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3 New Narcolepsy Medications (2015) In Clinical Trials

Narcolepsy is a neurological disorder associated with the brain’s inability to regulate sleep-wake cycles (and the circadian rhythm).  As a result, individuals diagnosed with narcolepsy often experience excessive daytime sleepiness and may fall asleep unexpectedly.  Some have suggested that the excessive daytime sleepiness stemming from narcolepsy is akin to how a normal person feels if they skipped 2 consecutive night’s worth of sleep (pulling back-to-back all-nighters).

There are robust genetic correlates associated with development of narcolepsy, particularly mutations of genes within the HLA complex of Chromosome 6.  In particular, the HLA-DQB1 gene with the *06:02 allele has been discovered in over 90% of individuals with narcolepsy.  This particular maladaptive gene generates an auto-immune response, thereby allowing the immune system to attack certain protein-producing neurons.

Among the neurons that get attacked are those responsible for producing orexin (or hypocretin), a neurotransmitter that regulates arousal, wakefulness, and appetite.  When levels of orexin are extremely low (as they are among those with narcolepsy), individuals often experience tiredness.  In fact, reducing orexin levels is so effective for sleep induction that new sleeping pills dubbed “orexin receptor antagonists” are being developed for insomnia.

3 New Narcolepsy Medications (2015): Drugs in Clinical Trials

That said, those with narcolepsy need medications that promote wakefulness – not induce sleep.  As a result, most medical professionals prescribe psychostimulants (e.g. Adderall, Dexedrine, etc.) or eugeroics (e.g. Provigil, Nuvigil, etc.) to individuals with narcolepsy as a means of counteracting sleepiness stemming from orexin deficiencies.  Although many of these drugs are effective, there are several new medications in the pipeline that attempt to improve upon existing treatments.

  1. JZP-386

  • Mechanism: Dopamine receptor agonist
  • Company: Concert Pharmaceuticals / Jazz Pharmaceuticals
  • Status: Phase II clinical trials

Concert Pharmaceuticals and Jazz Pharmaceuticals have teamed up to investigate the efficacy of JZP-386 for the treatment of narcolepsy.  JZP-386 functions as a dopamine receptor agonist, meaning it stimulates dopamine receptors to increase arousal and ramps up psychomotor activity.  As of 2015, the drug is currently in Phase II clinical trials and has demonstrated favorable efficacy.

JZP-386 is considered a deuterium-modified analogue of sodium oxybate – making it similar to the already-approved drug Xyrem.  Results from Phase I clinical trials demonstrated that JZP-386 had a favorable side effect and pharmacokinetic profile compared to Xyrem.  The drug appeared to be safe and well-tolerated among a group of 30 participants.

As the drug is subject to further investigation in Phase II clinical trials we will better understand its safety profile and side effects.  Furthermore, it will become increasingly apparent as to whether JZP-386 is significantly superior to Xyrem.  Assuming this drug gets approval, it may provide Xyrem users with a similar acting alternative.

  1. JZP-110 (ADX-N05)

  • Mechanism: DAT / NET inhibitor
  • Company: Jazz Pharmaceuticals
  • Status: Phase III clinical trials

JZP-110 (formerly ADX-N05)  is a wakefulness-promoting drug under development by Jazz Pharmaceuticals.  The drug functions primarily as a dopamine transporter (DAT) and norepinephrine transporter (NET) reuptake inhibitor.  The DAT and NET reuptake inhibition increases extracellular concentrations of stimulatory neurotransmitters dopamine and norepinephrine.

Increases in dopamine and norepinephrine promote wakefulness, increase psychomotor activity, and stimulate the CNS.  Preliminary data from clinical trials suggests that simultaneous targeting of the DAT and NET may promote wakefulness to a significantly greater extent than agents solely targeting dopamine reuptake and/or agents failing to target the transporters.  JZP-110 is said to contain a hydrochloric acid salt of a pure phenylalanine derivative ((R)-2-amino-3-phenylpropylcarbamate hydrochloride).

