The Ozempic For Sleep? How A New Class of ‘On/Off’ Switch Drugs Could Help With Insomnia and Ward Off Dementia

My Favorite Drug and My Next Favorite Anti-Drug: A Personal Journey into Sleep Optimization

I am not a medical doctor, so do not use any of the below as any form of medical advice. Moreover, this article is written with the help of generative tools so beware of hallucinations. Now, I will tell you about one of my favorite drug classes - DORAs.

Fifteen years ago, long before Bryan Johnson made longevity hacking a household term, I was deep in the trenches of personal optimization. I swallowed over 100 supplements daily, pushed my body through rigorous exercise routines, and even curated my social circle to avoid toxic or burdensome relationships where I was looking for common interests in aging than anything else. Fast forward to today, and I've streamlined my regimen to the bare essentials: only those supplements with the lowest risk of oncogenesis and significant burden of proof. Unfortunately, when it comes to aging, there is no drug that demonstrated efficacy in a sizable clinical trial yet. But in the process, I've amassed a wealth of experience with modern targeted therapeutics. When it comes to human longevity, only human clinical trial and post-approval meta data matters. Mice and other mammals are great for fundamental research but I would not trust a drug that did not go through rigorous human clinical trials.

This background equips me with a sharp eye for risk-benefit analysis, especially when it comes to my own health challenges. One of my biggest hurdles? Non-stop travel. With 80+ lectures worldwide each year and irreplaceable in-person meetings, my sleep cycles have been obliterated.

I experimented with melatonin and other regulators, but melatonin just doesn't cut it for me—and I'm wary of potential cancer risks.³⁶ A couple of years ago, I turned to the orexin antagonist Dayvigo (lemborexant).⁴ One small pill, and I'm asleep in 20 minutes, clocking 4-4.5 hours total with 1.2-1.5 hours of deep sleep. Best part? I wake up fully operational, no grogginess. This is not the case for many who experience drowsiness.

The DeepSeek Moment: A Neuroprotective Revelation

Recent evidence is even more compelling: orexin-targeting drugs, particularly antagonists, show promise in protecting against dementia and Alzheimer's by reducing amyloid-beta buildup and addressing sleep disturbances linked to neurodegeneration.²⁶ Studies suggest that by modulating orexin, these drugs could mitigate the hyperactivity in the neuropeptide system that exacerbates anxiety and cognitive decline in Alzheimer's patients.⁴³

Now, with Takeda having wrapped up Phase III trials for their orexin agonist oveporexton (TAK-861) in narcolepsy, I'm on the edge of my seat. It looks like a game-changer for combating daytime fatigue.

The De-Orphaning of a Master Regulator

To understand the revolution these drugs represent, one must go back to their origin story. The orexin system was discovered in 1998, a relatively recent development in neuroscience, by two independent research groups almost simultaneously.¹ This led to a dual nomenclature that persists today. One group, at Scripps Research Institute, identified genes expressed exclusively in the lateral hypothalamus and, noting the resulting neuropeptide's similarity to the gut hormone secretin, named it "hypocretin".¹ Fun fact, I learned about this discovery after chatting with a colleague from Novartis, who attended the ARDD conference in Copenhagen and was on the original hypocretin paper.

At the same time, a lab at the University of Texas Southwestern Medical Center was screening for the ligands of "orphan receptors"—receptors whose activating molecule was unknown. They found two peptides that activated these receptors and, upon injecting them into rats, observed a marked increase in food intake, leading them to name the peptides "orexin," from the Greek word orexis, meaning "appetite".¹

While the initial focus was on appetite, the system's true purpose was dramatically revealed shortly thereafter. Researchers discovered that a mutation in the orexin receptor 2 gene was the direct cause of canine narcolepsy in Doberman Pinschers.¹ This was the Rosetta Stone. It established an undeniable causal link between a dysfunctional orexin system and a major sleep-wake disorder. It became clear that orexin's primary role was not in regulating hunger, but in stabilizing wakefulness.¹ The neurons that produce orexin, located exclusively in the hypothalamus, act as the brain's master wake switch.

