GERD 치료최신지견및 P-CAB 의역할 성균관대학교의과대학삼성서울병원소화기내과이준행

Transcription

1 GERD 치료최신지견및 P-CAB 의역할 성균관대학교의과대학삼성서울병원소화기내과이준행

2 P-CAB (Tegoprazan, K-CAB TM ) 국내제30호신약 (code명: RQ-4, CJ-12420) Potassium Competitive Acid Blocker

3 위산과위산분비억제제 성균관대학교의과대학삼성서울병원소화기내과이준행

4 William Beaumont 와 Alexis St. Martin Dr. William Beaumont Photo of Alexis St. Martin at about age 81 years (Accident: 19 years old) Illustration by W. Beaumont

5 1822 년 6 월사고직후첫만남에대한 William Beaumont 박사의기록 I was called to him immediately after the accident. Found a portion of the Lungs as large as a turkey's egg protruding through the external wound, lacerated and burnt, and below this another protrusion resembling a portion of the stomach, what at first view I could not believe possible to be that organ in that situation with the subject surviving, but on closer examination I found it to be actually the stomach, with a puncture in the protruding portion large enough to receive my fore-finger, and through which a portion of his food that he had taken for breakfast had come out and lodged among his apparel. In this dilemma I considered my attempt to save his life entirely useless.

6 The man and the opportunity had met. He began those experiments in May 1825 at Fort Mackinac and completed the last in 1833 at Plattsburgh. In 1833, at age 48, Beaumont published his Experiments and Observations on the Gastric Juice and the Physiology of Digestion, a 280-page book divided into two sections. It contains a description of the 238 experiments.

7 Google 에서 e-book 을볼수있습니다.

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9 Stimulated Resting J Clin Invest 2007;117:60 69

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11 위산분비억제제개발의역사 H 2 RA Cimetidine, Ranitidine, Famotidine, Nizatidine, Roxatidine 1 st PPI Omeprazole, Lansoprazole, Pantoprazole 2 nd PPI Rabeprazole, Esomeprazole, Dexlansoprazole, Ilaprazole P-CAB Revaprazan, Vonoprazan, Tegoprazan (K-CAB)

12 PPI vs P-CAB 성균관대학교의과대학삼성서울병원소화기내과이준행

13 Structure of proton pump Shin. JNM 2013;19:25

14 PPIs Conversion to a reactive form Irreversible binding to the external surface of acid pump Need to stimulate proton pump P-CAB Directly binds to K+ Binding domain at resting and stimulated state Reversible binding No need to stimulate proton pump

15 Tegoprazan and other P-CAB and PPIs 분류 P-CABs PPIs Drug Tegoprazan Revaprazan Vonoprazan Esomeprazole Dexlansoprazole Rabeprazole Chemical Structure Formula (MW) C 20 H 19 F 2 N 3 O 3 (387.38) C 22 H 23 FN 4 (362.44) C 17 H 16 FN 3 O 3 SC 4 H 4 O 4 (461.46) C 17 H 19 N 3 O 3 S (345.41) C 16 H 14 F 3 N 3 O 2 S ( ) C 18 H 21 N 3 O 3 S ( ) Derivatives Benzimidazole Carboxamide Pyrimidine Sulfonyl Pyrrole Sulfinyl Benzimidazole Chemical Name (S)-(-)-4-[5, 7-Difluoro-3, 4- yl]pyrimidin-2-amine dihydro-2h-chromen-4- yl)oxy]-n,n,2-trimethyl-1hbenzimidazole-6-carboxamide N-(4-fluorophenyl)-4,5- dimethyl-6-[(1rs)-1-methyl- 3,4-dihydroisoquinolin-2(1H)- 1-[5-(2-Fluorophenyl)-1- [(pyridin-3-yl)sulfonyl]-1h- pyrrol-3-yl]-n- methylmethanamine (S)-5-Methoxy-2-[(4-methoxy- 3,5-dimethylpyridin-2- yl)methylsulfinyl]-3hbenzimidazole (R)-(+)2-([3-methyl-4- (2,2,2- trifluoroethoxy)pyridin-2- yl]methylsulfinyl)-1hbenzo[d]imidazole (RS)-2-([4-(3-methoxypropoxy)- 3-methylpyridin-2- yl]methylsulfinyl)-1hbenzo[d]imidazole pka T max * 1.25h ( h) 1.4~2.2h 1.5h (0.75~3 h) 1.6h 4~5h 3.5h Half life* 3.7~7.1h 14.8~26h 6.1~7h 1~1.5h 1~2h 1~1.5h Indications NDA (EE, NERD), P3 (GU, HP) GU, DU EE, GU,DU, HP EE, NERD, GU,DU, HP EE, NERD EE, NERD, GU, DU, HP * Phase 1 clinical study report/fda Label (Healthy subjects, Multiple dosing) ** EE: Erosive Esophagitis, NERD: Non-Erosive Reflux Disease, GU: Gastric Ulcer, DU: Duodenal Ulcer, HP: eradication of Helicobacter pylori.