The drug was initially noted for its antidepressant effects in animal research, but has not been tested among humans for the treatment of depression.  Like most psychostimulatory agents, the most common side effect of JZP-110 is insomnia.  It appears as though it’s merely a matter of time before JZP-110 is approved for the treatment of narcolepsy – and possibly investigated as an antidepressant augmentation strategy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26298786
  1. Xyrem (Sodium Oxybate)

  • Mechanism: GABA(B) agonist
  • Company: Jazz Pharmaceuticals
  • Status: Phase III clinical trials

Xyrem (sodium oxybate) is already FDA approved for the treatment of excessive daytime sleepiness (EDS) associated with narcolepsy.  Outside the United States, Xyrem is approved for the treatment of cataplexy, alcohol withdrawal, and alcohol dependence.  Xyrem’s active ingredient of sodium oxybate is considered a sodium salt version of GHB (gamma hydroxybutyrate).

Though its specific mechanism of action hasn’t been fully elucidated, many suspect that it acts as a GABA(B) agonist.  Additionally, some believe that it may act as a partial inhibitor of receptor-mediated excitatory NMDA and AMPA neurons within the hippocampus.  Due to Xyrem’s efficacy for the treatment of excessive daytime sleepiness, Jazz Pharmaceuticals is hoping to expand its approval from adults with narcolepsy to children and adolescents (ages 7 to 17 years).

Its investigation as a therapeutic agent for children and adolescents with narcolepsy is currently in Phase III clinical trials.  Preliminary evidence suggests that it is safe and well-tolerated.  However, should the drug get FDA approval for pediatrics, patients will require close monitoring to minimize potential for abuse and/or dangerous contraindications.

Which new narcolepsy medications seem most promising? A discussion.

Of the narcolepsy medications in the clinical trial pipeline, all seem to have significant promise.  Despite their promise, it is unclear as to whether these drugs will have any major advantages over current-market options.  JZP-386 is a deuterium-modified analogue of sodium oxybate (a sodium-salt version of GHB) with a different mechanism of action.

Early trials suggest that the drug is likely better tolerated and has favorable pharmacokinetic properties compared to the already-approved Xyrem.  However, developers of the drug have expressed concern about potential deuterium-induced adverse effects.  For this reason, JZP-386 likely isn’t the most promising of narcolepsy drugs in the pipeline.

Perhaps the most exciting drug in clinical trials for narcolepsy is JZP-110 (formerly ADX-N05).  This drug directly respectively targets dopamine and norepinephrine transporters, resulting in significant increases in extracellular dopamine and norepinephrine levels.  Targeting both dopamine and norepinephrine may enhance cognitive function and mood.

Animal research suggests that administration of JZP-110 yields antidepressant effects.  Should JZP-110 prove safe and effective, it may be tested as an adjunctive option for the treatment of depression.  The other agent undergoing testing for the treatment of narcolepsy is Xyrem, which has already been approved for usage in adults.

However, Jazz Pharmaceuticals is hoping to expand its approval for usage among pediatric patients between ages 7 and 17.  It is likely that at appropriate doses, Xyrem will be considered safe and effective for pediatric patients.  Therefore it is appropriate to infer that the two most promising agents include: JZP-110 and Xyrem (for pediatrics).

It is important to note that Jazz Pharmaceuticals seems to be the only company with medications for narcolepsy in clinical trials.  Perhaps other pharmaceutical companies feel as if the market for narcolepsy is saturated with effective options or maybe they’d rather focus on developing drugs for other neurological disorders.  Either way, there’s certainly room for improved treatment options in the future.

Problems with current medications for narcolepsy

There remain some significant drawbacks associated with currently prescribed medications for narcolepsy.  Perhaps the biggest problem is the fact that most commonly prescribed agents are associated with rapid tolerance onset, dependence, and abuse.  An individual that’s prescribed a drug like Adderall XR to treat narcolepsy may find that over time (e.g. after several months), their initial dosage stops delivering the same stimulatory (wakefulness-promoting) effect.

