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Regulations Are Cause For Concern

Patient advocates and companies are encouraged by the recent introduction of new regulatory tools to speed the development of drugs for rare diseases but worry they may not go far enough for the smallest patient groups

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


This is a photo of Case Hogan in his cowboy boots.
Credit: Lisa Jarvis/C&EN
Case Hogan, who loves his red cowboy boots, rests after his dose in a clinical trial to treat the neurological effects of Hunter syndrome.

Even as Jill Wood breathes a little easier knowing several drug discovery programs to treat her son’s rare disease, Sanfilippo syndrome type C, are under way, she’s also aware that the hardest part is yet to come. Testing a drug in kids for rare diseases and gathering enough evidence to convince the Food & Drug Administration it is safe and effective is no cakewalk.

Trying to win approval by showing that disease progression has slowed or stopped is one of the bigger challenges in the rare disease space. Patient populations are often heterogeneous, meaning everyone declines at different rates and with different symptoms. With so few patients and so much variation, it’s difficult to choose endpoints for a clinical trial that can show a drug is, statistically speaking, making a difference.

Few clinicians know the challenges better than Joseph Muenzer, a pediatrics professor at the University of North Carolina, Chapel Hill. Muenzer has run clinical trials for several mucopolysaccharidosis (MPS) enzyme replacement therapies, including Aldurazyme, for MPS I, and Elaprase, for MPS II, or Hunter syndrome.

Joseph Muenzer, a pediatrics professor at the University of North Carolina, Chapel Hill, breaks down the difficulty of clinical trial design for ultrarare diseases.
Credit: Lisa Jarvis/C&EN

Muenzer’s experience with treating certain MPS diseases is so vast that his office is often the first stop for families with a recently diagnosed child. As Jeff Leider, whose two sons recently enrolled in a UNC study of the cognitive progression of boys with Hunter syndrome, puts it, “He’s the guru.”

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Now Muenzer is contributing to the development of Shire’s HGT-2310, an enzyme replacement therapy for Hunter syndrome that is delivered directly into the spinal canal. Known among Hunter families as the IT trial because it is administered intrathecally, the study is intended to address the neurological effects of the disease.

Last month, on a sunny day in Chapel Hill, Muenzer was sequestered inside UNC’s North Carolina Children’s Hospital to give two boys in the study their monthly dose of HGT-2310. One of the boys was Case Hogan, a deliciously rambunctious six-year-old who, that morning, was darting around the hospital in red cowboy boots and a hat.

After about an hour of shuttling between rooms to check Case’s vitals and go over a long list of questions from Case’s mom, Melissa Hogan, Muenzer was ready to get the show on the road. A crew of nurses trailed the lanky physician into yet another room, where he hopped up on an examining table and lifted Case up next to him.

Hogan hovered over Case, who clutched his DVD player, not wanting to shift his focus from “The Princess Bride.” A mask delivering anesthesia was placed over Case’s mouth, and as he squirmed in protest, Hogan and the nurses broke into song to soothe him. After three short rounds of “You Are My Sunshine,” Case was out.

A team of nurses sings to comfort Case Hogan, who has Hunter syndrome, during his monthly drug dose.
Credit: Lisa Jarvis/C&EN

The nurses quickly slipped off his cowboy boots—purchased days earlier in Gatlinburg, Tenn., during the family’s trip from their home in Nashville to the hospital—and Hogan left the room to let Muenzer work his magic.

More than two years into Case’s participation in the IT study, the team has this routine down pat.

Between April 2010, when the family first suspected he might have Hunter syndrome, and early 2011, when he entered the clinical trial, Case’s mental decline was precipitous. He began to stutter and lose words, going from nine-word sentences to two- or three-word phrases. Hogan looks back at photos from a family vacation about a week before they realized Case might have an MPS disorder and sees a boy who looks vacant.

But by winning a spot in the clinical trial, the Hogans now have reason for hope. On each visit, Muenzer draws out a bit of spinal fluid—or, as he calls it, liquid gold—that he sends to Shire for analysis. Muenzer then injects a dose of the enzyme that Case’s body is unable to produce.

The entire process takes minutes, but for Hogan it’s nothing short of a miracle. As she broadcasts on her blog, Saving Case, the changes in her son’s behavior and cognitive ability were almost immediate after the first injection.

