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Cover Story

November 9, 2009
Volume 87, Number 45
pp. 16 - 22

Partnering For Global Health

Drug companies and nonprofits are taking novel approaches to refill the pipeline of new drugs and vaccines for neglected diseases

Lisa M. Jarvis

FEVERISH SEARCH: Scientists study dengue in a lab in the Philippines during an NITD symposium. NITD
FEVERISH SEARCH Scientists study dengue in a lab in the Philippines during an NITD symposium.
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Front line</span> An MMV worker administers malaria tests. Anna Wang/MMV
Front line An MMV worker administers malaria tests.

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Véronique Dartois had a revelation three years ago on a trip into the Tanzanian bush. Tagging along as local doctors made their rounds, she encountered a six-year-old boy whose tiny body was ravaged by disease. In addition to HIV passed on from his mother at birth, he was severely anemic as a result of the latest in a series of malaria episodes. That day, his father had brought him to the remote dispensary to treat what was clearly tuberculosis.

It wasn’t the first time Dartois had stood before a person with malaria or TB, but her previous encounters had all been part of organized visits to hospitals. “It is very different when a group of 20 people led by a local doctor goes from ward to ward and he explains things to you,” she says. “You don’t really feel that much.”

This trip was different. “A couple of times I went back to my hotel and was in tears,” she recalls. “You see things that impress you for life.” Witnessing this sick child and others like him was a profoundly personal experience for Dartois, and one that she says changed the way she does her job.

Dartois isn’t a doctor or an international aid worker. She heads the pharmacology unit at the Novartis Institute for Tropical Diseases (NITD), a public-private partnership helmed by the Swiss pharmaceutical giant, and her trip to Tanzania was something of a fact-finding mission. She is one of a growing number of scientists at big drug companies working with nonprofits to find better and cheaper treatments for the diseases that claim millions of lives in the developing world each year.

By going into the bush, Dartois gained a deeper understanding of the magnitude of the challenges she and her colleagues are up against. It isn’t enough to find a drug that works and is cheap. Rather, a medicine’s effectiveness depends on a complicated matrix of disease, poverty level, environment, and cultural mores.

Scientists from companies such as Novartis, GlaxoSmithKline, and Merck & Co. have started collaborating with experts across the nonprofit and academic sectors to send new drugs and vaccines into the pipeline. As this partnership model evolves, more companies appear ready to take on an active role in researching treatments that will probably never make a profit.

Only a few years into their alliances, the partners are starting to see successes, ranging from reformulating a malaria drug for children to discovering compounds that show promise in treating tuberculosis. But rapid growth in the drug and vaccine pipeline is overshadowed by questions about who is going to pay for the expensive late-stage clinical trials, registration, manufacturing, and distribution of products with no profits.

When organizations such as the Medicines for Malaria Venture (MMV), the Global Alliance for TB Drug Development, and the PATH Malaria Vaccine Initiative (MVI) were first established nearly a decade ago, industry had largely abandoned R&D for neglected diseases. Even government funds were scarce, recalls Regina Rabinovich, director of infectious diseases development at the Bill & Melinda Gates Foundation.

Rabinovich The Gates Foundation

Yet the need for new drugs was astounding. According to the World Health Organization, malaria and tuberculosis each cause more than 1 million deaths every year. Cases of dengue fever, a mosquito-borne infection that WHO says causes hundreds of thousands of fatalities each year, are rising exponentially. And scientists are concerned that a warming global climate will translate into explosive growth in these and other tropical diseases.

Public-private partnerships—known in the field as PPPs—were conceived of as a way to address the gulf between drug need and availability by bringing together resources across the public, private, and philanthropic sectors. The idea was to fund and manage a portfolio of research projects across a specific disease, much like a pharmaceutical company manages a portfolio of drugs across many diseases. A scientific advisory board composed of all the stakeholders would guide the process, and an open exchange of knowledge would help accelerate each project.

The goal was to capture the entrepreneurial spirit of a biotech or venture investment fund, “but for furthering public good, as opposed to pure financial good,” says Melvin Spigelman, chief executive officer of the Global Alliance for TB Drug Development, also known as the TB Alliance.

But to succeed, the founders of nonprofit organizations like the TB Alliance would need the “private” half of the proposed PPPs to get on board with the plan.

The first step for the nonprofits was to find molecules or vaccines to start working on, and the obvious place to look for them was in the cupboards of pharmaceutical companies. After all, they had potential drug candidates to spare. Not only were their libraries full of compounds waiting to be screened for activity against neglected diseases, but they also owned molecules from earlier research efforts, particularly in malaria and TB, that had shown promise but were no longer being pursued.