  1. Abuse potential
  2. Dependence
  3. Tolerance onset
  4. Side effects
  5. Untargeted
  6. Withdrawal symptoms

As a result, the individual will consult their doctor and typically end up getting prescribed a higher dosage.  The higher dosage will likely work for awhile, but inevitably the dosage will be subject to further increases until it is at the maximum approved dose; some doctors may even consider prescribing supratherapeutic doses.  At the highest possible dose, individuals are typically more prone to adverse effects including: cardiovascular irregularities, extreme weight loss, insomnia, anxiety, irritability, etc.

While starting with the minimal effective dose is always smart, it is generally difficult to remain on that same dose without building up tolerance – especially with dopaminergic drugs.  Eventually, an individual may become fully dependent on their medication for functions unrelated to wakefulness (e.g. school work, job performance, mood, social skills, etc.).  This dependence (reliance on the dopamine boost) will result in greater functional impairment compared to baseline upon cessation of the medication (e.g. Adderall withdrawal).

Furthermore, many drugs used to treat narcolepsy (not limited to psychostimulants) may be subject to abuse such as: Adderall, Dexedrine, and Xyrem.  While abuse is not a problem for the majority, consequences of abuse could be significant – especially over a long-term.  Though there are some safer psychiatric drugs such as eugeroics Provigil and Nuvigil, even these have unknown long-term effects.

How could narcolepsy medications could be improved upon in the future?

There remain a multitude of ways in which narcolepsy medications could be improved upon.  Efforts should be made in the future to specifically devise medications that promote wakefulness without any potential for abuse or dependence.  Furthermore, pharmaceutical developers should attempt to develop drugs without: rapid tolerance onset (as is common with psychostimulants), significant side effects, and discontinuation symptoms.

  1. Target specific neurophysiological causes of narcolepsy
  2. Introduce novel modalities of drug delivery
  3. Minimize abuse potential
  4. Avoid agents with rapid tolerance onset
  5. Attempt to minimize side effects / discontinuation

Most obviously, pharmaceutical companies should aim to target the neurophysiological underpinnings that are unique to narcolepsy (e.g. orexin dysfunction).  Current medications simply aim to increase wakefulness by any means necessary and are merely masking a symptom (of excessive sleepiness) rather than directly treating direct correlates.  Since it is known that orexin-producing neurons are depleted in the brains of individuals with narcolepsy, perhaps targeting the orexin system could provide more targeted benefits.

In the future, it is suspected that pharmaceutical companies may devise methods to administer narcolepsy directly to the brain such as via injections and/or an intranasal spray.  Increasing levels of orexin is thought to offset excessive daytime sleepiness.  It could also be recommended that pharmaceutical companies develop and test selective orexin receptor agonists.

Selective orexin receptor agonists could stimulate specific orexin receptors to promote wakefulness.  These may be less habit-forming than dopaminergic-based drugs and have less severe discontinuation symptoms.  Furthermore, with new drug delivery technology, perhaps a futuristic drug could be developed to modulate orexin receptors – preventing overstimulation, while simultaneously agonizing receptors upon onset of excessive sleepiness.

A new drug could thereby keep an individual within a normative range of arousal, rather than being too overstimulated (as a result of a medication) or too understimulated as a result of low orexin.  It could also be considered that nanotechnology could enhance the delivery and efficacy of these futuristic drugs.  In the far future, perhaps orexin-producing neurons could be regenerated and/or strategic usage of RNAi may inhibit auto-immune-induced apoptosis.

Novel neuroregenerative drugs may also benefit individuals with narcolepsy.  A pharmacological agent that aims to stimulate growth of orexin neurons may be possible – especially when considering the fact that Neuralstem has already managed to create a drug (NSI-189) that stimulates hippocampal neurogenesis.  In addition to developing neuroregenerative drugs, another option is to engineer drugs with novel modalities of administration (e.g. intranasal sprays, long-acting injections, transdermal patches, etc.).

