FAQs about narcolepsy, treatment options, and research terminology
Below are some common sleep and research terminology defined to better help you understand your disorder, treatments, and how this type of research is conducted.
Who created this site and why?
Clinilabs Drug Development Corporation created this site. Clinilabs is a company specializing in the development of medications to treat central nervous system disorders and sleep disorders. This site was developed for the benefit of patients, so they can learn about narcolepsy and idiopathic hypersomnia, current clinical trials, medications being developed, and possible participation in these trials.
What is a clinical trial for medications?
A clinical trial is a research study that tests a medication or treatment and studies the effects it has on patients or healthy volunteers. The main two goals of clinical trials for medical treatments is to determine:
1.) How safe is it for people to take as treatment for a disorder or medical situation?
2.) How effective is it for the treatment of a disorder or medical situation?
Every research study involving people involves some amount of risk. However, the benefits of participating in the study may outweigh the risks. All of this is written in detail in the informed consent form (ICF) that each person must read, understand, and sign before beginning participation as a subject in a study.
The pharmaceutical company that is developing the new drug is the study sponsor. A protocol is written by the sponsor that contains all of the details of the trial, including the drug history, reason for the study, study design, all study activities for the study sites and subjects, all the data to be collected (including medical tests), safety measures, and statistical analysis to be done on the data collected. The protocol must be followed very closely by the sponsor and study investigators throughout the trial. Any deviations from this study protocol must be reported to the sponsor and the governing body called the Institutional Review Board (IRB). Sometimes the sponsor hires a company, called a Contract Research Organization (CRO) to help administrate the study. The CRO ensures that all the activities of the study are conducted in compliance with the protocol and good clinical practices, and they assist the sites in recruitment, data collection, data review, and other administrative activities.
What does the study phase mean?
Clinical trials are classified into 4 phases. The drug development process will normally proceed through phases I–IV over many years, frequently taking 10 years or longer.
PHASE I studies involve small groups of healthy people (20-80) to determine drug safety, adverse effects, and maximum tolerated dose. These studies also assess pharmacodynamic effects (what the drug does to the body) and pharmacokinetic effects (what the body does to the drug). Some of the factors reviewed include how the drug is absorbed, distributed, metabolized, cleared from the body, if this occurs safely, and how it is expected to occur based on previous testing.
PHASE II studies are done in people (100-200) diagnosed with the target indication to assess efficacy, safety, and dose response.
PHASE III studies are done in larger groups of patients (200-3000) with the target indication to assess efficacy and safety. These are also known as “pivotal trials.” If the drug successfully passes through phases I, II, and III, it will usually be approved by the national regulatory authority (Federal Drug Administration – FDA in the US) for use in the general population.
PHASE IV studies are done in large, diverse gorups of patients (thousands) after a drug has been approved to further assess safety and efficacy and best uses.
What is an Open-Label and a Double-Blind Trial?
An open-label trial is a type of clinical trial in which information is not withheld from trial participants. Therefore, both researchers and participants know that active drug is being administered during the trial. Usually, the duration of these trials is extended – lasting several weeks to several months. An open-label trial differs from a double-blind trial, where treatment information is withheld from both researchers and participants to reduce bias.
What is Narcolepsy?
Narcolepsy is a chronic neurological disorder that involves a decreased ability to regulate sleep-wake cycles. It is considered an autoimmune disorder resulting in a loss of orexin-producing neurons in the brain. Narcolepsy includes symptoms of disrupted night-time sleep, hallucinations when falling asleep or waking up, sleep paralysis when falling asleep or waking up, and severe daytime sleepiness.
Excessive daytime sleepiness (EDS) occurs throughout the day and is especially notable when the person is doing something boring and repetitive, however, it can occur even when the person is engaged in an activity. Short naps can be refreshing temporarily, but sleepiness returns in a few hours.
Sleep paralysis is the experience of not being able to move or speak when falling asleep or waking. In this experience, the person is fully awake and aware of what is happening. People may also experience anxiety in these situations even though they are brief.
