• Recently approved narcolepsy medications provide new treatment options to manage excessive daytime sleepiness and cataplexy.
• Several more treatments for type 1 and type 2 narcolepsy are in development and expected to become available in the months and years ahead.
• Clinical research is vital for finding new and better treatments for narcolepsy.

Narcolepsy is a chronic, neurological disorder characterised by excessive daytime sleepiness (EDS). Narcolepsy affects approximately 1 in 2,000 people. Most people with narcolepsy have type 1 narcolepsy, also known as narcolepsy with cataplexy. Those who experience narcolepsy with EDS but without cataplexy are diagnosed with type 2 narcolepsy. There currently is no cure for narcolepsy, but with medication and behavioral changes, the condition can be managed.

In the past, people living with narcolepsy have had limited treatment options. Existing narcolepsy treatments often have significant side effects. Current narcolepsy treatments are also predominantly controlled substances, due to their risk of abuse. The benefits of treatments have to be weighed with the risk of side effects, and they don’t always manage to bring symptoms under control.

In the past two years, clinical research has led to several exciting new treatment options for narcolepsy. More treatments still under research in the development pipeline offer hope for those struggling to manage their narcolepsy symptoms.

Current Treatments for Type 1 and Type 2 Narcolepsy

No two cases of narcolepsy are alike. Narcolepsy treatment must be tailored for each person. Narcolepsy is usually treated with a combination of medication and lifestyle changes that promote good sleep hygiene.

Current narcolepsy treatments are aimed at managing the disruptive symptoms of narcolepsy that impact a person's quality of life. Goals of narcolepsy treatments work in different ways.

• Stimulants and wakefulness-promoting drugs, such as Provigil (modafinil) and Nuvigil (armodafinil), enhance wakefulness.
• Xyrem (sodium oxybate) and Effexor (venlafaxine) reduce the frequency and severity of cataplexy attacks.
• Sodium oxybate also reduces sleep-cycle disruptions, including sleep paralysis and sleep-related hallucinations.

There are several medications approved by the U.S. Food and Drug Administration (FDA) to treat narcolepsy’s key symptoms — EDS, cataplexy, and other sleep disruptions. Drugs that have wake-promoting or stimulating effects are used to decrease EDS. Certain medications that block reuptake of serotonin or norepinephrine, like some antidepressants, may reduce cataplexy attacks. Xyrem is approved to treat cataplexy in type 1 narcolepsy.

Several medications are prescribed off-label to treat symptoms of narcolepsy. Stimulants like Adderall (amphetamine/dextroamphetamine) and Ritalin (methylphenidate) are prescribed to combat EDS due to narcolepsy. Antidepressants like Effexor and Prozac (fluoxetine) have been prescribed for many decades to help treat cataplexy, the defining symptom of type 1 narcolepsy.

Newly Approved Treatments for Narcolepsy

In the past 18 months, the FDA has approved three promising new medications for narcolepsy.

Wakix (pitolisant) and Sunosi (solriamfetol) received approval in 2019. Wakix is the only drug currently approved to treat narcolepsy that is not a scheduled, controlled substance in the United States. Sunosi was approved by the FDA to treat narcolepsy-related EDS. In October 2020, Wakix was also approved by the FDA for the treatment of cataplexy in adults with narcolepsy.

In July 2020, the FDA approved Xywav (calcium, magnesium, potassium, and sodium oxybates) to treat cataplexy or EDS. Xywav, which is approved to treat people ages 7 and older with narcolepsy, is expected to become available by the end of 2020.

These three new medications offer more choices for those whose narcolepsy symptoms have proven resistant to previously existing treatments.

The Research and Development (R&D) Pipeline and Narcolepsy

The FDA approval process for new drugs, also known as the R&D process or pipeline, is rigorous and lengthy. It takes an average of 10 years for a new drug to enter the market. From the idea stages to the pill bottle you pick up from your local pharmacy, the research and development of health-related interventions follows strict, well-established guidelines.

Who Oversees the R&D Pipeline?

The rules governing clinical studies were put in place by the National Institutes of Health (NIH) and the FDA. These guidelines ensure the highest levels of safety, efficacy, and ethical standards are maintained throughout the process.

The Office for Human Research Protections is tasked with protecting the rights, welfare, and safety of volunteer participants in clinical trials. There are built-in checks and balances to achieve the most effective and safe treatments for people. The strict protocols and procedures are also in place to protect the subjects’ health and rights.

Clinical trials are overseen by institutional review boards comprising scientists, doctors, and lay people. The institutional review board must approve clinical trial protocols before the trials can begin.

What Are the Stages of the R&D Pipeline?

