Pharmacology Research Developments

Zepbound (tirzepatide) is now the first prescription medication for treating sleep apnea in adults with obesity. --- On December 20th, the FDA approved Zepbound for moderate-to-severe obstructive sleep apnea in adults with #obesity (announcement in the comments). This approval was based on the phase 3 results of the SURMOUNT-OSA trials (published study also in the comments). The results were clinically impressive. The average participant with #SleepApnea had 50 events each hour of sleeping (that's trouble breathing almost every minute each hour!). You can see in the attached image that Zepbound decreased those events by more than half on average. After one year, 50% of participants had no symptoms of sleep apnea at all. --- Some people will wonder: "Isn't Zepbound already approved for obesity? What's the point of getting it approved for sleep apnea...in adults with obesity?" One major reason is likely that this allows Medicare patients with sleep apnea + obesity to qualify for Zepbound coverage, no matter what happens with the current proposed rule to expand obesity coverage in #Medicare. Another is to connect Zepbound to a disease with much clearer costs and short-term health effects to prove its value. We intuitively understand that obesity has costly health effects that compound over time, but the current data doesn't show strong evidence for big cost decreases in short time horizons (1-2 years). Sleep apnea is the opposite. The therapeutic benefits are immediate and obvious, and the time to improved costs are much shorter than obesity. Sleep apnea is an independent risk factor for cardiovascular disease and hypertension, and increases the risk for other costly diseases like diabetes and depression. There are also increased risks of accidents. This all makes sense if you consider that the average participants in this trial were unable to breathe well almost every minute they were sleeping! As I've said in previous posts, sleep in THE foundation of health, and sleep apnea shakes that foundation. --- There are now FDA indications for #GLP1s for: -Diabetes -Obesity -Heart disease with obesity/overweight -Sleep apnea with obesity What will be next?

Daily Spirulina (2g/day) was shown to improve sleep quality by 29% and reduce symptoms of depression, anxiety, and stress in adults with mild to moderate depression (a trend towards improvements in depressive symptoms). A recent 8-week double-blind, placebo-controlled RCT (PMID: 400516055) evaluated the effects of Spirulina (Arthrospira platensis ) supplementation on sleep and mental health in 66 adults. The intervention used 2,000 mg/day of in softgel form. Study: - Spirulina group: 2g /day at night - Outcomes: Pittsburgh Sleep Quality Index, DASS-21, and Sleep Hygiene Index. Findings: 🔹 Sleep Quality: - ↓ from 7.03 → 4.97 in Spirulina group ( 29.3% improvement) - Placebo showed minor improvement by week 4, then reversed by week 8 🔹 Sleep Latency: - Spirulina group fell asleep significantly faster 🔹 Mental Health: - Gradual reductions in depression, anxiety, and stress over 8 weeks - Placebo group plateaued by week 4 Spirulina contains high levels of tryptophan, a precursor to serotonin and melatonin, both of which regulate sleep and mood. It also delivers: - Phycocyanin – a pigment with antioxidant and anti-inflammatory effects. - Gamma-linolenic acid – a fatty acid that modulates inflammatory pathways. - B vitamins and carotenoids that may support neurotransmitter balance. Together, these compounds likely contributed to better sleep regulation, mood stabilization, and stress reduction through serotonergic and antioxidant pathways. Limitations: 🔸 8-week duration 🔸 No biochemical markers collected 🔸 Spirulina was not standardized to phycocyanin or tryptophan content

