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Patients Advocate For Change

Although companies ultimately bring treatments to market, it’s patient groups that are creating the awareness needed to start the drug discovery process

by Lisa M. Jarvis
May 13, 2013 | A version of this story appeared in Volume 91, Issue 19


Credit: Dodi Holm/Rustic Pear Photography
Jonah’s mom, Jill Wood, is fighting for her son’s life. Her foundation, Jonah’s Just Begun, supports academic drug discovery efforts for Sanfilippo type C.
This is a photo of Jill Wood with her son Jonah.
Credit: Dodi Holm/Rustic Pear Photography
Jonah’s mom, Jill Wood, is fighting for her son’s life. Her foundation, Jonah’s Just Begun, supports academic drug discovery efforts for Sanfilippo type C.

Most people think of a patient advocate as someone who is raising money for a charity. Many e-mail in-boxes and Facebook pages contain pleas for donations to the latest walk for breast cancer awareness or bike ride for AIDS research. But in the rare disease space, patient advocates aren’t just walking in the 5K, they’re organizing it and immediately sending the proceeds to a researcher. They tweet, they blog, and they create apps to update patients on research or keep tabs on clinical trials.

Jill Wood’s son, Jonah, was diagnosed in May 2010 with Sanfilippo syndrome type C, one of four subtypes of mucopolysaccharidosis (MPS) III, each of which is caused by the lack of an enzyme needed to break down heparan sulfate. No treatments exist for Sanfilippo, and although the subtypes progress at different rates, each type leads to dementia and loss of motor function. Ultimately, patients succumb to the disease in adolescence or early adulthood.

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“He’s in the prime of his life at four-and-a-half years old,” Wood explained to congressional staffers at a lobbying event in Washington, D.C., during a week of activities in February marking World Rare Disease Day. “This disease will progress substantially over the next few years. He’ll most likely be confined to a wheelchair, feeding tube, and won’t really know who I am by the time he’s 15 years old.”

Whether it’s to a congressman or a reporter, Wood speaks about Jonah’s disease with urgency, rattling off scientific facts at a speed that can be disorienting for rare disease newbies. After she walks away from a group, there’s often a moment of stunned silence while people digest what they’ve heard, followed by a quiet comment: “Wow. She is amazing.”

Jill Wood, whose son has the rare disease Sanfilippo type C, explains why she needs government support for research.
Credit: Lisa Jarvis/C&EN

She’s also quick to laugh and has a warmth that inspires people to join her fight for Jonah. Indeed, in the three years since Jonah’s diagnosis, Wood has amassed a network of collaborators whom she groups into three categories: “my scientists,” “my moms,” “my mentors.” With their help, she started a nonprofit that has raised substantial money for Sanfilippo type C research. More recently, she founded a virtual biotech company to develop any drug candidates that might arise from their work.

Wood is part of a legion of advocates taking on more active roles in the drug development process. Patient advocates “really are at the core” of the recent progress in rare disease R&D, according to Stephen C. Groft, director of the National Institutes of Health’s Office of Rare Diseases. Because of their hard work and determination, he says, “all of a sudden, there are a lot of pieces of the puzzle coming together.”

Their motivation springs from necessity. Not all 7,000 rare diseases attract the same level of attention or offer the same commercial potential.

Under the Orphan Drug Act, a drug developed for any disease that affects fewer than 200,000 people is eligible for orphan designation. When created 30 years ago, the legislation was intended to draw orphan diseases out of the wilderness by creating incentives to develop drugs for small patient populations. A drugmaker that wins approval for an orphan drug enjoys seven years of marketing exclusivity regardless of its patent status, gets a waiver for the fee the Food & Drug Administration charges when a New Drug Application is filed, and is granted tax credits for half the cost of the drug’s development.

The incentives have worked: Whereas just 10 treatments for orphan indications were approved in the decade before the act was introduced, more than 400 have come to market in the subsequent 30 years.

But there’s the legal definition of an orphan disease, and then there’s the reality that not all diseases have the same commercial potential. In the post-blockbuster-drug era, it’s a no-brainer to take on a disease with a patient population nearing 200,000, no existing treatments, and reasonable science behind it. Convincing companies to invest in a disease affecting only 200 people is a much harder sell.

The 7,000 rare diseases include a long tail of disorders that affect anywhere from a few dozen to a few thousand people. The tiniest patient populations struggle to get NIH funding for the kind of research that can spark interest from industry. Even if academic research efforts are under way, advocates think the regulatory incentives aren’t enough to catch the eye of industry. “The Orphan Drug Act is great, but it doesn’t meet our needs yet,” Wood told her state’s representatives at the lobbying day.

Some advocates for diseases with tiny patient populations have started to identify themselves as part of the “ultrarare” community. The term carries no legal significance, Groft warns, but patient advocates say it helps them unify the thousands of disparate patient groups. Alone, they are the orphans of the orphans. Collectively, their voice has heft.

The divide between the rare and the ultrarare became crystal clear for Wood in May 2010. When Jonah was diagnosed with Sanfilippo type C, which affects just a few dozen kids in the U.S., she was heartbroken to learn that not only were there no treatments, but scant research was under way to find them.