Furthermore, although much of the funding in neglected diseases at the time was going to academic labs, it was industry that knew how to translate ideas into actual products. And importantly, in the time- and cost-sensitive world of neglected diseases, industry was good at managing a portfolio of projects and deciding when a molecule or vaccine should be moved forward and when it should be abandoned, Gates’s Rabinovich notes.

Meanwhile, philanthropies including the Gates Foundation and Wellcome Trust were also seeing the value of bringing together public and private organizations. MVI and the TB Alliance were both founded with Gates Foundation money, and MMV was kick-started by money from the Rockefeller Foundation.

But as nonprofits set out to bring in compounds and set up partnerships, critics doubted industry would ever be a ready participant. Big pharma firms are at the behest of shareholders who want to see profits. And although companies could reap nontangible rewards through such activities, they tended to do it with donations rather than assets and manpower.

“In the early days, a lot of people were basically saying to us—some of them quite publicly—that the model wouldn’t work,” says Chris Hentschel, MMV’s CEO. “Essentially, they didn’t think the pharma industry would buy into the concept.” The naysayers wondered: What’s in it for the pharma industry?

Those questions weren’t unfounded. “In retrospect, the TB Alliance was started as an experiment,” Spigelman says. “If I look back on it, there was absolutely not a shred of evidence that this thing could work or how it would work.”

As it turns out, the time was right to create the partnerships. The drug industry was being put through the ringer by activists who were irate over the high price of HIV medications. Some companies were looking for an opportunity to improve their profile and do more than simply donate money or drugs. Suddenly, organizations that were recently pharma’s biggest adversaries were offering a mechanism to work together to create affordable drugs for neglected diseases.

In 2002, Novartis established NITD, a partnership between the drug company and the Singapore Economic Development Board. Two years later it moved into permanent labs in Biopolis, Singapore’s biomedical hub. Initially, the venture was focused on finding antivirals to combat dengue and anti-infectives against the most resistant strains of TB. Both organizations contributed funds, which were quickly supplemented with resources from other organizations.

The same year, GlaxoSmithKline established a unit at its Tres Cantos facility in Spain that was dedicated to finding drugs for neglected diseases. The company had a malaria project in the works, and after concentrating scientists at one site, it started to reach out to academic institutions, public health organizations, and nonprofits to determine whether pooling resources would help move projects forward faster, says Fraser Gray, GSK’s infectious diseases director.

As companies began interacting with nonprofits, there were no hard-and-fast rules for how the collaborations were structured. Today, PPPs continue to adopt a range of models for how work and costs are shared, how decisions are made, and who owns the intellectual property that comes out of the joint research.

“In essence, there’s only one aspect that stays constant in every one of our deals or partnerships: affordability,” the TB Alliance’s Spigelman says. “That’s the line in the sand with all of our partnerships. Over and above that, anything is on the table.”

In most of the partnerships, the corporate half brings access to cutting-edge technology and know-how, which can be invaluable when an assay needs to be developed or a crystal structure resolved. It’s not necessarily free, “but we get a good price,” says Paul Herrling, head of corporate research at Novartis and chair of NITD. “Our colleagues stretch their budgets as much as they can.”

Also important, industry brings with it several lifetimes of project management experience that helps cash-strapped nonprofits make better and quicker decisions about which projects they should move forward. As Rabinovich says, pharma companies “get to the ‘no’ faster.”

A test of how tight a ship Herrling runs came soon after the launch of NITD, when Wellcome Trust approached Novartis about forming a 50-50 partnership in malaria research. Herrling declined. When asked why he wasn’t interested, he explained that he had the resources to work on only two diseases: dengue and TB. Six months later, Wellcome Trust came back and offered to pay 100% of the costs. That time, Herrling took them up on their offer, and two years ago the partnership opened a malaria unit in Singapore.

The nonprofits make their own contribution to the partnerships. They have incomparable knowledge of the basic science related to their target disease and a finger on the pulse of any clinical developments that might feed back into drug discovery efforts. Furthermore, their intimate knowledge of every project in the pipeline for a particular disease can help shape research.

These efforts “need to be totally collaborative, peer-to-peer, working on science,” Spigelman says.

