[Updated and corrected 9/10/14, 10:05 am. See below.] On August 28, Anthony Fauci, the U.S. National Institutes of Health’s top infectious disease specialist, announced a major trial in concert with GlaxoSmithKline (NYSE: GSK) to test new Ebola vaccines in humans. Fauci called it an “all-hands-on-deck response” to the growing global health emergency in which more than 2,000 people have died in West Africa.
Plenty of other weapons are being marshaled, too, but in the fight against Ebola, the U.S. government’s quiver is at least one arrow short. Since 2007, a relatively little-known financial incentive program has been in place to encourage the private sector to develop medicines for neglected tropical diseases. Companies that bring a treatment to market for such a disease receive a priority review voucher to apply to any drug in their pipelines. It’s an intriguing carrot to dangle: cutting a few months from the review process of a potential blockbuster drug can mean tens, perhaps hundreds, of millions of dollars in extra sales if it’s approved.
Bill Gates, speaking in Davos, Switzerland in 2008, was a fan of the idea: “I believe the highest-leverage work that governments can do is to set policy to create market incentives for business activity that improves the lives of the poor… If you develop a new drug for malaria, your profitable cholesterol-lowering drug could go on the market a year earlier.”
[UPDATE: The Gates Foundation announced Wednesday $50 million in emergency relief funds to fight Ebola. An undetermined portion of those funds will go toward R&D for drugs, vaccines, and diagnostics.]
While the voucher program has its flaws, it reached an important milestone this summer: the first sale of a voucher from one drug company to another, establishing a secondary market for those who don’t want to apply the voucher to their own pipeline.
Sixteen tropical diseases qualify a company for the program, including some of the world’s biggest scourges: tuberculosis, malaria, cholera, and dengue fever.
But when lawmakers drew up the list seven years ago, Ebola did not make the cut. It’s never been a widespread killer like many others on the list, and it’s not on the World Health Organization’s list of neglected tropical diseases, either. (“There is no hard-and-fast definition of neglected diseases, but they tend to be persistently present in low-income countries and populations, whereas Ebola is an epidemic disease that only breaks out rarely,” according to WHO spokeswoman Donna Eberwine-Villagrán.)
But the list of diseases eligible for the voucher program differs from WHO’s list in other ways as well (malaria isn’t on the WHO list, for example). And besides, modern population movement and Ebola’s virulence, killing more than half of those it infects, make Ebola’s exclusion from the voucher list puzzling.
“It really should have been included,” BIO Ventures for Global Health president Jennifer Dent tells Xconomy.
In an op-ed published last month in the Seattle Times, Dent wrote, “The current, conventional drug-development approach does not work when it comes to creating treatments for rare and uncommon diseases like Ebola.” She called for “a new paradigm” of cooperation and coordination between the public and private sectors. We’re seeing that cooperation to some extent in a recent spate of news, including Fauci’s August 28 announcement, about programs ramping up quickly.
One could argue whether the action has been fast enough. The outbreak was first detected in March, after all, and WHO outlined one scenario in late August in which the outbreak could run nine months and infect 20,000 people. But there has been action. In parallel with the NIH/GSK activity in the U.S., a public-private consortium is conducting a Phase 1 safety trial with a slightly different GSK vaccine in the United Kingdom, Mali and the Gambia. That effort is being funded by the Wellcome Trust, the Medical Research Council, and the UK Department for International Development.
In addition to the collaboration with GSK (which acquired the vaccines when it bought the Swiss firm Okairos last year), the NIH is fast-tracking a vaccine program that combines technology from Crucell, part of the Johnson & Johnson (NYSE: JNJ) conglomerate, and Danish drug maker Bavarian Nordic. A Phase 1 safety trial could start early next year.
In an emergency session last Friday, WHO tagged the GSK vaccines as the field’s “most advanced” candidates which, if successful, could be ready for healthcare workers by the end of this year.
That’s an important point: nine months since the outbreak first registered, the most advanced vaccine being rushed into clinical trials would, best-case scenario, be available only to healthcare workers. Not to the general population.
Meanwhile, drugs to treat people already infected do not exist, although there is hope. You’ve probably heard of ZMapp by now. It’s never been tested in formal human trials, but it should be soon, thanks to a huge injection of federal dollars.
Five of seven people with Ebola who received ZMapp on an emergency basis have recovered. And the drug’s maker, Mapp Biopharmaceutical of San Diego, and other researchers reported last week in Nature that ZMapp had excellent results in monkeys.
As promising as the treatment sounds, it absolutely needs to go through clinical testing and prove viable in a larger-scale manufacturing program—no small task for a mixture of three monoclonal antibodies extracted from genetically modified tobacco plants. “We may eventually need and rely on those types of drugs, they’re very important,” says Christian Sandrock, a critical-care doctor in Sacramento, CA, and a top public health official for the surrounding county. (Sacramento had an Ebola false alarm in August.)
But Sandrock, an infectious disease specialist who has spent time in Africa and would be on the front lines of an epidemic response the U.S., understands the need to proceed with caution. “Just a couple of cases don’t mean anything,” he says. “It’s hard sometimes, but as doctors, we live in a world where we want hardcore science to help us make decisions.”
Would that science—and approved treatments—be available today if, seven years ago, the U.S. government had included Ebola on its list for the priority review voucher program? Several people I talked to called the program “interesting” or “useful.” But on its own, the program isn’t powerful enough to “motivate a company to direct their drug discovery and development programs,” BVGH’s Dent told me.