Her response was to take action. Just months after Jonah’s diagnosis, Wood’s mom and her best friend organized a wine-tasting fund-raiser in Oregon. With their help, by August 2010 Wood had pulled together $20,000, started a nonprofit called Jonah’s Just Begun, and wrote her first check to a scientist.

The money went to University of Montreal biochemist Alexey Pshezhetsky, one of two researchers who popped up on Wood’s Internet search about the disease. In 2006, Pshezhetsky and his team discovered the genetic mutations that cause Sanfilippo type C, in which an enzyme called heparan-α-glucosaminide N-acetyltransferase (HGSNAT) is lacking.

Pshezhetsky was able to turn Wood’s $20,000 gamble into a five-year grant from the Canadian Institutes of Health Research. The $130,000 in annual funding from the government agency helped the scientist better understand the pathology of the disease and create a mouse model for Sanfilippo type C, a critical tool if a drug is going to be developed.

Researchers have shown that sugar molecules don’t aggregate in the cells of Sanfilippo type C mice that make as little as 10% of the normal amount of HGSNAT. With this in mind, Pshezhetsky is looking for drugs that can assist the faulty enzyme produced by Sanfilippo patients. This “chaperone therapy” approach is being pursued for several lysosomal storage diseases and is the basis of Amicus Therapeutics’ drugs in development for Fabry and Gaucher’s diseases.

Meanwhile, Wood teamed up with three other families with Sanfilippo type C foundations—based in Massachusetts, France, and Spain—to jointly fund drug discovery and development efforts in labs across the globe. They brought researchers together for the first time with patients and physicians and in the past three years have supported many approaches to tackling the disease. In addition to Pshezhetsky’s chaperone therapy, they have high hopes for a gene therapy project by stem cell specialist Brian Bigger at the University of Manchester, in England, and separate efforts by two scientists at the Telethon Foundation, in Italy.

Together, the four family-run organizations have sunk roughly $500,000 into Sanfilippo type C research over the past two-and-a-half years. Wood has even started a company, prompted by a chance encounter at a conference with former pharma researcher Sean Ekins.

They launched Phoenix Nest last year. For now it’s inactive while the families wait for their investments in academic science to pay off. If one of the projects is promising and an industry partner doesn’t step in to support it, the idea is to develop it through Phoenix Nest.

The bootstrapping done by Wood and her partners reflects an increasingly common approach to early drug development. They are walking in the footsteps of venture philanthropy pioneers like the Cystic Fibrosis Foundation and nonprofits supporting Duchenne muscular dystrophy (DMD).

CF Foundation, which began investing in drug discovery efforts in 1998, reached the ultimate goal last year when FDA approved Vertex Pharmaceuticals’ Kalydeco, the first drug to correct the underlying genetic defect in a subset of CF patients. Similarly, the DMD foundations are supporting several disease-modifying drugs, two of which are currently racing toward approval.

Small, family-run nonprofits look to larger organizations with both awe and envy. The hundreds of millions of dollars raised to support CF research seems out of reach for nonprofits supporting diseases with names that are hard to pronounce and that personally touch so few. Although rare disease groups have gotten creative to pull in funds, they see the limits to that approach.

“How long can you keep going to your tight-knit supporters of family and friends and ask for compassion for your story?” asks Lori Sames, who has raised millions of dollars to support Hannah’s Hope Fund, a nonprofit focused on an ultrarare disease called giant axonal neuropathy. “That well can only get drained so many times.”

Even as Wood and her collaborators move as fast as they can to develop potential drugs, they are keenly aware of the unlikelihood that any firm—be it biotech, venture capitalist, or big pharma—will be willing to risk trying to commercialize their product.

Dozens of patients may seem like an impossibly small market, but drug executives say the bar for corporate investment is dropping. At the time the Orphan Drug Act was passed, no one was interested in investing in diseases affecting fewer than 100,000 people, says John F. Crowley, chief executive officer of Amicus. Crowley, whose two kids have Pompe disease, was instrumental in bringing the first treatment for that lysosomal storage disease to market.

“Now, if you find something that’s 1,000, it’s a home run,” Crowley says. “Really, the break point in the last couple of years has been 500 to 1,000—and now we’re measuring sub-500.”

Many in the rare disease field hold up Ultragenyx Pharmaceutical’s ability to raise $75 million in venture funding in late 2012 as a sign that investors see opportunity in the ultrarare space. The company is pursuing a treatment for MPS VII, which affects just 200 patients in the developed world.

But Ultragenyx’ CEO, Emil D. Kakkis, cautions against making sweeping assessments based on that product. “I’d say we’re an outlier,” he says. MPS VII affects tissues—the liver, spleen, and joints—that are accessible with an enzyme replacement therapy. “When you start talking about the bone and the brain, it becomes ever more difficult. Clinical trials are challenging, and the cost of doing them is high.”

Kakkis, who earlier in his career developed Aldurazyme, a BioMarin Pharmaceutical product that was the first drug for an MPS disease, thinks the bar is higher. “You probably will have trouble getting financial support to do development for a disease with less than 500 patients in the developed world,” he says.