Landscape of OXR2 targeting drugs attacking narcolepsy Yesterday, Takeda announced it's oral OXR2 agonist cleared two Phase 3 studies in narcolepsy, opening up a >$3B peak sales opportunity I asked Sleuth to pull together a competitive landscape and flag why analysts believe this is a huge market Some takeaways: Narcolepsy is a neurological sleep disorder affecting 150-300K Americans, but only ~40% are diagnosed and <40% of those get branded therapy. The underlying issue in Type 1 (T1): orexin neuron loss. The market opportunity for new treatments is massive. The current standard of care manages symptoms, not the underlying cause. Sodium oxybates and stimulants deliver modest 15-18 min improvements on the key Maintenance of Wakefulness Test (MWT) endpoint and with significant side effects. These drugs don't address the underlying orexin deficiency at the root of NT1, but OX2R agonists could - underpinning the excitement for overporexton and other assets in this class. The current generation of drugs targets OX2R selectively, rather than OX1R AND OX2R as earlier programs did, as recent evidence has shown narcoleptic effects are mediated by OX2R alone, but not OX1R alone. OX2R data has been game changing: • MWT improvements of 25-35 minutes, nearly maxing out the 40-min scale and significantly higher than the 15-18 minutes observed with oxybates • Next gen treatments have a clean safety profile vs. earlier programs (hepatotoxicity, CV effects and visual disturbance issues) with the conversation now shifting towards tolerability • Potential for a much more simplified polypharmacy regimen for patients - just oxybates (for nighttime sleep issues) and orexin agonists (once daily) Looking ahead, the next major catalysts will be: • ALK-2680 Ph2 NT1 data in Q3'25, which will be closely compared to Takeda's overporexton • ALK-2680 Ph2 NT2 data in the fall 2025 • ORX750 Ph2 NT1 / NT2 / IH data in late 2025 By the end of the year, we should have a good sense of how this landscape will shake out, but regardless, Takeda should be the first to market, and with a follow-up asset in TAK-360 (Ph2), looks to be in a great position to break open this market. If you'd like the full competitive intel on this space, we've mapped 60+ orexin assets (including discontinued programs) - comment below or DM me for a PDF

For the first time, a pharmacological agent has demonstrated a significant impact on obstructive sleep apnea. Sleep apnoea is a terrible disease that increases the risk of cardiovascular death and multiple comorbidities. Those that have moderate to severe sleep apnoea benefit significantly from The Gold Standard treatment CPAP. Over 1 billion people across the planet have sleep apnea. Some patients cannot tolerate or afford the CPAP machine. Since OSA is primarily due to obesity, effective obesity treatment would be beneficial. The first study with Liragltude 3.0 mg showed mild improvement, but not significantly enough for the community to take notice. This new study with Tirzepatide which appeared in the New England Journal of Medicine demonstrated a 50 to 60% decrease in apneic episodes. The weight loss was 18 to 20%. I believe the significant degree of weight loss and the potential for the sustainability of this will allow this condition to be very well treated with pharmacological agents. A40-50% of patients got into the mild sleep apnoea range and the majority got into the moderate sleep apnoea range from severe. This is not a cure, but it certainly a significant impact that we’ve never seen before. It is exciting times.

