Clete Kushida, MD, PhD

: So, Lois, what do you think are some important next steps?

: Well, I really appreciate having this evidence to incorporate into my clinical practice. There are a number of new medications for the treatment of narcolepsy, and this will give me the opportunity to understand what my patients needs are, and then to select a medication that best reflects their needs. And for this medication, I do think that the once-a-night dosing is going to be something welcomed by many patients and their families. So just having more choices is very welcome. Now we have the opportunity to clarify in the clinical practice setting which medications are best for which patients. I do want to say 1 other thing that was pointed out in this paper, which I think is good practice for patients with any type of sleep problem. In order to help a person not have enuresis, remind them to be careful about their fluid intake at bedtime, and to empty their bladder before they go to bed is a good practice. I encourage that for patients with a variety of sleep disorders, but that was 1 point made in this paper to help with the side effects of enuresis that I will also pass on to all my patients with sleep disorders, but especially those on oxybate therapy.

: Thank you, Lois. One additional point that was pointed out in the article was that the study concentrated on the grouping of narcolepsy, both NT1 [narcolepsy type-1] and NT2 [narcolepsy type-2]. But it would be interesting to explore the effects of the once-nightly sodium oxybate on the end points that were studied, looking at it in a subgroup analysis—looking at NT1 versus NT2—and also in subgroups of patients who were, or were not, receiving concomitant stimulant medication. Also, 1 thing that would be interesting is that looking at the pharmacokinetic profile of this once-nightly sodium oxybate, it’s striking that it kind of mimics sleep depth, whereas most of the deep sleep, the N3 sleep is in the first part of the night, and then it tapers down. So, it would be nice to really explore that profile or that type of sleep architecture.

: I very much agree. We know that these medications improve sleep quality, likely by increasing N3 sleep. And to just gain a deeper understanding of how that works and how it benefits patients, with it being a once-a-night formulation it will be more straightforward to look at that without worrying about the timing of the second dose. I also hope from a patient perspective that we can increasingly understand how valuable this is for patients who come to us. And some of their initial concerns are not so much about excessive daytime sleepiness and cataplexy, although those will be part of the picture for a patient with narcolepsy. But those that say, “I keep waking up at night and I have terrible scary dreams,” I suspect like all oxybate therapy that the once-a-night form will be particularly beneficial to that group of patients. So, I look forward to the subgroup analysis as the data becomes available.

 Between the Lines presentation, and both Dr Lois Krahn and I sincerely hope that you’ll be able to incorporate some of the content that we discussed during this presentation into your clinical practice. Thank you very much.

Videos

Important next steps studying once-nightly sodium oxybate and other therapies for narcolepsy treatment.

Future Opportunities Using One-Nightly Sodium Oxybate for Narcolepsy Treatment

: Dr Kushida, what can we learn from this paper that may impact our practice?

: So, this study was actually the first randomized control trial that demonstrated the efficacy and safety of a 7.5-gram dose of sodium oxybate. And given that the efficacy was nearly comparable to the 9-gram dose compared to placebo, as stated in the article, this may afford confidence for prescribers and patients that a lower dose can be effectively used in practice. Also, this, I believe is a first known publication describing a statistically significant reduction of cataplexy compared to placebo at week 1 with a 4.5-gram dose of sodium oxybate. Thirdly, clinical practice guidelines for the American Academy of Sleep Medicine set a change from baseline compared to placebo of 2 or more minutes on the maintenance of week of the test, including the 95% confidence samples as being the clinical-significant threshold. This study showed that the once-nightly sodium oxybate achieved the standard for all 3 doses evaluated, which included the 6-gram, the 7.5-gram, and the 9-gram doses.

: If I can follow up on that as a psychiatrist, we have many medications used for other conditions where we have to prepare our patients to wait a long time to have the treatment response. And all of us are impatient. So, the data that suggests and indicates that cataplexy can improve after 1 week, I think will be very well received by our patients. Many of whom can be embarrassed or maybe even put at risk if their cataplexy continues. And if this medication can help them faster, I think that that is a very important finding.

The potential benefits of integrating once-nightly sodium oxybate into routine clinical practice to help address treatment limitations for patients with narcolepsy.

