New Trends in Anti Obesity Drugs

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1 New Trends in Anti Obesity Drugs KyoungKon Kim, MD, PhD Gachon University Gil Hospital

2 Why Are the Anti- Obesity Drugs Necessary?

3 Efficacy of Treatment kg % Orlistat 1) 2.7 ( ) 2.9 ( ) Sibutramine 1) 4.3 ( ) 4.6 ( ) Diet (alone) 2) 6.6 ± 0.5 Exercise (alone) 3) 2.4 Bariatric Surgery 4) 39.7 ( ) 61.2 ( ) 1. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev. 2004;(3):CD Miller WC, Koceja DM, Hamilton EJ. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. Int J Obes Relat Metab Disord. 1997;21: Wing RR. Physical activity in the treatment of the adulthood overweight and obesity: current evidence and research issues. Med Sci Sports Exerc 1999;31:S Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004;292:

4 비만치료성공률이 주는교훈 치료가아니라관리의개념으로

5 Anti-Obesity Drugs Used Lately

6 비만치료약물효과 를판정하는기준 FDA efficacy benchmarks for antiobesity agents 1) mean weight loss of at least 5% compared with placebo 2) at least 35% of subjects in the active arm of the study, and at least double the percentage in the placebo group, must show at least 5% loss of baseline body weight

7 FDA approved antiobesity drugs 단기간사용 Diethylpropion Phentermine Benzphetamine Phendimetrazine 장기간사용

8 For Long-Term Management Reductil (sibutramine) neurotransmitter reuptake inhibitor that reduces the reuptake of serotonin (by 53%); norepinephrine (by 54%); dopamine (by 16%) Acomplia (rimonabant): FDA 승인실패후유럽에서도판매중단된상태 Xenical (orlistat): pancreatic lipase inhibitor

9 Appetite Suppressant

10 Sibutramine 1997 년 11 월 FDA 승인, 2010 년 10 월시장철수 Norepinephrine, serotonin, dopamine 의재흡수억제 Sibutramine 자체보다 M1, M2 의약리적활성이더크다. M1, M2 의최대혈장농도는복용후 3-4 시간정도에도달한다.

11 Sibutramine Cardiovascular OUTcomes Trial 1

12 15 SCOUT trial: Overview of plan Brazil Mexico Australia European Countries Belgium Czech Republic Denmark France Germany Hungary Italy Poland Portugal Romania Slovakia Spain UK James WPT, Eur Heart J Supplements 2005: 7 (Suppl 7): L44-48

Overall data summary during 6-week lead-in period with sibutramine Median changes in anthropometric and vital sign parameters (P < 0.

13 Overall data summary during 6-week lead-in period with sibutramine Median changes in anthropometric and vital sign parameters (P < by Wilcoxon signed rank test) Torp-Pedersen et al. European Heart Journal European Heart Journal (2007) 28, doi: /eurheartj/ehm217

14 SCOUT: Outcomes Primary outcome Time from randomization to the first occurrence of any Cardiovascular Outcome Event. Secondary outcome Time from randomization to onset of each of protocol specified events; Allcause Mortality.

15 SCOUT: Inclusion Subject's BMI is > 27 kg/m and < 45 kg/m or their BMI is > 25 kg/m and < 27 kg/m with waist circumference of > 102 cm in males or > 88 cm in females. Medical history positive for: Cardiovascular disease Type 2 diabetes disease

16 Contraindications of Sibutramine History of CAD (e.g., heart attack, angina) History of stroke or transient ischemic attack (TIA) History of heart arrhythmias History of congestive heart failure History of peripheral arterial disease - Uncontrolled hypertension (e.g., > 145/90 mmhg)

17 Phentermine HCl (37.5 mg)

18 Benzphetamine, Phendimetrazine 1970 년대이후의비만치료효과에대한임상연구자료없음

19 Phendimetrazine: Hadler(1968), 105 대상자수 ( 위약 / 약 ) mg/d 시작 42/45, 완료 32/36 기간 : 12주 체중감량 ( 위약 / 약 ) Kg: 0.5/3.4

20 금기 Mazindol Administration 시작 : mg/day 통상 : 1-3 mg/day 투여기간 : 3 개월을한도로함 1 개월내에효과가없는경우에는투여중지 Side effects Dry mouth: 7.1% Constipation: 6.4% Nausea, vomiting: 4.2% Insomnia: 2.1% 장기간사용시에는 pulmonary hypertension 발생가능성을배제할수없다!