L-theanine protects the brain from sleep-deprivation-induced ferroptosis in the hippocampus according to a new study. Researchers found that L-theanine “enhances learning and memory in sleep-deprived mice by mitigating NOX4-mediated ferroptosis,” effectively preventing iron-driven oxidative damage in neurons caused by lost sleep. Translation: this amino acid from tea stopped the brain from breaking down its own neurons under sleep debt. I’ve battled insomnia for years, and L-theanine has been one of my most consistent allies. It quiets the mind without sedation and lets me slip into deep, restorative rest. I’ve used 100–400 mg before bed, but this new study used 200 mg/kg in mice, translating to ~1.1 g for a 70 kg human, a range I plan to explore under measured conditions. L-theanine operates in two modes: At night: promotes alpha-wave calm, reduces glutamate excitotoxicity, and supports GABA–dopamine balance. After poor sleep: acts as a neural stabilizer, reducing NOX4 activity, preventing ferroptosis, and supporting mitochondrial integrity. It helps restore equilibrium rather than force stimulation. My preferred form is fermented L-theanine, which provides the pure L-isomer found naturally in tea. Evidence has been found across studies: ▪️Promotes relaxation without sedation (Biol Psychol, 2008) ▪️Reduces cortisol during acute stress (Nutrients, 2016) ▪️Improves attention, cognitive performance (Nutr Neurosci, 2019) ▪️Enhances sleep quality, reduces latency in mild insomnia (Nutrients, 2019) ▪️Maintains healthy glutamate–GABA balance (Neurochem Res, 2018) ▪️Supports mitochondrial resilience and neuroprotection (Front Nutr, 2023) Stack for sleep & recovery: Before bed: ▪️L-theanine (SunTheanine, 200–400 mg) Promotes alpha-wave calm and sleep readiness. ▪️Fermented glycine (NNB, 3 g) Lowers core body temperature and extends deep-sleep duration. Morning (after poor sleep): ▪️Creatine (Pürest Creatine, 20+ g) Replenishes brain phosphocreatine and ATP for cognitive recovery. ▪️L-theanine (SunTheanine, 200–400 mg) Mitigates oxidative stress and stabilizes neurotransmission. ▪️Paraxanthine (enfinity) Cleaner adenosine antagonism than caffeine; sustained alertness without jitter or crash. ▪️Alpha-GPC (GeniusPure) Delivers highly bioavailable choline; shown to double focus and processing speed in one dose (Nutrients, 2024, Kerksick et al.*) ▪️GoBHB (Ketone Labs, 2–5 g L-BHB) Fast-acting neuronal fuel that bypasses glucose fatigue; the L-isomer preferentially supports brain energy and neurotransmission, while the D-isomer fuels muscle and peripheral metabolism. Enfinity with theanine represents a cleaner evolution, smoother dopaminergic signaling, less tolerance buildup, and minimal rebound fatigue. Adding GoBHB stabilizes neuronal metabolism, enhances mitochondrial efficiency, and bridges the energy gap that follows sleep deprivation. NNB Nutrition TSI Group NutriScience Innovations Ketone Labs

Targeting melatonin receptors in the brain can increase REM Sleep using a novel active compound Melatonin MT1 receptor activation boosts REM sleep in preclinical study REM sleep is crucial for memory consolidation, emotional regulation, and brain health, yet most sleep medications primarily target non-REM sleep. A new preclinical study in male rats tested a first-in-class compound, UCM871, a selective partial agonist of the melatonin MT1 receptor, to see whether it could specifically enhance REM sleep. Researchers found that UCM871: - Increased REM sleep duration in a dose-dependent manner—especially during the light (inactive) phase—without altering non-REM sleep. - Did not disrupt overall sleep architecture, meaning the balance between different sleep stages was preserved. - Worked by inhibiting norepinephrine neurons in the brain’s locus coeruleus, a key wake-promoting region. - Lost its REM-boosting effect when MT1 receptors were blocked or genetically “knocked down” in these neurons, confirming the mechanism. The findings suggest that selectively activating MT1 receptors could be a novel approach for treating disorders where REM sleep is reduced, such as certain psychiatric conditions. While this research was in animals, it opens a pathway for developing future melatonin-based therapies with more targeted effects on sleep quality. Study in Journal of Neuroscience: https://lnkd.in/daSeCaP6 #melatonin #sleep #brain #neuroscience #education #medicine #science #research

