Historic Confluence Promotes Malaria Breakthroughs

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[This article was published in 2009 and updated in May 2012. Read the update here.]

Malaria is an ancient red blood cell-encroaching parasite that has seen species come and go. There are specific malaria protozoa for lizards, birds, rodents and, finally, higher primates. The most widespread and virulent form of human malaria, Plasmodium falciparum, is 100,000 years old. But malaria as a human scourge did not take off until the advent of agriculture, about 10,000 years ago. From that point on, the spread was supported by the expansion of conditions favorable to the mosquitoes that carry the plasmodium parasites. In some parts of Africa, residents are exposed to malaria through mosquito bites nearly every day. Malaria kills about one million Africans a year, mostly children and pregnant women. The disease is also prevalent in large parts of Asia and Latin America.

The United States and European countries succeeded in eradicating malaria after World War II. These were the easy places, where cool temperatures for large parts of the year limit replication by both the mosquitoes and the parasites they harbor. With the end of DDT-based mosquito control efforts in the late 1960s, the stage was set for resurgence in tropical countries. Countries that previously eradicated the disease, including the United States, are at risk for a return. The mosquito carriers are still present in those countries, and there is a small but steady stream of infected travelers bringing the disease home.

Lacking assiduous mosquito control, the only line of defense against malaria is treatment, and the parasite is notoriously prone to develop drug resistance. Inadequate treatment has led to widespread resistance to current malaria treatments. The only exception is the new combination therapies that include artemisinin compounds derived from a type of wormwood. These relatively expensive regimens too are susceptible to parasite resistance, however. Citing recent reports, Tim Wells, chief scientist for the Medicines for Malaria Venture concludes, “Artemisinin, like all drugs, will eventually engender resistance.”

Malaria has proved capable of evolving to escape whatever humans throw at it, whether through the immune system or through chemistry. With 5,300 genes, plasmodia are much more complex targets than a virus like HIV. What is more, their 12-step lifecycle includes a variety of distinct physical forms that grow in human liver and red blood cells as well as in mosquitoes. Fortunately, human bioscience is also evolving, and modern biotechnology brings to the battle highly sophisticated tools for picking apart the parasite and finding its weaknesses. The question is whether these tools can deliver affordable medicines accessible by the nearly three billion people inhabiting malaria-infested regions. Even more fortunately, some of the major biotech players are establishing novel cooperative partnerships, based on no-royalty intellectual property agreements that promise to alter the economics of future malaria treatments.

One major instance is the cooperative agreement between the Medicines for Malaria Venture (MMV), headquartered in Geneva, and two American biotechnology research leaders based in Cambridge, Mass., Genzyme Corp. and the Broad Institute. These three bring together a combination of advanced genetic and drug screening techniques, high motivation and global contacts to speed drug development. Their goal is to establish an endless pipeline of malaria drugs—one new clinical candidate every five years—and stay ahead of the parasite’s capacity for evolution.

Origin of the Partnership

In the beginning there was Professor Dyann Wirth, who chairs the Department of Immunology and Infectious Diseases at Harvard University’s School of Public Health. Wirth’s specialty is drug resistance in protozoan parasites such as the malaria-causing plasmodia. She employed genetic sequencing and gene modification to identify the cellular mechanisms inducing drug resistance. In 2002, other researchers reported that they had sequenced the entire P. falciparum genome. As a follow up, Wirth and colleagues in 2006 published an analysis of the worldwide diversity in that genome. They paid special attention given to mutations associated with drug resistance.

The malaria genome diversity project took place at the newly founded Broad (rhymes with road) Institute, a collaboration between Harvard and the Massachusetts Institute of Technology (MIT). In the words of Roger Wiegand, associate director of Broad’s Infectious Disease Initiative, one important purpose of the new institute is to “foster local collaborations within Boston’s biotech community. Before, MIT, Harvard and all the companies were acting as independent players. There was no integration.”

