The Founder and CEO of NeuroTrials Research spoke about the current landscape of insomnia, noting that lemborexant holds promise as a potential therapy.
Russell Rosenberg, PhD, D.ABSM
Despite being recognized as the most common sleep complaint, insomnia continues to remain a conundrum for physicians. Over the last 30 years, the insomnia toolbox has not addressed some of the key issues that are necessary in order to develop effective treatments.
One therapy currently under investigation for the treatment of insomnia is lemborexant. NeurologyLive spoke with Russell Rosenberg, PhD, D.ABSM, Founder and CEO of NeuroTrials Research and former Chairman of the Board of the National Sleep Foundation and a principal investigator in the lemborexant studies to further discuss this investigational therapy.
While Rosenberg noted that there is no perfect sleep-promoting agent, lemborexant is a step in the right direction. Rosenberg shares his excitement not only the potential therapy, but for the new research that will push the whole field of understanding insomnia forward.
Russell Rosenberg, PhD, D.ABSM: Insomnia is the most common sleep complaint on the planet and 7%—10% of the population of the United States could be diagnosed DSM-5 with insomnia disorder. When you think about it, we have 350 or so million people in the United States, that’s a tremendous number, and so while there certainly have been attempts with various therapies for treating the disorder, it still remains much of a conundrum for physicians on how to deal with it and how to deal with most effectively. The tools we’ve had over the last 30 or so years have not been horrible, but they really have not addressed some of the main issues that are important when it comes to treating insomnia and I’ll just sort of lay those out for you—it’s not only important to get to sleep quickly, it’s important to sustain sleep or not have fragmented sleep and I think maybe every bit is as important as being able to sleep to being able to wake up to feeling well and refreshed and feel like you have the energy and cognitive wherewithal to get through the day.
Those are things that have been a bit amiss, certainly the sleep maintenance issue and the cognitive issue and one other thing is that my patients over the last 30 years have always been concerned, especially more so women than men just because women end up being the primary caretakers of their children, they want to know they can wake up safely in the middle of the night. I don’t think this is just a female thing really, but anecdotally I can tell you that’s the kind of question I get often times. Waking up and feeling functional is particularly important in the elderly as well, there’s 1000s of individuals that have sustained falls and injuries, and they are a population that often have sleep problems like waking up in the middle of the night for a variety of reasons, whether it be pain or the urge to use the restroom.
That’s sort of the broad picture of what the landscape looks like now and some of the things we target or want to target in new drugs treating this very prevalent disorder.
RR: There are shortfalls in terms of what we have now in the insomnia toolbox, there’s undoubtedly shortfalls in what we have. Like I said, there are some things that are approaching the goals that I have mentioned, but none have really hit most of them or hit all of them.
In recent years, probably over the last 20 or so years, the neuropeptide sometimes thought of as a neurotransmitter or orexin, was identified especially as a neuropeptide involved in the wake-up system and early work in narcolepsy was pointed to this as a very important set of neurons in the brain for keeping us alert and awake. Orexin neurons are particularly important in insomnia because when we think there’s an over signaling of those orexin neurons then that could potentially be for a large group of people the pathophysiology involved in the insomnia process. The process is quite complex and we’re still learning more about the orexin system and other neurotransmitters involved in that sleep-wake system, but what lemborexant does is it basically tamps down the signaling of orexin neurons and in a very time-limited way. If you tamp down those neurons at the same level for 24 hours, 36 hours you get somebody who might sleep too long, so the real sort of science here is understanding how to find a compound that will tamp down the orexin system enough to make it easier to fall asleep, it doesn’t really put the person to sleep as we once thought of using an endozepine receptor agonist and other sedating drugs, it really allows sleep to occur. Lemborexant is really trying to tamp that down for a limited period and to a degree that allows individuals to wake up in the middle of the night and be able to function and be able to maintain postural stability, not fall, and then wake up feeling again feeling rested, awake and ready to go the next morning.
RR: There are a couple of studies I would like to mention. There is a pivotal trial that was completed relatively recently that utilized both objective and subjective outcome measures to determine efficacy of lemborexant, and those still are required by the FDA, you still need to provide the objective evidence and the objective evidence that we have is what’s known as polysomnography or full nights in the sleep laboratory. This pivotal study that involved objective and subjective data was a 1-month, double-blind placebo-controlled trial with a comparator of zolpidem tartrate extended release. This was the first time that there was this head to head study with zolpidem ER and a new compound, but zolpidem ER is widely used and has been widely used despite some of it’s difficulties, and we’ve all heard some of the problems in the past with unwanted behaviors that occur in and around sleep, like sleep walking, sleep driving and sleep eating, those are particularly troublesome and you talk to anyone that’s prescribed zolpidem or zolpidem ER and they are often at risk for serious problems when they’re out and about walking and not fully awake.
