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Lessons Learned from CB1 Blockers: Rethinking Our Approach to Weight Management Drugs

This article analyzes the challenges and missteps in the development of CB1 blockers for weight management, emphasizing unforeseen side effects and the complexities of targeting the endocannabinoid system. The discussion covers the obesity and metabolic syndrome market, highlighting the unmet medical needs and the pharmacological battle surrounding weight-loss drugs. Key insights include the importance of improving clinical trial designs, understanding patient populations, and the necessity of creativity in translational research. The analysis seeks to inform future drug development strategies for effective weight management therapies.

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Lessons Learned from CB1 Blockers: Rethinking Our Approach to Weight Management Drugs

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  1. Lessons learned from CB1 blockers: did we try to crack a nut with a sledgehammer ? Prof. Renger F. Witkamp Nutrition and Pharmacology

  2. Lancet, 2007

  3. Clearly, these side-effectswerenotexpected, but.... • Where did it go wrong (if at all) ? • Could (should) we have foreseen this ? • What can we learn from it ?

  4. Analysis: elements and drivers • The obesity and metabolic syndrome market • A pharmacological battle difficult to win • A pleiotropic system as target • First in class & relatively new target • Risk-benefit balance : nottoo much credit

  5. Weight management market • Problem with high prevalence • Clear unmet medical and social need • Not much competition so far • Succesful drug will become blockbuster

  6. Pharmacological management of body weight: a battle against the most powerfull instincts

  7. Story of weight loss drugs is cumbersome and full of serendipity Bray GA & Greenway FL (2007) Pharmacological Reviews 59(2): 151-184.

  8. Somepharmacological targets underdevelopment Witkamp, Pharm Res (2011) 28:1792–1818

  9. Development pipeline (mid 2012) Nature Reviews Drug Discovery sept 2012

  10. cannabinoids endo-cannabinoids

  11. The endo-cannabinoid system (ECS): • Endocannabinoids: • Formed “on demand” from lipid precursors in postsynaptic cells • Many ligands, partly non-specific and overlapping with TRPV1, PPARα etc • Retrograde messengers, but also other routes • Receptors: CB1,CB2…. • Essential role in energy metabolism, satiation, rewarding, craving, inflammation etc • CB1 : central but also peripheral • CB2 : mainly peripheral

  12. Effects of CB1 stimulation: non homeostaticoverconsumptionand fat storage Insuline resistance ^ HDL-cholesterol Triglycerides ^ Glucose uptake Adiponectine Hypothalamus: hunger N. Accumbens: motivationtoeat Entero endocrine regulation: continue eating Liverandadipose tissue: lipogenesis en lipid storage

  13. Consumption of food just for pleasure and not to maintain energy homeostasis. Food is consumed uniquely because of its gustatory rewarding properties. In the brain: ECS stimulates Hedonic Hunger

  14. CB1 receptor is highly abundant in brain ….. and linked to “hedonic hotspots”

  15. Rimonabant was an effective and promising drug • Produced consistent weight loss. • Caused also direct metabolic effects of peripheral CB1 blockade (next to weight-dependent cardiometabolic effects) • Approximately half of the overall effect of rimonabant was due to direct action on peripheral tissues for HDL-cholesterol, triglycerides, HbA1c, insulin and adiponectin ECS: endocannabinoid system; HDL: high-density lipoprotein

  16. But whatwere the problems? • CB1 = Pleiotropic target; ligands determine selectivity. • Inverse agonistsmaynotbegoodideahere • Difficultkinetics, linkedto side-of-action (lipofillic) • Difficultendpoint: Rewarding/Hedonics • Side-effectslesswell acceptedin relationtoindication • CNS side-effects difficult tomeasure in animals

  17. Possiblerescue of the target: Second generation CB1 blockers • Different kinetics : relativelylowerbrainconcentrationsand more peripheral action • Different dynamics : no inverse agonistslike rimonabant, but neutralantagonists or partialagonists

  18. Conclusions • Weight loss is a difficultindication • Linkedto well-being; hedonics • Multi-factorial, so are complicationslikeMetSyndrome • Didit go toofast ? • Stillrelatively new and complex target • Pharmacologynotoptimal • Risk-benefit balance of class = challenging

  19. Lessons for the future ? • Improvements of clinical trial design taking into account mechanism of action. • Improve technical attrition (translational target to medicine) • Develop/Hire experienced drug hunters (who don’t just kill but ask the right questions)

  20. Lessons for the future (2) ? • Human patient data and identification of best indication in early clinical development • Tailoring for specific patient (sub)populations (pathology, genotype, etc.) • Introduce creativity in translational and clinical research

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