Sleep apnea research links gut health to new treatment possibilities Link: https://lnkd.in/erFXfV6U The article, published earlier this month in the journal Sleep Medicine, was led by Marshall medical student Rebecca Hicks, in collaboration with faculty researchers. It explores how gut microbiota—the diverse community of microorganisms living in the digestive tract—may influence the development and severity of sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA). Alterations in gut microbiota composition have been consistently observed in individuals with sleep apnea, and may induce "leaky gut," or impaired intestinal barrier integrity, that in turn promotes systemic inflammation that worsens sleep apnea symptoms and facilitates the emergence of end-organ injury. "Recent studies suggest that changes in gut microbiota diversity and composition may play a role in the onset or progression of sleep apnea," said Hicks, lead author on the review. "This connection may be mediated by impaired gut barrier function, inflammation, immune responses and gut-brain communication pathways." The review also highlights the role of extracellular vesicles (EVs)—tiny particles released by cells that carry molecular signals—as potential messengers between the gut and brain. These EVs may affect sleep regulation by modulating immune responses or transporting microbial signals to the brain and could serve as biomarkers or therapeutic targets in modulating the gut-brain axis in sleep apnea. The authors, which include David Gozal, M.D., M.B.A., Ph.D. (Hon), Sarfraz Ahmed, Ph.D., and Abdelnaby Khalyfa, M.S., Ph.D., all of Marshall University, call for future longitudinal studies to better understand how gut microbiome changes over time may influence the development or consequences of sleep apnea. They also advocate for deeper investigation into the mechanisms by which microbial species and their metabolites affect sleep, and for the development of new treatments aimed at improving gut health as a strategy for managing sleep apnea. "It is exciting to see medical students taking the lead in exploring complex and emerging areas like the gut-sleep connection," said Khalyfa, professor of biomedical sciences at Marshall University, corresponding author on this study and Rebecca's mentor. "This kind of research not only advances our understanding of sleep apnea but also demonstrates the vital role early career trainees can play in shaping the future of medicine in general, and of sleep medicine in particular through innovation and collaboration." #sleep #guthealth #sleepapnea #osa #sleep2025 #sleeptrends #cpap #health #healthcare #research

Among the areas of interest with the MC4R agonist approach for treating obesity is the potential to improve pulmonary function in areas like sleep apnea. The team at Johns Hopkins led by Veselov Polotsky recently produced a paper https://lnkd.in/e-uUBfsS "Targeting melanocortin 4 receptor to treat sleep-disordered breathing in mice" in April 2025 demonstrating in mice how setmelanotide or a next generation MC4R agonist or other obesity drugs could improve sleep apnea treatments with a therapeutic.

As a doctor, I see it every week, 𝘀𝗹𝗲𝗲𝗽𝗶𝗻𝗴 𝗽𝗶𝗹𝗹𝘀 being prescribed too easily, and continued for too long. Yes, sleep medications like 𝗯𝗲𝗻𝘇𝗼𝗱𝗶𝗮𝘇𝗲𝗽𝗶𝗻𝗲𝘀 (𝗔𝗹𝗽𝗿𝗮𝘇𝗼𝗹𝗮𝗺, 𝗖𝗹𝗼𝗻𝗮𝘇𝗲𝗽𝗮𝗺) 𝗮𝗻𝗱 𝗭-𝗱𝗿𝘂𝗴𝘀 (𝗭𝗼𝗹𝗽𝗶𝗱𝗲𝗺) have their place. But the real issue is long-term, unsupervised use often without addressing the underlying cause. 𝗜𝗻𝗱𝗶𝗮’𝘀 𝘀𝗹𝗲𝗲𝗽 𝗮𝗶𝗱𝘀 𝗺𝗮𝗿𝗸𝗲𝘁 is growing at 9.4% 𝗖𝗔𝗚𝗥, expected to reach over $300 𝗺𝗶𝗹𝗹𝗶𝗼𝗻. That’s not just demand, it’s dependency. Here’s what we see in clinic: ✅𝗡𝗲𝘂𝗿𝗼𝗮𝗱𝗮𝗽𝘁𝗮𝘁𝗶𝗼𝗻: Over time, the brain becomes less responsive, needing higher doses. ✅𝗖𝗼𝗴𝗻𝗶𝘁𝗶𝘃𝗲 𝘀𝗶𝗱𝗲 𝗲𝗳𝗳𝗲𝗰𝘁𝘀: Memory lapses, reduced alertness, poor decision-making. ✅𝗦𝗹𝗲𝗲𝗽 𝗮𝗿𝗰𝗵𝗶𝘁𝗲𝗰𝘁𝘂𝗿𝗲 𝗱𝗶𝘀𝗿𝘂𝗽𝘁𝗶𝗼𝗻: These drugs sedate, but they suppress deep sleep and REM. ✅𝗥𝗶𝘀𝗸 𝗼𝗳 𝗿𝗲𝗯𝗼𝘂𝗻𝗱 𝗶𝗻𝘀𝗼𝗺𝗻𝗶𝗮: When stopped suddenly, symptoms often return worse. ✅𝗜𝗻𝗰𝗿𝗲𝗮𝘀𝗲𝗱 𝗱𝗲𝗺𝗲𝗻𝘁𝗶𝗮 𝗿𝗶𝘀𝗸: Long-term use has been linked to higher rates of cognitive decline (UCLA Health, 2023 study). The solution to insomnia is not sedation. We need to talk more about: ✅𝗖𝗼𝗴𝗻𝗶𝘁𝗶𝘃𝗲 𝗕𝗲𝗵𝗮𝘃𝗶𝗼𝗿𝗮𝗹 𝗧𝗵𝗲𝗿𝗮𝗽𝘆 for Insomnia (CBT-I) ✅𝗦𝗹𝗲𝗲𝗽 𝗵𝘆𝗴𝗶𝗲𝗻𝗲 ✅Managing 𝗮𝗻𝘅𝗶𝗲𝘁𝘆 and 𝗰𝗶𝗿𝗰𝗮𝗱𝗶𝗮𝗻 𝗿𝗵𝘆𝘁𝗵𝗺 disorders If you're prescribing or taking sleep medication, the goal should always be short-term use under supervision. As doctors, we need to reframe the conversation: Sedation isn’t sleep. And symptom relief isn’t treatment. #SleepHealth #ClinicalNeurology #InsomniaCare #MentalHealth

