OBESITY (1).pptx............................

.........................................................................................................................................................................................................................................

1. Anti-Obesity Drugs Mentor- Dr. D.S. Doneriya Presenter- Dr. SEEMA GOGOI, Asso.Professor P.G. III Year

2. INTRODUCTION WHO defines obesity as abnormal or excessive fat accumulation that presents a risk to health Overweight and obesity are defined by the World Health Organization (WHO) as a BMI of 25-29.9 kg/m2 and a BMI ≥ 30 kg/m2. In 2016, more than 1.9 billion adults were overweight, 650 million were obese. By 2030 an estimated 38% of the world’s adult population will be overweight, 20% will be obese An escalating global epidemic of overweight and obesity – “globesity” 2

3. Classification 3 Weir CB, Jan A. BMI Classification Percentile And Cut Off Points. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541070/

4. 4

5. Sequelae of obesity 5

6. ETIOPATHOGENESIS Two related but distinct processes are involved: Sustained positive energy balance Leptin and energy homeostasis Fuel partitioning, insulin, and obesity Neurobiology of energy homeostasis Resetting of the body weight “set point” at an increased value. 6

7. 7

8. Peripheral hormones that regulate eating behaviour 8

9. Treatments benefit both weight and comorbidities:   Primary, secondary, and tertiary prevention Improvements in cardiometabolic risk factors and reduced diabetes risk have been consistently reported in the Phase 3 trials for AOM’s. OBESITY PHARMACOTHERAPY Principles  Lifelong treatment:   A comprehensive management plan that includes nutrition, physical activity, and behavioral counseling. Expect heterogeneity in weight loss response:   Phase 3 trials have consistently demonstrated that AOMs achieve significantly greater weight loss than placebo when combined with lifestyle modifications Significant inter-individual response variability has been reported, including the possibility of no weight loss (non-responders) to 25% or greater weight loss. AOMs affect pathophysiological pathways that lead to obesity: Neurohormonal dysregulations that cause weight gain and prevent sustained weight loss. Reduction in the anorexigenic hormone leptin and increase in the orexigenic hormone ghrelin. Adaptation responses to diet-induced weight loss affecting energy expenditure, r eductions in basal metabolic rate, challenge weight loss maintenance.

10. Current Non-Pharmacological Therapy Component Weight loss Weight loss maintenance Counselling ≥ 14 in person counselling session × 6 months ≥ 14 in person or telephone sessions × ≥ 1 year Diet low calorie diet with macronutrients based on health status reduced calorie diet, consistent with body weight Physical activity ≥ 150 min/week aerobic activity 200-300 min/week aerobic activity Behavioural monitoring of food intake and physical activity Occasional monitoring of food intake and physical activity 10

11. Anti-obesity drugs used in past Drug Approved Mechanism Withdrawal reason Amphetamine 1947 Central NE release Abuse potential Aminorex 1965 Central NE release PHTN Fenfluramine 1973 Serotonin agonist Heart valvulopathy Phenylpropanolamine 1976 α adrenergic agonist Haemorrhagic stroke Caffeine & ephedra 1994 Non selective adrenergic agonist Cardiac, psychiatric SEs Sibutramine 1997 NE/serotonin reuptake inhibitor MI, stroke , death Rimonabant 2005 Cannabinoid 1 antagonist Depression & suicide 11

12. Currently available anti-obesity drugs Drug MOA C/I Side effect Phentermine Appetite suppressing, causes NE release+ minor DA release CVD, Hyperthyroidism glaucoma, pregnancy Insomnia, dry mouth, constipation, HTN Orlistat Modulates dietary absorption of fat by reducing fat hydrolysis, inhibits gastric & pancreatic lipase Chronic malabsorption syndrome, cholestasis , pregnancy Flatus with discharge, diarrhoea, fecal urgency Phentermine / Topiramate ER Topiramate : enhance thermogenesis Phentermine : appetite suppressant Glaucoma, hyperthyroidism, pregnancy Dizziness, dysguesia , insomnia, constipation, dry mouth

13. Currently available anti-obesity drugs Lorcaserin Selective 5HT receptor agonist, elevation of satiety Pregnancy Headache, fatigue, dizziness, dry mouth, back pain Naltrexon / bupropion SR Bupropion : stimulates POMC Naltrexone : blocks orexigenic effect of ß endorphin activity Uncontrolled HTN, seizures, pregnancy Nausea, constipation, headache, diarrhoea, dry mouth Liraglutide GLP 1 agonist, directly stimualtes POMC, activates reward system h/o medullary thyroid Ca, MEN type 2, pregnancy Nausea, hypoglycemia , diarrhoea, dyspepsia, decreased appetite 13

14. Need for new drugs Huge void in current pharmacological therapy, despite high prevalence and associated cost Poor safety & efficacy of earlier drug prevents active development of anti obesity drug Obesity needs to be managed like a chronic disease with combination therapies in order to achieve sustained success Discovery of newer targets require an understanding of the complex circuitry controlling energy homeostasis 14

