Reshaping Insomnia Treatment Via the Orexin Receptor Pathway

Thomas Roth, PhD, Henry Ford Detroit

Thomas Roth, PhD

Thomas Roth, PhD, knows what it's like to operate on insufficient sleep. After making it through the grueling days of post-graduate studies, he has an acute understanding of what sleep deprivation can do to the mind and body. It’s no surprise, then, that many primary care physicians fail to observe and diagnose cases of insomnia when patients appear in their examination rooms complaining of lack of sleep.

“Many physicians don’t think it’s that important because they’ve lived it for 5 years,” Roth, director of the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, Michigan, told NeurologyLive^TM. “It’s not normal, but [physicians] don’t realize these people live it day in, day out.”

Insomnia is a relatively common sleep disorder and is not particularly difficult to diagnose, Roth said. Yet the condition is often missed.

“It’s complicated if you don’t have the training,” said Roth, who has consulted for companies developing insomnia therapeutics. “And it’s complicated if you don’t have the time.”

Time is important because diagnosing insomnia generally requires the physician and patient to talk through an insomnia history. After all, an insomnia diagnosis is about more than just trouble sleeping; it is also tied to a particular set of causes and effects. Many providers are reticent to invest that kind of time to diagnose a condition that many others do not consider to be a major health problem.

“They have lots of things to do with their time, and unfortunately they don’t think of insomnia,” Roth said. “If you miss [diagnosing] insomnia, you don’t think that’s a big deal, which I totally disagree with.”

However, the relatively recent emergence of the neuropeptide orexin (also known as hypocretin), related to the brain’s regulation of wakefulness, could help raise awareness of insomnia and give physicians another treatment tool. One orexin receptor antagonist, suvorexant (Belsomra; Merck), is currently on the market, with potential competitors not far behind. Although many experts consider this an important breakthrough in the treatment of insomnia, the degree of its impact remains to be seen.

Defining the Problem

The first step in treating insomnia is diagnosing it. With proper training and a little time, Roth said, clinicians make a relatively straightforward diagnosis. Personally, he said in the interview, he looks for 4 things: The first, and most obvious, is that the patient has difficulty falling asleep or staying asleep. Second, some kind of morbidity needs to be associated with the sleep problems—if a person has trouble sleeping but is in otherwise good mental and physical health, there is probably nothing to treat. The third factor has to do with the length of time the patient has been struggling, as the American Academy of Sleep Medicine defines chronic insomnia as trouble sleeping at least 3 nights per week for at least 3 months. Finally, the patient must have adequate opportunity and circumstances to sleep.

“If you’re waking up 15 times a night because your baby is crying, that is a problem, but it is not insomnia,” Roth said.

Quantifying just how many people have insomnia can be difficult. A 2018 study from the University of Pennsylvania study found that 1 in 4 Americans experiences acute insomnia each year,¹ but about three-quarters of those patients return to normal sleep patterns on their own without medical intervention. Only about 6% of those patients will go on to have chronic insomnia.

Nonpharmaceutical Treatment

Although the number of medications available to treat insomnia is growing, pharmacologic solu- tions are not the only option, or even the first option, for patients suffering from insomnia. “The first-line treatment for insomnia should be cognitive and behavioral,” said Roxanne Prichard, PhD, a professor of psychology and neuroscience at the University of St. Thomas in Minnesota, in an interview with NeurologyLive^TM.

Cognitive behavioral therapy for the treatment of insomnia (CBTI) helps promote healthy sleep patterns by targeting thoughts and actions that can hurt a patient’s ability to sleep. One of the major tenets of CBTI is to train the body and mind to see the bed as being for sleep only. Patients should conduct other activities, such as reading or watching TV, in a separate setting to avoid confusion with their sleep association with the bed. Individuals who are in bed but unable to sleep should get out of bed rather than toss and turn.

Other CBTI strategies include placing limits on sleep time to boost tiredness and increase the likelihood that a patient will fall asleep during their speci ed but limited sleep periods. Many CBTI practitioners also recommend relaxation techniques or meditation to relax the body and induce sleep.