One of the program’s originators has a different view. “It’s largely gone according to our expectations,” says David Ridley, one of three Duke University health economists whose 2006 paper set the idea in motion. “We thought it would motivate companies, especially smaller companies, and give managers within larger companies the justification to move forward on drugs that are less profitable.”
How tempting a carrot has it really been? To date, three companies have won vouchers for bringing tropical disease treatments to market. First was Novartis (NYSE: NVS) for the anti-malarial combination of artemether and lumefantrine (Coartem), controversial because some felt the program should spur new drug development, and Coartem had already been on the market around the world for nearly a decade. The second went to J&J’s Janssen Pharmaceuticals for bedaquiline (Sirturo), to treat drug-resistant tuberculosis, the first TB drug in 40 years with a new approach to attack the bacterium.
The third voucher went earlier this year to Knight Therapeutics of Montreal for the leishmaniasis treatment miltefosine (Impavido). Knight was spun out of Paladin Labs, which bought miltefosine in 2008. The drug was already approved in Europe, says Knight’s chief financial officer Jeffrey Kadanoff, and Paladin spent roughly $10 million to ready it for U.S. regulators.
Whether freshening up a drug’s profile to aim for a voucher violates the spirit of the program or not, Ridley acknowledges the program needs fixes. He and others thought they were on the way when the Congress, pushed by a Washington, DC, mom whose son died of a rare brain cancer, moved to expand the voucher program to rare pediatric diseases. The expansion became law in 2012, but last-minute, closed-door negotiations left the tropical-disease side of the program untouched. For example, the pediatric vouchers can change hands many times, but tropical disease vouchers, as stipulated in the 2007 law, can only be sold once, which could limit their value.
The first pediatric voucher was awarded in February this year. It went to rare disease specialist BioMarin Pharmaceutical (NASDAQ: BMRN), which four months later sold it to Tarrytown, NY-based Regeneron Pharmaceuticals (NASDAQ: REGN) for $67.5 million. Regeneron announced it would apply the voucher to speed up review of alirocumab, a cholesterol lowering treatment. (Good call, Bill Gates.) Alirocumab is in a race to market with evolocumab, which Amgen (NASDAQ: AMGN) just submitted to European regulators for approval.
Duke’s Ridley thinks the program will soon hit a higher gear, with two vouchers awarded annually. But there’s an odd catch, which is also one of the flaws of the market-driven program: If it gets too popular, a glut of vouchers could drive prices down. “The market can only absorb a couple a year for high price,” Ridley says. “If there are 20 awarded each year, they won’t be valuable, because there aren’t 20 companies willing to pay tens of millions for a voucher,” he says.
Keeping voucher prices at a premium is critical to their effectiveness as an incentive. Small companies that score vouchers aren’t likely to have a second drug poised for approval, so they need a lively resale market for them. Even a midsize biotech with a deep pipeline like BioMarin preferred to test the voucher market and use the cash near-term to expand its headquarters, rather than wait a year or two for its next drug to approach regulatory review.
Looking to sell its voucher, Knight Therapeutics has been crunching some numbers, too. The company has pinpointed 60 drugs owned by 40 companies that could potentially use a voucher to speed up review, says the CFO Kadanoff. Knight has hired a banker to run an auction, and Kadanoff is keeping an eye on other companies that might soon qualify for a voucher—some have even called for advice, he says—but he’s not worried about oversupply any time soon.
If Knight can sell its voucher for a price in BioMarin’s ballpark, it will help quell some reservations about the program and give small developers an additional story to tell investors: Help us get this program approved, the pitch might go, and we’ll have a voucher worth $50 million or so in our hip pocket—a nice boost to a company’s value, especially if the investors’ money is padded with nondilutive grants.
If the voucher program’s “time has come,” in Ridley’s words, it’s also time to put Ebola on the list of eligible tropical diseases. Not to stem the current outbreak, but to save people from the next one. The U.S. Health and Human Services secretary has authority to add “any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations.”
That’s right from the law, so yes, Ebola seems to fit the bill. But an HHS spokeswoman wrote via e-mail that adding a disease to the list requires “rule making,” which includes a period of public comment. “It is a lengthy process,” she wrote.
Put another fix on the to-do list, probably for the next FDA budget authorization in 2017: The program might need a more flexible way to respond to pathogens that don’t behave according to bureaucratic timelines. Sure, there are other mechanisms: the clinical trial cooperation I mentioned earlier, for example, or FDA’s orphan drug and fast-track designations. And the HHS division Biomedical Advanced Research and Development Authority, known as BARDA—created last decade to fund biomedical responses for public health emergencies—can move money quickly. In fact, it has: BARDA was the funding source to move ZMapp to the next level. (Those $42 million are the only BARDA funds ever allocated for Ebola, an HHS spokeswoman said.)
But there’s less funding out there for Ebola medicines than you might think. WHO doesn’t have any. The Gates Foundation, until today, had never funded any research. The NIH’s NIAID has been a big source, with $456 million from 2000 to 2013 and $91 million the previous two years alone. Much of that, of course, is for basic research. [A previous version of this story listed an incorrect NIH funding total for 2012-13. We regret the error.] The Defense Department also funds Ebola and related research, but amounts couldn’t be ascertained by press time.
Several health officials also emphasized that Ebola isn’t like the flu. A carrier can’t travel the world, spreading infection in stealth with coughs and sneezes. Ebola is relatively hard to spread, and so health officials emphasize that nonpharmaceutical measures should stop outbreaks eventually. But as we’ve seen the past couple months, “eventually” is a frightening word. So why not have all the tools available—like the incentive of the voucher program—to help prepare for the next outbreak, and the one after that, and the one after that?
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