Two-and-a-half years into the study, Case can do simple puzzles, count to 20, and stay nimble on his feet. His behavior and ability to focus have improved as well. When he first arrived at UNC to be evaluated, Case was in a stroller with a six-point harness because he was too unfocused and hyperactive.

On their long drive to Chapel Hill last month, Hogan had a moment of panic when she thought she had forgotten something; then she took a breath and realized they were simply traveling like a “normal” family—no wheelchair stroller, no special equipment or food. Indeed, the boy sitting in the recovery room after the procedure eating pudding, flirting with the nurses, and generally charming anyone in his vicinity was far from vacant.

In March, Muenzer and colleagues presented early data from the IT enzyme trial at the American College of Medical Genetics & Genomics’ annual meeting in Phoenix. They reported a drop in the level of the built-up sugars, glycosaminoglycans, in the cerebrospinal fluid of patients receiving two high doses of the enzyme, compared with high levels of glycosaminoglycans in four untreated patients.

Credit: Lisa Jarvis/C&EN
Case Hogan has a medical tattoo to distinguish his two ports; one is for intravenous delivery of Elaprase, and the other is for intrathecal delivery of an enzyme.
This is a photo of Case Hogan’s medical tattoo to mark the intrathecal injection point.
Credit: Lisa Jarvis/C&EN
Case Hogan has a medical tattoo to distinguish his two ports; one is for intravenous delivery of Elaprase, and the other is for intrathecal delivery of an enzyme.

Muenzer detailed signs of improvements in cognitive measures. Case is one of four boys in the small study who have shown stable or improved cognitive measurements. One child, who has been in the IT trial the longest, is now able to attend a regular kindergarten class, Muenzer notes.

Hogan is over the moon about Case’s progress, which also has raised hopes in the Leider household that Justin and Jason, their sons with Hunter syndrome, might benefit from the approach. But Muenzer is cautious about the next steps for the drug. The looming question is what kind of data FDA will want to approve the treatment. The challenge will be to come up with appropriate endpoints, or measurements to prove a drug’s efficacy, for an upcoming late-phase clinical trial, which Shire expects to begin by the end of this year.

As Shire considers the design of the trial, industry observers say the company’s experience mirrors what other firms face when trying to develop drugs for rare diseases. Those with a history in rare diseases argue that the challenge of pulling together the right patients and designing the right trials to get drugs approved goes underappreciated.

Newcomers look at the relatively small trials and see an easy path to approval. According to a recent study by Evaluate­Pharma, a Phase III study for an orphan drug enrolls on average 528 patients; the average Phase III trial for a nonorphan drug enrolls 2,234 patients. And several drugs have been approved on the basis of studies with just a few dozen patients. Moreover, FDA offers a slew of incentives designed to trim the timeline and cost for getting a rare disease drug to market.

Rare disease veterans suggest tempering those rosy assessments. “It’s a bit of a fallacy that it’s easier, or that the bar is lower,” says Genzyme’s Chief Executive Officer David Meeker.

The flip side of having so few patients is having only one chance to get things right. In April, Muenzer flew to Washington, D.C., to join Shire executives in a meeting with FDA to discuss the data needed to approve the drug. Earlier that day, Hogan quizzed him on what FDA wants. Muenzer, whose relationship with Hogan feels more like teacher and student than physician and parent, walked her through the complexities and realities of drug development for ultrarare diseases.

As he explained, all the kids in the study appear to have stabilized. They aren’t all necessarily seeing the same cognitive improvements that Case is, but they also aren’t declining. Yet that kind of soft measurement is unlikely to be enough to convince FDA that the IT delivery is working.

“I can’t tell FDA at what rate they decline because we didn’t ever have that quantitative data to say, ‘Here’s what we anticipate for this population,’ ” Muenzer says.

For more common diseases, information about patients is compared with a large pool of historical data culled from others with the disease. But another major challenge for rare disease drug development is the lack of understanding of the natural history of a rare disease—that is, how it progresses in the absence of medical intervention.

Companies usually have to conduct their own natural history study, an expensive and lengthy process in which a group of untreated patients is watched over time to determine what biomarkers could be useful in a clinical trial and to define endpoints that can show a potential drug is effective.

