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.
- 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.
- 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
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.
- Abuse potential
- Tolerance onset
- Side effects
- 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.
- Target specific neurophysiological causes of narcolepsy
- Introduce novel modalities of drug delivery
- Minimize abuse potential
- Avoid agents with rapid tolerance onset
- 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.