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Magazine: The Medical Crusade of Dr. Emil Kakkis '82

Dr. Emil Kakkas

Dr. Emil Kakkis felt as if he were in the midst of a courtroom drama.

Kakkis ’82 waited tensely in the witness area of the hushed advisory committee discussion convened by the Food and Drug Administration. The votes of the assembled scientists would help determine whether doctors could provide Kakkis’ life-saving treatment to hundreds of children with a rare disease called MPS I.

“There were many lives hanging on it,” Kakkis recalls of that 2003 hearing. “You don’t know what’s going to happen until people start voting.” It was five years since Kakkis had shown his therapy worked in people, and 10 years since he’d treated the disease in dogs. But the FDA--which is best equipped to evaluate medicines aimed at thousands of people, not dozens--remained skeptical.

One by one the votes came in: Yes… yes… yes. The committee voted 12-0 for Kakkis’ drug. “I was sort of expecting someone to clap,” Kakkis says. “In my head, I was cheering and screaming … no one would break the courtroom demeanor.”

That moment was a high point in Kakkis’ ongoing mission to bring treatments to rare or “orphan” diseases. Straight out of medical school, Kakkis set himself the goal of treating a disease that had no therapy. After the MPS I success, he kept working on medicines for rare conditions. And now he’s crusading to change a regulatory system he sees unnecessarily slowing or even blocking potentially life-saving therapies. “We need to fix the process,” he says, and in 2009, he started the Kakkis EveryLife Foundation to help make that happen. To an idealist like Kakkis, wasting time on the way to a cure is not acceptable.

Kakkis has shifted his focus from the clinic to the halls of Congress, but his Novato, Calif., offices contain constant reminders of the pressing human needs that drive his campaign. The walls are a collage of pictures of children and their colorful artwork, and right at the entrance sits a director’s chair emblazoned with the handprints and names of the first 10 kids to try his MPS I treatment. “Dr. Kakkis, Our Hero,” it reads.

“Emil’s somebody who makes things work,” says Dr. Adam Jonas, chair of the Pediatrics Department at Harbor-UCLA. “He is always in a hurry.”

GETTING MEDICINES TO PEOPLE with rare diseases is a unique challenge. Companies prefer to invest in blockbuster drugs that many people will buy. But rare diseases--often called “orphan diseases” since no one wants to adopt them--are those that affect fewer than 200,000 people in the United States. Most affect fewer than 6,000 Americans. It’s hardly a vast market base, and since it takes millions of dollars to develop and test a drug, these conditions often fall by the wayside.

Yet, if you add up all the people who have one of the more than 6,800 orphan diseases, it comes to 25 million Americans. Only 200 of those illnesses come with any treatment option.

Over the past couple of years, Congress--with a nudge from Kakkis and others--has earmarked monies to support drug research and development in a handful of acts and amendments. The pharmaceutical industry is also wading into the orphan market. For example, both GlaxoSmithKline and Pfizer created rare disease units in 2010.

“There’s a lot of interest and energy,” says Mary Dunkle, vice president for communications at the National Organization for Rare Disorders. “I sense a real commitment to finding treatments.”

THERE WAS NO SUCH ENERGY and interest from drug companies when Kakkis began working on treatments for rare diseases. With minimum funds, and nearly single-handedly, he would spend more than a decade working on his first treatment. From the start of his career, Kakkis’ focus on science left him with scant time for anything beyond work and family; he met his wife, with whom he has three children, over adjacent cadavers in medical school.

Kakkis’ interest in biology dates from his childhood in Southern California. Born in 1960, he was a kid who preferred Marineland, with its killer whales and aquariums, to nearby Disneyland. He came to Pomona College in 1978 planning to become a veterinarian.

But a summer project in the laboratory of Chemistry Professor Corwin Hansch changed his mind. Hooked on the thrill of discovery, he decided to become a scientist. Kakkis earned a combined M.D./Ph.D. at UCLA in 1989. Then, he looked for a disease in need of a cure.

UCLA biochemist Elizabeth Neufeld had just the project. She had spent decades working on mucopolysaccharidosis, or MPS I. The disease affects a few hundred people in the country, Kakkis estimates.

People with MPS I have a faulty gene, which fails to produce an enzyme called iduronidase. Iduronidase works in the body, breaking down a starch called glycosaminoglycan (GAG). That starch holds the body’s tissues together, but must be removed where it’s no longer needed. In people without iduronidase, GAG builds up and gums up the works. This one flaw can take down the whole system.

Neufeld had just identified the gene for iduronidase, and isolated a minute amount of the enzyme, when Kakkis approached her. “He landed in the project at exactly the right time, with the right skills and enormous dedication,” Neufeld says.