Not a Sledgehammer, but a Dimmer Switch

This discovery opened a completely new therapeutic avenue for treating insomnia. For decades, sleep medicine had relied on what can be described as pharmacological sledgehammers. Benzodiazepines (like Valium) and the so-called "Z-drugs" (like Ambien and Lunesta) work by enhancing the activity of GABA, the brain's primary inhibitory neurotransmitter.² They function by causing broad depression of the central nervous system, effectively forcing the brain into a state of unconsciousness. This brute-force approach comes with a host of well-known side effects, including impaired cognition, motor balance difficulties, and the risk of complex sleep behaviors.²

The discovery of the orexin system offered a far more elegant solution. Instead of globally powering down the brain, a drug could selectively target the specific system responsible for powering it up. The Dual orexin antagonists (DORAs), are this solution. They function like a dimmer switch, not an off switch. They don't induce a global state of sedation. Instead, they selectively and competitively block orexin from binding to its receptors, OX1R and OX2R.⁴ This action specifically turns down the overactive "wake drive" that prevents insomniacs from falling and staying asleep, allowing the body's natural sleep-promoting systems to take over.⁶

This represents a fundamental paradigm shift in neuropharmacology, moving from broad sedation to targeted neuromodulation. The philosophy is no longer "induce unconsciousness" but rather "permit natural sleep by removing the barrier of hyperarousal." This shift from targeting an inhibitory system (GABA) to targeting an excitatory one (orexin) is a testament to a maturing understanding of the brain's complex circuitry. It demonstrates that for complex neurological states like wakefulness, a more precise intervention aimed at the specific circuits that promote the state can be more effective and have a cleaner side-effect profile than a global suppression of brain function. This principle has profound implications, offering a blueprint for developing more sophisticated treatments for other neurological conditions, from anxiety to attention disorders.

Merck was the first to develop DORAs. But first-in-class leadership often comes at a cost. Their molecules’s half life was about 12 hours. The less drowsy and newer chemistry was needed.

The Architects of a New Sleep Paradigm: Idorsia and the Clozel Legacy

In the corporate race to capitalize on the orexin system, no story is more compelling than that of Idorsia and its founders, the husband-and-wife team of Jean-Paul and Martine Clozel. Their journey is a masterclass in scientific entrepreneurship. They first co-founded Actelion in 1997, building it into a Swiss biotech powerhouse.⁷ In 2017, Johnson & Johnson acquired Actelion for a staggering $30 billion.⁷ But this was no ordinary acquisition.

Instead of simply cashing out, the Clozels engineered a brilliant and unconventional deal. J&J took Actelion's commercialized products and revenue streams, while the Clozels spun out the entire R&D engine—the discovery pipeline, early-stage clinical assets, and a core team of approximately 650 of their most talented scientists—into a new, independent company: Idorsia.⁷ They launched this new venture with a formidable war chest of CHF 1 billion in cash, including a significant investment from J&J itself.⁷ It was a strategic masterstroke: they sold the present to fund a more ambitious future.

Idorsia was founded on a clear philosophy, articulated repeatedly by the Clozels: to build a sustainable, innovation-driven biopharmaceutical company, not a quick-flip asset for another acquisition.⁹ Their passion is for the science of drug discovery, with a particular focus on small molecules, which they believe can address diseases that newer modalities like antibodies cannot.⁷ "I want Idorsia to become the best small molecule company in the world," Jean-Paul Clozel has stated, emphasizing a commitment to tackling difficult scientific challenges.⁹

This is a company led by scientists for the purpose of science. Martine Clozel, a celebrated physician and researcher in her own right, serves as Chief Scientific Officer.¹¹ Her deep involvement ensures that the company's direction is guided by medical need and scientific possibility, not just market trends. "We are trying to be very pragmatic and follow where the science takes us," she has explained.¹⁰ This ethos permeates the company, which was designed to be an efficient, R&D-focused organization, free from the bureaucratic heft of a large pharmaceutical giant.¹⁰

