Marketing a Disease, and Also a Drug to Treat It
By ANDREW POLLACK
Is it a drug in search of a disease, or simply an affliction in need of better publicity?
One of the afflicted is Peter Pagan. After suffering a severe brain injury in a fall, he would burst into tears at the slightest provocation, even when he was not feeling sad.
"The physical therapist would say, 'You're doing well' and he would just start crying," said his wife, Julie. "He cried, I would say, 40 or 50 times a day. It was awful. I just didn't know what to do."
But Mr. Pagan, 73, a retired engineer from La Palma, Calif., who still has trouble speaking, has been keeping his tears in check, his wife said, since he started taking an experimental drug developed by Avanir Pharmaceuticals of San Diego.
Avanir hopes that the drug, Neurodex, will win federal approval by the end of this year as a treatment for the uncontrollable laughing or crying that can be caused by various neurological diseases or injuries. As one doctor described the odd syndrome in a 1989 article, "Pathologic laughter is devoid of any inner sense of joy and pathologic weeping of any feeling of inner sorrow."
Besides federal approval, though, Avanir faces two other potential obstacles. Some critics say that the condition, in people who are typically fighting much more serious health problems, does not warrant drug therapy. And many affected patients and their doctors may not be aware that it is a syndrome with a variety of names and a possible treatment.
So Avanir has recruited neurologists and psychiatrists as scientific advisers and is trying to prime the market by elevating an ill-defined group of symptoms into a condition under the name pseudobulbar affect, or PBA, in hopes of establishing awareness of it among doctors and patients.
Gerald J. Yakatan, the company's chief executive, compares the effort to the way drug companies helped make erectile dysfunction and attention deficit hyperactivity disorder into well-known terms. "Before there were drugs, these conditions didn't exist," said Dr. Yakatan, who has a doctorate in pharmaceutical sciences and a long history in the drug business.
The cause of the condition is not clear. Scientists suspect it occurs when the brain stem, which generates laughter and crying, loses communication with parts of the brain that control emotional expression. It is because the condition mimics damage to the brain stem, or bulb, that the company decided to call it pseudobulbar affect.
Avanir has conducted two clinical trials showing that Neurodex, whose active ingredient is a common cough suppressant, reduces unwanted laughter or tears. One trial involved people with Lou Gehrig's disease, or amyotrophic lateral sclerosis, and the other people with multiple sclerosis. Avanir plans to present the results to the Food and Drug Administration by the end of June as part of its approval application. Gene Mack, an analyst at Lazard who recommends Avanir stock, estimates that sales of Neurodex, if approved, could exceed $500 million annually in a few years.
Avanir, founded as Lidak Pharmaceuticals in 1988, also developed the over-the-counter cold-sore cream Abreva, which is sold by GlaxoSmithKline
. But Avanir is still unprofitable. In its last fiscal year, it lost $28.2 million on revenues of $3.6 million.
Critics have accused pharmaceutical companies of hyping dysfunctions into diseases to sell drugs. And some skeptics of Avanir's drug say that inappropriate laughing or crying is the least of the problems for people with life-threatening diseases.
"They don't need to be treated; they don't ask to be treated," said Vincent Meininger, head of the national referral center in France for amyotrophic lateral sclerosis.
Harry M. Tracy, publisher of NeuroInvestment, a newsletter about companies developing neurological drugs, is another skeptic. "Basically," he said, "they've had a drug they've been trying to find a disease for."
But some doctors and patients say the syndrome is real and can be a social liability.
"Some of my patients have had it and would suddenly start laughing in the middle of a funeral or church service," said Hillel Panitch, a professor of neurology at the University of Vermont, who presented the results of Avanir's multiple sclerosis trial at the recent meeting of the American Academy of Neurology.
"It's socially disabling and people tend to hide it, which is one reason you don't hear much about it," said Dr. Panitch, who has agreed to give speeches for Avanir but has not yet done so.