Another job for the nonprofit is to help industry understand the realities of medicine in the developing world. In a recent meeting with a new partner, Spigelman spent time walking scientists through the qualities that make for a good TB drug. An important one is raw material costs. “For most commercial projects, cost of goods is 5% of the ultimate price. For us, it’ll be 95%. And forget about profit—that’s not even on the table,” he says.

Other factors besides costs also count. For example, when developing a vaccine for a neglected disease, a company needs to take into account the lack of consistent refrigeration along the supply chain. Frequency of dosage is also a consideration. “I cannot make a dengue vaccine where I have to give three boosts. How would I get patients back?” Herrling asks.

The partners try to share any ancillary benefits that come out of their research. Companies often own the rights to compounds in markets where there is a chance of a profit or for any indications beyond the neglected disease.

And as governments create incentives to entice companies to develop drugs for neglected diseases, the partners try to be fair about how they are distributed. For example, priority review vouchers, given out by the U.S. Food & Drug Administration when a company gets approval for a novel drug for a tropical disease, might go to the partner taking on the most financial risk.

Although these partnerships are relatively young, early signs are that they are working. In 2005, the London School of Economics unveiled a report, commissioned by Wellcome Trust, showing that between 2000 and 2004, PPPs spent $112 million to develop a combined 46 drug projects. That’s a bargain compared with the money big pharma spends on a similarly sized pipeline.

At that time, more than 200 scientists across industry were devoted to neglected diseases, the report noted. Today, NITD alone has 100 scientists in addition to dozens of students and visiting researchers at its site in Singapore, as well as another 25 scientists at a vaccines center in Italy. GSK has 52 full-time scientists working on neglected diseases at Tres Cantos and accommodates another 55 people supported by partner organizations.

PPPs are reporting concrete achievements, as well. Through partnerships, critical new formulations of existing drugs that otherwise would have not been pursued have reached patients. In an “Aha!” moment similar to the one Dartois experienced in Tanzania, Rabinovich recalls going to a clinic in Mozambique where doctors were crushing or cutting bitter-tasting malaria pills to give to children. She realized that was the wrong approach and that treatment could easily be improved with a children’s version of the drug.

“The interface between proof of concept and global availability is an important one.”

Normally, a company wouldn’t spend the money on a pediatric formulation unless it hoped to extend patent life. But earlier this year, Novartis, through a partnership with MMV and with clinical study funding from the Gates Foundation, launched a form of Coartem, its artemisinin-based malaria treatment, that tastes sweet and dissolves in water.

Today, more than 65 drugs and vaccines are in clinical trials to treat a range of neglected diseases. The TB Alliance has one drug in Phase III trials—moxifloxacin, a third-generation fluoroquinolone that Bayer already uses to treat cancer—and two drugs with new mechanisms of action in Phase II trials, one of which is being developed in partnership with Johnson & Johnson.

In May, MVI started a Phase III trial of RTS,S, a malaria vaccine developed by GSK that in Phase II studies proved effective in 53% of children. The trials are across 11 sites in Africa, and the first set of data is expected by early 2012, says MVI Director Christian Loucq. He hopes that regulatory agencies and WHO will approve the vaccine by 2015 or 2016.

Going forward, industry appears ready to help keep the momentum going. “We are no longer in a position where we have to persuade people—almost to the contrary,” MMV’s Hentschel says.

The companies first involved in PPPs were mostly European, but U.S. firms are now stepping up with substantial commitments. In 2003, Eli Lilly & Co. launched the MDR-TB Partnership, through which the company transfers technology for manufacturing the active pharmaceutical ingredients in TB drugs that it developed but no longer makes. Four years later, it unveiled the Lilly TB Drug Discovery Initiative. Last year, the venture made its first acquisition of compounds that could become drug candidates, and it continues to search for promising new drugs in Lilly’s vast compound library.

This summer, Johnson & Johnson, through its Tibotec subsidiary, joined forces with the TB Alliance to develop TMC207, a TB drug in Phase II trials. If approved, TMC207 would represent the first new mechanism of action to treat tuberculosis in 40 years.

And Merck, which for years helped distribute a drug for river blindness, recently upped its stake in curing neglected diseases. In September, the company formed a 50-50 joint venture with Wellcome Trust aimed at finding or improving vaccines for diseases that affect the developing world.

“We for many years have been making vaccines that have relevance to global health, but in many ways the landscape of potential partners really wasn’t anywhere near where it is now,” says Mark Feinberg, vice president of medical affairs and policy for Merck’s vaccines and infectious diseases unit.

