Pharmacology Research Developments

Sleep disturbances affect 20% of Americans, with 70% comorbidity between anxiety and insomnia. Our recent RCT found that mindfulness training targeting worry—not sleep directly—reduced sleep disturbances by 27%. The key insight: letting go of the goal of sleeping allows sleep to happen. New article on the neuroscience and practical applications: 

Important very large scale individual participant data meta analysis (IPD MA) published today in The Lancet Group. It finds that only 4 of 66 currently listed side effects of statin therapy are in fact causally related to statins. This raises some fundamental questions about how observational data is used to list what patients and doctors perceive as known side effects of drugs, but may often be artefactual findings. It also raises the importance of being aware that the further use of RCT data for IPD MA is a hugely important secondary objective of RCTs, and of seeking to standardize key outcome measures to enable such meta analyses ( eg see the COMET initiative)   Given that appropriate statin therapy has very large benefits for cardiovascular disease primary and secondary prevention, is widely available and highly affordable, clarifying any true harms is very important.   Congratulations to the collaborative group that performed this analysis, led by University of Oxford (lead author Christina Reith), a Global Clinical Trial Forum member. https://lnkd.in/e-ZBMQjD This issue is likely fundamental and probably spans very many medicinal products. Should prompt some serious consideration as to how to address this issue.

A Single Injection That Could Change Heart Disease Forever For decades, cardiovascular disease has been managed, not cured. Millions of people take daily statins or regular injections to keep cholesterol in check. The science works, but adherence is hard, side effects are real, and lifelong treatment is the price of survival. Now, a new chapter may be opening. In early human clinical trials, scientists have demonstrated that a single CRISPR-based gene-editing treatment can dramatically reduce LDL (“bad”) cholesterol by roughly 50% and triglycerides by more than 50% after just one administration. These results were presented in peer-reviewed scientific settings and represent one of the first times CRISPR has been used in humans to address a common chronic disease, not a rare genetic disorder. That alone is historic. How it works (in plain language) Instead of treating cholesterol repeatedly, researchers used CRISPR gene editing to switch off a gene in the liver that plays a major role in cholesterol regulation (most notably ANGPTL3, with similar work ongoing for PCSK9). The liver produces the majority of cholesterol-related proteins in the body. By editing the DNA in liver cells, the therapy essentially tells the body to stop overproducing harmful lipids at the source. No daily pills. No monthly injections. Just one intervention, followed by sustained reductions observed months later. How this differs from statins and current drugs Traditional cholesterol treatments work downstream: Statins must be taken daily for decades, PCSK9 inhibitors require repeated injections. CRISPR is different. It’s not managing cholesterol, it’s reprogramming how the body handles it. That’s why researchers describe this approach not as maintenance medicine, but as genetic intervention. These trials are early-stage (Phase 1) Follow-up so far spans months, not decades Scientists expect durability, but lifetime permanence is not yet proven Long-term safety monitoring is essential, because gene editing is not reversible In other words: this is not ready for routine clinical use, but it is real science with real results, not hype. Why this matters globally, Cardiovascular disease remains the leading cause of death worldwide. Many patients stop taking medications over time due to cost, side effects, or fatigue. A one-time therapy could: Improve outcomes for high-risk patients, reduce long-term healthcare costs and transform prevention from daily discipline to single-event intervention. It marks a transition in medicine, from treating symptoms repeatedly to changing biological instructions directly. It may end the era of “one pill at a time” medicine. What replaces it will define healthcare for generations. #CRISPR #GeneEditing #CardiovascularHealth #MedicalInnovation #Biotechnology #FutureOfMedicine #LeadershipInScience #HealthEquity

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

A groundbreaking new treatment known as VERVE-102 is poised to revolutionize the way we prevent heart attacks. Unlike traditional cholesterol-lowering medications like statins, which must be taken daily for life, VERVE-102 offers a one-time gene-editing injection that could provide lifelong benefits. The therapy works by targeting and deactivating a specific gene in the liver, PCSK9, which plays a crucial role in regulating levels of low-density lipoprotein (LDL) cholesterol — commonly referred to as "bad" cholesterol. By switching off this gene, the liver becomes more efficient at clearing LDL from the bloodstream, resulting in a sustained 50% reduction in cholesterol levels. This treatment is currently in clinical trials and has already been administered to patients in the UK, including at University College London and Barts Health NHS Trust. According to Prof. Riyaz Patel, an academic cardiologist involved in the trials, the results so far have been “spectacular.” He emphasized that this is not a concept out of science fiction — it is real, in practice, and may fundamentally change the landscape of cardiovascular health management. For patients who struggle with daily medications or who experience side effects from statins, VERVE-102 represents a potential lifesaving alternative that simplifies long-term care. What makes VERVE-102 especially significant is its gene-editing approach, which involves altering a very small section of DNA to suppress PCSK9 production. This strategy not only ensures a permanent effect but also opens doors to similar interventions for other chronic conditions. If approved after further safety and efficacy trials, it could mark a paradigm shift in preventive medicine, reducing the global burden of heart disease, one of the leading causes of death worldwide.