Hallucinations occur when the person is falling asleep (hypnagogic) or waking up (hypnopompic) either during nighttime sleep or a nap. In this experience, the person is aware of being awake, but they see or hear things that are not real. The images usually consist of shapes, parts of objects, people, or animals. The sounds that occur can be quite realistic. Sometimes people can also imagine that their body is moving or being touched.
Cataplexy occurs in 60-70 percent of people with narcolepsy. It is a temporary, brief loss of muscle tone in response to strong emotion or stress. The loss of muscle tone is typically localized in one region of the body. It may be subtle like drooping eyelids, or blurred vision, or more dramatic and noticeable with slurred words, stuttering, or buckling knees. It can involve many body parts such as weakness in the hands leading to dropping things, spilling things, or shaking. Cataplexy attacks typically occur in response to positive emotions like laughter, engaging in or recalling a fun or happy event, or even when watching or reading something emotional. However, it can be caused by anger or fear. Narcolepsy symptoms typically appear in people between the ages of 15 and 25, but it has been diagnosed in other age groups. Obtaining a diagnosis of narcolepsy is often difficult and a slow process. Some doctors may misdiagnose it as something else, especially if the person does not have the symptoms of cataplexy.
Sleep disruption is typical and includes many brief awakenings, caused sometimes by intense dreams, and leg movements.
It should be noted that there often is an overlap of clinical symptoms with hypersomnia, and it has been proposed that NT1, NT2, and IH are part of a disease continuum called the Narcolepsy Spectrum Disorders.
What is Narcolepsy Type 1 (NT1)?
Narcolepsy Type 1 (NT1) is narcolepsy as described above but WITH the experience of cataplexy. It is estimated that 60-70% of patients with narcolepsy do have cataplexy as a symptom. It occurs in people with specific genetic markers including Human Leukocyte Antigen (HLA DQB1*06:02).
What is Narcolepsy Type 2 (NT2)?
Narcolepsy Type 2 (NT2) is narcolepsy as described above but WITHOUT the symptom of cataplexy. It has been proposed that NT2 is related to Idiopathic Hypersomnia (IH).
What are the treatments for Narcolepsy?
PHARMACOLOGIC TREATMENTS – Pharmacologic Treatment: Currently, narcolepsy can be treated with a wide variety of medications with differing mechanisms of action (see Knowledgebase page). Most of the medications that are FDA-approved for treating narcolepsy are focused on treating daytime sleepiness and cataplexy. However, some of the medications do affect some of the other symptoms of narcolepsy.
BEHAVIORAL TREATMENTS – Behavioral interventions are also used in people with Narcolepsy. Taking a couple of short daytime naps can be very helpful in reducing the severity of daytime sleepiness. In addition, keeping a consistent sleep-wake schedule is advised as well as avoiding frequent time zone changes. The reason is that changing time zones is confusing to the internal clock and can worsen sleep onset and maintenance problems. Following good sleep hygiene guidelines is highly advisable to prevent the worsening of symptoms.
SUPPORT – Finally, people with narcolepsy are advised to participate in a local support group for help with emotional issues and practical support for work and daily living issues.
How is a patient diagnosed with Narcolepsy?
The patient spends the night in a sleep laboratory or hospital and their sleep is observed and recorded.
The next day the person is allowed to take 5 naps occurring every 2 hours for 20 minutes each, and it is called the Multiple Sleep Latency Test (MSLT). The purpose of this test is to see how quickly the person falls asleep and if they have Rapid Eye Movement (REM) during those naps, called Sleep Onset REM Periods (SOREMPs). Narcolepsy patients will have REM near the start of a nap in 2 or more of the 5 nap opportunities. The time it takes them to fall asleep is very short – less than 8 minutes on average. This does not occur in the normal population. The person is awakened after falling asleep and/or REM sleep is detected. The person must remain awake between nap opportunities.