In this study, subjects were asked to undergo sleep studies over a period of time as well as keep subjective data—what percentage of the time they’re actually in bed, trying to sleep, sleeping. To explain that a bit more, if you’re trying to sleep for 8 hours and you only sleep for 4 hours, that’s a 50% sleep efficiency and so it’s a good measure of the maintenance of sleep. In terms of endpoints that was certainly one of them, and primary endpoints included things like how latency to persistent sleep, how quickly people got to sleep, how they felt the next day, what sort of adverse events they experienced. What was promising about lemborexant in this particular pivotal study was that patients got to sleep faster, they stayed asleep longer, their total sleep time was longer than placebo, and essentially, they tolerated the medication quite well. This hits on some of the endpoints I mentioned before, getting to sleep and staying asleep through the night and this particular population by the way was older adults, and I think that’s particularly important because older adults are certainly more vulnerable to insomnia disorder than younger adults, primarily because some of the other disorders that effect the older population can also have an impact on sleep.
There was another study, an outpatient study of about 900 subjects, but this included a whole range of ages from 18 to 88 and in this particular study through diary data, the primary outcome measure was subjective sleep onset latency, but of course there was interest in sleep maintenance again, and as well as the adverse events. In that study patients fell asleep quicker, they stayed asleep longer, they had fewer minutes awake in the middle of the night, a metric that we often use is called WASO, wake after sleep onset, but sleep efficiency again, is tied directly to their WASO. I think the data here is quite promising.
There were some earlier phase 1 studies that were safety based that I was a principal investigator on, and one in particular was quite novel and had not been done with most of the hypnotics that are currently available. This was a forced awakening study in which patients were given drugs, 5 mg or 10 mg, those are the two doses of lemborexant, then awakened in the middle of the night by an auditory tone. We were interested in identifying if people taking this drug were more difficult to wake up then say after placebo and how were they with regards to postural stability—that is would they be at risk for falls. I can tell you that lemborexant did not impair these subject’s ability to wake up in the middle of the night to an auditory tone, and that’s important that there was not really a significant difference from placebo for waking up in the middle of the night to a tone. Then with regards to postural stability, we did find quite a difference between lemborexant and not only placebo but also zolpidem ER.
There was a significant increase in postural instability in the middle of the night in the zolpidem ER group, which was not seen in the lemborexant group, and the next day what happened is once we woke them up, we put them back to sleep and those that were on lemborexant fell back to sleep faster than zolpidem ER and not only that, the next morning residual effects of zolpidem ER with regards to postural stability remained intact, that is, they had higher levels of instability on zolpidem ER then those on lemborexant 5 mg or 10 mg. Those are some safety studies I applaud Eisai and Purdue for doing that safety study.
RR: As excited as I am about the results that this investigational sleeping agent is going to put people to sleep faster, safely and they can wake up in the middle of the night and they can sleep longer and then wake up refreshed or feeling better the next day and functioning better, we ought to make sure that we talk about potential adverse events.
The most common ones that occurred greater than 5% were things like somnolence and headache. In the outpatient study influenza occurred at a rate greater than 5% in the lemborexant group, but I don’t think there’s an increased risk for influenza based on taking either 5 mg or 10 mg.
RR: Let me just say from a fairness perspective, there’s no perfect sleep-promoting agent, we know what the ideal sleep agent is, but I think we’re getting closer with lemborexant. If clinicians have patients who either have trouble getting to sleep and/or staying asleep and they have safety concerns over previous uses of benzodiazepine receptor agonist, which are widely known, then this is something that they should seriously consider, and I think will be a valuable tool in their toolbox of treating insomnia and potentially other sleep disorders down the road.
As I hope you can tell I’m excited about lemborexant and all the work that will come after once it’s approved.
RR: There are other potential applications for lemborexant which Eisai and Purdue are exploring. One disorder is irregular sleep-wake rhythm disorder, where the circadian process for sleep wake is really important and it’s often overlooked, but lemborexant has been investigated as a potential drug that might help these patients. One group that suffers from irregular sleep-wake rhythm disorder, a group that is very valuable to target clinically, are patients with Alzheimer disease, and I believe that study is ongoing now.
I think there are other potential applications beyond just insomnia that are worth considering and I’m always excited when there’s a new compound for sleep because there will be a tremendous amount of research that pushes the whole field of understanding insomnia, understanding the sleep-wake process forward, and this is going to be one of those compounds that will get a lot of attention in the next 3 years.
Transcript edited for clarity.