Wirth was one of the Infectious Disease Initiative’s co-directors. During the period when the malaria genome work was coming out, Henri Termeer, Genzyme’s chairman and chief executive officer, was searching for ways in which he could harness his company’s resources to find solutions for ignored diseases in the developing world. This goal in 2006 took the form of Genzyme’s Humanitarian Assistance for Neglected Disease (HAND) program.

The Broad-Genzyme connection was a natural one. “We started talking in 2005,” recalls Genzyme Senior Vice President James Geraghty. “Dyann Wirth said her lab at Broad was doing breakthrough work. They were looking for an industrial partner to develop new drugs based on the targets genetic sequencing was identifying. As we talked, we realized we had the technology they needed.”

Genzyme had the ability to turn drug concepts into drug candidates, but it did not have the clinical expertise to test the candidates in humans. For that, the new partnership turned to the Medicines for Malaria Venture (MMV), which bills itself as “philanthropic venture capital.” It was founded in 1999 and specializes in public-private partnerships for drug development.

MMV, among other strategies, creates “miniportfolios” with pharmaceutical companies that involve developing antimalaria compounds from the earliest lab experiments. MMV developed a miniportfolio with Genzyme and Broad Institute that became the largest of three such arrangements. MMV also has partnerships with other research sites around the world. This network enables it to organize clinical trials to bring drugs to market. In return for MMV’s drug development work, Genzyme and the other miniportfolio companies have granted the organization royalty-free licenses for distributing any approved drugs in malaria-endemic countries. Government and nonprofit malaria programs will receive these drugs at cost.

Fitting the Pieces Together

MMV’s Wells observes, “The collaboration is a tribute to Jim Geraghty’s and Dyann Wirth’s vision. Always in a successful partnership, there have to be people at the top committed to changing global health. Then you need people below who are motivated to make it happen.” The talks between MMV, Genzyme and Broad mapped out a collaboration that takes advantage of each partner’s special capabilities.

The Broad Institute, with its push-the-envelope technology, is central to the partnership. Broad researchers are actively examining variations in plasmodium and human genes associated with differences in disease severity. This research can yield new treatment strategies, such as inhibitors for the plasmodium version of dihydroorotate dehydrogenase (DHODH), a critical cell enzyme.

Apart from target discovery, the Broad Institute’s Infectious Disease Initiative also has a drug discovery component. The rise of drug screening assays that test hundreds of compounds simultaneously has greatly accelerated drug development. Broad uses two types of assays. One checks for malaria parasite killing capacity—it basically consists of red blood cells and parasites in an array of 384 small wells. Another assay tests for inhibition of specific molecular targets identified through genetic analysis. The first type of assay identified a lead family of potent compounds whose exact mechanism of action has yet to be defined. The second advanced lead compound arose through the second method, by testing inhibitors of plasmodium DHODH.

Aside from that antimalaria compounds that Broad has independently spotted, Genzyme brings a library of 300,000 compounds for the institute’s scientists to test. “Plasmodium is not particularly protected against drugs. We find about four promising agents per thousand compounds screened,” reports MMV’s Wells.

Genzyme’s more important contribution is after those compounds are detected. The company’s scientists first work to optimize the compounds’ structures. They also test for cell toxicity. This is a point at which many agents are rejected. They have to be selective malaria killers; they can’t kill the human cells too. If they pass this hurdle, Genzyme then tests the compounds in animals. First come the tests for stability—a drug will not be much good if the body eliminates it rapidly. Next are tests for effectiveness in animal models of malaria. Genzyme hopes to be able to have a compound ready for early human testing in 2011.

MMV also brings money to the table. The organization spent $54 million dollars in 2008 on malaria research, of which $3.8 million went to the Genzyme/Broad miniportfolio. After Genzyme does its preclinical work and readies a drug candidate for human testing, MMV’s clinical trial network will go into action. If the trials are successful, MMV will escort the drug through regulatory approval and find manufacturers and distributors for it. Genzyme and Broad may or may not be involved in this later phase. MMV usually grants the rights to the relatively small, private, for-profit market to a corporate partner when developing new drugs. The company in exchange pays part of the human trial costs. The Broad/Genzyme/ MMV collaboration has not yet had to face this issue.