Quviviq: The Flagship Product

The first major product to emerge from this new entity is Quviviq (daridorexant), the third DORA to enter the market. Quviviq is the embodiment of Idorsia's strategy. As Martine Clozel described, the molecule was deliberately designed with specific properties in mind: potent inhibition of both orexin receptors, rapid absorption to help with sleep onset, and a pharmacokinetic profile that ensures around 80% of the drug is eliminated by morning, minimizing residual effects.¹¹

The FDA approval of Quviviq in January 2022 was a landmark moment, transforming Idorsia from a promising R&D venture into a fully-fledged commercial biopharmaceutical company.¹¹ The launch was ambitious, aimed at disrupting the established treatment paradigm for insomnia.¹³ While facing a competitive market, the company has made significant headway, with Quviviq generating total net sales of CHF 58 million in the first half of 2025, driven largely by strong performance in Europe.¹⁴

The Idorsia story offers a powerful lesson in corporate strategy. In an era of rampant consolidation where Big Pharma often acquires innovative biotechs only to absorb their assets and dilute their unique R&D cultures, the Clozels forged a different path. Their "structured spin-out" model allowed them to preserve what was most valuable: their experienced team, their proprietary library of molecules, and their agile, risk-taking culture. By selling their first company's commercial success, they secured the long-term, stable funding needed to pursue high-risk, high-reward science without the constant pressure of quarterly earnings or venture capital fundraising cycles. It represents a novel "third way" for serial biotech entrepreneurs to maintain their innovative edge, providing a blueprint for how to keep the engine of discovery running even after a blockbuster exit.

My problem with Quiviq is that it is not as easy to buy in Asia as is Dayvigo and I tolerate Dayvigo well.

A Connoisseur's Guide to Modern Sleep: Comparing the Orexin Antagonists

The Three Contenders: Belsomra, Dayvigo, and Quviviq

For the discerning consumer or investor, it is crucial to understand that not all DORAs are created equal. The three FDA-approved drugs in this class—Belsomra, Dayvigo, and Quviviq—offer distinct profiles tailored to different needs.¹⁵

• Belsomra (suvorexant), Merck: As the first DORA to receive FDA approval in 2014, Belsomra blazed the trail for the entire class.¹⁶ It validated the mechanism and established a market. However, its pharmacokinetic profile is notable for a longer duration in the body, and its labeling includes a warning that people with a higher body mass index may experience higher blood levels of the drug, increasing the risk of side effects.¹⁸

• Dayvigo (lemborexant), Eisai: Approved in 2019, Dayvigo has a longer half-life than its competitors, which can be particularly effective for sleep maintenance—helping users stay asleep through the night.¹⁹ This added potency, however, comes with a trade-off. It also has the most extensive and compelling data supporting its potential neuroprotective effects against Alzheimer's pathology.²⁰

• Quviviq (daridorexant), Idorsia: The newest entrant, approved in 2022, was explicitly designed to address the primary concern with earlier DORAs: next-day drowsiness. Its key feature is a significantly shorter half-life, intended to provide a full night's sleep with minimal risk of morning impairment.¹¹

The Critical Difference: Half-Life and Next-Day Function

The most critical differentiator among these drugs is their half-life, which directly impacts the balance between sleep maintenance and next-day alertness.

• Quviviq's short half-life of approximately 8 hours is its signature feature. This profile is ideal for individuals who must be mentally sharp shortly after waking. The data supports this design: FDA driving simulator tests revealed that impairment 9 hours after a 50 mg dose was similar to that of a placebo.¹⁹

• Dayvigo's longer half-life, estimated between 17 and 19 hours in some analyses, provides a more sustained effect throughout the night.¹⁹ This makes it a powerful option for those whose primary problem is waking up in the middle of the night. The trade-off is a documented higher risk of residual effects. Post-marketing surveillance shows a higher report rate for next-day drowsiness interfering with driving (5.8% for Dayvigo vs. 3.2% for Quviviq), and its FDA label advises caution even after a full night's sleep.¹⁹