Adopting Once-Nightly Sodium Oxybate into Clinical Practice to Treat Narcolepsy

: So, Lois, what interesting questions did this paper raise?

: Well, for me, there’s a fundamental question, which is “Can a once a night form of this medication work, and is it well tolerated? Is it safe?” And I greatly appreciate that this data is now available, that we all can look at it because, in my view, the answers are yes. And so, we have more choices for patients, especially those who have life circumstances where awakening part through the night is disruptive to their bed partner. They have disliked that practice if they’ve previously taken the twice a night form of sodium oxybate. And for younger, newer users, where they and their families are just getting used to being on oxybate therapy, learning how to take this medication, the fact that they only need to take it once a night and not worry about a repeat dose, I think will greatly increase their comfort with considering all the necessary preparations to take these medications safely.

: Those are perfect points, Lois. One additional question that I had in my mind was about the sleep architecture. That wasn’t something that was addressed within this study, but it would be interesting to look at that the data to see would this once-nightly, sodium oxybate result in more normal sleep architecture compared to twice-nightly dosing.

: I think that that’s very important data, and I hope that it gets attention and is looked at more closely. Because, of course, we all want medications where they make a difference for the patient’s symptoms, but that the levels of the medication in the patient’s body aren’t higher than they need to be and are just released in a more continuous gradual way and come closer to normalizing sleep. That’s what we want for our patients, with all of our therapies and with the once-a-night form of oxybate therapy. The Cmax data is very promising.

Questions raised by a recent paper by Kushida CA, et al., highlighting symptom improvement with once-nightly sodium oxybate in patients with narcolepsy.

Questions Regarding Once-Nightly Sodium Oxybate for Narcolepsy

: So, the study that will be discussed is that once-nightly sodium oxybate, or FT218, demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. And it is my great pleasure to introduce Dr Lois Krahn at the Mayo Clinic College of Medicine in Phoenix, Arizona.

 Well, thank you, Dr Kushida. Very nice to be here with you.I was going to say that the data from this paper is incredibly valuable to those of us who treat patients with narcolepsy. I mean, it shows that patients are better able to stay awake, as measured by the Maintenance of Wakefulness Test (MWT) and by the Epworth Sleepiness Score. It also shows that cataplexy is controlled on once a night sodium oxybate as compared to placebo. And lastly, that the patient’s quality of life improves. So, on all 3 of those important measures, this medication appears to be effective. That’s very useful to the medical community and to our patients. Thank you.Dr Kushida, how does this paper contribute to our understanding of the use of once-nightly sodium oxybate for the improvement of symptoms in patients with narcolepsy?

: These type of modified release formulations are commonly applied to different therapies, mainly to decrease patient burden since they can improve the adherence with a regimen and, ultimately, enhance the overall patient experience. For chronic medical conditions, such as narcolepsy, this is very important because, as we all know, narcolepsy is significantly debilitating to almost every aspect of a patient’s life when it is not successfully treated. Now, the once-nightly sodium oxybate has received orphan drug designation from the U.S. Food and Drug Administration based on its plausible hypothesis that it may be clinically superior to the twice-nightly formulation of sodium oxybate already approved from the same indication. And there are several discreet advantages to once-nightly dosing. First, it may result in better medication adherence for patients. It may also result in a beneficial effect on nocturnal sleep. Additionally, a once-nightly sodium oxybate will avoid the patient having a scheduled awakening and also, potentially, awaking the bed partner, since the patient would have to self-administer the second dose of twice-nightly sodium oxybate. And lastly, the plasmic concentrations decline steadily after the first and only Cmax, which occurs early in the night, post-dose, with this once-nightly sodium oxybate. So it’s possible that this formulation, compared to twice-nightly sodium oxybate, may be less likely to be associated with falls given the lower peak plasma concentration, lower concentration of 8 hours, and the once-nightly dosing. Thank you.

: I’m going to add 1 other point on that. You know, when a person is starting oxybate therapy and we explain to them that this is a medicine that’s been available now for some time, but they need to take it twice during the night, my experience is that they are surprised because they have never heard of a medication that is repeated partway through the night. And sometimes they are hesitant; for younger patients, sometimes their families are hesitant. And this formulation, now proven to be effective, clearly simplifies it, and I think will take away some of the reluctance that patients who have never used sodium oxybate have experienced previously.