A natural history study is at the top of the mental checklist Wood keeps of things needed to get a treatment for Sanfilippo type C into the clinic. The consortium of families she works with is funding a natural history study of the disease, slated to start in the next month, that will collect the data they think will be essential if a drug candidate makes it into the testing clinic.

Wood is aware that a misstep in how resources are spent could cost both her son and other kids with Sanfilippo type C who haven’t been diagnosed yet. “I’m the kind of person that jumps in headfirst, but I’ve found really fast that this is going to affect generations to come,” she says. “I can’t make rash decisions.” She feels an immense pressure to get the design of the natural history study right.

“We’ll never be able to do it again,” Wood says. “We don’t have the patient population to do it again.”

Patient advocates are hopeful that FDA is becoming more willing to accept surrogate endpoints, or measurements such as biomarkers that suggest a drug is working, rather than data that directly prove that a potential treatment helps people live longer or feel better. They are encouraged by a series of incentives and changes introduced with the passage last year of the FDA Safety & Innovation Act, or FDASIA, which reauthorized FDA’s ability to collect fees from industry.

Advocates are most excited about a measure that expands to rare diseases the accelerated approval path, which allows early approval of a drug on the basis of surrogate markers, and a measure creating “breakthrough status,” an incentive to speed development of innovative drugs that show promise in early human studies. The legislation also calls for patients to have more of a voice in the review process.

The National Organization for Rare Disorders (NORD) calls FDASIA the most important piece of legislation for the rare disease community since the Orphan Drug Act. John F. Crowley, CEO of Amicus Therapeutics, puts it succinctly, “We’ve just turbocharged regulatory science.”

FDA appears to be taking the leeway offered by the new law seriously. Between July 2012, when FDASIA was signed into law, and April 25, FDA received 39 requests for breakthrough therapy designation. All of the requests were reviewed within 60 days of receipt, and 11 treatments received the designation.

Still, FDASIA alone isn’t enough to bring more rare disease drugs to market, says Anne Pariser, associate director for rare diseases at FDA’s Center for Drug Evaluation & Research (CDER). “If you look at drug development and disease research along a continuum, a lot of the work goes on pre-FDA,” she notes. New ways to involve the National Institutes of Health, academia, and other stakeholders will be equally important to finding treatments.

And rare disease veterans point out that the new incentives and tools introduced with the passage of FDASIA are, for now, largely theoretical. The policy “creates a framework which has a high potential to have a positive impact,” says Philip J. Vickers, global head of R&D for Shire’s rare disease unit. “But it’s really a framework at the moment, and the details need to be worked out.”

The devil is indeed in the details. Although the agency has been quick to hand out the breakthrough designation, no one is sure what the status means in practice. FDA also has agreed to include patient voices, but it has yet to define a role for advocacy groups. The question of the role of surrogate endpoints, like the ones that the Hogans and other Hunter families hope will be useful in a trial of Shire’s drug, also remains.


Still, some executives are confident common ground is forming between companies and regulators about clinical trial design. Genzyme’s Meeker sees FDA moving toward an era where data suggesting a positive effect, combined with changes in biomarkers, could be enough for approval. “I think increasingly there will be a willingness to allow these products to be approved,” Meeker says, provided that companies commit to monitoring patients over time.

While families and companies worry about what regulators want, FDA officials point out that the agency has a long history of being flexible when reviewing New Drug Applications for rare disease treatments.

It’s “a pretty common misconception” that FDA has the same expectations for rare disease drug applications as it does for ones for more common diseases, says Gayatri R. Rao, director of the Office of Orphan Products Development at CDER. “I think folks believe that two randomized, well-controlled trials will always be required, even for small patient populations.”

That’s true in cases where there are enough patients, Rao says. But more often than not, FDA is willing to work with companies to support a clinical program that makes sense for the disease. At the same time, patients and drug developers need to remember the efficacy bar is not lower just because patients lack treatment options, Pariser says.

She stresses that FDA has “a long and established record of flexibility” when it comes to small patient populations. Pariser points to a 2011 study by NORD as proof of FDA’s willingness to adjust its standard mode of operation when it comes to rare diseases. NORD waded through the 135 noncancer orphan drugs approved between 1983 and June 2010 and found that the agency exercised a degree of flexibility in two-thirds of the cases.

