At the sleep research meeting in San Antonio this year, there were signs of an impending pharmaceutical arms race in the realm of narcolepsy.
The big fish in a small pond, Jazz Pharmaceuticals, was preparing to market its recently FDA-approved medication: Sunosi/solriamfetol. Startup Harmony Biosciences was close behind with pitolisant, already approved in Europe. On the horizon are experimental drugs designed to more precisely target the neuropeptide deficiency in people with classic narcolepsy type 1 (for narcolepsy with cataplexy: hypocretin/orexin agonists).
Amidst this commercial maneuvering, a new clinical trial is underway at Emory Sleep Center. The study compares modafinil versus amphetamines for narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).
These are not new drugs; they are old standards, when used to treat other sleep disorders. What’s remarkable here is that they are being tested “head-to-head.” In addition, the study explicitly tracks outcomes that people with NT2 and IH often talk about: sleep inertia, or difficulty waking up and getting out of bed in the morning, and brain fog, which is difficulty thinking/concentrating/paying attention. The main outcome measure is the Epworth Sleepiness Scale, which asks how likely someone is to fall asleep during daytime situations such as reading or while stopped in traffic.
Modafinil has a reputation for being gentler than amphetamines. It has been marketed as a “wake promoting” medication rather than a conventional stimulant, partly because it did not produce rebound sleep in animals, in the same way that amphetamines did. Amphetamines have cardiovascular side effects, and some people find them difficult to tolerate because of jitteriness/irritability; modafinil has its own side effect issues (a sometimes severe skin rash) as well.
Lead investigator Lynn Marie Trotti, a neurologist at Emory Sleep Center, says one of the goals of the study is to have more information to guide treatment decisions. Previous studies have shown other treatments are less beneficial for NT2 than NT1, and few randomized controlled trials have been performed for IH.
The Emory study is meant for people who have not been treated for their sleep disorder before. Participants will not know which drug they are getting. Trotti says each participant will be given a low dose of either modafinil or amphetamines to start out, and a titration schedule will allow the dose to increase if necessary over the next few weeks.
IH and NT2 are disorders in which the dominant symptom is excessive daytime sleepiness, and not much is known about the mechanisms or pathology – in contrast with NT1. We touched on this issue in an article about a man who came from Iceland to be treated at Emory. Using current tests, it is often possible for someone to be diagnosed with NT2 on one visit to the sleep lab and IH on a following visit.
Sleep scientists have been debating revision of how these disorders are diagnosed and defined. At the San Antonio meeting, French narcolepsy specialist Yves Dauvilliers made a case for measuring total sleep time in a 32-hour bed rest protocol as a stringent diagnostic for IH. (His American colleagues chuckled at how costly it would be to implement here. He countered that it would be more appropriate for research on the “IH plus long sleep” population.)
The Emory study is supported by the American Academy of Sleep Medicine, which also supported Trotti’s study on the GABA receptor antagonist clarithromycin.