Novartis just bet $1.4B on a biotech most people hadn't heard of 2 years ago. Here's why this deal could reshape cardiovascular medicine: Sept 9: Novartis announced it will acquire Tourmaline Bio for $48 per share, a 60% premium over its $30 close the day before. Valuation: $1.4B The entire bet revolves around a single drug called pacibekitug. Pacibekitug is an antibody that targets IL-6, a proinflammatory cytokine. Why IL-6? Because inflammation drives atherosclerosis. The liver responds by producing CRP, a biomarker that predicts cardiovascular risk. High CRP equals high risk of heart attack and stroke. In May, Tourmaline released data from its Tranquility Phase 2 trial. 143 patients with kidney disease and elevated CRP. Results: • 50mg dose → CRP down 86% • 25mg dose → CRP down 75% • 15mg dose → CRP down 85% • Placebo → 15% That signal changed everything. Why does this matter? Today, there are no widely adopted anti-inflammatory therapies for cardiovascular risk. If pacibekitug holds up, it could become the first therapy to address residual inflammatory risk in Atherosclerotic Cardiovascular Disease (ASCVD). That is a paradigm shift. Novartis is uniquely positioned here. Its portfolio already includes Entresto for heart failure, Leqvio for cholesterol, and pelacarsen in late stage. Adding pacibekitug broadens the franchise into inflammation biology. Tourmaline's path is also remarkable: • 2022: licensed pacibekitug from Pfizer (($5M cash upfront + 15% equity stake) • 2023: reverse merger with Talaris + $75M raise • 2025: $1.4B buyout One asset. One trial. One transformative exit. For Novartis, this is textbook franchise-building. Novartis is doubling down on inflammation, one of the largest unmet needs in cardiovascular disease. Why pacibekitug could win: • 86% CRP reduction is compelling • Quarterly dosing vs monthly injections • Platform potential beyond ASCVD • Already in trials for thyroid eye disease But the hard part starts now. Phase 2 de-risks biology, not commercial reality. Novartis must prove outcomes in Phase 3, secure approvals, and negotiate payer adoption. Execution will decide if the premium pays off. Competition is fierce: • Novo Nordisk's ziltivekimab is moving fast • Multiple IL-6 programs in development • Superiority on outcomes will be the deciding factor Zoom out, and the sector trend is clear. Phase 2 conviction commands outsized premiums for best-in-class assets. For biotech leaders, there are 3 core lessons: • Big Pharma looks for a pipeline in a product to sustain large operations • Franchise-building beats single-asset bets • Cardiovascular is being reframed as an immunology market Novartis bet $1.4B to show the playbook. If later trials disappoint, the premium may look ambitious. But bold bets define sector leadership. That's why this deal matters far beyond one antibody.

We are excited to share our latest publication, "Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis" published today in Nature. Nature Magazine https://rdcu.be/ej7AZ https://lnkd.in/gcnj4CAa   Congratulations to Sangkyun Cho and Siyeon Rhee who co-led the study, and to the amazing team from Stanford Cardiovascular Institute, Stanford University School of Medicine, University of Pennsylvania, The Ohio State University, University of California, Davis: Christopher Madl, Arianne Caudal, Dilip Thomas, Hyeonyu Kim, Ana Kojic, Hye Sook (Danielle) Shin, Abhay Mahajan, James W.S. Jahng, Xi Wang, Phung N Thai, David T. Paik, Mingqiang Wang, McKay Mullen, Natalie Baker, Virginia D. Winn, Y. Joseph Woo, and Helen Blau.   Special thanks to computational scientists Jeremy Leitz and Souhrid Mukherjee from our startup company Greenstone Biosciences for their help with the in silico screen and molecular dynamics work.   Why is this study important? Fibrosis--the stiffening of tissue that results from excessive extracellular matrix accumulation--is a major component of most, if not all forms of cardiovascular disease. Despite its widespread impact, fibrosis has remained notoriously difficult to treat.    Major technical/biological challenges that have hampered the development of successful therapies include: 1) The lack of fibroblast-specific druggable targets, and 2) an often-overlooked feedback loop in which the mechanically stiffened tissue environment continues to activate fibroblasts--the very cells that drive fibrotic remodeling--even after the initial pro-inflammatory signals subside.   Our solution: We developed a new strategy that shuts off not only the soluble signals that initiate fibroblast activation, but also the mechanical cues that perpetuate the vicious cycle of fibrosis. To achieve this selectively in fibroblasts, we identified a druggable 'mechanosensor' that is particularly enriched and activated in stromal populations of the heart--the focal adhesion-associated kinase SRC. Through a virtual screen of >10,000 compounds, we identified saracatinib as a potent SRC inhibitor. Combining saracatinib with known drugs that block TGFbeta signaling led to synergistic attenuation of fibrosis and recovery of contractile function. We demonstrated the drug combination's antifibrotic effects at the cellular, tissue, and animal levels.   Broad clinical implication: Our study provides a new type of 'mechanotherapy' for the treatment of cardiovascular fibrosis. While many challenges remain, the general approach has the potential to be extended to other organ systems (lungs, liver, kidney, skin), given the near-universal implications of fibrosis in disease and aging of solid tissues. Additional links to the story: https://lnkd.in/gnmPpnkb https://lnkd.in/giYXDPAW

