One of my biggest takeaways from the APSS 2018 SLEEP Meeting last month was the great amount of drug development underway for narcolepsy! Below is a list of some of the emerging treatments “abuzz” at #SLEEP2018. These are at various stages in development, and it’s hard to predict how quickly each will advance to (hopefully) gain regulatory approval and become available in the U.S. and other locations worldwide. Some are in clinical trials with opportunities to get involved. If you’ve participated in a clinical trial  — THANK YOU! You’re making a huge difference to improve the lives of people with narcolepsy for years to come.

Please remember, I failed high school biology, (sorry mom!). But seriously, I am not a scientist or doctor. You should always speak with your narcolepsy specialist about treatment options and whether a clinical trial would be a good option for you. However, I hope this post helps provide access to information. When navigating a serious condition like narcolepsy, information is power. 

Pitolisant

• Background: Pitolisant is a histamine H3 receptor inverse agonist that activates histamine neurons, under development in the US to treat excessive daytime sleepiness and cataplexy in people with narcolepsy. This an exciting advance because pitolisant works via a different mechanism of action than other treatment options currently available. This great article talks about the mechanisms of action and offers some ideas on how the treatment may work. 
• Pitolisant has been on the market in Europe for two years now, since it’s approval by the European Medicines Agency in 2016. In Europe, pitolisant is known by its trade name “Wakix”. In October 2017, Harmony Biosciences, LLC acquired the rights to develop, register and market the drug in the United States.
• Research Findings:
  • Phase 3 study results focused on excessive daytime sleepiness: https://www.ncbi.nlm.nih.gov/pubmed/24107292
  • Subsequent Phase 3 study results focused on cataplexy: https://www.ncbi.nlm.nih.gov/pubmed/28129985
• Current status: On May 21, 2018, Harmony Biosciences, LLC announced here that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy and Fast Track designations to pitolisant for the treatment of excessive daytime sleepiness and cataplexy in people with narcolepsy.
• Get Involved: While the clinical trials necessary for the FDA to consider the approval of the drug are complete, there is a system set up for some eligible individuals to gain access the treatment at this point through an open-label Expanded Access Program. Learn more here.

Solriamfetol

• Background: Solriamfetol (also known as JZP-110) is a wake-promoting agent, a dopamine and nonrepinephrine reuptake inhibitor to treat excessive daytime sleepiness in people with narcolepsy and obstructive sleep apnea. Clinical and preclinical data suggest that the wake-promoting effects of solriamfetol differ from medications such as modafinil and amphetamine.
• Current Status: In March 2018, the FDA accepted for filing Jazz Pharmaceutical’s New Drug Application (NDA) seeking marketing approval for solriamfetol (also known as JZP-110) for the treatment of excessive sleepiness in adults with narcolepsy or obstructive sleep apnea.
• Research Findings: There were a ton of posters and presentations at the 2018 SLEEP meeting on solriamfetol. Jazz’s full announcement is here. Four phase 3 clinical trials support solriamfetol’s NDA, including:
  • One study evaluating excessive sleepiness in adult patients with narcolepsy (TONES 2)
  • Two studies evaluating excessive sleepiness in adult patients with OSA (TONES 3 and TONES 4),
  • An open-label long term safety and maintenance of efficacy for the treatment of excessive sleepiness in patients with narcolepsy or OSA (TONES 5).

Once-nightly formulation of sodium oxybate

• Background: This is a once-nightly formulation of sodium oxybate using Avadel Pharmaceuticals’ proprietary Micropump® technology to provide an extended-release of the drug. It is currently undergoing testing in a Phase 3 clinical trial for the treatment of excessive daytime sleepiness (EDS) and cataplexy in people living with narcolepsy.
• Current status: On January 10, 2018, Avadel Pharmaceuticals announced that their once-nightly formulation of sodium oxybate has been granted Orphan Drug Designation from the FDA.
• Research Findings:
  • First-in-Human Study
  • Second Clinical Trial Results
• Get Involved: Currently recruiting participants in U.S. and other locations internationally to participate in the Phase 3 REST-ON trial. For more information, visit www.rethinknarcolepsy.com and ClinicalTrials.gov Identifier: NCT02720744

Pediatric indication for sodium oxybate

• Background: While some children currently take sodium oxybate to treat cataplexy and excessive daytime sleepiness of narcolepsy, it is currently considered “off-label” use because the treatment had not been formally evaluated and FDA-approved specifically for a pediatric population. (Off-label use is NOT improper use, and many people rely on “off-label” use to access critical treatments, especially in children and rare disease populations. However, this supplemental application, if approved, should help to improve access to sodium oxybate for children with narcolepsy.)
• Current status: On June 27, 2018, Jazz Pharmaceuticals announced here that the FDA accepted for priority review its supplemental new drug application (sNDA) seeking revised labeling for Xyrem (sodium oxybate) oral solution, to include an indication to treat cataplexy and excessive daytime sleepiness (EDS) in children with narcolepsy. The goal date for an FDA decision is October 27, 2018!
• Research Findings: E Mignot, G Plazzi, Y Dauvilliers, C Rosen, C Ruoff, J Black, R Parvataneni, D Guinta, Y Wang, M Lecendreux; 0813 Sodium Oxybate Treatment of Narcolepsy in Pediatric Patients: Long-term Efficacy and Safety, Sleep, Volume 41, Issue suppl_1, 27 April 2018, Pages A302, https://doi.org/10.1093/sleep/zsy061.812

Low sodium version of sodium oxybate

• Background: JZP-258 is a low-sodium version of sodium oxybate that has 90 percent less sodium.
• Get Involved:
  • Phase 3 clinical trial currently underway for people with narcolepsy with cataplexy: ClinicalTrials.gov Identifier: NCT03030599
  • Phase 3 clinical trial preparing to open for people with idiopathic hypersomnia: ClinicalTrials.gov Identifier: NCT03533114

Advancing Orexin-Related Therapies!

