest parts of the world. Whereas organizations such as Medicines for Malaria Venture (MMV) and the Global Alliance for TB Drug Development have marshaled public and private support against major scourges, DNDi is targeting diseases that offer the least commercial incentive to drug companies and for which research is currently scattered among academic labs with few resources and no coordinated management. The malaria therapies, Armstrong says, were "low hanging fruit"—proofs of concept for the group's approach to coordinating research.
MSF committed to forming DNDi shortly after winning the Nobel Peace Prize in 1999. It launched the initiative in 2003 in partnership with groups including the Indian Council of Medical Research; the Kenya Medical Research Institute; the Oswaldo Cruz Foundation, in Brazil; and the Institut Pasteur, in France.
Partnership management is a primary goal at DNDi, according to its executive director, Bernard Pécoul. "We set up a clear objective to deliver new treatment for diseases affecting a limited section of patients," he says. DNDi set the goal of delivering six to eight new treatments for leishmaniasis, sleeping sickness, Chagas disease, and malaria by 2014.
Making connections, especially with big drug companies, has proved a daunting task, Pécoul says. "It is no exaggeration to say that 10 years ago, when MSF started diagnosing the situation, the major drug companies were failing on this kind of activity," he observes. "There was no collaboration, no IP sharing, and companies were phasing out neglected diseases."
PROMPTED in part by pressure from activists, some companies renewed their focus toward the end of the 1990s, Pécoul says. He cites the protests at the 1999 World Trade Organization (WTO) summit in Seattle and protests over the price of AIDS drugs in South Africa two years later as calling attention to a lack of corporate and government action in the quest for affordable cures. "These things changed the dynamic," Pécoul says. GSK's Tres Cantos facility and the Novartis Institute for Tropical Diseases, in Singapore, were opened by 2002 in part as a response to the public's call for action.
IP, on the other hand, remains a barrier to collaborative research, Pécoul says. The Trade-Related Aspects of Intellectual Property Rights agreements enacted by the newly formed WTO in 1994, he notes, established international patent protection for 20 years, locking access to IP from collaborative research efforts.
Nonetheless, drug companies quickly got involved in DNDi's first projects, according to Jean-René Kiechel, senior project manager for the initiative's fixed-dose artesunate-based combination therapy (FACT) project, which worked on the malaria compounds. "We started with a consortium of organizations all over the world," Kiechel says. "But from the start we had a collaboration with industry, since the active pharmaceutical ingredients we were working with were, of course, manufactured by pharmaceutical companies." Pfizer, for example, supplied at-cost amodiaquine, a starting ingredient for the malaria drugs.
Kiechel, who is retired after working in R&D at large drug companies including Sandoz, Bristol-Myers Squibb, and Aventis, says collaboration with big pharma also involves scale-up, registration, and commercialization of new drugs. Sanofi-Aventis, for example, is involved at this level on ASAQ.
François Bompart, Sanofi's vice president of medical affairs, says DNDi approached his company in 2004 with research done at the University of Bordeaux, in France, on formulating artesunate and amodiaquine in a fixed-dose combination. Sanofi already marketed the drugs as separate dosages and was working on its own combination.
The DNDi-orchestrated partnership accelerated the work being done at Sanofi, Bompart says. "Working with a small outfit like Bordeaux is much less time-consuming than working only within a large pharma company where you have people who are not fully dedicated to the task," he says. "We managed to do in a short time something that would normally take a year."
DNDi made some tough demands, Bompart acknowledges. "First, they insisted that we take no patent," he says. "We quickly agreed because there is such a large need for the drug that no single manufacturer could meet the need. But I don't know if, prima facie, Sanofi would have proposed such a thing."
THE SECOND STIPULATION was that the drug cost no more than $1.00 for an adult and 50 cents for a child. "At the time, it seemed like an aggressive objective," Bompart says. "This was identified as an objective to reach over time, but we reached it with DNDi right from the beginning."
DNDi has injected a similar sense of urgency, as well as funding, into projects that GSK may or may not have pursued on its own, says Jon Pender, director of government affairs at GSK. "Their funding has enabled us to scale up to a level that would be difficult to justify commercially otherwise," he says.
In addition to big pharma partners, DNDi is working with contract research organizations (CROs) in the U.S., Europe, India, and elsewhere. Although some CROs see research on drugs for neglected diseases mainly as a supplement to work with large pharma companies, others are dedicating a significant effort to the task.
Scynexis, a CRO based in Research Triangle Park, N.C., contracted with DNDi in 2006 to discover compounds for HAT sleeping sickness. The company hopes to announce a preclinical candidate sometime this year, CEO Yves Ribeill says.
Although he is partially motivated by frustration with the lack of progress he sees on neglected diseases, Ribeill also sees a business opportunity. "A lot of research has been conducted in academic settings that don't have the knowledge necessary to take a compound from drug discovery to drug development," he says. Funding from DNDi facilitates partnerships between academic researchers and firms like Scynexis.
Such partnerships are not as lucrative as contracts for commercial drug development, but the work is still profitable, Ribeill points out. "The overall advantage to us is that it will allow us to have in place long-term contracts," he says. "Big-pharma contracts run a maximum of three years. DNDi works with five- to six-year contracts."
Meanwhile, in India, Advinus Therapeutics, a research firm based in Bangalore, has contracted with DNDi to discover treatments for leishmaniasis. According to CEO Rashmi Barbhaiya, about 10% of Advinus' drug discovery work is on neglected diseases. DNDi can save money by contracting in India rather than with Western partners, he says.
"We are very proud that we are just about to be profitable and that we have been doing the kind of research most large drug companies have not been willing to do up to this point," Barbhaiya says. Advinus also works with large pharmaceutical makers such as Johnson & Johnson.
"THINGS ARE starting to move," DNDi's Pécoul says. "Today, there is more being invested internationally in research on neglected diseases, and there are a number of global initiatives such as MMV. DNDi, as an example, has been able to attract some key fund-raisers to our initiative." The initiative currently has $150 million in funding from public and private donors, including the Bill & Melinda Gates Foundation and the National Institute of Allergy & Infectious Diseases of the National Institutes of Health. DNDi's goal is to raise an additional $200 million by 2014.
DNDi's Armstrong also sees progress. "The good news is that we have been able to develop credibility with these kinds of partnership relationships—just getting people to stop criticizing each other and make something work within the system," she says. And she points to Witty's patent-pool proposal as an indicator that collaboration is indeed happening.
Pécoul agrees, but he remains vigilant at holding stakeholders' feet to the fire on meeting the health care needs of neglected populations. "Clearly, GSK's announcement marks a change of attitude and the beginning of a system that will give us the best science for the most significant need," he says. "My only fear is an announcement that is not translated into action."
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