This is where my personal choice of Dayvigo becomes a calculated decision. For combating severe, multi-day jet lag after a 12-hour time zone shift, my primary goal is to force my body into a new rhythm with powerful, uninterrupted sleep maintenance. In this specific context, the robust, all-night efficacy of Dayvigo outweighs the potential for some next-morning grogginess, which is an acceptable price for rapidly resetting my internal clock. For someone with chronic but less severe insomnia who needs to perform complex tasks at 8 AM every day, the cleaner profile of Quviviq would likely be the superior choice.

Beyond the Basics: Sleep Architecture and Other Considerations

The differences extend to more subtle, yet important, aspects of sleep quality. A key advantage of DORAs over older hypnotics is their more favorable impact on sleep architecture. Benzodiazepines, for example, are known to suppress deep, slow-wave sleep (Stage N3).²³ In contrast, studies on lemborexant (Dayvigo) have shown it can significantly increase time spent in REM sleep compared to both placebo and zolpidem, and also increase total non-REM sleep duration.²³ While data on Stage N3 specifically is less definitive, the overall trend suggests that DORAs promote a more natural and potentially more restorative sleep structure.

All three drugs are classified as controlled substances due to a theoretical risk of dependence or misuse, though this appears to be lower than with traditional hypnotics.²⁵ They also have different drug interaction profiles because they are broken down by different enzymes in the body, a crucial consideration for anyone taking other medications.²⁵

Comparative Profile of FDA-Approved Dual Orexin Receptor Antagonists (DORAs)

The "On" Switch Arrives: Takeda's Landmark Orexin Agonist Triumph

The Other Side of the Coin: The Promise of an "On" Switch

Just as the story of orexin antagonists was maturing, a new chapter began—one that explores the other side of the coin. If blocking the orexin system gently turns down the wakefulness dial to permit sleep, what would happen if you could actively turn that dial up? This is the promise of orexin agonists: drugs that mimic the action of orexin to promote a state of crisp, stable wakefulness. This is my "next favorite anti-drug"—a potential tool for on-demand alertness, the perfect complement to the on-demand sleep offered by antagonists.

A High-Stakes Race to a Breakthrough

For years, developing a safe and effective orexin agonist proved elusive. While the therapeutic target was obvious, activating a critical brain system carries significant risks. The path to success was littered with high-profile setbacks; Takeda itself had previously shelved an earlier orexin agonist, TAK-994, due to liver toxicity, and Jazz Pharmaceuticals paused an early-stage trial after reports of visual and heart-related side effects.²⁷ This challenging history makes the recent breakthrough by the Japanese pharmaceutical giant Takeda all the more spectacular. On July 14, 2025, Takeda announced results from two pivotal Phase 3 trials of its oral orexin receptor 2 (OX2R) agonist, oveporexton (formerly TAK-861), and the data was nothing short of breathtaking.²⁷

Anatomy of a Decisive Victory: The Phase 3 Data

The two large, global studies, named FirstLight and RadiantLight, were an overwhelming success.³⁰ The key takeaways are a litany of clinical trial superlatives:

• Comprehensive Success: The drug met all primary and secondary endpoints in both studies.²⁷ The global trials, which enrolled 168 and 105 participants respectively, evaluated oveporexton against a placebo over 12 weeks.³⁰

• Statistical Power: The results were not just positive; they were profoundly significant, with p-values of less than 0.001 across all major endpoints. This indicates an exceptionally low probability that the results were due to chance.³⁰

• Clinically Meaningful Impact: Oveporexton demonstrated dramatic improvements in objective measures of wakefulness (Maintenance of Wakefulness Test), patient-reported daytime sleepiness (Epworth Sleepiness Scale), and the frequency of cataplexy (sudden muscle weakness), a hallmark symptom of narcolepsy.³⁰

• A True Disease-Modifier: For the first time, a drug has been shown in Phase 3 trials to address the underlying cause of Narcolepsy Type 1—the profound loss of orexin-producing neurons in the brain.³²

• Excellent Safety: The drug was generally well-tolerated, with no serious treatment-related adverse events reported.³⁰ The most common side effects were insomnia and urinary urgency.³⁰ In a strong vote of confidence, over 95% of participants who completed the trials chose to continue into a long-term extension study.²⁷

This achievement is a monumental feat of pharmaceutical R&D, and the leadership at Takeda deserves immense credit especially its legendary President of Research & Development, Dr. Andy Plump and his neuroscience team.