Takeaways of the REST-ON clinical trial results as presented in Sleep that help clinicians learn more about the management of patients with narcolepsy.

Key Takeaways and Management of Narcolepsy

: Hi. It’s my pleasure to discuss this study, which is the “Once-Nightly Sodium Oxybate (FT218) Demonstrated Improvement of Symptoms in a Phase 3 Randomized Clinical Trial in Patients with Narcolepsy.” My name is Dr Clete Kushida at the Stanford University School of Medicine in Palo Alto, California.

Narcolepsy is a neurologic problem in which the brain isn’t able to control the sleep-wake cycle, as shown on this slide. And one of the key features is it causes a sudden, irresistible sleepiness during almost any time of the day. And it is prevalent in about 1 of every 2000 people and does affect men and women equally. Some of the common signs and symptoms are illustrated here. There’s cataplexy, a sudden decrement in muscle tone that’s frequently associated with strong emotions such as laughter, anger, surprise. Then there are hallucinations, which are at the onset of sleep or coming out of sleep, and these hallucinations can be auditory, visual, or somatic. And oftentimes they’re accompanied by sleep paralysis or an inability to move voluntary muscles. Excessive daytime sleepiness is one of the key features of this condition, and it also tends to disrupt nocturnal sleep. There are 2 subtypes of narcolepsy. Narcolepsy type 1 [NT1] and narcolepsy type 2 [NT2]. The key distinguishing features between these 2 types are that NT1 is associated with cataplexy and low levels of hypocretin-1 orexin-A, whereas [with] NT2 cataplexy’s absent and levels of hypocretin-1 and orexin are not as low as found in NT1.

So REST-ON was a phase 3, double-blind, 2 arm, multi-center, randomized clinical trial that was designed to investigate the efficacy and safety of ON-SXB, which is once-nightly sodium oxybate for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. The trial comprised a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period. Randomization was 1:1 to either once-nightly sodium oxybate or placebo and was stratified by narcolepsy type NT1 or NT2. Participants initially received 4.5 grams for 1 week, followed by 6 grams per weeks 2 to 3, 7.5 grams for weeks 4 to 8, and then 9 grams for weeks 9 to 13. The Maintenance of Wakefulness Test, or MWT; as well as the number of cataplexy attacks, the Epworth Sleepiness Scale, which tests subjective daytime sleepiness; and the PSG, which is the polysomnography sleep study, where it sets that baseline at weeks 3, 8, and 13 of treatment. Now, the number of cataplexy attacks, hypnagogic hallucinations, which are hallucinations as a person is going to sleep, and sleep paralysis events were recorded daily in sleep symptom diaries which were reviewed at weeks 3, 8, and 13. The clinical global impression of severe, or CGI-S, for sleepiness was recorded at baseline. The clinical global impression of improvement, or CGI-I, was recorded at weeks 3, 8, and 13. Adverse events were documented at weeks 3, 8, and 13, but could be recorded at any time during the trial.

So this shows the patient demographics and baseline characteristics. Baseline demographics were well-balanced between the once-nightly sodium oxybate and placebo arms. The mean age was 31 and 32 years in the once-nightly sodium oxybate and placebo arms, respectively. Most participants were women. For the once-nightly sodium oxybate it was 64.5% women and for placebo it was 71.4% women. Also, most participants were white; In the once-nightly sodium oxybate arm it was 74.8% and in the placebo arm it was 76.2%. Geographic distribution of the participants in the U.S. and the rest of the world were equally distributed in the placebo group and the once-nightly sodium oxybate group, but slightly greater for the U.S. in the once-nightly sodium oxybate group.

Median and mean body mass indices for the 2 groups were similar. Approximately 75%, or three-quarters of participants had NT1. It’s important to note that hypertension was not an exclusion criterion. Approximately 8% of participants enrolled had a medical history of hypertension.

