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On March 31, 2026, Eli Lilly and Company announced that it had entered into a definitive agreement to acquire Centessa Pharmaceuticals for an upfront cash payment of approximately $6.3 billion plus potential contingent payments of approximately $1.5 billion. The upfront payment represents a premium of approximately 40.5% to Centessa’s 30-day volume-weighted average trading price ending March 30, 2026.

Carole Ho, executive vice president and president, Lilly Neuroscience described the fascinating biology behind Centessa’s lead drug cleminorexton (formerly ORX750), a selective orexin 2 (OX2) agonist in narcolepsy. She remarked, “Orexin receptor biology represents one of the most compelling mechanistic opportunities in neuroscience as a direct intervention on the master switch of the sleep-wake cycle. Centessa has assembled a portfolio with the breadth and depth to improve wakefulness across a broad array of indications. Joining forces with Centessa colleagues means we can now pursue that potential at the speed and scale it deserves.”

Here, we aim to shed more light on the history of narcolepsy, orexin biology, and the clinical data that had been shown to date.

While descriptions of “sleepy” individuals exist in ancient texts, the formal medical history began in the late 1800s. In 1877, the German physician Dr. Karl Westphal was the first to provide a clinical description of the condition, noting a patient who suffered from both uncontrollable sleep attacks and “falling spells” triggered by emotion. Three years later in 1880, the French physician Dr. Jean-Baptiste-Édouard Gélineau coined condition’s name: he combined the Greek words narke (numbness/stupor) and lepsis (to seize) to create “Narcolepsy”. Furthermore, he correctly identified it as a distinct clinical entity rather than a symptom of other diseases.

For several decades, the medical community struggled to understand the “why” behind the sleep attacks. In the Freudian Era of the early 20th century, narcolepsy was often misdiagnosed as a psychological defense mechanism or “neurosis.” Some theorists suggested patients were simply retreating from reality into sleep. It wasn’t until the 1930s when the dogma surrounding the condition shifted back to biology when Dr. Frederick Prinz introduced the use of ephedrine and later amphetamines as treatments. The next breakthrough occurred in the 1960s with advent of the Electroencephalogram (EEG) and the discovery of REM (Rapid Eye Movement) sleep. Drs. Vogel & Dement discovered that people with narcolepsy enter REM sleep almost immediately after falling asleep. In healthy individuals, REM usually takes about 90 minutes to occur. Scientists realized that narcolepsy symptoms (like cataplexy and sleep paralysis) are actually components of REM sleep “bleeding” into the waking state.

The “Modern Era” of narcolepsy research is often described as a “scientific lightning strike.” In a span of just three years (1998–2000), the field went from having no known cause for the disease to identifying the exact chemical deficiency and the specific cells lost in the brain.

In 1998, two different research teams independently discovered the same neurotransmitter at the same time, leading to its dual name.

Initially, everyone thought these chemicals were just about hunger. It wasn’t until the following year that the connection to sleep was realized. The following year in 1999, two landmark studies were published that proved that this new chemical system was the “master switch” for wakefulness.

While the 1999 studies showed that genetic mutations caused narcolepsy in animals, human narcolepsy isn’t usually inherited. Researchers needed to find out what was happening in human brains. In 2000, Dr. Jerome Siegel (UCLA) and Dr. Mignot (Stanford) independently examined the brains of deceased individuals with narcolepsy. They found that a healthy brain has about 70,000 to 100,000 hypocretin-producing neurons, whereas 90% of these cells were gone in narcoleptic brains.

If the cells are missing but there’s no genetic mutation, what killed them? This led to the modern consensus that narcolepsy is an autoimmune disease. Scientists noticed that 98% of people with Narcolepsy Type 1 carry a specific immune system gene marker called HLA-DQB1*06:02. A major clue surfaced after the 2009 H1N1 flu pandemic. In China and parts of Europe (related to the Pandemrix vaccine), there was a sudden spike in narcolepsy cases. Researchers believe that a protein in the flu virus looks so similar to the hypocretin receptor that the body’s immune system gets “confused.” It trains its T-cells to attack the virus, but those same T-cells then cross the blood-brain barrier and destroy the hypocretin neurons by mistake.

Current research has shifted from just masking symptoms with stimulants to targeted therapies, given that we know the exact “missing ingredient” (orexin). We are currently seeing the development of orexin agonists; drugs that mimic the missing chemical, which aims to address the underlying neurochemical deficiency associated with sleepiness for the first time in history.

The delineation between the two orexin receptors, OX1R and OX2R, transformed narcolepsy from a vaguely understood “sleepiness” into a precise neurochemical deficiency. In the late 1990s, researchers used three primary methods to separate the functions of these two closely related receptors (which share 64% of the same amino acid sequence).

While both receptors play a role, the goal of modern drug development is selective OX2R agonism. OX2R is the “Heavy Lifter” for staying awake. Activating it directly stimulates the histaminergic system, which is the brain’s most powerful wake-promoting engine. OX1R is heavily involved in the brain’s reward and motivation circuits (the “mesolimbic” system). If a drug activates OX1R too strongly, it could lead to addiction or drug-seeking behavior, as OX1R influences dopamine release. Selective OX2 agonists provide the “alertness” without the “high” or the potential for abuse, making them much safer for long-term daily use. Pure OX2R stimulation is often sufficient to stabilize the “sleep-wake flip-flop” switch, preventing the REM intrusions that cause cataplexy.

The drug development history of orexin agonists is a “fail-forward” saga. It moved from intravenous proof-of-concepts to a catastrophic liver toxicity setback, finally arriving at the current generation of highly potent, selective investigational molecules currently being evaluated in clinical trials or under regulatory review.

