One evening in late May, four senior employees of Merck, the pharmaceutical company, sat in the bar of a Hilton Hotel in Rockville, Maryland, wearing metal lapel pins stamped with the word “team.” They were in a state of exhausted overpreparedness. The next morning, they were to drive a few miles to the headquarters of the Food and Drug Administration and attend a meeting that would decide the future of suvorexant, a new sleeping pill that the company had been developing for a decade. Merck’s team hoped to persuade a committee of seventeen, composed largely of neurologists, that suvorexant was safe and effective. The committee, which would also hear the views of F.D.A. scientists, would deliver a recommendation to the agency. If the government approved suvorexant—whose mechanism, inspired partly by research into narcoleptic dogs, is unlike anything on the market—it would be launched within a year. Some industry analysts had described it as a possible blockbuster, a term usually reserved for drugs with annual earnings of a billion dollars. Merck had not created a blockbuster since 2007, when it launched Januvia, a diabetes drug. The company was impatient. A factory in Las Piedras, Puerto Rico, was ready to start production.
David Michelson, who runs Merck’s clinical research in neuroscience, said of suvorexant, “It’s huge. It’s a major product.” He was sitting perfectly still in his chair; his hair flopped a little over his forehead. He looked as if he were waiting in an airport for a very late flight.
For months, in rooms across Merck’s archipelago of mismatched buildings north of Philadelphia, Michelson had taken part in role-playing rehearsals for the F.D.A. meeting. The focus had been on readying Joe Herring, another Merck neuroscientist; he would be the primary speaker, having run the later clinical trials of suvorexant. Herring, a straight-backed, athletic-looking man in his fifties, had just gone up to his room, for an early night. “Joe had to find a way to be authentic,” Michelson recalled. “He had to find a way to engage with the audience without becoming too informal.” During the meeting, Herring would have access to a library of twenty-one hundred and seventy PowerPoint slides.
The Merck team was frustrated. The F.D.A. had just shown them the draft of a presentation, titled “Suvorexant Safety,” that would be delivered by Ronald Farkas, an F.D.A. neuroscientist who had reviewed thousands of pages of Merck data. In a relentless PowerPoint sequence, Farkas made suvorexant sound disquieting, almost gothic. He noted suicidal thoughts among trial participants, and the risk of next-day sleepiness. He quoted from Merck’s patient notes: “Shortly after sleep onset, the patient had a dream that something dark approached her. The patient woke up several times and felt unable to move her arms and legs and unable to speak. Several hours later, she found herself standing at the window without knowing how she got there.” A woman of sixty-eight lay down to sleep “and had a feeling as if shocked, then felt paralyzed and heard vivid sounds of people coming up the stairs, with a sense of violent intent.” A middle-aged man had a “feeling of shadow falling over his body, hunted by enemies, hearing extremely loud screams.”
An F.D.A. presentation that focusses on individual “adverse events”—and draws attention to patients feeling “hunted by enemies”—is discouraging to a drug’s sponsor. Michelson called the presentation “somewhat unusual,” and emitted a dry laugh.
Darryle Schoepp, the head of Merck’s neuroscience division, was at the other end of the table. During the human trials of suvorexant, he noted, it had been taken two hundred and seventy thousand times, and “every time you take a drug it’s an opportunity for something to happen that the user can report.” He added, “Go back to the early days of Ambien. I wonder how many patient days of data they had with Ambien.”
Ambien, which is now available generically as zolpidem, is one of America’s most popular drugs, and it played a role—silent or spoken—in many conversations that I had heard on visits to the Merck offices. Zolpidem was the cheap drug that suvorexant had to take on, if not unseat, in order to succeed in the sleep-medication market. In addition, rising public worry about risks associated with taking Ambien—ranging from amnesiac devouring of Pop-Tarts to premature death—had reduced the F.D.A.’s tolerance for side effects in sleep medications.