16 Benefits of P-CAB compared to PPI More potent acid suppression More rapid acid inhibition Better NAB control Less dependent on CYP2C19 No food effect Optimal for H. pylori eradication

17 1. More potent acid suppression Shin et al. KDDW 2017

18 2. More rapid acid inhibition Day 1. Fast onset (within 0.5~1h ) Day 7. Fast onset (within 0.5~1h ) Faster onset of acid-inhibitory effect (Time to ph 4) Greater acid-inhibitory effect in H. pylori (-) (Mean % time of ph 4) Day 1 Day 7 TEGOPRAZAN 50 mg Within 1 hour Within 1 hour TEGOPRAZAN 50 mg Day % Day % Ref. Clinical study report of [CJ_APA_108] study

19 Intragastric ph 3. NAB control Nocturnal Acid Breakthrough (NAB): >1 hr with ph<4 Does not necessarily denote a temporal relationship with symptom Can deteriorate symptom and progress of GERD PPIs can t control NAB properly due to MOA & properties NAB control of Tegoprazan Nocturnal Acid Breakthrough (NAB) vs. Tegoprazan: NAB control (morning dose) PPI PPI :00~4:00 am Time after dosing (hr) at Day 7 Ref. Modified illustration from Am J Gastroenterol 1998; 93: 763

20 Intragastric ph NAB control of Tegoprazan: evening dose (phase 1 ) PD study for night time dosing at 9:00 pm (single dose, day 1) NAB control: Tegoprazan >> Dexlansoprazole Dosing (IP) Meal Meal Meal Tegoprazan 50 mg Dexlansoprazole 60 mg Baseline Time after dosing (hr) Ref. Clinical study report of [CJ_APA_105] study

21 4. Less dependent on CYP2C19 PPIs are strong inhibitors of CYP2C19. Individual variation by CYP2C19 polymorphism. Drug-drug interaction especially for clopidogrel. Dominant pathway of tegoprazan is CYP3A4 (75%).

22 Individual variation Adachi. Aliment Pharmacol Ther 2000;14:1259

23 Individual variation Variations (PM vs. EM) X5.2 X6.5 X4.9 X3.0 X6.7 PM: poor metabolizer, EM: extended metabolizer. Basic Clin Pharmacol Toxicol 2004:95:2 8

24 Factors of clopidogrel Tx failure Predictors 1-month follow-up 1-year follow-up Adjusted HR P value Adjusted HR P value Age 65 years 2.79( ) ( ) <0.001 MI (diagnosis at PCI) 4.39( ) < ( ) <0.001 Chronic renal failure 6.72( ) < ( ) <0.001 CYP2C19 PM 2.55( ) ( ) PON1 192QQ 3.37( ) ( ) Co-administration of PPIs 2.90( ) ( ) Kim. Circ Cardiovasc Genet. 2013;6:514