Takeda's success is more than just a win for narcolepsy patients; it represents the ultimate validation of the entire orexin hypothesis. To create a safe and profoundly effective agonist is a far greater challenge than creating an antagonist, as it involves actively stimulating a powerful neurological circuit. Takeda's triumph provides the final, definitive proof that the orexin system is indeed the master regulator of wakefulness. This de-risks the entire field, giving regulators, investors, and scientists immense confidence in the target. It unlocks the second half of the therapeutic map, proving that we can not only safely turn the system down for sleep but also safely turn it up for wakefulness. The circuit is now complete.

The Future is a Switch: A World of Programmed Sleep and Wakefulness

With the proven success of both highly effective orexin antagonists and a profoundly effective orexin agonist, the future of sleep and wakefulness management is no longer a matter of science fiction. We are on the cusp of having a pharmacological "on/off switch" for human consciousness. The implications are staggering.

Imagine a future scenario: A global executive facing a critical negotiation in Tokyo takes a precisely-timed dose of an orexin antagonist like Dayvigo or Quviviq upon boarding their flight, experiencing eight hours of deep, restorative, neuro-protective sleep. Upon landing, instead of battling days of debilitating jet lag, they take a dose of an orexin agonist like oveporexton. Within an hour, they are in a state of crisp, unwavering alertness, cognitively sharp and ready to perform at their peak for the next 16 hours. This is the ultimate biohack: the complete and deliberate control of the human sleep-wake cycle, divorced from the constraints of geography and time zones.

Beyond the Obvious: New Frontiers for Orexin Modulation

This "on/off" capability extends far beyond the realm of executive performance. It has the potential to revolutionize work and life for millions of people in physically and cognitively demanding roles:

• Shift Workers: Over 10 million U.S. adults work night shifts, a practice the International Agency for Research on Cancer has deemed "probably carcinogenic to humans" due to chronic circadian disruption.³⁶ An antagonist/agonist cycle could help mitigate these profound health risks by enforcing a stable sleep-wake pattern, regardless of external light cues.

• Military and First Responders: For soldiers on long missions, surgeons performing marathon operations, or firefighters battling multi-day blazes, the ability to command wakefulness and then command restorative sleep could be a life-saving tool, dramatically enhancing operational readiness and reducing fatigue-related errors.

• Students and Knowledge Workers: The ability to schedule periods of intense, agonist-fueled focus for deep work, followed by antagonist-aided restorative sleep for memory consolidation, could redefine the limits of learning and productivity. I fall into this category.

Furthermore, Takeda's ambitions for its orexin franchise extend beyond narcolepsy to other debilitating disorders of hypersomnolence, such as Narcolepsy Type 2 and idiopathic hypersomnia, potentially bringing relief to a wider population of patients plagued by excessive sleepiness.³⁵ The era of passively accepting the dictates of our internal clocks is ending. A new era of actively programming our cognitive states is about to begin.

The Multi-Trillion Dollar Question: Is Orexin the New GLP-1?

Sizing the Problem: The Epidemic of Poor Sleep

To grasp the true market potential of the orexin drug class, one need only look at the recent trajectory of GLP-1 agonists like Ozempic and Wegovy. They transformed from niche diabetes drugs into a multi-hundred-billion-dollar cultural phenomenon by effectively treating obesity. The parallel with the orexin system is striking. The market is not just those with a diagnosed disorder; it is the vast, underserved population struggling with a fundamental aspect of human health.

