Tegoprazan (K-CAB) SKKUSOM 이준행

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

위산과위산분비억제제 성균관대학교의과대학삼성서울병원소화기내과이준행

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)

새롭고강력한위산분비억제제에대하여어떤점을고려해야할것인가? 약효측면에서기존약제와무엇이다른가? 얼마나새롭고얼마나강력한가? 안전한가? 장기사용은가능한가? 고령, 신질환, 간 질환에서용량조절이필요한가? 편리한가? 약물복용시점, On demand therapy, 야 간증상, 유전자형에따른차이 또다른새로운특장점은무엇인가? MMC

오늘의 topic 위산과위산분비억제제 PPI vs tegoprazan Safety issues GERD에서 tegoprazan의역할 결론 : 새롭고강력한위산분비억제제 tegoprazan의다양한잠재적적응증

PPI vs Tegoprazan 성균관대학교의과대학삼성서울병원소화기내과이준행

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

어떤약의 onset 이빠를까요? Prodrug Conversion 후작용 Active form 처음부터바로작용

Reversible, competitive 란 in vitro 의현상일뿐입니다. 중요한것은 in vivo!

분류 P-CABs PPIs Drug Tegoprazan Revaprazan Vonoprazan Esomeprazole Dexlansoprazole Rabeprazole Chemical Structure In vivo 반감기 : 4-6 시간 - PPI 의반감기가보통 1-2 시간임에비하여 tegoprazan 의반감기는매우길다. 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 (369.363) C 18 H 21 N 3 O 3 S (359.444) Derivatives Benzimidazole Carboxamide Pyrimidine Sulfonyl Pyrrole Sulfinyl Benzimidazole Chemical Name (S)-(-)-4-[5, 7-Difluoro-3, 4- 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)- yl]pyrimidin-2-amine 1-[5-(2-Fluorophenyl)-1- [(pyridin-3-yl)sulfonyl]-1hpyrrol-3-yl]-nmethylmethanamine (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 5.2 6.68 9.37 4.06 3.83 4.53 T max * 1.25h (0.5-4.0h) 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.

Radioactivity (ng eq/mg) In vivo: 위조직농도가오래유지됨 Radioactivity of 14 C-tegoprazan in SD rats 10,000 7,500 5,000 At 0.5hr 2,500 0 0 4 8 12 16 20 24 Time (hr) Plasma Stomach At 8hr Ref. Clinical study report of [CJ_APA_101] study, KDDW 2017, P-UG-077, 078

More stable in canaliculi Akazawa. Therap Adv Gastroenterol. 2016;9:845-52

Fast, strong and long Andersson. Pharmacol Ther. 2005;108:294-307

Benefits of K-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

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

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 1 54.5% Day 7 68.2% Ref. Clinical study report of [CJ_APA_108] study

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 7 6 5 4 3 2 1 12:00~4:00 am 0 2 4 6 8 10 12 14 16 18 20 22 Time after dosing (hr) at Day 7 Ref. Modified illustration from Am J Gastroenterol 1998; 93: 763

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%).

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

Tegoprazan metabolic pathway - 75% by CYP3A4 2018-9-29. K-CAB conference ( 신재국 )

5. No food effect No food effect on systemic exposures (AUC) Tegoprazan 200 mg Esomeprazole 40 mg* - 9.8% - 39.8% No food effect on PD Ref. Br. J. Clin. Pharmacol 64:3 386 390. 5.41 5.71 74.4 85.7 71.1 1) Arithmetic Mean Ref. Clinical study report of [CJ_APA_102] study

Intragastric ph 6. > ph 6: Tegoprazan bid > PPI bid - Optimal for H. pylori eradication Day 7 Mean % time of > ph 6 10 88.03 % 58.34 % 8 6 4 2 0 Tegoprazan 50 mg, BID Pantoprazole 40 mg, BID 0 4 8 12 16 20 24 Time (hr) Clinical study report of [CJ_APA_107] study

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

두개의 3 상연구가진행되고있습니다. CJ_APA_306 CJ_APA_307

[CJ_APA_306] [CJ_APA_307] 등록률 350 명 /350 명 (100%) 138 명 /284 명 (48.6%) 선정 제외기준 H. pylori 진단방법 H. pylori 양성인자상부위장관내시경검사상다음의어느하나에해당하는자 - 소화성궤양 ( 위궤양또는십이지장궤양 ) - 반흔기상태의위궤양또는십이지장궤양 - 위궤양또는십이지장궤양기왕력이있었던자 - 만성위축성위염 (chronic atrophic gastritis) UBT( 필수 ) & CLO, 조직검사, 혈청검사, 대변항원검사중택 1 UBT(+) & 추가검사 (+) 양성으로판정 H. pylori 양성인자상부위장관내시경검사상다음의어느하나에해당하는자 - 소화성궤양 ( 위궤양또는십이지장궤양 ) - 저등급위 MALT 림프종 - EMR/ESD 치료후완전절제된조기위암환자로서제균치료가필요한경우 - 만성위축성위염 (chronic atrophic gastritis) UBT( 필수 ) & CLO, 조직검사중택 1 UBT(+) & 추가검사 (+) 양성으로판정 임상시험용의약품 투여방법 1 일 2 회, 7 일, 식후 1 일 2 회, 7 일, 식전 항생제감수성검사위전정부에서 2 개 위전정부및체부대만에서각각 1 개씩 PUD 치료 Active, Healed Stage GU, DU: 라니티딘 (H2-RA) 28 일처방 Active stage GU: 판토프라졸 (PPI) 28 일처방 DU: 판토프라졸 (PPI) 14 일처방

Safety issues 성균관대학교의과대학삼성서울병원소화기내과이준행

강력한위산분비억제의영향을주시해야 Tegoprazan?