25 Vonoprazan metabolic pathway CYP3A4: main catalyzing enzyme Others: CYP2B6, CYP2C19, CYP2D6, SULT2A1 Yamasaki. Xenobiotica 2017;47:1027

26 Tegoprazan metabolic pathway - 75% by CYP3A K-CAB conference ( 신재국 )

27 5. No food effect No food effect on systemic exposures (AUC) Tegoprazan 200 mg Esomeprazole 40 mg* - 9.8% % No food effect on PD Ref. Br. J. Clin. Pharmacol 64: ) Arithmetic Mean Ref. Clinical study report of [CJ_APA_102] study

28 6. > ph 6 by Tegoprazan qd and bid - Optimal for H. pylori eradication Tegoprazan 50mg qd Tegoprazan 50mg bid with clarithromycin and amoxicillin Clinical study report of [CJ_APA_107] study

29 Intragastric ph 7. > ph 6: Tegoprazan bid > PPI bid - Optimal for H. pylori eradication Day 7 Mean % time of > ph % % Tegoprazan 50 mg, BID Pantoprazole 40 mg, BID Time (hr) Clinical study report of [CJ_APA_107] study

30 표준 3 제요법의제균율감소추이 Gong EJ.J Korean Med Sci 2014

31 강력한산분비억제가필요한이유 H. pylori is more likely in a non-replicative state when gastric ph is low (ph 3 6). By raising ph, bacteria enter the replicative state and become susceptible to amoxicillin and clarithromycin. Increase the chemical stability of amoxicillin and clarithromycin in gastric juice, thus preventing the antimicrobials, which are fragile at lower ph levels, from degradation Malfertheiner. Gut 2016, Murakami. Gut 2016

32 Vonoprazan 기반제균치료초기연구 Murakami. Gut 2016

33 Vonoprazan 기반 Hp 제균치료성적 Meta-analysis of 10 studies (n=10,644) Jung. APT Vonoprazan-based triple therapy : 87.9% in ITT analysis - PPI-based triple therapy : 72.8% in ITT analysis

34 두개의 3 상연구가진행되고있습니다. CJ_APA_306 CJ_APA_307 CJ_APA_306: 17 개기관, 등록률 89.1%, CJ_APA_307: 15 개기관, 등록률 23.9% (2018 년 9 월말기준 )

35 GERD 최신치료및 P-CAB 의역할 1. 비약물요법과체중관리, 2. 수술, 3. P-CAB 성균관대학교의과대학삼성서울병원소화기내과이준행

36 Nr of TLESRs / h 1. 비약물요법과체중관리 - transient LET relaxation (TLESR) TLESRs with acid reflux Pre-prandial Post-prandial Asymptomatic volunteers Pre-prandial Post-prandial GERD patients Trudgill NJ & Riley SA Am J Gastroenterol 2001;96:

37 Postprandial acid pocket ph 1.6 ph 4.7 Fletcher & McColl (Glasgow). Gastroenterology 2001:121:

38 In healthy subject fasting 3 min 17 min 43.5 min 47.5 min 73.5 min Clarke & McColl (Glasgow). Gut 2009;58:904-9

39 Location of acid pocket matters. = HH matters. diaphragm 7-20% of TLESRs were accompanied by acid reflux % of TLESRs were accompanied by acid reflux. Beaumont. Gut 2010;59:

40 작지만고정되어있는 hiatal hernia Hernia sac Squamocolumnar junction = B-ring Diaphragmatic orfice Diaphragmatic orfice Ampulla A-ring B-ring

41 All hernias are not equal Nearly all patients with severe reflux disease have hiatus hernia, however, a substantial proportion of patients with mild reflux disease do not. This may be a result of intermittent or partial hiatal hernia undetectable by current methods. Lee YY. BPRCG 2013;27:

