NeuroVoices: Jennifer Gudeman, PharmD, on the Effect of Once-Nightly Sodium Oxybate in Narcolepsy Subtypes

Jennifer Gudeman, PharmD

Earlier this year, the FDA approved Avadel’s once-nightly sodium oxybate (Lumyrz) formulation for the treatment of cataplexy or excessive daytime sleepiness (EDS) in adults with narcolepsy. The approval was based on the phase 3 REST-ON trial (NCT02720744), in which the efficacy and safety of the agent were evaluated in patients aged 16 years and older with either narcolepsy type 1 (NT1) or type 2 (NT2). At the conclusion of the trial, the 3 coprimary end points were significantly improved at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g; P <.001 vs placebo).

Recently, investigators published a post-hoc analysis of REST-ON highlighting the impacts of once-nightly sodium oxybate regardless of narcolepsy type. At the conclusion of the 13-week treatment period, the least square mean (LSM) change in mean sleep latency was 11.1 (SE, 1.1) min for once-nightly sodium oxybate 9 g vs 5.1 (SE, 1.1) min for placebo in patients with NT1 (LSM difference vs placebo, P <.001) and was 9.6 (SE, 1.8) min vs 3.3 (SE, 1.9) min, respectively, for NT2.

Despite having similar baseline patient-reported sleep quality and refreshing nature of sleep, treated patients on ON-SXB began to separate themselves from placebo as early as week 3, with improvements that lasted through the 13-week study. In addition, patients on active treatment saw significant improvements vs placebo in Epworth Sleepiness Scale (ESS), a subjective measure of sleepiness in everyday situations.

To learn more about the findings and the importance of studying both NT1 and NT2, NeurologyLive® sat down with Jennifer Gudeman, PharmD, senior vice president of medical and clinical affairs for Avadel Pharmaceuticals. As part of a new iteration of NeuroVoices, Gudeman, an investigator on the newly published analysis, discussed some of the major differences between NT1 and NT2 and how previous studies may have misconstrued the way NT2 should be approached. In addition, she spoke on the current unmet needs for patients with narcolepsy, as well as how clinical trials have changed over the years.

What was the reason behind conducting this post-hoc analysis?

This particular publication by (Yves) Dauvillers and colleagues is one of my favorites because it really adds to the body of literature in understanding the efficacy of oxybate medication, not only in narcolepsy type one but also narcolepsy type two. Historically, trials of sodium oxybate have either been limited to narcolepsy type one, which, of course, is narcolepsy with cataplexy, or it's been unspecified narcolepsy. It hasn't been known if there are type two or how many type two are in that particular cohort. Because our pivotal clinical trial known as "Rest-On" had stratified by narcolepsy type one and narcolepsy type two, it afforded us the opportunity post hoc to analyze the efficacy of low rise compared to placebo across the various endpoints. One of the reasons that we felt that this was so important is there's a tendency for some clinicians to reserve the use of sodium oxybate only for patients who have type one narcolepsy. And I think this has a little bit to do with the fact that initially, sodium oxybate, the immediate-release form that's given twice nightly known as Xyrem, was only approved to treat cataplexy; that FDA approval came in 2002. It was subsequently expanded in 2005 to include the treatment of excessive daytime sleepiness. But perhaps because there was a little bit of a lag in that approval or perhaps because there hasn't been specific data available in narcolepsy type two, there is this tendency to maybe not consider sodium oxybate for type two, and we've even had patients who have asked if LUMRYZ is appropriate if they have type two. So that was really our prime motivation to be able to conduct this analysis.

What are some of the major differences between narcolepsy type 1 and 2?

Sure, absolutely. So fundamentally, the primary difference is people who have type one narcolepsy experience cataplexy, or a sudden loss of voluntary muscle control. And this typically happens in response to some sort of emotion like laughter or being surprised or becoming angry. Cataplexy can vary from being generalized and can result in something as dramatic as a full-body collapse. Or oftentimes it's more subtle, and a patient may not even realize that what they're experiencing is connected to their narcolepsy. Some of the more subtle manifestations would be facial drooping slurred speech. We encounter many patients who until they were successfully treated thought they were a clumsy person who would just drop things or stumble when they were walking. And so, ensuring that clinicians are having conversations with patients with narcolepsy routinely and asking about the more subtle presentation of cataplexy is really important, and many patients may have their diagnosis changed from NT2 to NT1. There's also a perception, and we discussed this in the publication a little bit. There's a perception by both patients and clinicians that narcolepsy type two is less severe in terms of the excessive daytime sleepiness or the nocturnal sleep disruptions. And because we were able to stratify by narcolepsy type one and type two, we analyzed not only the efficacy in those two subgroups, but we also looked at the baseline values before any treatment had been given. And what we saw were fairly comparable levels of excessive daytime sleepiness as well as the sleep disturbances.

Are there reasons for some of the misconceptions surrounding narcolepsy type 2?

Yeah, it's a great question. I think there's been some limited publication, but most of it is more so anecdotal in terms of clinicians caring for patients. But that's where the data in a trial like this is really important to be able to examine and to show this, and it may start to help change some perceptions.

Since its approval, how has our knowledge on the use of once-nightly sodium oxybate improved?