Kakkis set up shop in a converted World War II-era barracks behind Harbor-UCLA’s hospital building, a former Navy facility. His wife helped scrub and paint the lab. His father-in-law, a contractor, crafted benches and cabinetry. Kakkis scrounged secondhand equipment from other labs and hauled it in his own truck.

Neufeld recalls asking Kakkis how many technicians he had. “Two,” he replied--and help up his right fist, and his left fist.

By 1994, Kakkis had made a good supply of iduronidase, and the researchers tried it in dogs that had an MPS I-like disorder. The excess GAG disappeared.

Thrilled, Kakkis and Neufeld sought a company to help develop the drug. But the pair could find no takers. Even a firm called Orphan Medical turned Kakkis down. “That’s when I knew we were in trouble,” he says. “It was very demoralizing.”

Around the same time, Jonas advised Kakkis that his focus on experiments and cures, instead of scientific publications, could endanger his academic career. Kakkis ignored the advice, putting cures before academic success--and earning the appreciation of those who most benefitted from his push for treatments. “The patients adore him,” says Dr. Patricia Dickson, who inherited his lab when he left Harbor. “Several of the mothers want to marry him.”

AS KAKKIS WAS STRUGGLING with drug development on a tight budget, a family in Carrollton, Texas, was facing tragedy. Ryan Dant was an energetic three-year-old when his mother, Jeanne Dant, took him to the doctor for a checkup. The pediatrician noticed Ryan’s head and liver were unusually large. “He had this disease no one had ever heard of, called MPS,” his father, Mark Dant, remembers.

There was no treatment. Severe MPS I kills children before the age of 10; people with milder forms may survive to young adulthood. By first grade, Ryan suffered overpowering headaches and nausea. His liver and spleen swelled to twice their normal sizes. His fingers curled up as the GAG stiffened his joints. He stopped talking about what car he would drive, or anything else related to his future, because he knew he wouldn’t have one.

As in many families faced with rare diseases, it fell to the Dants to seek their own cure. In 1992, they started the Ryan Foundation for MPS Children, eventually raising thousands of dollars through bake sales and golf tournaments. But they weren’t sure what to do with the money.

In December of 1994, the Ryan Foundation convened a conference on MPS I at Disney World. There, Elizabeth Neufeld told Mark Dant about Kakkis. After meeting Kakkis, the Dants knew they had a place to send their funds.

For Kakkis, meeting Ryan turned what had been an academic puzzle into a truly human challenge. “This kid and his family were depending on us to do something,” he says.

Although Kakkis jokes about the roadblocks now, he was desperate for further funding to wade through the complicated process of clinical testing and FDA approval.

The next savior came in 1997, when a Novato-based startup called BioMarin contacted Kakkis. They were interested in the therapy, and ultimately gave him an initial $5 million for the research. (In time, the cost would exceed $100 million.) By the end of that year, Kakkis was ready to try his enzyme in people. He made his employees work over Christmas so enough iduronidase would be available for a trial in 10 children.

“I didn’t have a vacation for 36 months,” Former lab manager Merry Passage says, but she didn’t mind. “His dedication is infectious.” Kakkis, Jeanne and Mark Dant pushed the button together for Ryan’s first infusion in February of 1998. A week later, Mark Dant heard Ryan yelling and rushed to the bathroom. He found Ryan gazing at his own stomach--it had already shrunk to near-normal size.

All 10 kids improved on the enzyme therapy. Their livers shrank. They could raise their arms and scratch their own heads. And they had more energy--parents complained that their usually lethargic children were unmanageably hyper.

Kakkis’ speech quickens as he recalls the exciting atmosphere of the time. “We were really on a high,” he says. Patients, doctors and scientists toasted their success with a black-tie party on the decks of the RMS Queen Mary in Long Beach, Calif.

But the FDA was doubtful, Kakkis says, his tone becoming a tad indignant. Part of the issue was that the trial data were somewhat unusual for an FDA application. For example, Kakkis had determined that kids on the therapy no longer excreted GAG in their urine, because the body was able to break it down. But so little was known about MPS I; regulators were unsure if that was a reasonable endpoint to measure. They insisted on a second trial.

In 1998, Kakkis moved to BioMarin, where he continued working on MPS I with a 45-patient trial. The FDA remained unconvinced, in part because the therapy couldn’t completely reverse the damage MPS I had already caused. But with the approval of outside experts, the FDA finally allowed BioMarin to market the iduronidase treatment, which they named Aldurazyme.

Ryan Dant is now 22. He drives a 2010 Mustang, attends junior college and manages football equipment for Southern Methodist University in Dallas. “It’s amazing,” Mark Dant says. “He’s doing so well.”