Organizational Hurdles

Jeffrey Klinger, Genzyme’s vice president for the HAND project, says that he was skeptical when he first heard about the malaria project. “We’re just a medium-sized company making a modest investment. How could we make an impact?” asks Klinger. “We had to enable each group to accomplish things it couldn’t get done by itself. We overcame personality and cultural issues to create a very efficient cross-disciplinary team.”

One of the issues involved differences in organization. Genzyme followed an industrial team approach. Klinger notes that while there are 40 or 50 Genzyme staff involved in the malaria research, their total work is the equivalent of only nine or 10 full-time employees. People come and go, contributing their skills as required. The process builds a dynamic synergy. “This flow requires just the right amount and flavor of project management,” says Klinger. “You have to be flexible, but still steer the ship. A colleague of mine, Carol Sherako, does exactly what a project manager is supposed to do.”

Broad Institute follows a somewhat different model, bringing together a collection of individual lead researchers with labs at Harvard and MIT as well as its own in-house scientists. Roger Wiegand recalls that he “flipped the priorities a bit” when he joined Broad because his history was in drug development rather than basic science. Since he asserted his influence, “Broad has hired more drug development people, with an emphasis on things the pharmaceutical companies aren’t doing”—one of these being malaria drug screening.

A major stumbling block at the beginning was the intellectual property rights issue. Although Genzyme had made clear at the beginning that it would assign rights to a nonprofit organization like MMV, the university lawyers were still interested in protecting their institutions’ interests. “We had to keep telling people that there was no pot of gold at the end of the malaria rainbow,” recalls Wiegand. Agreement was reached when Harvard and MIT agreed to follow Genzyme’s lead. They too gave MMV royalty-free licenses allowing the organization to supervise drug development.

Wiegand concludes, “In the end we obtained a completely transparent exchange of information. You can’t tell who is from where at the meetings.” The collaboration’s management team now meets on a daily basis with larger whole project meetings occurring biweekly.

As drugs start to advance, those meetings are expanding to include chemists, toxicologists and other specialists. The collaboration itself is expanding. To further identify and refine drug candidates, it has worked with contract research partners in India, as well as the International Centre for Genetic Engineering and Biotechnology laboratory in New Delhi. Chem Partners in Shanghai synthesizes many of the prototype compounds that have emerged. Exchanges with these entities take place weekly.

Overseeing this process is MMV’s yearly review of its projects, conducted by the organization’s advisory board. “We got grilled,” Wiegand reported after the July 2009 annual conclave and before the board issued its findings. “They asked a lot of probing questions and wanted a few things tweaked. But mostly things seemed OK.”

Enlightened Self-Interest

One question that stands out in this collaboration is why Genzyme, a biotech success story with $5 billion in annual revenues, is interested in malaria. Klinger responds, “We couldn’t do what we are doing without the new funding organizations, the advances in biomedical knowledge and the commercial sector’s change in attitude. Before, the companies were not interested in malaria drugs because there was no money in it. Now many are showing enlightened self-interest.”

Klinger argues that there is a real desire among pharmaceutical company personnel to make a positive contribution to neglected epidemics like malaria. “It is very attractive to people,” he says. “When I tell people about this everyone wants to sign on.” Challenging work using the most advanced scientific methods, along with having a personal impact on improving the world—who can resist?

But there is also the self-interest side to his company’s efforts. All poor nations have a middle class able to buy advanced medications. In countries like China or India, that population is very large. Genzyme’s Geraghty says, “Our goal is to be a partner and improve countries’ health. We have our own products to market [in developing countries], although those products are very expensive and for a small group. We need to gain the cooperation of national governments, and malaria is very important to them.”

A certain confluence of interests sparked Genzyme’s involvement. The company is not alone in this. A number of larger, more established pharmaceutical companies are also working with MMV. These include GlaxoSmithKline, Novartis and sanofi-aventis. But, observes Wells, “Genzyme is a smaller organization, and the vision has permeated further there.”

By David Gilden

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