The joint venture, MSD Wellcome Trust Hilleman Laboratories, will be based in India and receive equal funding from each organization. The combined $130 million should be “sufficient to get the infrastructure up and running, to take on a portfolio of projects, and to reach the goals of the initiative,” says Richard Davis, business development manager in Wellcome Trust’s technology transfer unit.

Merck believes it can offer unique experience not just in discovering vaccines but also in providing access for patients. For example, by partnering with the Clinton Global Initiative and the government of Nicaragua, it was able to launch Rotateq, its rotavirus vaccine, in Nicaragua the same year it was launched in the U.S.

“The interface between proof of concept and global availability is an important one,” Feinberg says. The venture was set up in a way that Merck and Wellcome Trust hope will create incentives for new partners to take on some late-stage development and manufacturing responsibilities, he adds.

Merck and Wellcome Trust expect to hire roughly 60 researchers to run Hilleman Laboratories. Their first task will be to select projects, one of which could be the development of a vaccine against group A streptococci, which claim a half-million lives each year, Feinberg says. By the end of the seven years of funding, the venture hopes to have optimized one vaccine and identified one vaccine candidate, as well as attracted other funding streams, Davis adds.

Meanwhile, Novartis is trying to replicate the success of NITD with the Novartis Vaccines Institute for Global Health. Launched two years ago in Siena, Italy, it now has 25 scientists, but Herrling believes it could eventually grow to the size of the Singapore operation. The first projects are to develop vaccines against several species of Salmonella; Herrling expects one could enter clinical trials next year.

With so much more intellectual capital working on treatments for neglected diseases, the pipeline is far from the bare-bones state it was in just five years ago.

But with success comes challenges. The current partnering model is set up to discover new drugs or vaccines and usher them into early-stage clinical studies. Now, the quandary is who will pay for expensive Phase III studies, the fees to register for regulatory approval, manufacturing, and, finally, distribution.

Ten years ago, “there was no need, other than in purely hypothetical terms, to talk about how we were going to work together in Phase III,” the TB Alliance’s Spigelman notes. With one drug in Phase III trials, two drugs in Phase II, and several others in preclinical studies, the alliance now has the practical issue of finding the resources to move projects forward.

“There’s no fixed answer yet,” Spigelman acknowledges. “All three of our clinical projects have very different models in terms of the relationship of the three partners when it comes to Phase III and beyond.”

With PA-A24, a compound in Phase II trials that was originally licensed from Novartis, the TB Alliance is on its own to pay for the clinical costs, regulatory filings, and distribution. “We’re right now in the process of thinking about how to finance and support these high-ticket items,” Spigelman says.

On the other end of the spectrum, the TB Alliance’s partnership with Bayer for moxifloxacin puts much of the financial burden on the company. Because Bayer already makes and sells the drug for cancer indications, it will take on the responsibility of applying for regulatory approval for use in TB, then manufacturing and distribution.

Industry could see an upside to sinking larger sums into the neglected disease arena. Nearly every major drug company has started looking to “emerging markets” as a growth opportunity. As countries get a leg up and can afford more medicine, companies with a long-term presence through their nonprofit ventures could benefit.

Even though “there will be no commercial returns in my lifetime, I say it is good business,” Novartis’ Herrling contends. The nonprofit work provides ready access to health ministers, local doctors, and other decisionmakers, effectively building a company’s reputation in a burgeoning market.

Meanwhile, the Gates Foundation is committed to playing a major funding role. Last month, the philanthropy agreed to provide another $115 million over the next five years to support MMV’s mission.

Yet Rabinovich points out that getting drugs out of the pipeline and to patients will require financial commitment from all sides. In particular, she suggests that governments of countries most afflicted by these diseases need to take a stake in solving the health crisis, whether by committing to buy drugs or by helping improve distribution channels.

MMV’s Hentschel agrees that governments, particularly those that are minor contributors, need to step up their support. Currently, some 80% of the funding for drug and vaccine development for neglected diseases comes from philanthropy, he points out, a proportion that is unsustainable.

Some are less worried about who will pay and are more excited for the steady stream of drug candidates. “Once we get many drugs in later stage development, it will be a nice problem to have to decide which ones to resource,” GSK’s Gray says.

He is confident that once a treatment has passed proof-of-concept studies, all the stakeholders—from industry to nonprofits to governments—will make every effort to get it to market. “I’m not underplaying the challenges it’ll bring, but I strongly believe there’s a real commitment from a funding perspective, whether it’s pharma companies or Gates or MMV, to really take things forward. They’ve been waiting too long for new medicines.”

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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