The American College of Physicians in 2016 endorsed CBTI2 as rst-line treatment for insomnia, though they noted that investigators have not thoroughly studied its impacts. “Although we have insufficient evidence to directly compare CBTI and drug treatment, CBTI is likely to have fewer harms,” said the group’s president, Wayne J. Riley, MD, MPH, MBA, MACP, in a press release.³ “Sleep medications can be associated with serious adverse effects.”

Still, Roth said one problem with CBTI is that finding a provider who specializes in CBT for insomnia can be difficult. Sometimes patients can get the therapy via telemedicine. However, many of those patients do not stick with the therapy long enough to benefit from it, he said. Pinning down a clear definition of CBTI can also pose a challenge because providers may interpret the therapy differently.

The Society of Behavioral Sleep Medicine offers a behavioral sleep medicine certification⁴ that clinicians can obtain by completing a society-accredited, graduate- or postgraduate-level program or 500 hours of training and supervised clinical experience.

Existing Pharmaceutical Options

Despite a growing preference to start insomnia treatment with CBTI, clinicians will eventually treat the majority of patients with prescription medication. “The most prominent drugs are sedatives/ hypnotics of varying half-lives,” said Prichard. “These drugs mainly work as [γ-aminobutyric acid] (GABA) receptor agonists, the same receptor that alcohol binds to.”

By binding to GABA receptors, drugs such as lorazepam can increase levels of GABA, causing the patient to relax to the point of sleep. The list of approved benzodiazepines and nonbenzodiazepines targeting GABA is lengthy, and clinicians have used many to successfully treat insomnia for years.

However, the drugs come with significant risks, Prichard said. “The primary issues with these medications are that they have a high potential for abuse, tolerance, [and] dangerous interactions with other drugs, including alcohol, pain, and anxiety medications,” she said. Some patients who take these drugs experience a “hangover” effect during the daytime, and the drugs can be associated with risk for daytime sleepiness and falls, as well as sleepwalking. “They are not approved for long-term use,” she said.

Another class of drugs, including doxepin, works by blocking histamine receptors. The neurotransmitter histamine plays a role in the sleep-wake cycle. Doxepin is an antidepressant; however, it is not listed as a controlled substance, and thus it may be appropriate for patients with a history of substance abuse.

The FDA has also approved ramelteon,⁵ which works by targeting 2 specific melatonin receptors, to treat insomnia. Like doxepin, it has the advantage of not being classified as a controlled substance.

Although several drugs have been approved specifically to treat insomnia, Roth said about half of prescriptions written to treat insomnia are off label. Trazodone, a serotonin antagonist and reuptake inhibitor approved to treat depression, is a leading example, he said. Clinicians also use antidepressants, such as mirtazapine, and antipsychotics, such as quetiapine (Seroquel; AstraZeneca), off label to treat insomnia. Alternately, some patients use OTC antihistamines and melatonin to combat insomnia.

Many common insomnia treatments, like benzodiazepines, are not recommended for elderly patients because of the risk of abuse as well as the potential adverse effects (AEs), including falls and daytime sleepiness.

As drugs targeting orexin receptors make their way further into the insomnia medication landscape, Prichard said, the main goal of clinicians will be to provide an additional treatment option—something that is important given the complexity of the mechanisms underpinning insomnia. “Sleep is an incredibly complicated process, involving more than a dozen neurotrans- mitters and hormones,” she said. “It’s unlikely there will ever be a single pill solution to something this neurologically complex. However, this new class of drug could be a nudge in the right direction for some.”

The Orexin Breakthrough

In 1998, 2 independent groups of investigators⁶—one studying sleep, the other studying obesity—published the first work describing orexins. The investigators located the orexin cells in the hypothalamus and determined that they were necessary to keep a patient awake.

Investigators soon published research⁷ demonstrating the role of orexin, or lack thereof, in conditions like narcolepsy. Patients with narcolepsy were found in studies to have a deficiency in orexin, leading to the inability to stay awake. Research published last year⁸ by investigators from the Czech Republic suggested orexin supplementation might be one way to help cure narcolepsy.

The newest class of insomnia drugs is based on the reverse premise.

“Orexin is a wakefulness-associated neurotransmitter that has many downstream targets in the nervous system, but it is less widespread than GABA,” Prichard said. “Blocking orexin might be a way to tone down the wakefulness signals without causing widespread inhibition overall.”