Poor sleep is a silent epidemic. Up to 40% of U.S. adults experience some form of insomnia each year, with 5-10% suffering from a chronic insomnia disorder that meets diagnostic criteria.¹⁸ The consequences are not trivial. Poor sleep is deeply intertwined with the largest public health crises of our time. The link to obesity is particularly strong and viciously cyclical: sleep deprivation alters the hormones that regulate appetite, ghrelin and leptin, promoting overeating and weight gain.³⁸ In turn, obesity itself is a major cause of poor sleep and sleep apnea, creating a feedback loop that is difficult to break.³⁸ The prevalence of insomnia among patients seeking bariatric surgery can be as high as 30%.⁴⁰ Beyond obesity, poor sleep is linked to depression, cardiovascular disease, and cognitive decline.³⁸

The GLP-1 Analogy: From Niche to Revolution

The analogy between the GLP-1 and orexin drug classes is built on several powerful parallels:

1. Targeting an Underlying System: GLP-1s succeeded because they didn't just treat a symptom (high blood sugar); they modulated the underlying metabolic signaling system that governs appetite and insulin. Similarly, orexin drugs don't just sedate; they modulate the brain's fundamental sleep-wake regulatory system.

2. A Massive, Poorly Served Market: For decades, the vast markets for obesity and insomnia were treated with suboptimal drugs that had significant side effects and limited efficacy. The arrival of a new class with a superior mechanism and cleaner profile creates the conditions for explosive market adoption.

3. An Unexpected "Superpower": The true catalyst for the GLP-1 revolution was its "superpower": profound weight loss, which expanded its use far beyond its initial indication for diabetes. The orexin antagonist class has its own potential superpower: neuroprotection. The growing evidence that these drugs may reduce the risk of Alzheimer's by clearing pathological proteins could transform them from a treatment for a bothersome condition (insomnia) into a long-term preventative therapy for a catastrophic one (dementia).²⁰ This would expand their addressable market exponentially to include millions of aging individuals at risk for neurodegeneration.

4. A Two-Sided Market Opportunity: Here, the orexin story becomes even bigger than the GLP-1 story. The GLP-1 narrative is about turning a system down (appetite). The orexin narrative is about turning a system down (wakefulness, via antagonists) and turning the same system up (wakefulness, via agonists). This creates a two-sided therapeutic platform, addressing both the massive market for sleep and the significant, emerging market for controlled alertness and cognitive enhancement.

Conclusion: Waking Up to a New Era

The convergence of these factors—a precisely targeted mechanism, a massive and underserved global market, a game-changing neuroprotective potential, and a validated two-sided therapeutic platform—places the orexin drug class on the precipice of a market disruption potentially on the scale of GLP-1s. The work of pioneers like the Clozels at Idorsia and the R&D teams at Takeda has moved us beyond the era of blunt-force sedation. We are entering an age of neuro-modulation, where we can fine-tune the very circuits that govern our conscious states. The dawn of the "on/off switch" for sleep and wakefulness is not a distant dream. It is arriving now, and it will fundamentally change our relationship with work, health, and time itself. The world is about to wake up to a new era of biological control.

In my ideal world of the future, DORAs are combined with safe brain-penetrant NLRP3 inhibitors that are yet to show their effects in human clinical trials but hold the key to inflammaging and neuroinflammation. We just completed the IND-enabling studies of the potentially best-in-class CNS-penetrant NLRP3 inhibitor and are in the partnering mode right now.

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Disclaimer: The information and views expressed in this article are for informational and educational purposes only and do not constitute medical advice. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this article.

The author is sharing personal experiences and opinions. These experiences are not a recommendation or endorsement for any specific treatment, drug, or course of action. The medications and therapeutic strategies discussed may not be suitable for everyone and can have significant risks and side effects. Some of the drugs mentioned are investigational and have not been approved by the FDA or other regulatory agencies for the uses discussed. The author has no financial or material connections to the companies mentioned in this article.

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