The earliest stages of the R&D process for a new medication are called discovery and development. All testing at this stage is done in the lab and in animal models. There are usually thousands of potential compounds at the discovery stage. Once researchers, or investigators, identify a promising treatment, it enters the development stage. However, very few candidates show enough promise to advance to human (clinical) research studies. Only a fraction of treatments move forward from discovery to the next step of the process.

Preclinical Research

Before testing an intervention in humans, researchers have to make sure it isn’t likely to cause serious harm (toxicity), and that its benefits outweigh its risks and side effects. Preclinical research studies are usually small and aren’t conducted using human beings.

Clinical Research

Clinical research is any research involving human trial subjects. Several different types of clinical research exist. Clinical studies use the information gathered during the discovery and preclinical stages to test the safety and effectiveness of health-related interventions on people.

Clinical trials have four phases. Each clinical trial phase serves a different purpose and helps researchers answer different questions.

• Phase 1 trials test a treatment’s safety, safe dosage range, and side effects. Phase 1 trials typically involve 20 to 80 people and take several months to complete. Approximately 70 percent of phase 1 treatments move on to the next phase.
• Phase 2 trials further test the safety and effectiveness of the intervention. Phase 2 trials comprise a larger group (100 to 300 people) and can last as long as two years. About a third of phase 2 treatments progress to the next phase.
• Phase 3 trials generally involve between 300 and 3,000 people and last between one and four years. Phase 3 trials confirm a treatment’s safety, monitor side effects, and compare it to existing treatments for benefits. Successful phase 3 trials are required for an intervention to go to market and become publicly available. Between 25 percent and 30 percent of phase 3 treatments move ahead.
• Phase 4 trials occur after the FDA has approved a treatment; they include post-marketing surveillance studies. In phase 4, researchers monitor people using the new treatment to glean more information about its longer-term effects, risks, and benefits, and to improve the way the treatment is used.

An estimated 90 percent of new drugs that reach the clinical testing stage do not make it to FDA approval. The likelihood that a drug starting clinical testing will be approved after a phase 3 trial is less than 12 percent.

Future Therapies for Narcolepsy

The discovery that hypocretin (also called orexin) plays a role in the development of narcolepsy has provided a rich new area of research for potential treatments. Emerging treatments for narcolepsy include drugs that boost hypocretin levels in the body and act on the histamine chemical system, as well as new options for gene therapy and immunotherapy.

Narcolepsy is an autoimmune disorder. Researchers are studying how the immune system is involved in narcolepsy’s onset and progression. The field of gene therapy is still in its early years. More exploration and experimentation is needed before it can furnish new approaches for treating narcolepsy.

Several new drugs are in the pipeline for EDS, narcolepsy, and cataplexy. There are more than 80 clinical trials relating to narcolepsy currently underway. These studies are in different phases and show varying degrees of promise. More research is necessary to assess whether these new treatments are safe and effective for individuals with narcolepsy.

Investigational drugs for narcolepsy include:

• an extended-release, once-nightly version of sodium oxybate
• a new selective norepinephrine reuptake inhibitor
• a novel Modafinil combination

Thanks to recent scientific advancements in neurological, sleep-related, and rare (orphan) diseases, there is growing interest, investment, and research in narcolepsy treatment. Narcolepsy is considered an orphan disease, which qualifies it for special research funding opportunities through a U.S. government program.

Clinical Trials and You

Clinical research finds more and better treatment for options for the future. Today’s narcolepsy treatment options would not be available without clinical research and trial volunteers. R&D is a process that requires a solid partnership between researchers, funders, and most importantly, the people affected by the condition being studied.

Why Do People Volunteer for Clinical Research?

There are several reasons why a person with narcolepsy might consider an investigational treatment or clinical trial. Some people with a health condition participate in clinical trials to help other people with the condition, while others are motivated by the opportunity to access the newest treatment or specialized care. More participation also means greater diversity in the research population, helping ensure that medical products are safe and effective for everyone.

Are You Interested in Furthering Narcolepsy Research?

If you are living with narcolepsy and are interested in participating in clinical research, these vital tips are for you:

• Research — Ask questions. Learn about what to expect and your rights as a volunteer trial participant. Make sure you understand how your health and rights will be protected.
• Evaluate — All trials have potential benefits and risks. Depending on the phase of the trial, the results of previous trials may be available to help you better understand the improvements and side effects seen so far.
• Communicate — Talk to your health care providers openly about your narcolepsy symptoms, treatments, and any side effects you experience. They can help you find clinical trials for which you may be eligible and determine whether a clinical study might be right for you.

To find out about ongoing clinical studies for narcolepsy, visit Clinicaltrials.gov. The government database lists studies around the world by condition and country.