People with narcolepsy have specific genetic markers including Human Leukocyte Antigen (HLA DQB1*06:02). Narcolepsy can be diagnosed by taking a sample of spinal fluid from the spinal column using a needle. This procedure is a lumbar puncture. The sample is tested for levels of orexin/hypocretin, and levels are typically very low for people with narcolepsy.
What is polysomnography (PSG)?
Polysomnography (PSG) is a sleep study performed overnight while a person is continuously monitored. It is a multi-parameter recording of body activity across a night of sleep to diagnose sleep disorders. A standard clinical PSG includes monitoring the following:
- Brainwaves
- Eye movements
- Chin muscle tension
- Heart rate
- Airflow (from nose and mouth)
- Snoring
- Respiratory effort
- Blood oxygen level
- Leg movements
The specific activity of these body functions that are recorded simultaneously determine sleep stages across the night, can highlight what deviates from normal sleep, and therefore helps in diagnosing a sleep disorder.
What is the MSLT?
The Multiple Sleep Latency Test (MSLT) is a series of 5 nap opportunities in a dark room occurring every 2 hours for 20 minutes each. This series of naps begins two hours after the person awakens from the night-time sleep period. For example, if the person awakens at 8 am, the naps would be at 10am, 12pm, 2pm, 4pm, and 6pm. During these nap opportunities, the person is instructed to lie quietly with eyes closed and allow themselves to fall asleep. Time to fall asleep is measured by polysomnography. It is also determined what stages of sleep occur and if the patient enters REM sleep during the nap.
What is the MWT?
The Maintenance of Wakefulness Test (MWT) procedures are similar to those used for the MSLT. The main difference is that the person is sitting up in a dim room and instructed to try to stay awake. This series of tests begins two hours after the person awakens from the night-time sleep period. For example, if the person awakens at 8am, the naps would be at 10am, 12pm, 2pm, 4pm, and 6pm. During these nap opportunities, the person is instructed to sit quietly with eyes open and try to stay awake. Time to fall asleep is measured by polysomnography. It is also determined what stages of sleep occur and if the patient enters REM sleep during the nap. The MWT is often used in clinical trials to assess sleepiness but is not used for diagnosis of sleep disorders involving sleepiness.
What is Idiopathic Hypersomnia (IH)?
IH is a sleep disorder that has excessive daytime sleepiness as the main symptom even though nighttime sleep is normal (7-9 hours) or long (> 10 hours). IH people are divided into 2 groups:
Idiopathic Hypersomnia with Long Sleep Duration – IH with Long Sleep Duration, people have long periods of nighttime sleep, greater than 10 hours. Despite sleeping long periods of time at night, they are still excessively sleepy in the daytime. Usually, giving these patients more sleep at night does not help them feel more alert in the daytime. It usually just causes the person to feel more frustrated by sleeping up to, and sometimes more than half of the day.
Idiopathic Hypersomnia without Long Sleep Duration – IH without Long Sleep Duration, people have sleep periods that are more typical of normal sleepers (7-9 hours). These people are not able to sleep longer at night, because when they try to do so, it takes them longer to fall asleep and they have more awakenings during the night.
In addition to sleepiness, both types of IH patients require long daytime naps, brain fog, automatic behaviors, and forgetfulness.
How is a patient diagnosed with IH?
Many disorders can cause daytime sleepiness, and ruling out other diagnoses can be difficult. The average time for a person to obtain a diagnosis of Narcolepsy is 8-15 years. To make a diagnosis of IH, a full sleep history, medical history, and psychiatric history are collected to determine if there are other possible causes for excessive sleepiness.
Rule Out Contributors Leading to Sleepiness – A person may be taking medications that are contributing to their sleepiness, or may have Obstructive Sleep Apnea (OSA), a breathing disorder that causes frequent awakenings, fragmented sleep, and daytime sleepiness. Insufficient opportunity for sleep must be ruled out using a sleep log or wrist actigraphy (a device worn on the wrist that determines sleep time).