John Renger was also at the bar. A forty-four-year-old neuroscientist, he has a round face, cropped hair, and a neat goatee. He helped lead the company to the suvorexant molecule, and ran the first tests on rats, mice, dogs, and rhesus monkeys. He, too, was politely indignant about the F.D.A. “They’ve taken the emphasis off efficacy,” he said, adding, “They’re saying any residual effects are bad. But they’re not looking at the balance—‘What is the improvement in this mechanism?’ ”
The central nervous system is in an ever-adjusting balance between inhibition and excitation. Ambien, like alcohol or an anesthetic, triggers the brain’s main inhibitory system, which depends on binding between gaba—gamma-aminobutyric acid, a neurotransmitter—and gaba receptors on the surface of billions of neurons. gabareceptors can be found throughout the brain, and when they’re activated the brain slows. Ambien encourages the process by sticking to the receptors, holding open the door to the neurotransmitter. Suvorexant, which Merck describes as “rationally designed”—rather than stumbled upon, like most drugs—influences a more precise set of neurotransmitters and receptors. Orexin neurotransmitters, first identified fifteen years ago, promote wakefulness. When suvorexant is in the brain, orexin is less likely to reach orexin receptors. Instead of promoting general, stupefying brain inactivity, suvorexant aims at standing in the way of a keep-awake signal. This difference may or may not come to mean a lot to insomniacs, but Merck’s marketing is likely to encourage the perception that suvorexant ends the dance by turning off the music, whereas a drug like Ambien knocks the dancer senseless.
If the Merck scientists succeeded at the F.D.A., they would be the first to bring an orexin-related drug to market. “It’s an amazing achievement,” Richard Hargreaves, the fourth colleague at the Hilton, said. “Everyone should be really proud.” But, he added, “my worry is that a new mechanism is being evaluated on the science of an old mechanism.”
“With Ambien, you’ve got a drug that’s got basically only onset,” Renger said, dismissively. That is, it sends you to sleep but might not keep you asleep. “Suvorexant has the onset, but it has the great maintenance, especially in the last third of the night, where other drugs fail.” And even though suvorexant keeps working longer than Ambien, suvorexant patients don’t feel groggier afterward, as you might expect. Impassioned, Renger imagined himself addressing the F.D.A.: “Why aren’t you giving this a chance?”
“Drugs usually have some side effects,” Schoepp said. “It’s all benefit-risk.” He added, “There is some dose where suvorexant will be ultimately safe—because nothing will happen. If you go low enough, it becomes homeopathic.”
They stood to go to their rooms. Schoepp murmured, “I’d love to take it right now.”
David Michelson, who runs Merck’s clinical research in neuroscience, said of suvorexant, “It’s huge. It’s a major product.” He was sitting perfectly still in his chair; his hair flopped a little over his forehead. He looked as if he were waiting in an airport for a very late flight.For months, in rooms across Merck’s archipelago of mismatched buildings north of Philadelphia, Michelson had taken part in role-playing rehearsals for the F.D.A. meeting. The focus had been on readying Joe Herring, another Merck neuroscientist; he would be the primary speaker, having run the later clinical trials of suvorexant. Herring, a straight-backed, athletic-looking man in his fifties, had just gone up to his room, for an early night. “Joe had to find a way to be authentic,” Michelson recalled. “He had to find a way to engage with the audience without becoming too informal.” During the meeting, Herring would have access to a library of twenty-one hundred and seventy PowerPoint slides.
The Merck team was frustrated. The F.D.A. had just shown them the draft of a presentation, titled “Suvorexant Safety,” that would be delivered by Ronald Farkas, an F.D.A. neuroscientist who had reviewed thousands of pages of Merck data. In a relentless PowerPoint sequence, Farkas made suvorexant sound disquieting, almost gothic. He noted suicidal thoughts among trial participants, and the risk of next-day sleepiness. He quoted from Merck’s patient notes: “Shortly after sleep onset, the patient had a dream that something dark approached her. The patient woke up several times and felt unable to move her arms and legs and unable to speak. Several hours later, she found herself standing at the window without knowing how she got there.” A woman of sixty-eight lay down to sleep “and had a feeling as if shocked, then felt paralyzed and heard vivid sounds of people coming up the stairs, with a sense of violent intent.” A middle-aged man had a “feeling of shadow falling over his body, hunted by enemies, hearing extremely loud screams.”