Regarding efficacy, the mean sleep latency on the MWT was similar between the once-nightly sodium oxybate and placebo arms at baseline. The actual values were 5 and 4.7 minutes, respectively. The increase in sleep latency was significantly greater with the once-nightly sodium oxybate versus placebo at week 3 for the 6-gram dose. The least square mean changed from baseline was 8.1 versus 3.1 minutes, respectively. At week 8, for the 7.5-gram dose, you can see that it was 9.6 versus 3.3 minutes, respectively. And at week 13, for the 9-gram dose, it was 10.8 versus 4.7 minutes, respectively. Now, the mean baseline CGI-severity was 5.1 in both treatment arms, indicating that participants were markedly impaired. A significantly greater proportion of participants in the once-nightly sodium oxybate treatment arm versus placebo were rated much or very much improved on the CGI-I scale at week 3 for the 6-gram dose. The values were 40.1% for the once-nightly sodium oxybate arm versus 6.1% in the placebo arm, respectively. At week 8, for the 7.5-gram dose, the values were 62.6% for the once-nightly sodium oxybate arm versus 22.8% in the placebo arm, respectively. And at week 13, for the 9-gram dose, it was 72% versus 31.6%, respectively. The mean baseline number weekly cataplexy attacks were similar in the once-nightly sodium oxybate and placebo arms. It was 18.9 versus 19.8, respectively. The decrease in least square mean changes from baseline, in the number of weekly cataplexy attacks, was significantly greater with the once-nightly sodium oxybate arm versus placebo at week 3 for the 6-gram dose. It was minus-7.4 versus minus-2.6, respectively. Then, at week 8, for the 7.5-gram dose, it was minus-10 versus minus-3.7, respectively. And at week 13, for the 6-gram dose, it was minus-11.5 for the once-nightly sodium oxybate arm versus minus-4.9 for the placebo arm.

At baseline, the Epworth Sleepiness Scale score was similar in the once-nightly sodium oxybate and placebo arms. The values were 16.6 and 17.5, respectively. The decrease in the least square mean change from baseline was significantly greater with the once-nightly sodium oxybate versus placebo at week 3 for the 6-gram dose. It was minus-3.5 versus minus-1.4, respectively. At week 8, at the 7.5 gram dose, it was minus-5.3 versus minus-2.2, respectively. And at week 13, for the 9-gram dose, it was minus-6.5 for the once-nightly sodium oxybate arm versus minus-2.7 for our placebo arm.

In the safety population, 83, or 77.6% and 49, or 46.7% of the participants in the once-nightly sodium oxybate and placebo arms, respectively, experienced a treatment-emergent adverse event. The most frequently reported treatment-emergent adverse events for all participants treated with once-nightly sodium oxybate at rates higher than placebo were nausea at 22.4%, headache at 18.7%, vomiting at 17.8%, dizziness at 15.9%, decreased appetite at 12.1%, anxiety at 7.5%, hyperhidrosis at 5.6%, and decreased weight at 5.6%. No participant in the once-nightly sodium oxybate arm and 1 participant in the placebo arm discontinued the study due to a treatment-emergent adverse event of worsening sleep or worsening of sleep apnea. A serious treatment-emergent adverse event was reported by 7 participants, or 3.3%, overall. And that included 5 in the once-nightly sodium oxybate arm, or 4.7%, and 2 in the placebo arm, or 1.9%. Only the serious adverse event in the 9-gram dose group, which was suicidal ideation, was considered treatment-related.

In the once-nightly sodium oxybate arm, when you look at the 3 dosing periods, rates of known sodium oxybate adverse events, such as nausea, vomiting, somnolence, dizziness, and enuresis were generally low, and, as shown here, there was no dose response relationship except for enuresis.

Dr Clete Kushida discusses the results of a phase 3 clinical trial that examined once-nightly sodium oxybate in patients with narcolepsy.

Clete Kushida, MD, PhD

Articles

Future Opportunities Using One-Nightly Sodium Oxybate for Narcolepsy Treatment

Adopting Once-Nightly Sodium Oxybate into Clinical Practice to Treat Narcolepsy

Questions Regarding Once-Nightly Sodium Oxybate for Narcolepsy

Key Takeaways and Management of Narcolepsy

Presentation: Improvement of Narcolepsy Symptoms with Once-Nightly Sodium Oxybate