For example, long-acting injections could eliminate the need of popping a daily pill, improve patient compliance, and improve upon pharmacokinetics.  Intranasal sprays could directly administer a drug to the brain, thereby reducing likelihood of gastrointestinal side effects.  Although novel drugs, modalities of administration, and other therapies would be promising – they haven’t yet been considered by most pharmaceutical companies.

What do you think about new narcolepsy medications?

Feel free to share your thoughts about the three new narcolepsy medications (JZP-386, JZP-110, and Xyrem) in the comments section below.  Mention whether you are looking forward to one getting approved or whether you think that none offer significant advantages over currently approved treatments.  Also discuss some potential ways in which you believe pharmaceutical drug developers could improve upon existing treatments for narcolepsy in the future.

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{ 16 comments… add one }
  • Heather October 10, 2015, 8:19 pm

    I am particularly interested in JZP-386.

  • Ian December 9, 2015, 1:41 am

    I’ve been on baclofen for over 3 months. It has worked as well for me as xyrem did with many fewer side effects. Cleared my cataplexy almost completely. It’s the other GABA(B) agonist (phenibut is one also). Baclofen isn’t a controlled substance so any doctor could prescribe it. Xyrem worked very well as well.

  • Kris Heim January 23, 2016, 3:32 pm

    Currently I take methylphenidate; I don’t like Modafinil and it does’t work well. This one only wakes me for a couple hours; then I have to sleep. Having a real day is impossible. I want to be in a clinical trial for orexin deficiency. I need someone to explain the peptides, chemicals in my brain, that affect my sleep-wake cycle.

    Also the suprachiasmic nucleus; can that or something lie the hypothalamus be damaged? Could my condition be related to years of temporalmandibular joint degeneration (extremely painful)? or head trauma? I’ve been treated for depression for decades; I’m 66 and a clinical trial may be my last hope for a few more good years of life.

    This way — sleeping, missing appointments, not cooking or getting to grocery, etc. because I’m sleeping or much too sleepy to drive — is not really living at all — people have to take care of me. Are there other people like this?

    • Kathryn January 29, 2016, 6:34 am

      Dear Kris, You are certainly not alone. You really do not have a life for all the reasons you stated. We a have identical symptoms. I too will try and get on a clinical trial, the phase III. Adding the norepinephrine will help with depression. The Baclofen, which is antispasmodic for a number of things, as a RN we would give this drug to paraplegics for bladder and muscle spasms. It’s safe, has been around for ages and is probably inexpensive.

      All new drugs when approved by the FDA, cost a fortune and should be observed for awhile for horrible side effects before taking any new drug. With that said, the ADX-NO5 seems to kill 2 birds with one stone. At the very least, we can try Baclofen until these drugs are approved. My heart and sympathy to you. It’s like living in a coma. I have Lyme disease that causes severe migraines, abdominal pain, and horrible back and neck pain.

      If I had a choice, I would live with the pain, and get rid of the narcolepsy. Life gets very small. But try your hardest to get out to a movie or go to the library. I’ve become almost agoraphobic ,but getting out to grocery store increases my spirits enormously by interacting with the world. You’re not alone and I will pray that you and I get into a trial.

      Hope and focusing on what we can still do encourages me and we can say No to invites we really didn’t want to attend. Shame, I used to love to sleep and I fight it until it wins, usually 5 minutes. I’m shooting for 10 minutes. Please don’t give up on these wonderful people who are trying to help us. Best, Kathryn

    • vivian June 13, 2016, 8:03 pm

      Kris I am 58 years old and am in the JZP110 drug study. Did the double blind, now on 3rd day of 70mg. I wake up and feel like I’m normal. Not tired or foggy. I can eat and am not sleepy after going on 150mg tomorrow. This med is a 12hr pill getting about a full 5hrs of feeling awesome and wide awake. They pay you to be in the study. Call 4402438044. Cleveland sleep research center. 18100 Jefferson park red. Ste 101. Middleburg heights Ohio 44130. There are 44 sites in USA and Canada doing the study. Call the number they can tell you of a site close to you. Good luck.