And some observers are doubtful that big pharma firms will ever cross into the realm of the ultrarare. “It’s not hard for me to imagine a big biotech company looking at a disease that affects 1,000 people in the Western world,” says Philip R. Reilly, a partner at the investment firm Third Rock Ventures. “It’s still hard for me to believe that big pharma would fit that into its portfolio.”

Alvin Shih, chief operating officer of Pfi­zer’s rare disease unit, says the firm doesn’t have hard-and-fast rules to decide whether a project is commercially viable but rather asks a few key questions: Are there clear endpoints for a clinical trial? Are there enough patients for a trial? And are there advocacy groups that can help the company navigate the space? “When you’re under 1,000 patients, it’s tough to have all that,” Shih says. A disease with several thousand patients is “more of our comfort zone.”

One way to get around the commercial limitations of the ultrarare world is to find treatments or technology that can benefit more than one disease. Back when Wood first heard a doctor utter the words Sanfilippo type C, just one company was working on a treatment that might help her son.


Zacharon Pharmaceuticals, with financial backing from the nonprofit Team Sanfilippo Foundation, was trying to prevent the cellular buildup by developing small molecules that block the synthesis of heparan sulfate. An effective drug could treat all four subtypes of Sanfilippo, bringing it into the realm of commercial viability.

Developing technologies that could yield multiple drugs or address multiple patient populations underpins Glaxo­SmithKline’s efforts in rare diseases. The big pharma firm’s establishment of a dedicated unit for rare disease research was a tacit acknowledgment that things must be done differently for this market.

With more traditional products, the commercialization plan is well defined, explains Mike Diem, head of business development for GSK’s rare disease unit. “Take diabetes,” he says. “GSK has been developing drugs here for many years, and we have a very simplified path we go down when we know a space well.” With small patient populations and no existing treatments, companies are walking into the unknown. “You’re defining the path as you go along,” Diem adds.

To mitigate that risk and create a sustainable model for rare disease drug development, GSK has moved beyond the one-drug approach. Diem points to the company’s collaboration with the Dutch biotech firm Prosensa as an example of how a technology-based approach can generate a whole pipeline of products. The companies are developing antisense therapies for DMD, a disease that is primarily caused by deletions of one or more exons in the DMD gene.

Much attention is focused on GSK2402968, the partners’ lead candidate, which is in Phase III studies and addresses the roughly 13% of patients who have a deletion at exon 13 in the DMD gene. But behind that program are five or six additional therapies addressing other exon deletions. The regulatory path for the first drug will be rocky, but GSK is betting that it can “learn from the first one to develop the second, third, fourth, and others in a more efficient manner,” Diem says.

GSK is replicating the approach in other collaborations. A partnership with Angio­chem around peptide-drug conjugates that can cross the blood-brain barrier is focused on treating the neurological impact of lysosomal storage diseases. “If you’re leveraging what you’re learning along the way, something ‘ultra orphan’ theoretically could be viable in the scheme of building a platform around five or six products instead of one,” Diem says.

Wood is well aware that attracting the attention of venture capitalists or biotech firms will require coming up with a drug or drug delivery method that could affect a larger patient group than the few dozen kids with Sanfilippo type C. She has one project up her sleeve that she thinks has a chance.

Montreal’s Pshezhetsky recently found something unexpected in the brains of mice with the Sanfilippo type C mutation. As the central nervous system of the mice is progressively debilitated by the buildup of sugar molecules, the mice become hyper­active, fearless, and lose their ability to learn. But Pshezhetsky made a curious observation: The symptoms aren’t caused by dying neurons.

That finding runs counter to common wisdom that the brain cells of Sanfilippo kids become clogged and die. The scientist hypothesizes that the buildup is instead causing defective synaptic transmission, or a disruption in the cross talk between brain cells, and he is searching for molecules that could protect or restore that neurological function.

Synaptic markers in the brain appear to be reduced in all four types of Sanfilippo. Moreover, Pshezhetsky thinks the effect could exist in the broader MPS population; academic studies are ongoing to confirm the hypothesis. He is also testing existing neuro­protective drugs to see whether any show signs of efficacy.

Wood, meanwhile, is still waiting for more news of Zacharon’s heparan sulfate inhibitors. In 2011, Pfizer partnered with the biotech firm to develop rare disease drugs. The partnership gave Wood and other Sanfilippo families hope that big pharma was swooping in to speed the molecules through development. But that deal ran into trouble, and in the end, investors sold Zacharon to BioMarin.

Despite the new owner’s long-standing commitment to rare diseases, Wood is worried that research momentum has slowed. The relationship she had developed with Zacharon’s research chief, Brett Crawford, has changed. Now, when Wood runs into Crawford at conferences, she dissects his every sentence and parses his every gesture, trying to get a sense of what’s going on with the program. “You just try to analyze everything,” she says. “Nobody can tell us what’s happened, so there are lots of rumors going around.”

BioMarin says heparan sulfate inhibitors are an active project but that it is still in the process of optimizing the molecules. “It is too early to predict when, or even if, we will be successful at making a compound suitable to move into clinical development,” the firm says.


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