💫 Exploring the Impact of Xenobiotics and Medications During Pregnancy Pregnancy is a transformative period in a woman’s life, but it also brings physiological and biochemical changes that can significantly influence how medications interact with the maternal body. These changes not only affect drug efficacy and therapeutic outcomes but also increase the risk of complications, including teratogenic effects and other adverse outcomes. 🙂↕️ In my thesis, I focused on assessing the exposure of pregnant and breastfeeding women to xenobiotics and medications. Through a combination of systematic reviews, meta-analyses, surveys, and advanced toxicological screenings, my research provides a comprehensive understanding of medication use during pregnancy and its associated risks. Key highlights include: ✅ Evaluation of self-medication practices and medicinal plant use among pregnant women. ✅ Toxicological screenings to identify medication intake during pregnancy. ✅ Publication of high-impact research articles in indexed international journals (Q1). ====> First Part: Literature Review: This part consists of three chapters: Chapter 1: Explores the peculiarities of pharmacokinetics and toxicokinetics during pregnancy and the factors influencing transplacental drug transfer. Chapter 2: Discusses medication prescription practices for pregnant women and the associated risks of teratogenicity. Chapter 3: Examines the risks related to the use of xenobiotics among pregnant and breastfeeding women. ====> Second Part: Practical Research : This section is also divided into three chapters: a. A systematic review aimed at evaluating the prevalence, motivations, and factors associated with medicinal plant consumption among pregnant women in the Mediterranean region. Reference: Bouqoufi et al. (2023). Pharmaceutical Biology, Taylor & Francis (IF = 3.8, Q1). b. A meta-analysis estimating the global prevalence and associated factors of self-medication among pregnant women. Reference: Bouqoufi et al. (2024). BMC Public Health (IF = 4.8, Q1). c. Surveys on self-medication practices among pregnant and breastfeeding women attending the Hassan II Regional Hospital in Agadir. Reference: Bouqoufi et al. (2024). Frontiers in Pharmacology (IF = 5.6, Q1). d. Surveys estimating the prevalence of medicinal plant use, identifying the plants used, and their preparation methods for managing pregnancy-related symptoms at the same hospital. Reference: Bouqoufi et al. (submitted). International Journal of Women’s Health (IF = 2.3, Q1). e.Biological and toxicological analysis of urine samples from pregnant women to identify medications consumed during pregnancy. Immunochromatographic tests were used, with confirmations via advanced LC-MS/MS and GC techniques. Reference: Bouqoufi et al. (submitted). Biomedical Chromatography (IF = 2.3, Q3). #Research #thesisfinding #scientificresearch #Phd #Phdresearch #Paper #Article #Thesis

Here's some 'behind the curtain' learnings from our first trial of Bright Light Therapy (BLT) - focusing on morning light: *Sunlight is the best source* Back in the 2000s, we encouraged sunlight - simply due to its superior brightness. We always instructed to never look at the sun. Don't be under a verandah. Don't wear a hat. Don't wear sunglasses. Don't shut your eyes. *Evening types "hate" morning light* Yes, we asked this extreme question, and 85% avoided morning light at all costs. *Motivation to go outdoors* If you're asking someone to do something they avoid, they need a positive reinforcer. The greatest uptake were 'walking to the shop to buy something' or 'walking the dog'. We noticed cases that walked may have resulted in a better outcome - later on, we tested adding physical activity to Bright Light Therapy, as well as testing exercise's independent circadian effects. *Artificial white bright light works* The 'Tecclight' in the study and accompanying video was a simple desk lamp, modified with a opaque plastic visor, leaving a gap for heat to escape. A 'stop-gap' while waiting for the Re-Timers to be available. We instructed to have the lamps at arm's length away from the face (the video producer thought it looked better on the floor). *Motivation to get artificial light* We recommended either watching TV or reading, such that the light was in their peripheral vision, and thus not in their foveal vision. *Bright light therapy is quick* They had experienced 'delayed sleep phase disorder' for a mean of 4 years 8 months. Bright light therapy produced sleep benefits within 3 weeks. *BLT fails when getting up too early* When teens put school classes before their sleep therapy, they got up earlier than they should've, wore sunglasses until the designated time to have their eyes exposed to bright light - and it inevitably failed. Light is not the only input to the circadian rhythm. *Less need to do cognitive therapy after BLT* Insomnia was prevalent in this circadian rhythm disorder. Yet after initial BLT, sleep and insomnia symptoms improved so much, teens worried less in bed, and depression symptoms gradually improved - which got us *really* curious about the mechanisms between sleep, insomnia, circadian rhythms and depression ... The Society of Behavioral Sleep Medicine has listings of experts in circadian therapies across the globe; people with world-leading expertise who can help. And it goes without saying, we can help too. #sleep #light #circadianrhythms #insomnia #depression #cbt