Polysomnography (PSG) – The patient spends the night in a sleep laboratory or hospital, and their sleep is observed and recorded. The data from the overnight study is used to rule out other sleep disorders and to verify sleep duration.
Multiple Sleep Latency Test (MSLT) – The following day a series of nap opportunities called the MSLT is conducted. The first nap is 2 hours after the morning awakening. The naps are each 20 minutes long and occur every 2 hours. The person is not allowed to sleep between naps. The average time to fall asleep across all the naps must be 8 minutes or less to be diagnosed with IH.
What is a Mechanism of Action (MOA)?
A mechanism of action (MOA) is the biochemical interaction in the body/brain through which a drug has a therapeutic effect.
What is an agonist, antagonist, inverse-agonist?
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. An antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite of that of the agonist.
What is a neurotransmitter?
A neurotransmitter is a brain chemical (example – serotonin) that is released from a brain cell (neuron) when it is stimulated and acts by inhibiting or exciting the target cell.
What MOAs are currently being studied for Narcolepsy and IH?
Orexin 2 agonism – Orexin has two receptor subtypes – orexin 1 (OX1) and orexin 2 (OX2). Many of the new drugs being investigated are OX2 receptor agonists. Agonism means that when a drug binds to a specific receptor, by doing so, it increases the effect of the receptor type.
Monoamine (dopamine, norepinephrine, serotonin) agonism -The neurochemicals dopamine, norepinephrine, and serotonin are neurotransmitters called monoamines. They are the main targets of most of the new antidepressants developed in the last 35 years. When the receptors for these chemicals are bound by the drug, it increases the effect of the receptor type. The monoamines have a stimulating effect, so agonism of these increases daytime alertness.
Monoamine (dopamine, norepinephrine, serotonin) reuptake inhibition – When the reuptake into the releasing neuron of any of the monoamines is blocked, the result is an increase in the availability of the chemical in the synaptic space (space between neurons) in the brain, and it increases the likelihood that it will reach the target or receiving neurons. Therefore, it increases the effect of the chemical. The monoamines have a stimulating effect when reaching target neurons, therefore, increasing alertness.
Histamine agonism / Inverse agonism – Histamine is stimulating and antihistamines are sedating. Therefore, when a histamine receptor is bound by a drug, the effect is stimulating or alerting. An inverse agonist is a drug that binds to a receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
What drugs are currently being studied for Narcolepsy & IH?
| Sodium oxybate calcium magnesium potassium (Xywav) | Sodium oxybate (Xyrem) is the predecessor of Xywav and was originally developed and marketed for the treatment of narcolepsy. The next version of sodium oxybate developed was Xywav, which is a low sodium version of the drug for people who have heart problems and high blood pressure. The low-sodium version of the drug (replacing some of the sodium from sodium oxybate with calcium, magnesium and potassium) makes it safer for these people to take. Both Xyrem and Xywav significantly reduce the number of cataplexy events and reduce daytime sleepiness. Both of these drugs require twice-a-night dosing. The person takes a dose at bedtime and another dose 4 hours later (in the middle of the night). Xywav is being further investigated by Jazz Pharmaceuticals in two Phase IV studies. (CLICK for trial details) |
| JZP-441 | JZP-441 is an orexin-2 agonist currently being tested in HEALTHY people. It has previously been shown to be wake-promoting and has an anti-cataplectic activity in nonclinical studies. The current research aims to assess the safety, tolerability, and pharmacokinetics of multiple increasing doses in healthy people. |