      • Susan O'Connor August 24, 2016, 10:14 pm

        My husband has had narcolepsy since he was in high school… and he is now 82. Prozac helped his cataplexy immediately when he was 60 and he wasn’t depressed at the time. He lived a good life, raised 3 kids with me and did many good things including a good career for 40 years. He took ritalin all that time with dexedrine in the beginning… but went off it after a heart attack and stayed with the ritalin now meth. And did fine. Now he has Alzheimer’s. There is no cure.

      • Kathy September 7, 2016, 2:55 pm

        Vivian, I am definitely interested in the drug study for JZP-110. Have you noticed any side effects. I’m currently on Adderall IR 20mg when I get up and 10 more in the afternoon. It’s taking longer to kick in each time. I struggle to get out of bed no matter how many hours of sleep I’ve had. I was on the ER for a few months, but it just wasn’t cutting it.

        It felt like hours before it kicked in. I need that instant boost when I first wake up or all I want to do is climb back under the covers. It’s affected me getting my kids up for school and getting them there on time. Thank god their older now and they hear their alarm. Luckily I’ve always had a flexible job and my hours are later in the morning. But I’ve had my share of being late to work also.

        I’ve dealt with this since I was a teenager and I’m now 45. It didn’t seem so bad in my twenties and early thirties. Good thing, because my kids wouldn’t have survived. It was always written off as something else and people just think you need caffeine or more sleep. Oh and let’s not forget they just think you’re lazy or depressed!!!

        Through the years I’ve had three sleep studies and they knew it was something, but just weren’t sure what it was. This past November I was finally diagnosed. They told me I fell asleep 4 mns after lying down. I told them I am out as soon as I hit the pillow. Years ago I was given Nuvigil and Provigil samples (back when they did that) before there were generics of them and they didn’t touch it.

        So for the $300 out of pocket it would have cost I opted out since it didn’t work anyway. Eventually they started trying me on the different ADD medications to see what would work and what wouldn’t. It gets really old feeling like you’re in a fog and half out of it constantly. I would so LOVE to be a morning person and have energy all day.

        For the people that say just exercise or take vitamins and you will feel great… hush I have and it doesn’t help. Spend a day in our shoes and see how peppy you are!!

  • Leslie January 28, 2016, 1:12 pm

    What about Pitolisant? It’s recommended for approval in Europe after finishing clinical trials. Any hope of approval here in the U.S.?

  • Kathryn January 29, 2016, 6:38 am

    How does one apply to get into a trial? I’m sure that is a regular question. This could be a life-changer. Thank you, Kathryn Ellison. LA area.

    • Ross August 26, 2016, 2:07 am

      Hi Kathryn, Check out this website – http://tonesstudy.com/index.html – and sign up for a clinical study! I’m in the LA area too, filled out the short questionnaire, and they told me I was “likely eligible” and that a rep from Cedars-Sinai would be in touch. Good luck! -ross

  • sonnyu February 2, 2016, 9:03 pm

    How could narcolepsy medication be improved? Make them AFFORDABLE!!! $500 out of pocket with insurance, in xyrems case $3600 out of pocket each months is just not something any normal pawn can afford. Once medication becomes affordable, require insurances to treat N like a real disease and not something that can be denied treatment (medication “not necessary”).

  • Jillian June 22, 2016, 7:56 pm

    I agree with you sonnyu! I have a High Deductible Health Insurance that requires me to pay the $4,000 a year maximum deductible before they’ll pay for Xyrem… takes me all year to save that amount up. Once a medicine is FDA approval, like Xyrem – the drug shouldn’t be so hard to get covered by insurance.