Scientists have discovered that norepinephrine, released in rhythmic waves during deep sleep, drives the brain’s glymphatic system, which pumps cerebrospinal fluid to clear toxins. However, sleep aids like zolpidem may disrupt this process, reducing the brain’s cleaning efficiency. Researchers in Denmark discovered that norepinephrine plays a crucial role in the brain cleaning process, at least in mice. During deep sleep, the brainstem releases waves of norepinephrine roughly every 50 seconds. These waves cause blood vessels in the brain to contract, creating slow, rhythmic pulsations that propel surrounding fluid to carry away waste effectively. The scientists found that norepinephrine waves correlate to variations in brain blood volume, suggesting it triggers a rhythmic pulsation in blood vessels. They then compared the changes in blood volume to brain fluid flow and found that brain fluid flow fluctuates in correspondence to blood volume changes, suggesting that the vessels act as pumps to propel the surrounding brain fluid to flush out waste. “It’s like turning on the dishwasher before you go to bed and waking up with a clean brain,” says senior author Maiken Nedergaard of the University of Rochester and University of Copenhagen, Denmark. “You can view norepinephrine as this conductor of an orchestra,” says lead author Natalie Hauglund of the University of Copenhagen and the University of Oxford, UK. “There’s a harmony in the constriction and dilation of the arteries, which then drives the cerebrospinal fluid through the brain to remove the waste products.” Hauglund then had another question: is all sleep created equal? To find out, the researchers gave mice zolpidem, a common drug to aid sleep. They found that the norepinephrine waves during deep sleep were 50% lower in zolpidem-treated mice than in naturally sleeping mice. Although the zolpidem-treated mice fell asleep faster, fluid transport into the brain dropped by more than 30%. The findings suggest that the sleeping drug may disrupt the norepinephrine-driven waste clearance during sleep. “More and more people are using sleep medication, and it’s really important to know if that’s healthy sleep,” says Hauglund. “If people aren’t getting the full benefits of sleep, they should be aware of that so they can make informed decisions.” The team says that the findings likely apply to humans, who also have a glymphatic system, although this needs further testing. Other researchers have observed similar norepinephrine waves, blood flow patterns, and brain fluid flux in humans. Their findings may offer insights into how poor sleep may contribute to neurological disorders like Alzheimer’s disease. For more on this study, see: https://lnkd.in/eSkdkSyP #Sleep #SleepHealth #Norepinephrine #zolpidem