Narcolepsy isn't easy to treat. Existing drugs manage patients' symptoms -- notably excessive daytime sleepiness and difficulty sleeping at night -- rather than the cause. Yet a new type of drug is emerging that targets the root of the disorder.
It might lead to better drugs for a whole range of sleep problems.
The Food and Drug Administration on Wednesday approved Takeda Pharmaceutical's Orzeyful, the first medication to treat narcolepsy by targeting a brain chemical that regulates wakefulness. It is the first in a series of similar medications being developed by drug companies such as Eli Lilly and Alkermes that analysts say could generate more than $10 billion in sales a year.
"It's really a complete revolution," said Dr. Emmanuel Mignot, a sleep-medicine professor at Stanford University who led Takeda's final studies and is credited for pioneering the science behind it. "The first time patients take it, it's like the light switch."
Orzeyful was approved for narcolepsy with sudden muscle weakness, a more severe form of the disorder.
Narcolepsy is unusual in neuroscience because researchers have long known exactly what causes it: A small group of brain cells that make a chemical called orexin die, disrupting a person's ability to stay awake during the day and to sleep at night. As a result, patients fall asleep without warning during the day, lose muscle control and hallucinate while nearly asleep. Patients often sleep poorly at night despite the daytime sleepiness.
To study the disease, scientists at Stanford in the 1970s and 1980s used narcoleptic dogs that collapsed paralyzed when excited.
Mignot came to Stanford to study those dogs (and still owns one narcoleptic Chihuahua today). He spent about 10 years looking for the gene behind the condition and ultimately discovered that people with narcolepsy who experience sudden muscle weakness were missing the chemical orexin.
The discovery gave drugmakers a clear target in a field where most diseases involve poorly understood biology. At Japan-based Takeda, scientists searched the company's library of chemical compounds, looking for one that could switch on the orexin receptor. In 2011, researchers discovered one that showed promise. It took several years to turn it into a pill.
Existing treatments are decades-old stimulants and sedatives that target one symptom at a time, but Orzeyful and its competitor drugs are designed to treat the disease as a whole. The science of targeting these chemicals has impact beyond narcolepsy. Takeda is testing orexin-targeting drugs in other conditions, including sleep apnea, chronic daytime sleepiness and in sleep-deprived healthy volunteers, and early results are promising.
Takeda has seen benefits using the orexin medication "in every population we've ever looked at," said Andy Plump, Takeda's head of research and development. "The potential is really quite immense."
Takeda's late-stage studies involved two 12-week trials of 273 adults. Patients who took Orzeyful showed improvements in staying awake, had fewer instances in which they lost muscle control and slept better at night than those on placebo.
Tyler Chapman was diagnosed with narcolepsy at age 14. He tried a powerful nighttime sedative to sleep, but the drug triggered severe psychological side effects. Going off it caused his symptoms to return more severely. He stopped playing sports, slept 16 hours a day and started failing several classes.
Chapman fell into the habit of consuming the equivalent of around 10 cups of coffee's worth of caffeine a day and tried 13 different medications.
This summer, at age 19, he volunteered to be a part of a study of Takeda's drug at Stanford's sleep clinic. He said the results were noticeable within minutes.
"My body was hot-wired," said Chapman, a sophomore at the University of Tennessee, Knoxville. "It was the first time I felt somewhat alive in the last 10 years."
Before U.S. patients can access Takeda's medication, the Drug Enforcement Administration has to formally schedule Orzeyful as a controlled substance -- a process that can take up to 90 days.
Takeda has projected peak sales could top $3 billion, a figure that depends partly on how many of the around 60,000 diagnosed U.S. patients start treatment and whether the market grows. The company estimates that nearly 120,000 people in the U.S. have the condition.
Several companies are right behind Takeda. In April, Eli Lilly announced a $6.3 billion acquisition of Centessa Pharmaceuticals to get its own orexin-targeting drug, which is still in testing. Alkermes has pushed its own version into late-stage trials. Drugmakers racing to develop orexin-mimicking compounds have poured more than $10 billion upfront in deals. Today, more than a dozen orexin drugs are in development and being tested in more than 70 trials, according to biopharma market-intelligence firm Sleuth.
Competitors are testing their drugs even more broadly. Alkermes' drug is already in early stage trials for fatigue tied to multiple sclerosis and Parkinson's disease, and for attention-deficit hyperactivity disorder.
Lilly's cleminorexton, acquired in the Centessa deal, is furthest along in a more common form of narcolepsy that doesn't involve muscle weakness, and the company has more orexin drugs in its pipeline aimed at a broader set of neurological and psychiatric conditions.
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