Prichard et al published a paper⁹ in 2018 outlining the pipeline of orexin-related insomnia medications. As she and her colleagues noted, Merck & Co in 2014 became the first drug company to win FDA approval for an insomnia medication that leveraged the new insights into orexin. Its drug, suvorexant, is a selective, dual orexin receptor antagonist (DORA). In clinical trials, the drug improved sleep maintenance and sleep latency better than placebo, as measured both in patient self-reports and in polysomnography.¹⁰ The drug became available in February 2015.

However, suvorexant will not be the lone approved orexin antagonist for much longer. Eisai and Imbrium Therapeutics announced in March 2019 the filing of a new drug application¹¹ for lemborexant for the treatment of insomnia. The small molecule DORA improved the sleep of patients in 2 phase 3 trials, SUNRISE 1 and SUNRISE 2, which evaluated the safety and efficacy of lemborexant in 1006 and 949 adult patients with insomnia, respectively.

Merck’s DORA candidate filorexant was the subject of a phase 2 study¹² published in 2016 that demonstrated positive results after 4 weeks of treatment in nonelderly patients with insomnia disorder. Idorsia Pharmaceuticals also recently published phase 2 results¹³ for its DORA candidate, ACT-541468, and GlaxoSmithKline is working on a drug, SB-649868, targeting orexin receptors. SB-649868 is the company’s second attempt at developing a DORA, after their first candidate, almorexant, was discontinued in phase 3 because of concerns over elevated liver enzymes.¹⁴

All the DORA candidates in development, if eventually approved, will significantly expand the insomnia armamentarium, but some questions remain.

“The scope of orexin signaling in the brain is much more targeted than that of the whole-brain population of GABA neurons, which may result in a more favorable AE pro le for some patients,” Prichard and colleagues wrote.⁹ “Initial research suggests that DORAs promote not only NREM [non—rapid eye movement] sleep but REM sleep as well, unlike the GABA-mediating agents and [selective orexin receptor antagonists].”

On the other hand, they noted, a large amount of literature regarding drug interactions does not exist, although some definitive contraindications have been identified. “People with narcolepsy, who have disruptions in the orexin system, should not take these medications, nor should people already taking sedative medications,” Prichard said.

Dosing has been a particular hurdle in the approval and use of suvorexant. The FDA approved the drug to treat insomnia at 4 dosing levels, ranging from 5 to 20 mg. However, the agency recommended a starting dose of 10 mg, taken half an hour before bed each night—significantly lower than the 40-mg maximum dose administered in clinical trials for the drug. Although that higher dose was associated with higher rates of AEs, “10 mg is not a very effective dose,” Roth said.

The FDA’s insistence on recommending a 10-mg dose is likely one reason that sales of suvorexant have been lower than some expected, Roth said. Although nothing is stopping physicians from trying higher doses if a patient does not respond to 10 mg, Roth said some might assume the drug is ineffective and be unwilling to invest the time to test the impact of higher doses. “If you’re trying a new medication and you start at 10 mg and it doesn’t work, you gure it’s the medication,” he said.

Yet Roth advised that orexin antagonists can be beneficial for patients who suffer from a hangover effect on other drugs or who do not respond well to other drugs. He said DORAs are particularly beneficial for patients who need to get up in the night, such as people who frequently wake to use the restroom, because the drug does not focus on increasing sleepiness, only on reducing wakefulness.

As noted for many other new drugs, Prichard and colleagues said that cost may also be a factor for some patients. In 2018, suvorexant cost about $1200 per 100 pills, more than double the price tag of some common sedatives also used to treat insomnia. Whether the approval of additional DORAs will have an impact on the price of suvorexant and the drug class as a whole is unclear.

Looking Ahead

Even as more drugs targeting the orexin receptor pathway move through the pipeline, Roth said, opportunities to treat other therapeutic areas may well present themselves as the medical community learns more about the role of orexins. Investigators are conducting early work to evaluate the ability of the drug class to treat drug addiction, and Roth said there is reason to believe orexins might also play a role in Alzheimer disease.

“It’s a very important neurotransmitter,” Roth concluded, “and we’re becoming more and more cognizant of that.”

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