An F.D.A. presentation that focusses on individual “adverse events”—and draws attention to patients feeling “hunted by enemies”—is discouraging to a drug’s sponsor. Michelson called the presentation “somewhat unusual,” and emitted a dry laugh.
Darryle Schoepp, the head of Merck’s neuroscience division, was at the other end of the table. During the human trials of suvorexant, he noted, it had been taken two hundred and seventy thousand times, and “every time you take a drug it’s an opportunity for something to happen that the user can report.” He added, “Go back to the early days of Ambien. I wonder how many patient days of data they had with Ambien.”
Ambien, which is now available generically as zolpidem, is one of America’s most popular drugs, and it played a role—silent or spoken—in many conversations that I had heard on visits to the Merck offices. Zolpidem was the cheap drug that suvorexant had to take on, if not unseat, in order to succeed in the sleep-medication market. In addition, rising public worry about risks associated with taking Ambien—ranging from amnesiac devouring of Pop-Tarts to premature death—had reduced the F.D.A.’s tolerance for side effects in sleep medications.
John Renger was also at the bar. A forty-four-year-old neuroscientist, he has a round face, cropped hair, and a neat goatee. He helped lead the company to the suvorexant molecule, and ran the first tests on rats, mice, dogs, and rhesus monkeys. He, too, was politely indignant about the F.D.A. “They’ve taken the emphasis off efficacy,” he said, adding, “They’re saying any residual effects are bad. But they’re not looking at the balance—‘What is the improvement in this mechanism?’ ”
The central nervous system is in an ever-adjusting balance between inhibition and excitation. Ambien, like alcohol or an anesthetic, triggers the brain’s main inhibitory system, which depends on binding between gaba—gamma-aminobutyric acid, a neurotransmitter—and gaba receptors on the surface of billions of neurons. gabareceptors can be found throughout the brain, and when they’re activated the brain slows. Ambien encourages the process by sticking to the receptors, holding open the door to the neurotransmitter. Suvorexant, which Merck describes as “rationally designed”—rather than stumbled upon, like most drugs—influences a more precise set of neurotransmitters and receptors. Orexin neurotransmitters, first identified fifteen years ago, promote wakefulness. When suvorexant is in the brain, orexin is less likely to reach orexin receptors. Instead of promoting general, stupefying brain inactivity, suvorexant aims at standing in the way of a keep-awake signal. This difference may or may not come to mean a lot to insomniacs, but Merck’s marketing is likely to encourage the perception that suvorexant ends the dance by turning off the music, whereas a drug like Ambien knocks the dancer senseless.
If the Merck scientists succeeded at the F.D.A., they would be the first to bring an orexin-related drug to market. “It’s an amazing achievement,” Richard Hargreaves, the fourth colleague at the Hilton, said. “Everyone should be really proud.” But, he added, “my worry is that a new mechanism is being evaluated on the science of an old mechanism.”
“With Ambien, you’ve got a drug that’s got basically only onset,” Renger said, dismissively. That is, it sends you to sleep but might not keep you asleep. “Suvorexant has the onset, but it has the great maintenance, especially in the last third of the night, where other drugs fail.” And even though suvorexant keeps working longer than Ambien, suvorexant patients don’t feel groggier afterward, as you might expect. Impassioned, Renger imagined himself addressing the F.D.A.: “Why aren’t you giving this a chance?”
“Drugs usually have some side effects,” Schoepp said. “It’s all benefit-risk.” He added, “There is some dose where suvorexant will be ultimately safe—because nothing will happen. If you go low enough, it becomes homeopathic.”
They stood to go to their rooms. Schoepp murmured, “I’d love to take it right now.”
by Ian Parker, New Yorker | Read more:
Image: Kenji Aoki