Since 1999, we’ve known that type 1 narcolepsy with cataplexy is caused by a selective loss of neurons producing the neuropeptide orexin (otherwise known as hypocretin), which plays a central role in maintaining wakefulness. However, finding compounds that can get past the blood-brain barrier and mimic the function of orexin has been scientifically challenging. Over the past 20 years, a few approaches have been explored, but the most recent progress comes from Japan!

YNT-185

• Background: In 2017, the nonpeptide orexin type-2 receptor agonist, YNT-185 was found to improve narcolepsy-cataplexy symptoms in mouse models. This study provided a proof-of-concept for mechanistic treatments of narcolepsy with orexin receptor agonists. The compound also promoted wakefulness in “wildtype” mice (meaning typical mice that didn’t have narcolepsy), suggesting that orexin receptor agonists could be useful for treating sleepiness due to other causes.
• Research Findings: Irukayama-Tomobe Y et al. (2017) A non-peptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc Natl Acad Sci USA https://www.ncbi.nlm.nih.gov/pubmed/28507129
• Current Status: The research team is currently refining the compound.

TAK-925

• Background: In 2017, also in Japan, a patent was claimed for orexin 2 receptor selective agonist, structurally different from YNT-185. The patent includes strong agonists including the clinical candidate TAK-925. 
• In April 2018, the orexin 2 receptor-selective agonist, TAK-925, was found to significantly increased wakefulness time and also completely recovered wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 transgenic mice. This study indicated that the treatment may have the potential to treat a broad range of narcolepsy symptoms such as excessive daytime sleepiness and cataplexy.
• A second publication reported on the pharmacological and electrophysiological characterization of TAK-925 from in vitro (petri dish-type studies) and in vivo (studies in wild-type mice and non-human primates including common marmosets, and cynomolgus monkeys).TAK-925 was shown to induce wake-promoting effects in the mice and nonhuman primates.
• Research Findings:
  • T Fujimoto, K Rikimaru, K Fukuda, H Sugimoto, T. Matsumoto, N Tokunaga, M. Hirozane SUBSTITUTED PIPERIDINE COMPOUND AND USE THEREOF WO2017135306 https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017135306
  • M Suzuki, H Yukitake, T Ishikawa, H Kimura; 0001 An Orexin 2 Receptor-selective Agonist TAK-925 Ameliorates Narcolepsy-like Symptoms In Orexin/ataxin-3 Mice, Sleep, Volume 41, Issue suppl_1, 27 April 2018, Pages A1, https://doi.org/10.1093/sleep/zsy061.000
  • H Yukitake, T Ishikawa, A Suzuki, Y Shimizu, M Nakashima, T Fujimoto, K Rikimaru, M Ito, M Suzuki, H Kimura; 0002 An Orexin 2 Receptor-selective Agonist, TAK-925, Shows Robust Wake-promoting Effects In Mice And Non-human Primates, Sleep, Volume 41, Issue suppl_1, 27 April 2018, Pages A1, https://doi.org/10.1093/sleep/zsy061.001
• Current Status: It’s exciting to see that TAK-925 has advanced to human studies!
  • In Japan, the first-in-human phase 1 clinical trial of TAK-925 is currently underway testing the compound in people with narcolepsy, healthy adults, and elderly people to learn about the safety, tolerability, and pharmacokinetics of a single intravenous administration. Learn more: ClinicalTrials.gov Identifier: NCT03332784
  • In the U.S., TAK-925 is in a Phase 1B  study comparing it to modafinil in sleep-deprived healthy adults. Learn more: ClinicalTrials.gov Identifier: NCT03522506

Please know this is NOT a full list of all emerging treatments under development for narcolepsy. I lost steam before even getting to GABA-A receptor antagonists under investigation for people with idiopathic hypersomnia. For a more thorough review of emerging narcolepsy treatments from March 2017: New developments in the management of narcolepsy.

A HUGE thank you to all those who are working to make this progress possible: scientists, drug developers, clinical research teams, and individuals with narcolepsy and  families around the world. Your contributions are making a very meaningful difference.

Support Narcolepsy Research

While the current pharmaceutical industry investment in narcolepsy drug development is encouraging, the current federal investment in basic and translational narcolepsy research is not as encouraging. In Fiscal Year 2017, the National Institutes of Health (NIH) funded an estimated $2.6 million total for all of narcolepsy and IH research.  This is a significant reduction in the past decade (full analysis here).

Many unanswered questions remain to better understand the biological mechanisms of all types of narcolepsy and lead to the next generation of treatment options. YOUR VOICE matters in this effort, so if advancing research is important to you, please join Project Sleep’s advocacy efforts.

Project Sleep is strategically elevating the voices of people living with sleep-related conditions and their loved ones to help decision-makers understand the urgency of our unmet needs. See our advocacy guiding principles here. Some projects are more general to advocate for “sleep health and sleep disorders research” and other efforts will be targeted to certain under-recognized priority need areas. Please participate in as much of this as you can.

Your time and energy is precious and limited. I will NOT waste your “spoons” on efforts that will go nowhere or lack strategic direction. I will only ask you to support high-impact work. Sometimes the progress we’re making is not so publicly obvious or immediate, but it’s building and I’m SO darn exciting.  

Thank you for all your incredible support over so many years now. I’m forever grateful for this community!