Doctor Spent Decades Getting Tetrabenazine to Market

CLICK HERE FOR PDF VERSION

Updated 10/28/2008 3:33 PM
By Rita Rubin, USA TODAY

	Dr. Joseph Jankovic sits in front of a computer containing video of patients analyzed for tremors and other signs of Huntington's disease at the Baylor College of Medicine's movement studies lab in Houston.
By Dave Einsel, for USA TODAY

Baylor College of Medicine neurologist Joseph Jankovic is a patient man.

With the Food and Drug Administration's OK, Jankovic has studied the drug tetrabenazine since 1979. Over the years, he estimates, he has dispensed tetrabenazine — or TBZ, as he calls it — to 1,000 people with Huntington's disease, probably more than any doctor in the world.
Tetrabenazine helps tame the uncontrollable movements, or “chorea,” that characterize Huntington's, an inherited degenerative brain disorder. It also appears to help treat other movement disorders, says Jankovic.

An orphan disease

Tetrabenazine was approved in the United Kingdom and Ireland in 1971. But U.S. companies were reluctant to invest in clinical trials of a drug for an “orphan disease,” defined by the FDA as one that affects fewer than 200,000 Americans. (Only 30,000 Americans have Huntington's disease.) Perhaps even more surprising, the FDA questioned whether patients' chorea was bothersome enough to justify treatment.

One problem, says University of Rochester neurologist Fred Marshall, is that before tetrabenazine, the side effects of drugs used “off-label” to treat chorea — namely antipsychotic drugs such as Haldol that can cause rigidity and drowsiness — could be worse than the symptom, so doctors advised against their use.

Jankovic says he started out trying to woo the largest drugmakers, "hoping that companies that have deep pockets would be in a good position to fund the studies that are necessary to get a drug approved. Obviously, big pharma was not interested. It is an orphan disease, and the profit margin is going to be small."

Americans with Huntington's who weren't Jankovic's patients ordered tetrabenazine from Canada if they could afford it. But the worsening exchange rate put the price out of reach for many. A recent check found Canadian Internet pharmacies selling generic 25-milligram pills for $1.75 or more each in U.S. currency, brand-name 25-mg pills for around $2.35 each. Patients typically take a pill or more a day, possibly for years.

When the Canadian prices became prohibitive, Marshall says, he began arranging for patients to get the drug from Cambridge Laboratories, its Irish maker.

Finally, Jankovic says, his friend Kathleen Clarence-Smith, a neurologist with experience in developing drugs and getting them onto the market, founded Washington, D.C.-based Prestwick Pharmaceuticals in 2002 specifically to launch tetrabenazine in the USA. Jankovic said Clarence-Smith, who left Prestwick in January 2007, did not want to talk to a reporter for this story. Prestwick helped fund Jankovic's research, and he served as a consultant to the company.

The FDA designated tetrabenazine a “fast track” drug in April 2004, and Prestwick submitted its "new drug application" in September 2005. Despite “fast track” status, it still took three more years to win FDA approval.

The agency was most concerned that tetrabenazine could exacerbate depression in Huntington's patients, who already have a high suicide rate, Jankovic says. The drug controls chorea by depleting dopamine, a neurotransmitter that, at abnormally high levels, causes involuntary movements. But tetrabenazine also depletes serotonin, and low levels of that neurotransmitter can cause depression.

While she wouldn’t prescribe it to someone who has repeatedly attempted suicide, says psychiatrist Karen Anderson, director of the University of Maryland's Huntington's clinic, “I have not seen anyone on tetrabenazine develop terrible depression.”

Antidepressants counter serotonin loss, Anderson says. Besides, “I’ve had a couple of people who were very incapacitated by their chorea whose quality of life improved hugely. These are hard things to measure.”

Marshall, who oversaw one study that led to FDA approval, is sanguine about the drawn-out process. Thanks to the agency's rigorous requirements for licensure, he says, “we know much more about tetrabenazine's effects — its side effects and its potentially good effects.”

Cost could be an issue

Last month, Ovation Pharmaceuticals in Deerfield, Ill., acquired the license from Prestwick to market Xenazine — tetrabenazine's brand name — in the USA. Ovation spokeswoman Sally Young says her company hopes to make Xenazine available by year's end.

Now that the FDA has approved tetrabenazine, health plans probably will start covering it. But cost is still an issue, because most Huntington's patients have lost their health insurance. Young says Xenazine's price has not yet been established.

“I'm obviously excited about reaching this milestone,” says Jankovic. This month, he received the Guthrie Family Humanitarian Award — named in memory of folksinger Woodie Guthrie, who died of Huntington's, and his wife, Marjorie — from the Huntington's Disease Society of America in recognition of his research and his efforts to make tetrabenazine available in the USA.

“But at the same time,” he says, “I’m worried that the drug is just going to be too expensive.”

