Could the next GLP-1 target the brain?

A new generation of drugs is targeting one of the brain's fundamental signaling systems. But their potential could eventually extend far beyond the disorder they were designed to treat.

The trajectory has prompted comparisons with GLP-1, a gut hormone that helps regulate blood sugar and appetite. Drugs that mimic it began as diabetes treatments before becoming powerful treatments for obesity, with medicines such as Wegovy and Zepbound now among the world's most prominent weight-loss drugs.

Orexins, the signaling system in question, are chemical messengers that help the brain maintain wakefulness. Their most advanced application is treating narcolepsy type 1, a disorder in which patients lose most orexin-producing neurons. But the system is also involved in attention, motivation, reward, appetite, stress and mood, creating potential applications beyond sleep disorders.

In August, the U.S. Food and Drug Administration approved the first medicine designed to restore orexin signaling in adults with narcolepsy type 1, following approval in China in July. The milestone provides the strongest evidence yet that the orexin system can be successfully targeted in humans, as drugmakers begin exploring how much further its potential might extend.

The GLP-1 comparison

GLP-1 offers a useful precedent for how a drug developed for one disease can prove valuable far beyond its original use. After their success in diabetes and obesity, GLP-1 drugs have expanded into cardiovascular and kidney disease, while researchers are investigating their potential in conditions ranging from addiction to neurodegenerative disease.

Orexin could offer a similar opportunity in the brain, although the evidence remains far more preliminary.

Pharmaceutical companies are beginning to explore those connections. Japan-based Takeda, which developed the newly approved narcolepsy drug, is studying other orexin-based medicines for sleep-wake disorders and says its research extends to areas including mood and metabolism. Other drugmakers are exploring applications in ADHD and fatigue associated with neurological conditions such as Parkinson's disease and multiple sclerosis.

The brain chemical behind narcolepsy

Scientists discovered orexin in 1998. Produced by a small group of neurons in the hypothalamus, its signals travel widely through the brain and help maintain wakefulness.

Narcolepsy provided some of the clearest evidence of what happens when that system fails. People with narcolepsy type 1 lose most orexin-producing neurons, causing overwhelming daytime sleepiness and cataplexy, a sudden loss of muscle control often triggered by strong emotions. Takeda estimates that narcolepsy type 1 affects about 120,000 people in the United States, while its China division estimates roughly 700,000 people there have narcolepsy, with type 1 accounting for 75% to 80% of cases.

Existing medicines can control individual symptoms but do not replace the lost signal. That opened another possibility: developing a drug that could mimic orexin itself.

Treating the cause instead of the symptom

Takeda's first major attempt showed both the potential and the risks. In a Phase 2 trial published in the New England Journal of Medicine in 2023, its experimental drug TAK-994 substantially improved patients' ability to remain awake. Average weekly cataplexy episodes fell from 14.4 at the beginning of the trial to between 0.27 and 1.14 across treatment groups, compared with 5.83 among patients receiving a placebo.

But the trial was stopped early after five patients developed concerning elevations in liver enzymes. The drug was abandoned, although its ability to improve narcolepsy symptoms offered evidence that replacing orexin signaling could work.

Takeda continued with a newer drug, oveporexton, eventually testing it in two larger Phase 3 studies involving 273 patients across 19 countries. In results presented in June 2026, approximately 70% of treated patients reported no significant cognitive difficulties after 12 weeks, compared with roughly 15% receiving placebo. Patients also showed improvements in daytime sleepiness, cataplexy, daily functioning and nighttime sleep.

More than a wakefulness switch

Orexin's influence beyond wakefulness has opened possibilities in both directions. Medicines that block its signaling are already used to treat insomnia, while researchers are studying whether the same approach could help treat addiction. A 2025 review in Translational Psychiatry found early human evidence that orexin-blocking drugs could reduce opioid craving and withdrawal symptoms while improving sleep.

Other companies are moving in the opposite direction, developing drugs that increase orexin signaling for conditions associated with excessive sleepiness, fatigue and impaired attention. Most applications beyond sleep disorders remain in early clinical trials or laboratory studies.

Orexin may therefore be better understood as a dial than a simple wakefulness switch. Drugmakers may have found a way to manipulate one of the brain's fundamental regulatory systems. The opportunity may lie not simply in turning orexin on, but in learning when to turn it up or down.

GLP-1 offers both inspiration and reason for caution. Orexin's success in narcolepsy does not mean it will reproduce GLP-1's expansion across medicine, and many proposed applications remain unproven. But if that trajectory offers any precedent, narcolepsy may ultimately be remembered not as the limit of orexin drugs, but as the condition that first proved their potential.