    Medication is totally necessary for N unless the government wants all N sufferers to file for Disability Service – which would NOT help patients, the economy or taxpayers in general. Without Xyrem helping me to sleep at night, I couldn’t do my job. I hope things change for the better so that more people can get the help they need.

  • Kelly June 23, 2016, 3:42 am

    I have tried all the medications for Narcolepsy, nothing worked. When I switched Dr. he put me on Desoyxn, I have been on it for 12 years. They are 5 mg tablets. I take a total of 6 tablets. 4 in the am and 2 in mid afternoon. For the most part it has worked great, the only time I struggle is around dinner time. I tend to fall asleep when eating. But for the last 10 months everything has changed.

    I average 2 hours asleep a WEEK. I go to bed usually around 9:00 pm, sometimes I fall asleep right away but only for 10 minutes. Then I lay there tossing and turning all night, with maybe sleep again for 5 to 10 minutes through out the night. I get up usually around 4;30-5:00am, then I’m up for the day. When I’m riding in a car is about the only time I sleep, and that is usually within minutes of getting in car.

    I also have cataplexy usually 10-15 attacks a day. Nothing helps, they have tried me on every medication for that too, yes even Xyrem, I also have restless leg syndrome. The Dr feels my Narcolepsy is caused from an AVM (articular vascular malformation) on the left side of my brain. I went through 2 years of radiation and when they removed it along part of the brain that was causing seizures, the mass they took out was the size of a grapefruit.

    That is when I was sleeping all time and when the cataplexy started to. I also have notice that I stopped dreaming too, I would climb into bed shut my eyes and the dreams just started flying all over in my head. I could hear the people taking around me, and they could hear me talking while I was dreaming, I was basically act talking what was going on in my dream.

    I don’t know if further testing can be done on me but I would like answers. I feel the Dr is stumped and don’t know where to go next with me. Please help me.

  • Tom July 20, 2016, 5:41 pm

    I’ve been having increasingly more frequent sleep issues for the past 25 years. Until I turned 40, I slept through the night. Then started waking up 1 to 2 time per night, ostensibly to urinate. Felt tired in the mornings, and would take a short nap at lunch (in my car) or after school (on the classroom carpet) let out.

    After a job change requiring much reading/analysis/reflection of educational research, was finally diagnosed with ADD after almost losing my job. Treated with low dose of Adderall XR which greatly improved my concentration, memory, focus, etc. Still continued to wake at night increasingly over the next 20 years (Just “aging” issues?) to the point of waking 4-6 times per night.

    Also continued to feel sleepy during the day, especially after lunch and dinner. Diagnosed with sleep apnea, but couldn’t tolerate the CPAP machines, as I’m a “side” sleeper, and frequently change positions during the night. This might explain the daytime sleepiness. Have currently discontinued the Adderall XR (summer meds “Vacation”) and am participating in the JZ-110 trial drug study.

    During the screening, I fell asleep quickly during each of the 7 daytime intervals in the wakefulness maintenance test. Not sure if the apnea is causing the daytime sleepiness, but will be interesting to see if the JZ-110 helps. Would suggest if you suffer from narcolepsy or excessive daytime sleepiness, that you get evaluated for possible sleep apnea. Just a thought…

  • Toni September 13, 2016, 6:11 pm

    To really treat the condition, we need to replace the orexin transmitter, or develop agonists for the orexin receptors. Is a manufacturer working on a drug with this mechanism? They have an antagonist, so it seems logical an agonist wouldn’t be difficult to produce.

  • Tisha September 19, 2016, 5:13 pm

    I do not believe that the description of narcolepsy is completely correct. The article seems to be speaking about Narcolepsy Type I (Narcolepsy w/cataplexy) and not Narcolepsy Type II.

    From what I have read, all of the information given in this article is for people with NI, which makes up about 70% of all diagnosed cases of narcolepsy. People with N2 do not have cataplexy and research the is not the evidence of the auto-immune attack on orexin like there is with N1.

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