Doctors, Families Fought for Approval of Huntington’s Drug

CLICK HERE FOR PDF VERSION

Updated 10/28/2008 3:33 PM
By Rita Rubin, USA TODAY

	Sheryl Monkemeyer has been taking tetrabenazine, the first drug for the inherited disease Huntington's, to improve her ability to focus and engage in physical activities, including tennis, which she and her son Jonathan, 10, play outside their Newton Square, Pa., home after school.
By Joan Fairman Kanes for USA TODAY

Jonathan Monkemeyer, an engineer by training, worked long and hard on the heartfelt four-minute talk he presented at a packed Food and Drug Administration advisory committee meeting last December. But even without saying a word, Sheryl Monkemeyer was far more expressive than her husband could ever be.

While seated, Monkemeyer's wife moved constantly. Her legs jerked so much that she kicked off her boots and scooted her chair back 6 inches, nearly into the lap of the person behind her. She couldn't help it. The former registered nurse, 45, has Huntington's disease, an inherited, incurable degenerative brain disorder that killed her father.

The uncontrolled movements that characterize the disease make it difficult for her to ride in a car, but she and her husband had driven 125 miles from their suburban Philadelphia home to the FDA meeting in a Sheraton Hotel ballroom in Beltsville, Md. Their goal: to help convince panelists that the FDA should approve tetrabenazine, which would be the first drug approved in the USA for any symptom of Huntington's disease. Huntington's afflicts 30,000 Americans, as many as cystic fibrosis, another, better-known genetic disorder.

Tetrabenazine neither cures nor slows the disease — no drug yet has been shown to do that — but it's the most effective treatment for the uncontrolled movement called chorea, Greek for "dance." (The disease is sometimes still referred to as Huntington's chorea.) Typically, Huntington's symptoms first appear in middle age, and death occurs 10 to 30 years later.

The FDA advisers voted unanimously to recommend approval. In August, the agency gave Prestwick Pharmaceuticals in Washington, D.C., permission to market tetrabenazine as Xenazine. Last month, Ovation Pharmaceuticals in Deerfield, Ill., acquired the U.S. license from Prestwick.

"Recognizing that patients have been waiting a long time for this treatment, we are working diligently to expedite availability of Xenazine, which we expect will happen before the end of the year," Ovation spokeswoman Sally Young said Friday.

Columbia University neurologist Nancy Wexler, who spearheaded the research leading to a genetic test for Huntington's, says she had hoped the FDA wouldn't need an advisory committee meeting "because the merits of this drug were so obvious." But, says Wexler, whose mother died of Huntington's, "I think there were a lot of misconceptions about how debilitating these incredibly engulfing, abnormal movements are."

Three people were needed to feed her mother, Wexler says: one to hold her head still, one to hold her arms and one to spoon food into her mouth.

"Even if you have just a tiny bit of abnormal movement," says Wexler, president of the Hereditary Disease Foundation, "it can make it difficult to do anything normal: brushing your teeth, eating, doing the dishes."

At his tidy, plant-filled home on a leafy street in Newtown Square, Pa., Jonathan Monkemeyer apologizes for the faint food stains on the ceiling above the kitchen sink and for the plastic tumblers in which he serves iced tea.

In another family's home, the stains and plastic cups would suggest the presence of an active toddler. At the Monkemeyers, they are mute testimony to the disease that began attacking his wife's brain a decade earlier.

"My wife bites her lip, her tongue, the sides of her mouth," Monkemeyer, 42, told the FDA advisers. "She grinds her teeth together and smashes into them with utensils. Unless she sits in the middle (car) seat, she smashes the side of her head into the passenger door window. Even with my help and padded walls in our shower, she split open her head on the towel rack."

After the meeting, Monkemeyer began getting tetrabenazine directly from Cambridge Laboratories, its Irish maker. He has become adept at splitting the pale yellow, aspirin-sized pills in half and, if need be, into quarters, and then serving them in applesauce. Too much tetrabenazine, and he has found his wife becomes sleepy and depressed. Too little, and her chorea worsens.

"I think Sheryl would be really, really far gone if she didn't have it," Monkemeyer says.

After her first dose, his wife could eat without choking, a common complication that can lead to deadly pneumonia if food goes down the wrong pipe.

Even on the medication, Sheryl Monkemeyer still fidgets non-stop as she sits on their couch, repeatedly knocking pillows off. Her speech is hard to understand, and you can feel her bones when you hug her. All that excess movement can burn thousands of calories a day, Wexler says.

But when her husband showed a reporter his prototype for an online gathering place for Huntington's researchers, she got off the couch and stood behind him at the computer for at least 15 or 20 minutes without falling.

At a graduation party this past summer, Monkemeyer says, his wife tickled guests by whacking a whiffle ball two times in a row. And she has amazed their neighbors by hitting a tennis ball in the front yard with their 10-year-old son, who's also named Jonathan.

Since his mom started taking tetrabenazine, "she's a lot more normal," says Jonathan, a fifth-grader who inherited his mother's delicate features and her love of reading and writing. He already has figured out that, like any child of an affected parent, he has a 50-50 chance of having inherited Huntington's disease.

One welcome side effect of tetrabenazine's approval has been hope, says Boyle of the Huntington's Disease Society. "This is something that said to our families: You know, we have a drug. We can get others. We're on our way to treating a disease."