Before an oral pill was possible, scientists had to prove that simply “adding orexin back” would actually work in humans. The Japanese pharmaceutical company Takeda developed danavorexton (TAK-925), the first potent OX2R agonist. However, it had poor oral bioavailability (the body couldn’t absorb it as a pill). In 2019, they administered danavorexton intravenously to patients with Narcolepsy Type 1. First-in-human data was presented at at the World Sleep Congress 2019 medical meeting and the results were stunning: patients who usually fell asleep in 2 minutes on the Maintenance of Wakefulness Test (MWT) were able to stay awake for the full 40-minute test7. The study was a sensation in the sleep medicine and biotech communities because it provided the first clinical proof that an orexin 2 receptor (OX2R) agonist could essentially “rescue” the wakefulness of patients with Narcolepsy Type 1 (NT1) by replacing the missing orexin signaling.

While the intravenous danavorexton proved the mechanism worked, the trial sponsor pivoted to developing oral versions for daily use. However, this switch would lead to some stumbles that would keep R&D scientists up at night. TAK-994 was danavorexton’s oral successor compound. It entered Phase 2 trials with massive expectations and was the first of its kind, but the program was abruptly terminated in October 2021 after several patients developed signs of Drug-Induced Liver Injury (DILI). Later research (2024–2025) revealed that the toxicity was not caused by the orexin mechanism itself, but by reactive metabolites from the specific scaffold of the TAK-994 molecule that induced covalent protein binding. It was found to undergo covalent binding, essentially, the drug’s metabolites were “sticking” to liver proteins, triggering an immune attack on the liver. This was a “molecule-specific” failure and the trial sponsor immediately shifted all resources to a back-up molecule with a different chemical structure: oveporexton (TAK-861).

The “Second Wave” (2023–2026) is the era where narcolepsy research shifted from “scientific discovery” to “clinical reality.” This period is defined by the recovery from the 2021 liver toxicity setback and the emergence of several ‘best-in-class’ contenders currently undergoing regulatory review. In the FirstLight and RadiantLight Phase 3 trials (presented in late 2025 at the World Sleep Congress), oveporexton demonstrated mean wakefulness scores within the normative range on objective tests: 64% of patients reached a normal sleep latency (the time it takes to fall asleep) on objective tests. Unlike its predecessor, there has been no evidence of hepatotoxicity (liver damage) reported to date across the Phase 3 program. The most common side effects are mild, including increased urinary frequency and initial insomnia. On February 10, 2026, the FDA officially accepted Takeda’s New Drug Application (NDA) and granted it Priority Review. Takeda has stated it anticipates a final decision from the FDA in Q3 2026.

While Takeda was the first to the finish line, Alkermes’ Alixorexton emerged, positioning itself as a more convenient alternative. While Oveporexton is typically tested as a twice-daily drug, Alixorexton is being developed as a once-daily oral tablet. n February 2026, the FDA granted Alixorexton Breakthrough Therapy Designation for Narcolepsy Type 1 (NT1). Alkermes officially launched its Phase 3 program on April 1, 2026. This study is unique because it is aggressively testing the drug for both NT1 and NT2, whereas Takeda has focused primarily on the orexin-deficient NT1 population following a strategic decision in 2024 to discontinue oveporexton development for NT2 due to a lack of clear efficacy in that subgroup.

This brings us back to Centessa which, similar to Alkermes, is also developing once-daily oral OX2 agonist.

The backstory of Centessa Pharmaceuticals is one of the most radical “pivot-to-success” stories in biotech history. While Takeda and Alkermes were following traditional pharmaceutical paths, Centessa was born as a venture capital experiment that experienced a crisis before being rescued by the very orexin science we’ve been discussing.

Centessa was launched in early 2021 by Medicxi, a venture capital firm, with a unique business model. Instead of one company with one pipeline, it was a merger of 10 startups implementing a “hub-and-spoke” business model. Each “spoke” (subsidiary) focused on a single drug. This included Orexia Therapeutics and Palladio Biosciences. A year after its IPO, Centessa’s lead drug for a rare kidney disease failed due to, ironically, liver safety concerns and many industry analysts wrote the company off. In 2023, the company abandoned its ‘hub-and-spoke’ model in late 2022, right-sized its staff, and consolidated its focus onto the Orexia program, specifically cleminorexton (ORX750).

Early Phase 2a data suggests cleminorexton is effective not just for narcolepsy, but also for Idiopathic Hypersomnia (IH), a condition where orexin levels are normal but patients are still pathologically sleepy. Scientists are now exploring if these agonists can treat Major Depressive Disorder (MDD) and other conditions involving “brain fog” and fatigue, moving the orexin story beyond just sleep medicine.

The story of narcolepsy is a remarkable narrative of scientific persistence; a journey from the 19th-century “sleepy” observations of Gélineau and Westphal to the discovery of a “master switch” in the brain.

For over a century, patients were sidelined by a lack of understanding, treated with general stimulants that only masked the symptoms of their condition. The Modern Era breakthrough changed everything, identifying the loss of hypocretin/orexin neurons as the root cause and opening the door to truly targeted medicine.

As we stand in 2026, the “Second Wave” of drug development represents the final bridge between discovery and a potential paradigm shift in treatment. With Oveporexton (TAK-861) under FDA Priority Review and competitors like alixorexton and cleminorexton close behind, the medical community is no longer just managing sleepiness. We are entering an era of orexin replacement therapy, a move that seeks to restore the biological balance of the brain and offer millions of patients the potential for significantly improved wakefulness.

The transition of Centessa’s cleminorexton to Eli Lilly underscores the massive potential of this science, suggesting that the “orexin story” is just beginning, with future applications potentially reaching far beyond narcolepsy into the broader realm of mental health and cognitive function.

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