| AXS-12 Reboxetine (Edronax) | Reboxetine is a highly selective norepinephrine reuptake inhibitor (NRI). This drug is not currently marketed or approved in the United States, but it is marketed in Europe and Asia as Edronax. It was originally developed as an NRI for the treatment of depression. Since its introduction overseas in the late 1990s, reboxetine has been effective in treating other psychiatric disorders, such as panic disorder and attention-deficit hyperactivity disorder (ADHD). It is currently being developed for the treatment of narcolepsy, as reuptake inhibition of norepinephrine (which increases the availability of norepinephrine in the brain) can improve daytime alertness and potentially treat cataplexy. Because of its MOA, if approved, it would not be considered a controlled substance. (CLICK for trial details) |
| Mazindol ER | Mazindol ER (proposed name Quilience) blocks the reuptake of dopamine, norepinephrine, and serotonin so that more of these brain chemicals are available in the brain. The increase of these chemicals is known to positively affect daytime alertness as well as mood. Mazindol is also an orexin 2 agonist, which increases daytime alertness. Mazindol is currently available in Europe (called Sanorex) but not approved in the United States. It is used in other countries for the treatment of obesity. This more recently discovered mechanism of orexin agonism in Mazindol increases the likelihood that it may be a good treatment for narcolepsy. It is currently being investigated by NLS Pharmaceutics for Narcolepsy Type 1 and Narcolepsy Type 2. Mazindol is thought to address several narcolepsy symptoms including EDS, cataplexy, sleep paralysis, and nocturnal hallucinations. The most recent open-label extension study completed showed positive results for Mazindol as a once-daily medication, as improvements were seen in both EDS and cataplexy. |
| TAK-861 | TAK-861 is an Orexin 2 (OX2) receptor agonist and is being developed by Takeda Pharmaceuticals. There are 3 studies (Phase II and Phase III) underway that are recruiting subjects with NT1 or NT2. It is being studied for NT1 and NT2. By targeting OX2 in the brain it compensates for loss of the orexin chemical, thereby promoting wakefulness and possibly reducing cataplexy events. (CLICK for trial details) |
| SUVN-G3031 (samelisant) | SUVN-G3031 (samelisant) is a histamine (H3) receptor inverse agonist being developed by Suven Life Sciences. Its effects on histamine, norepinephrine, and dopamine indicate that it may have wake-promoting and anti-cataplectic effects. Phase I studies of samelisant (SUVN-G3031) provide strong support for its usefulness in the treatment of sleep disorders related to EDS, and the phase II study in the US for the treatment of NT1 and NT2 has recently been completed. |
MK-6552
The current research is evaluating the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-6552 in participants with Narcolepsy Type 1 (NT1). Part 1 will evaluate safety, tolerability, and PK of MK-6552 after administration of ascending doses in a single day to support a dose level decision for Part 2. Part 2 will investigate the PD of MK-6552 after single-day and multiple-day administration. Participants who complete Part 1 and demonstrate that they can tolerate at least one dose level of MK-6552 will participate in Part 2.
KP-1077 (serdexmethylphenidate – SDX)
The current research is being conducted by Zevra to evaluate the safety and efficacy of KP1077 capsules in patients with IH. KP1077 capsules contain serdexmethylphenidate (SDX), a prodrug of dexmethylphenidate. It is an investigational medication for treating excessive daytime sleepiness (EDS) and other symptoms of IH, including sleep inertia (difficulty of waking up in the morning), and brain fog (lack of focus and mental clarity; forgetfulness and confusion). SDX has a unique, slow-release profile that could potentially provide stable control of sleepiness throughout the day, with low abuse potential. KP1077 is currently approved for the treatment of ADHD as Azstarys.
What Narcolepsy / IH drugs have been recently approved?
Sodium Oxybate Extended Release (Lumryz™) from Avadel Pharmaceuticals was recently approved (May 2023) by the FDA as a single nightly dose, which differs from the twice-per-night dosing regimen for Xyrem and Xywav. A once-per-night dose is greatly appealing to narcoleptic people, as it is often difficult to awaken during the night to take the second dose of sodium oxybate. Many people end up skipping the second dose for this reason. Therefore, the availability of a single dose ensures that they will obtain adequate treatment for their symptoms.