21 US Drug Enforcement Agency Classification Schedule II: amphetamine, dextroamphetamine, methamphetamine Schedule III: benzphetamine, phendimetrazine Schedule IV: phentermine, diethylpropion, sibutramine

22 Dexfenfluramine: INDEX, 30mg/d 대상자수 ( 위약 / 약 ) 시작 418/404, 완료 229/254 기간 : 52주 유의한부작용 : tiredness, diahhrea, dry mouth, polyuria, drowsiness

23 Orlistat Nov orlistat 120mg approved Feb orlistat 120mg Launch in Korea Jun 120mg generics Feb orlistat 60mg Launch in Korea Korean Market Global Market Sep orlistat 120mg First Launch Jun orlistat 60mg Launch in US Mar orlistat 60mg Launch in EU

24 Under Development

25 Lorcaserin 경구용제제 5-HT2c agonist Phase 3 trial: BLOOM, BLOSSOM, BLOOM-DM

26 Lorcaserin: Effect BLOOM BLOSSOM Weight loss 10mg bid Placebo 10mg bid 10mg qd Placebo 5%(PP) 66.4% 32.1% 63.2% 53.1% 34.9% 5%(ITT) 47.5% 20.3% 47.2% 40.2% 25.0% 10%(PP) 36.2% 13.6% 35.1% 26.3% 16.1% 10%(ITT) 22.6% 7.7% 22.6% 17.4% 9.7% Mean(PP) 8.2% 3.4% 7.9% 6.5% 3.9% Mean(ITT) 5.8% 2.2% 5.9% 4.8% 2.8%

27 Amylin 37 amino acid compound Co-secreted with insulin from beta cells Deficient in type 1 and type 2 DM Renal clearance

28 Physiologic Effects of Amylin Suppression of endogenous glucagon production (esp. in the postprandial state) Postprandial hepatic glucose production Gastric emptying time Centrally mediated induction of satiety Postprandial glucose level

29 Pramlintide Synthetic analogue of amylin (3 a.a. substitution) Subcutaneous injection Effects in type 1 and 2 DM Prandial glucose HbA1c Prandial glucagon Slowed gastric emptying Weight loss

30 Combination

31 Qnexa Topiramate 100mg + Phentermine 15mg daily Clinical trial (phase II) Duration: 6 months BMI: Qnexa, phentermine, topiramate, placebo Dropout Qnexa 4 (8%)

32 Adverse Events in Qnexa Trial Qnexa Topiramate Phentermin e Placebo Alt. taste 16% 2% 2% 2% Paresthesia 38% 22% 4% 2% Urinary freq. 14% 2% 2% 6% Headache 10% 8% 14% 2% Memory 8% 4% 0% 12% Insomnia 2% 4% 2% 12%

33 Bupropion, Naltrexone, Zonisamide Bupropion 은 norepinephrine 과 dopamine 의활성을올림으로써식욕을 억제하는효과가있는것으로추정 Naltrexone과같은 opioid peptide는음식섭취에서음식자체의쾌락적인측면 을조절하는것같음 Zonisamide는 serotonine과 dopamine 의농도를올려서식욕에영향을주는것 같음

34 Bupropion + Naltrexone (Contrave): Phase III (56 주 ) COR-I COR-II ITT-LOCF PP ITT-LOCF (28주) ITT-LOCF (56주) Placebo 511; - 1.3% 290; - 1.8% 456; - 1.9% 456; - 1.2% NB16 471; -5% 284; - 6.7% NB32 471; - 6.1%* 296; - 8.1%* 825; - 6.5% 702; - 6.4%

35 Adverse Events; COR-I Placebo (569) NB16 (569) NB32 (573) Subjects with 1 AE Nausea Constipation Headache URI Vomiting Discontinuation due to AE Nausea Dizziness

36 Leptin + Pramlintide Leptin은시상하부에비교적장기간의체내지방량을반영하는신호를전달 Amylin은단기간포만감을전달 이둘을함께말초투여 (Pramlintide 360 μg bid + Leptin 5mg bid) 했을때각각의 식욕억제효과가함께상승작용을일으 켜서단독투여시에비해유의하게뚜렷 한체중감량효과 ( 평균 12.7%) 를보였 다.

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract