[NOTE: This is an UPDATE to a case study initially published in 2009. Read the original case study for appropriate context.]
Development of new malaria treatments has been a neglected area for a long time. Meanwhile, the single-celled Plasmodium parasites that cause malaria developed resistance to one drug after another. Helping to change this picture are new types of partnerships between the pharmaceutical industry, academic researchers and nongovernmental organizations.
Geneva-based Medicines for Malaria Venture (MMV), MIT-Harvard’s Broad Institute (pronounced like “road”) and the Genzyme Corporation comprise one such collaboration that has focused on finding promising new antimalarial compounds. These three organizations respectively contribute high motivation plus global contacts, advanced genetic and drug screening techniques, and expertise in transforming molecular candidates into sophisticated treatments for difficult diseases. Their differing strengths in turn stem from their different organizational premises: advocacy, basic research, and commercial pharmaceutical research and development.
MMV Changes Priorities
The collaboration produced two optimized lead drugs. One is an inhibitor of DHODH, an enzyme critical to cellular genetics and energy production. DHODH in Plasmodium differs substantially from the human variety, so an antimalarial DHODH inhibitor may be both deadly to malaria parasites and acceptably safe for patients. The second drug is an “aminoindole,” a three-ringed, nitrogen-containing molecule whose mechanism of action against malaria is unknown. This molecular family was identified during laboratory screening assay of 70,000 compounds as particularly lethal to Plasmodium. An exciting feature of the aminoindole is that in laboratory experiments, malaria parasites have not acquired resistance to this drug.
There are, however, many ways that drug development can go awry, both as a result of further research findings and of evolving organizational politics. The first hitch was that MMV decided to stop funding the collaboration. In the words of Tim Wells, MMV’s chief scientific officer, the Broad and Genzyme drug discovery program “has been overcome by events. After our first two programs chose development candidates, there weren’t particularly any new proposals coming out, so we stopped working in discovery.”
Thanks to the highly productive drug screens used by its partners, MMV now has a list of 25,000 molecules with antimalarial properties. The torturous drug development process can only absorb the few with the most interesting properties. For Wells, these are the candidates that emerge from parasite-killing tests, like the aminoindole. Wells favors such “whole cell” assays because they show immediately that the “compound works.”
Broad concentrated more on testing for inhibitors of particular parasite components, like DHODH. But the Broad-Genzyme DHODH inhibitor stalled when MMV decided to press forward with another DHODH inhibitor, which it judged superior. That one came from a team at the Texas Southwestern Medical Center in Dallas and GlaxoSmithKline.
Genzyme Changes Hands
A further complication occurred when, in April 2011, Genzyme was acquired by the international pharmaceutical giant Sanofi. Genzyme’s mission as a result has increasingly focused on its original specialty, rare genetic diseases. Still, the management team of Sanofi as well as Genzyme support further research in neglected diseases. Sanofi has its own drug discovery collaboration with MMV; while Sanofi and its new subsidiary consider how to apportion their efforts in this area, Genzyme is pursuing its malaria research, too.
The aminoindole lead compound recently underwent a 14-day toxicology study in rats that was funded by the U.S. National Institutes of Health (NIH) preclinical development program. Unfortunately, the rats lost weight during the study, and a closely related compound is now under consideration as a replacement. Talks are continuing between MMV, Sanofi and Genzyme over these compounds’ future. Genzyme and Sanofi are also considering pursuing the DHODH inhibitor under the NIH preclinical program.
Genzyme has two ongoing malaria development partnerships. One drug discovery program extends its past cooperation with the International Centre for Genetic Engineering and Biotechnology laboratory in New Delhi, India. Another is a new Bill & Melinda Gates Foundation-funded collaboration with the Harvard School of Public Health to research therapies specifically for Plasmodium vivax, the most common malaria parasite. This type of malaria has proved especially difficult to study in the laboratory, and treating it is particularly troublesome.
Reviewing Genzyme’s role in malaria, company Vice President Jeffrey Klinger says, “To a large extent, perhaps Genzyme’s greatest contribution has been in catalyzing unique collaborations and encouraging risk-taking in those relationships. In part, this has been based on ‘right place, right time, right people.’ ”
Broad Institute Changes Strategy
At the Broad Institute, Roger Wiegand, associate director of the Infectious Disease Initiative, reports that the malaria project has been through a period of “adjustment and reorganization” in the aftermath of MMV’s changing priorities and Sanofi’s acquisition of Genzyme. “Although our program was spectacularly successful by pharma industry standards,” he says, “we are returning to more academic pursuits rather than continuing to pursue drug discovery per se.”
Broad scientists are now utilizing their expertise in massive, high-speed assays to reveal the genetic changes underlying drug resistance in malaria parasites. Malaria parasites have more than 5,000 genes, which provide them with a variety of mechanisms for escaping medical therapies. Understanding the genetic basis for drug resistance can point the way to more durable combination treatments that suppress malaria despite the parasite’s drug resistance toolkit. Along these lines, Broad hopes to work with malaria drug developers to track how malaria parasites acquire resistance in response to experimental drugs. Its grant applications, like Genzyme’s, are going to the NIH.
In a presentation to the American Society of Tropical Medicine and Hygiene’s 2011 Annual Meeting, Jeffrey Klinger commented that “discovery may be the easy part.” The real challenge, he said, was downstream drug development: “Who does it, and how does it get financed?”
The Broad-Genzyme collaboration was established for the early phase, drug discovery. Klinger expects that further collaborative work will be necessary should Sanofi decide to bring any of the new malaria therapies into the clinic. “We have always envisioned that human trials for such compounds would likely depend on the input of multiple organizations, including MMV, Sanofi, and/or other pharmaceutical partners,” he says.
By David Gilden