Michael J. Thorpy, MBChB, spoke about solriamfetol’s success and the possibility of it treating other sleep conditions.
Michael J. Thorpy, MBChB
In December, the FDA will review an application for solriamfetol (JZP-110), a Jazz Pharmaceuticals product being explored for the treatment of excessive sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).
In its clinical trial program, TONES, the therapy showed efficacy compared to placebo in both conditions. In the TONES 5 trial, after approximately 6 months of maintenance treatment, a randomized 2-week placebo-controlled phase was performed. In this phase, there was a -3.7 Least Squares (LS) mean change in Epworth Sleepiness Scale (ESS) with solriamfetol versus placebo (95% CI, -4.80 to -2.65; P <.0001). The mean LS was 1.6 with solriamfetol compared with 5.3 with placebo.
Meanwhile, in the TONES 2 study in patients with narcolepsy, solriamfetol decreased ESS by -3.8 to -6.4 across 3 doses, while the mean change for placebo was -1.6. Mean sleep latency on maintenance of wakefulness test (MWT) was 12.3 minutes at the highest dose of 300 mg, to 4.7 minutes at the lowest dose of 75 mg. For placebo, the mean latency was 2.1 minutes.
In TONES 3, in patients with OSA, the mean sleep latency was 13 minutes at the highest dose of solriamfetol (300 mg) and 4.7 at the lowest (37.5 mg), while in the placebo group, it was 0.2 minutes. The ESS was -7.9 in the highest dose arm and -5.1 with the lowest versus -3.3 with placebo. In TONES 4, also a trial in OSA, the mean sleep latency by MWT was -1.0 minute with solriamfetol compared with -12.1 minutes for placebo. The ESS was -0.1 with solriamfetol versus 4.5 for placebo.
Aside from 4.2% of patients reporting headache, nausea, insomnia, nasopharyngitis, dry mouth, and anxiety in TONES 5, the therapy had little to no serious adverse events (AEs) reported.
Michael J. Thorpy, MBChB, the director of the Sleep-Wake Disorders Center at Montefiore Medical Center, spoke with NeurologyLive about solriamfetol’s success in the TONES program and the possibility of using therapies like it in other sleep conditions.
Michael J. Thorpy, MBChB: Now, solriamfetol is an effective agent, and with the data that we have, it looks as though it’s more effective for sleepiness than the other drugs we have. So, when you compare the study endpoints—the ESS, the MWT—and you compare that against other drugs that are used for narcolepsy, we find that there are greater beneficial changes with regards to solriamfetol. It seems to be very effective in helping people to stay awake, but we don’t know whether it improves the background feeling of sleepiness that’s there—we suspect that that’s probably going to still be very much the same as with modafinils. But it’s possible that there may be some patients who feel less drive for sleepiness and improved alertness with solriamfetol. We’re hopeful that this drug is going to be an improvement over current medications—it’s more effective in improving alertness, has a good safety profile, doesn’t seem to have the same potential for cardiac issues as some of the other medications. It has a very minimal increase in blood pressure and heart rate, but very little, and it’s really not going to be an issue for the vast majority of patients who take it. So, the adverse effect profile seems to be good and we’re really hopeful that solriamfetol will get FDA approved.
MT: We believe that most of the drugs that improve alertness work through a dopaminergic mechanism, and this one is a little bit different in that solriamfetol works through norepinephrine as well as dopamine. Norepinephrine is an important wake-promoting neurotransmitter. Although we don’t know exactly how it’s working, it’s interesting that you’re getting this direct stimulation of wake-promoting neurons through the dopaminergic mechanism, and norepinephrine is important in turning off sleep drive through a nucleus called the ventrolateral preoptic nucleus, also known as a VLPO. There’s a possibility, and we don’t really know this fully, but it may be turning off the drive for sleep as well as stimulating the wake-promoting neurons. So, it may be quite a different effect from other medications that are working predominantly through dopaminergic mechanisms.
MT: It seems that most of these drugs have a non-specific effect on sleepiness. It looks as though no matter what the disorder is, the final common pathway seems to be the same in terms of the production of sleepiness through these both aminergic and monoamine mechanisms. It doesn’t seem that there are any drugs that have a selective specific effect on sleepiness itself. Now, there are drugs, like sodium oxybate, that also work on cataplexy—a different effect of narcolepsy—but for sleepiness, they all seem to be working predominantly through the same mechanism. There are other conditions that produce sleepiness and one that is being looked at for solriamfetol, is Parkinson's disease. Parkinson patients are extremely sleepy during the daytime. They’re very complicated patients, they have a lot going on neurologically, so they’re not easy patients to treat. Previous studies have been done with modafinil, for example, and it didn’t turn out to be an effective agent in the treatment of sleepiness in Parkinson patients. Partly, probably because they are so complicated—there are many reasons why Parkinson patients are sleepy. One can be the anti-Parkinson medications themselves can produce sleepiness. Also, these patients can have a dementia and have a disruptive sleep-wake schedule. The Parkinson process affects the neurons that are involved in sleep wake-mechanisms, so there is probably a direct effect on impairing ability to remain awake by a neuronal mechanism.
Parkinson patients are difficult to treat, but there is a study underway with solriamfetol. If we can find a medication that can be safely given to these elderly patients that have Parkinson’s and can improve their alertness during the day, I think that’s going to be really positive. That’s the next step after narcolepsy and sleepiness of OSA syndrome. But then there are other questions, such as: If this is a safe drug, can it be used for shift-work sleepiness, or jet-lag? These are disorders that have yet to be explored with solriamfetol, but, if it gets approved for narcolepsy and sleepiness of OSA, and is safe and effective, then I’m sure it will be studied in the circadian rhythm sleep disorders such as jet-lag and shift-work.
Transcript edited for clarity.