FOLLOWING THE ALDURAZYME SUCCESS, BioMarin focused solely on orphan drugs. While there, Kakkis led drug development for several other orphan treatments, including two that have been approved.

But progress was slow, and the company still had to pick and choose diseases based on profitability. BioMarin almost went out of business more than once, Kakkis says.

“You have the science that could become treatments for people, but the system forces us into this pattern of spending huge amounts of money for really rare diseases,” Kakkis says. “If you create hurdles that are too extreme, you will end up preventing things from getting developed.”

To keep the hurdles surmountable, Kakkis decided to leave BioMarin and start the EveryLife Foundation, pushing Capitol Hill to accelerate research and approval of orphan drugs. He travels the world to speak at conferences and has testified before Congress. And now Kakkis’ efforts are getting attention beyond the rare disease field--he recently was billed alongside Nobel Prize winners and TV’s Dr. Oz as one of 2010’s “Rock Stars of Science” in a scientist/musician photo spread that appeared in December’s GQ magazine. He posed in a black suit and high-tops with rapper Jay Sean.

Still, the role of schmoozing policy advocate is not a natural one for a stubborn idealist; Kakkis admits he’s working harder to be political in his relationships now. And he certainly has some of the skills: when Kakkis speaks, it’s easy to follow his logic and believe his conclusions.

Yet he realizes that change will be slower than he might like. “The idea is to take small, winnable battles,” Kakkis says. In his current campaign, he hopes to convince the FDA to set up a dedicated unit to evaluate drugs for diseases like MPS I. For now, biochemical and genetic disease are thrown in with the gastroenterology department. He also wants to improve access to accelerated approval for such drugs.

In addition, Kakkis wants to change the way orphan drugs are evaluated. It’s difficult to run large trials for diseases that are so rare. For example, Dickson, who is following up on the iduronidase work, has been recruiting for one trial since 2005. As of the fall of 2010, she had five patients.

Whether a drug is deemed effective comes down to how statisticians crunch the numbers. Different statistics, Kakkis says, can mean the difference between soaring success and abysmal failure. “It’s shocking how far off it can be,” he says. So the foundation is bringing together statisticians, FDA officials, scientists and drug developers to discuss how better to perform and evaluate small trials for rare diseases.

The Kakkis EveryLife Foundation has invested approximately $1 million in the campaign, Kakkis says, some 95 percent of it out of his own pocket. But the Foundation is not the last of Kakkis’ projects, and he’s already planning his next move: a new company called Ultragenyx.

Ultragenyx will focus on ultra-rare disease therapies. Even as he is lining up financing and hiring staff, Kakkis has research partnerships underway. Kakkis’ goal is to bring Ultragenyx’ first treatment to clinical trial by June, and complete the study within two years. He thinks he can get FDA approval within four years of initiating clinical studies.

Between Kakkis’ work at the bench, in the clinic and on Capitol Hill, he’s made the future for people with rare diseases look that much more attainable.

Crossing the Valley of Death

The first government initiative for rare disease treatment was 1983’s Orphan Drug Act. It provided financial incentives for companies to invest in rare (or “orphan”) diseases. Most importantly, it promised that a company with a drug to treat a rare disease would enjoy a seven-year monopoly.

“It’s better than a patent,” says Dr. Anne Pariser, associate director for rare diseases in the FDA’s Office of New Drugs. Orphan drug-makers receive exclusive rights to sell treatments for their foundling disease, unless something clearly superior comes along.

More than 200 orphan drugs have been approved since 1983. In comparison, there were only 34 orphan products before then. However, the process of developing, testing and evaluating orphan treatments remains slow.

It takes two to four years, and an average of $10 million, before drugs are tested in people. And 80 to 90 percent of ideas fail well before human trials. Drug developers call this pre-trial stage the Valley of Death-—“where drugs go to die,” Pariser says.

The National Institutes of Health in 2009 announced a program to shepherd certain drug ideas through that treacherous valley. The $24 million-a-year Therapeutics for Rare and Neglected Diseases (TRND) program is a unique initiative that means the drug pipeline will run right through the national labs.

TRND will work much like a pharmaceutical company, but target less-profitable diseases. For drugs that reach the Valley’s far side, TRND will seek industry partners to carry the medicines to the next stage.

The FDA is conducting workshops to help researchers and companies submit orphan drug applications. It is also evaluating its rare disease processes, and is expected to implement changes by fall of 2011.

TRND and other programs are good “supplements,” says Dr. Emil Kakkis ’82 of the Kakkis EveryLife Foundation, but he says there are still improvements that could be made.