Marc Beer, CEO of Aegerion Pharmaceuticals, is confident that the agency is evolving. Over the past two decades, he has participated in four review panels for orphan products, and in each case, “the FDA got it right,” Beer recounted earlier this year at a conference in New York City. The agency took the time to understand the intricacies of each disease and understand the drug at a deep level, he noted.

The difference between the FDA of the early 1990s and the FDA that reviewed Aegerion’s Juxtapid, approved last year for a rare form of high cholesterol, was the level of communication between the company and the agency. “It wasn’t a ‘pass it over the transom’ type relationship,” Beer said. “It wasn’t just ‘give us the data.’ ”

With more companies dipping their toes into the rare disease market, many question the ability for the inverse relationship between patient group size and drug cost to hold up. Already, some governments are toughening their stance on big-ticket drugs. The U.K., for example, agreed to cover the cystic fibrosis drug Kalydeco, which costs nearly $400,000 per year, only after a highly publicized campaign by patients. And although high prices are generally accepted in the U.S., more than 100 oncologists recently lodged a public protest over the cost of cancer drugs.

If scientists are to develop treatments for the 10% of the population that has a rare disease, the price of health care under the current model will skyrocket, warns Emil D. Kakkis, Ultragenyx Pharmaceutical’s CEO. “More access to accelerated approval could reduce the cost of development by almost two-thirds,” he says, citing a study he authored in Orphanet Journal of Rare Diseases. Instead of developing six or seven drugs with $1 billion in investment, 36 drugs could be developed, he adds.

“We need to find that place where there’s comfort with the amount of data you really need and number of patients needed,” Kakkis says, “and accept the fact that we can’t spend hundreds of millions of dollars for every single rare disease and expect the system to work.”

The Kids Are Waiting

Progress can’t happen fast enough for patient advocates, who worry that time is slipping away for their children

If Shire does succeed in getting the Hunter syndrome treatment HGT-2310 over the finish line, the door is opened for other lysosomal storage diseases where the brain is affected. The company is already testing an intrathecally (IT) delivered enzyme for Sanfilippo syndrome type A and has started a natural history study for Sanfilippo type B that could lay the groundwork for a clinical development program. “We’re very actively considering other programs,” says Philip J. Vickers, global head of R&D for Shire’s rare disease unit.

Even the mention of other lysosomal storage diseases that affect the brain brings hope to a legion of parents. But hope is a tricky word. It leads to a roller coaster of emotions with guaranteed highs and impossible lows.

For Melissa Hogan, Shire’s IT trial has fundamentally changed her outlook for her son Case. “When we started the trial, my whole goal was just to save his life. All I wanted was life,” she says. Now, with the dramatic improvement she sees in Case, she’s gone from no expectations to finding herself imagining her son as a grown man.

Around Christmas, someone sent the family a gift made by adults with special needs. Hogan was hit with the realization that Case could live and even have a job. And yet, she’s afraid to hope and has a hard time not analyzing the tiniest details about her son’s behavior and wondering whether the drug has stopped working.

Hogan’s progress reports about Case have kept hope alive for Jeff and Deena Leider. But they are in a torturous holding pattern while Shire settles the details of the next IT trial. They worry that by the time it is under way, their sons’ IQs won’t be in the right range or that they will miss other criteria to be included. They worry that each day they have to wait, Jason, who is older and whose disease is more advanced, will not benefit from treatment.

With no treatments available for her son Jonah, Jill Wood is careful about the word hope. She prefers to talk about action. As she says, “I busy myself controlling the controllable.”

Wood does believe that 2013 will be a big year for Sanfilippo research. Jonny Lee Miller, the star of “Elementary,” a television show that Wood’s husband, Jeremy, works on, agreed to fund-raise on behalf of Jonah’s Just Begun in conjunction with an ultra­marathon he ran earlier this month. Thanks to corporate sponsorships, Miller’s tweets, and television appearances to promote the event, the nonprofit collected more than $130,000. Wood already has plans for every last dime and is plotting where the next influx of cash might come from.

But amid that momentum came a reminder of the urgency of her efforts. While in Oregon in March, Wood got word that another child with Sanfilippo type C died in her sleep. Mia Pruett, who was 19, had been high functioning and hadn’t even been sick prior to her death. “I’m just heartbroken,” Wood says.


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