We received FDA approval on May 1, 2023. LUMRYZ was made available for patients about a month later. We've had approximately six months where LUMRYZ has been in the market. And it's been incredibly gratifying to either hear directly from patients or through their clinicians about the benefit that being able to take a single dose at bedtime and sleep through the night has provided for some of these patients who are switching from a twice-nightly regimen. They've been chronically waking up in the middle of the night for years. Many times it's not only the person living with narcolepsy, but also their spouse or bed partner or for some people who have to have multiple alarm clocks, other people in the household could face that disruption as well.

One specific tangible example that I was so proud to hear was a mom telling me that her son, who is 18, received LUMRYZ two days before he left for college. And this mother had been administering the twice-nightly form of sodium oxybate since her son was eight years old. She'd been waking up for 10 years to give him that second dose. And that family did not know what they were going to do as he was getting ready to leave home for the first time and go to college. To be able to bring this solution to that family, that's why we do what we do at Avadel, and it goes beyond that. One example. We know a lot of sweet clinicians; they may reserve the use of sodium oxybate for college-aged students because they are concerned about a controlled substance being left out on the nightstand. You know, when you consider the conventional first-generation oxybate, it requires pulling up two doses, taking that first dose at bedtime, going to sleep, and then having that second dose there for taking in the middle of the night. Many would be worried in a college setting about having a controlled substance being left out. With the single bedtime dose of LUMRYZ, it obviates that concern and hopefully expands the availability of this very effective treatment for patients.

What are some of the major unmet needs for patients with narcolepsy?

I love this question because it's one that I asked our key opinion leaders that we work with quite a bit. And one of the responses that I consistently receive and a place where Avadel really hopes that we can provide education and close the gap is the fact that sodium oxybate, despite being FDA approved for more than 20 years, approved in Europe for more than 15 years, there are still clinicians who are not comfortable with the thought of an oxybate. There are patients who are not comfortable with the thought of an oxybate. And that can be for a variety of reasons. I mean, one of it simply could be a provider not wanting to try to persuade a patient to wake up in the middle of the night. We also look at those conventional forms of sodium oxybate. And they come in large multi-dose bottles that necessitate a person having to draw out and measure their dose for both of their doses. With LUMRYZ, it's available in your traditional discreet doses the way you have with the vast majority of medications. And so we think that's going to help take some of the guesswork out. We also want to continue to try to overcome the stigma that exists with GHB. So sodium oxybate, it's the sodium-salted GHB. As soon as you say GHB, many people will recognize it, unfortunately for the quote-unquote, date rape drug. And this is exactly the reason that FDA requires to have a risk evaluation and mitigation strategy or REMS, there's a very tight control over who is able to prescribe oxybate, what pharmacies can dispense it, and the education associated for the patients as well as tracking and monitoring.

Having a REMS program in place has helped to ensure that sodium oxybate is used safely. And those concerns of abuse misuse and diversion have been mitigated by having these safeguards in place. When we move beyond the realm of sodium oxybate. One of the pervasive challenges that I hear all the time from patients is brain fog. During the COVID pandemic, we heard a lot about brain fog. I think that's when it started to reach more of a mainstream discussion. Brain fog has been a common complaint for people with narcolepsy and idiopathic hypersomnia for a long period of time. And unfortunately, there's no validated patient-reported outcome to be able to measure brain fog both as a baseline and see improvements with treatment. And I'd love to see that be an area that different pharmaceutical companies can come together and really help to advance the field by beginning to standardize how brain fog is assessed.

How have clinical trials for narcolepsy drug development changed over the years?

When you look from a drug development perspective, looking specifically at the type of clinical trials where they're registration, all you're ultimately going to be seeking FDA approval. Those really have not changed much over the past 20 years. One of the nuances when you compare different treatments is for some medications. The primary endpoint is the Epworth sleepiness scale. That is a patient-reported outcome. It's not been validated in narcolepsy. And even though it's widely used in clinical practice, most clinicians are not super satisfied with it. That informed why we use the gold standard of the maintenance of wakefulness test to be able to evaluate excessive daytime sleepiness and the improvement with LUMRYZ. This is an objective measurement where we also included the Epworth scale as a secondary endpoint. One of the areas that are not part of an indication for the riser for any of the narcolepsy treatments is disrupted nighttime sleep.

When we think about narcolepsy, we tend to focus mostly on the daytime with the excessive daytime sleepiness. But about two-thirds of people with narcolepsy also experience DNS (disrupted nighttime sleep), they fall asleep quickly. But their sleep is not restorative. It's not satisfactory. They're constantly moving in and out of different sleep state shifts, they're experiencing nocturnal arousals, we included secondary endpoints, which we've published separately showing that LUMRYZ reduces nocturnal arousals reduces those shifts in sleep stage, and ultimately results in patients reporting better sleep quality, as well as more refreshing sleep. That's an area that I think is really helpful with the data we have. And it's something that could continue to be built upon. And then I would just go back to encouraging looking, as you said, with specific results in narcolepsy type 2.

Transcript edited by artificial intelligence.

REFERENCE
1. Dauvilliers Y, Roth T, Thorpy MJ, et al. Efficacy of once-nightly sodium oxybate (FT218) in narcolepsy type 1 and type 2: post hoc analysis from the phase 3 REST-ON trial. Sleep. 2023;11(46). doi:10.1093/sleep/zsad152