현장에서걱정하는부분은? 2019-1-24. Tegoprazan launching symposium (Seoul)

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

PPI 는모두유사한모양이지만 P-CAB 은서로다른구조식을가지고있음 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 (369.363) C 18 H 21 N 3 O 3 S (359.444) Derivatives Benzimidazole Carboxamide Pyrimidine Sulfonyl Pyrrole Sulfinyl Benzimidazole Chemical Name (S)-(-)-4-[5, 7-Difluoro-3, 4- 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)- yl]pyrimidin-2-amine 1-[5-(2-Fluorophenyl)-1- [(pyridin-3-yl)sulfonyl]-1hpyrrol-3-yl]-nmethylmethanamine (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 5.2 6.68 9.37 4.06 3.83 4.53 T max * 1.25h (0.5-4.0h) 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.

Tegoprazan safety profile

현재까지의임상연구에서유의한 heptotoxicity 를보이지않음

Vonoprazan 은 hypergastrinemia 가문제

Tegoprazan 은 lansoprazole 과유사한정도

Esomeprazole 과도유사한정도

GERD 에서 Tegoprazan 의역할 성균관대학교의과대학삼성서울병원소화기내과이준행

현장에서기대하는부분은? 2019-1-24. Tegoprazan launching symposium (Seoul)

1. Erosive esophagitis 의초치료 성균관대학교의과대학삼성서울병원소화기내과이준행

% Total healed % Total heartburn free Erosive esophagitis 에서 PPI 가효과가좋다는것은누구나아는일입니다. Endoscopic healing Relief of symptoms 100 PPI 11.7%/wk 80 PPI 11.5%/wk 80 60 40 H 2 RA 5.9%/wk 60 40 H 2 RA 6.4%/wk 20 0 Placebo 2.9%/wk 20 0 2 4 6 8 12 1-2 3-4 5-6 Weeks Weeks Chiba N et al. Gastroenterology 1997;112:1798

Tegoprazan (K-CAB) for ERD

아마도위산분비억제능력이더좋기때문일것입니다. Shin et al. KDDW 2017

환자들이 PPI 를매우좋아했습니다. 그런데증상호전에는며칠이필요했습니다.

첫 dose 부터 onset 이아주빠른 tegoprazan 이라면어떤효과를보일까요? Shin et al. KDDW 2017

어쩌면증상개선은훨씬더빠르고장기적인 healing rate 는비슷하거나조금더나은정도일지모릅니다. Andersson. Pharmacol Ther. 2005;108:294-307

GERD 초치료와유지요법의새로운전략 Mori and Suzuki. J Neurogastroenterol Motil 2019;25:6-14

2. Non-erosive reflux disease 성균관대학교의과대학삼성서울병원소화기내과이준행

Tegoprazan (K-CAB) for NERD

Tegoprazan (K-CAB) for GERD

3. Refractory GERD 성균관대학교의과대학삼성서울병원소화기내과이준행

Approaches to PPI-refractory GERD ph-impedance (= physiologic subtype) Empirical approach

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

ph-impedance monitoring allows identification of subgroups of patients with symptoms that are suspected to be caused by reflux Gut 2014;63:1185 1193

Approach based on phenotype Type Interpretation Personal approach 1 GERD 더강력한산분비억제제 2 3 정상범위산역류에대한과감각 산역류가있으나그와무관하게 globus 가있는경우 Pain modulator (amitryptiline) + ( 더강력한 ) 산분비억제제 Globus 때문에산분비억제제를쓸필요는없음. 산역류증상은산분비억제제로조절 4 GERD 아님 산분비억제제중단

Refractory GERD 의과거전략과신전략 Mori and Suzuki. J Neurogastroenterol Motil 2019;25:6-14

4. PPI 의 unmet needs 영역 성균관대학교의과대학삼성서울병원소화기내과이준행

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

Tegoprazan 은 PPI 의 unmet needs 에대응하는여러좋은특징을가지고있음 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

Breaktrough symptoms on PPI

Intragastric ph PPI 사용에도불구하고야간증상을가진환자에서사용할수있음 Dosing (IP) Meal Meal Meal 7 6 5 4 3 2 1 Tegoprazan 50 mg Dexlansoprazole 60 mg Baseline 0 2 4 6 8 10 12 14 16 18 20 22 24 Time after dosing (hr) Ref. Clinical study report of [CJ_APA_105] study

식전식후복용할수있어편리하다. On demand therapy 에적용할수있다. 5.41 5.71 74.4 85.7 71.1 1) Arithmetic Mean Ref. Clinical study report of [CJ_APA_102] study

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

Some more comments 성균관대학교의과대학삼성서울병원소화기내과이준행

Migrating motor complex (MMC) 를촉진 J Pharmacol Exp Ther. 2018

Stomach 에서의역할은?

Gastric ESD 의주된합병증은출혈 - ESD 당일아침 tegoprazan 을한번먹으면어떨까?

다른 P-CAB 과의비교

새롭고강력한위산분비억제제 Tegoprazan 의다양한 ( 잠재적 ) 적응증 Erosive esophagitis 의초치료및유지요법 Non-erosive reflux disease (NERD) 초치료유지요법 Refractory GERD 의일부 subtype 혹은경험적치료 Long-term treatment with on-demand method PPI 의 unmet needs 에해당하는경우 야간증상, 아침식전투약이어려운경우 Drug-drug interaction 이우려되는경우, PPI 의부작용 Rapid metabolizer, Clopidogrel 복용자 Helicobacter 제균치료

K-CAB: Fast, Strong and Long