42 Single & double high pressure zone Bredenoor. Gastroenterology 2006;130:

43 Hiatal hernia 와 obesity 의관계는? 박무인. GERD academy 2 강

44 TLESR Acid pocket Obesity Hiatal hernia

45 우리가할수있는것은무엇인가? - Conceptual model Gut 2014;63:

46

47 2. LARS (laparoscopic antireflux surgery) - 외과의사주도의 GERD academy

48 3. 새롭고강력한위산분비억제제 : P-CAB Major unmet needs of PPIs Enteric coating & Alu/Alu package 6 1 Delayed onset High potential of DDI High individual variations 5 PPIs 2 Poor control of NAB Poor PD for H. pylori eradication 4 3 Poor compliance due to food effect

49 Healing and symptom control by PPI is different! Dekel R. Drugs 2004;64:277-95

50 Breaktrough symptoms on PPI

51 ph monitoring ph-impedance Gastroenterol Clin N Am 2014;43:89 104

52 ph-impedance monitoring allows identification of subgroups of patients with symptoms that are suspected to be caused by reflux Gut 2014;63:

53 Approach based on phenotype Phenotype 1 은가장깔끔한경우로 pathological reflux가있고 symptom association도있으므로추가적인더강력한위산분비억제제또는다른 antireflux treatment로효과를기대할수있습니다. Phenotype 4 경우 physiological reflux가있고 symptom association은없는경우로 GERD를배제할수있고증상종류에따라 functional heartburn / chest pain 이라고할수있습니다. 이경우 antireflux treatment는효과적이지않을것이라고예상할수있습니다. 자료제공 : 민양원교수님

54 Approach based on phenotype Phenotype 2는다소어렵습니다. Physiological reflux이지만 symptom association이있는경우로 esophageal hypersensitivity가증상발생에관여하면서 PPI 치료효과가떨어지는것이므로, evidence는높지않지만 low dose TCA나 SSRI 같은 perception modulator 사용을고려해볼수있겠습니다. Phenotype 3이가장문제입니다. Pathological reflux가있으나 symptom association는없는경우로, technically GERD라고할수있겠으나 anti-reflux treatment의효과는크지않을것입니다. 하지만 SI의 sensitivity가높지않은점을고려했을때 phenotype 1과같이더강력한위산분비억제제를시도해볼수있을것같습니다. 자료제공 : 민양원교수님

55 P-CAB (Tegoprazan, K-CAB) Simple formulation & package 6 1 Fast onset Low potential of DDI Low individual variations 5 K-CAB Tegoprazan 2 On demand control of NAB Optimal PD for H.pylori eradication 4 3 No food effect

56 Tegoprazan (K-CAB) for GERD

57 Tegoprazan (K-CAB) for GERD

58 Tegoprazan (K-CAB) for GERD

59 Tegoprazan (K-CAB) for GERD

60 Tegoprazan (K-CAB) for GERD

61 Tegoprazan (K-CAB) for GERD

62 Acid-inhibition related PPI 부작용

63 Tegoprazan safety profile

64 간독성등으로개발이중단된약제들 - Chemocal class effect of imidazopyridine 기존개발진행중에중단되었던 P-CAB 중에일 부물질들이공통적으로가지고있던구조가 "imidazopyridine" 으로서 imidazopyridine 이간 독성을유발하는 chemical class effect 를갖고 있음

65 Tegoprazan safety profile

66 Simple formulation of K-CAB Tegoprazan 50 mg 10.0 mm x 6.8 mm Nexium 40 mg 16 mm x 8 mm Nexium 20 mg 14 mm x 7 mm Vonoprazan 20 mg 11.2 mm x 6.2 mm

67 New P-CAB, tegoprazan (K-CAB) More potent & rapid acid suppression Better NAB control Less dependent on CYP2C19 No food effect Optimal for H. pylori eradication Excellent safety profile