15. Recent Advances

16. Metreleptin Leptin Analogue- Injectable recombinant M.O.A.: Improves hyperglycemia and hypertriglyceridemia and decreases hepatic fatty steatosis, role in congenital or acquired lipodystrophic disorder Approved in USA in 2014: first and only drug for non HIV related forms of generalised lipodystrophy Limitation: anti metrileptin antibody, C/I in general obesity not a/w congenital leptin deficiency. 16

17. Setmelanotide MC4R agonist (Melanocortin 4 receptor) Orphan drug status for Prader Willi Syndrome Approved in November 2020 M.O.A.: Appetite suppressant effects by binding to and activating MC4R in PVN of hypothalamus Increases resting energy expenditure in both obese animals & humans Developed for the treatment of obesity arising from POMC, PCSK1, or LEPR deficiency.  Once daily S/C injection. 17

18. Mazdutide M.O.A. : D ual agonist for the glucagon-like peptide 1 receptor (GLP-1R) and the glucagon receptor (GCGR). It has the potential to simultaneously reduce weight, blood sugar, and other comorbidities associated with obesity. Current Status: Completed Phase III in January 2024. 18

19. Tesofensine SNDRI (Serotonin-norepinephrine-dopamine reuptake inhibitor) Phase III trial M.O.A.: presynaptic reuptake inhibitor of Dopamine, Norepinephrine & 5 HT Tesomet : FDC of tesofensine & metoprolol On July 26,2021 FDA granted orphan drug designation for hypothalamic obesity. 19

20. Velneperit NPY (Neuropeptide Y) antagonist M.O.A.: prevents binding of NPY to Y5 receptors, thus decreasing hunger and increasing satiety Discontinued, after results showed no significant benefit over placebo in phase II trial. 20

21. Rimonabant M.O.A.: CB1 (Cannabinoid) Receptor Blocker Activation of CB1 stimulates orexigenic signalling, antagonism stimulates anorexigenic signalling Withdrawn d/t mood fluctuation & suicidal tension Pre clinical trial: Novel compound AM6545 with limited CNS penetration being evaluated in mice in whom it inhibited food intake and weight gain without any aversive side effect. 21

22. Zonisamide -Bupropion Zonisamide: antiepileptic, Na channel modulation, Carbonic Anhydrase inhibition, enhancement of Dopamine and 5HT transmission, used to treat partial seizure with weight loss as side effect. Bupropion: Dopaminergic agent, approved for depression & smoking cessation. 22

23. Zonisamide -Bupropion Rationale for combination: All 3 major Neurotransmitters that regulate appetite and energy homeostasis being targeted Zonisamide induced sedation, psychomotor slowing, cognitive dysfunction and depression coupled with its antiseizure properties complement well to insomnia, psychomotor agitation and anti depressive effect of bupropion. 23

24. Bimagrumab M.O.A. : Antibody blockade of activin type II receptor ( ActR II) signaling stimulates skeletal muscle growth. Current Phase : Phase II 24

25. Cetilistat Pancreatic lipase inhibitor Phase III trial M.O.A.: inhibition of pancreatic lipase reduces absorption of FFA in intestine, resulting in increased excretion of TG in urine Phase II: as effective as orlistat with superior safety profile and less GI side effects 25

26. Resveratrol M.O.A.: Allosteric activator of SIRT 1, also increases mitochondrial activity in brown adipose tissue and skeletal muscle Phase III Silent Information Regulator 1 Protein or Sirtuin, participate in lipid metabolism and insulin resistance, suppresses expression of PPAR γ responsible for fat storage 26

27. Orfoglipron P artial agonist of the GLP‐1 receptor. It has a stronger effect on cyclic AMP signaling than on  β ‐ arrestin recruitment, resulting in a lower risk of receptor desensitization than other GLP1Ras. Current status: Phase III 27

28. Tirzepatide M.O.A. : combines a dual glucose‐dependent insulinotropic polypeptide (GIP) and GLP1RA, has demonstrated a reduction in body weight. Approved in December 2023 Adv. Effects: G.I. symptoms. 28

29. Retatrutide M.O.A. : Retatrutide is a single peptide with agonist activity at the G.I.P., glucagon‐like peptide (G.L.P.)‐1, and Glucagon receptors. Current status: Phase III 29

30. DRUG PHASE MECHANISM Zonisamide-Bupropion Approved in 2000 & 1985 Sulfonamide anti-epileptic and Dopaminergic antagonist Metreleptin Approved in USA in 2014 Leptin Analogue Setmelanotide Approved in Nov. 2020 MC4R Agonist Tesofensine Approved as Orphan Drug in July 2021 for hypothalamic obesity Presynaptic reuptake inhibitor of DA, NE & 5 HT Tirzepatide Approved in December 2023 Dual action GLP-1RA activator & GIP inhibitor Mazdutide Completed Phase III in Jan. 2024 Dual GLP-1R & GCGR Agonist Velneperit Discontinued after Phase II NPY Antagonist Rimonabant Discontinued due to psychiatric side effects in humans CB1 Blocker Cetilistat Phase III Pancreatic Lipase inhibitor Resveratrol Phase III Activator of SIRT-I Orfoglipron Phase III Partial GLP-I Agonist Retatrutide Phase III Triple agonist GLP-1, GIP & Glucagon Receptors Bimagrumab Phase II Actr II Blocker SUMMARY 30

31. THANK YOU