Some doctors prescribe antidepressants, with mixed success, for the condition. But no drug has yet been specifically approved for pseudobulbar affect.
Last year, after Avanir signed up more than a dozen neurologists and psychiatrists to help devise a strategy and try to influence other doctors, one of group's first tasks was to decide which to use for the syndrome. The condition has been variously been known as emotional lability, emotional incontinence, pathological laughing and crying, or uncontrollable laughing and crying, in addition to pseudobulbar affect.
"When you have a syndrome that's not widely recognized, what you call it is important," said Randolph B. Schiffer, chairman of neuropsychiatry at Texas Tech University Health Sciences Center and the chairman of Avanir's scientific advisory board.
He said that the board opted for pseudobulbar affect because it was more medically precise than emotional lability, which can encompass other syndromes. Dr. Yakatan, Avanir's chief, said that he would have preferred a name easier to understand, but he deferred to the board.
Avanir and its advisers, on the basis of a few papers in the medical literature, came up with an estimate that 880,000 Americans have pseudobulbar affect, which the company rounds to about 1 million in its corporate literature and presentations. These include about 10 percent of the people with multiple sclerosis, half of those with Lou Gehrig's disease, 18 percent of those with Alzheimer's, 18 percent with stroke and 5 percent with traumatic brain injury.
Avanir has been sponsoring speeches, symposiums and continuing medical education courses for doctors. It sponsors a quarterly newsletter called "PBA Update," much of it written by its consultants, that is sent to more than 10,000 neurologists and psychiatrists.
The company also recently took out its first advertisement in a psychiatric journal. The ad could not mention the name of the drug, which is unapproved, but talked about Avanir's new approach to therapy for pseudobulbar affect.
The company has also approached patient advocacy groups to publicize the condition. "You want the patient to know 'You're not alone, you're not crazy,' " Dr. Yakatan said.
With a grant from Avanir, the National Multiple Sclerosis Society commissioned an article, which is has posted on its Web site, telling doctors how to diagnose pseudobulbar affect. The patient-oriented magazine of the National Stroke Association published an article late in 2003 entitled, "New Hope for Emotional Lability Patients." Avanir has set up its own Web site, www.pseudobulbar.com
, and is even considering helping to start a patient advocacy group.
In one clinical trial involving 140 patients with Lou Gehrig's disease, symptoms of pseudobulbar affect were reduced roughly 50 percent in those getting Neurodex compared with those getting only one or the other of the drug's two ingredients. A multiple sclerosis trial, in which 150 patients were treated for three months, showed about a 60 percent decrease in symptoms in patients receiving Neurodex compared with those getting a placebo.
But there are side effects.
One-quarter of the patients getting Neurodex in the Lou Gehrig's trial dropped out because of adverse side effects including nausea, dizziness and sleepiness, compared with only 6 percent to 8 percent of those getting just one of the drug's ingredients.
And Dr. Meininger of France wrote in the journal, Lancet Neurology, in February that there was some evidence that dextromethorphan - the cough suppressant in Neurodex - might worsen Lou Gehrig's disease but that Avanir's trial was too short to examine that possibility. Dr. Richard A. Smith, the inventor of Neurodex, in a response published in the journal, said that the drug had no adverse effect on the disease in animal studies.
Avanir has not run a trial with Alzheimer's patients, which accounts for the largest number by far of people with pseudobulbar affect. But Avanir executives say that the F.D.A. has told them it would approve Neurodex for pseudobulbar affect regardless of the underlying disease, if it succeeded in two clinical trials based on different diseases. The F.D.A., by policy, does not comment on its discussions with companies.
Avanir is also testing Neurodex for neuropathic pain, a much bigger potential market. Dr. Yakatan said that the drug might help limit anger outbursts as well. "I call this drug, dextromethorphan, the aspirin of the neurology world," he said.
Dr. Schiffer of Texas Tech said there was a risk the drug might be used for other conditions. "If it works for road rage, everyone in Los Angeles is going to take it," he said.