vozaneris (1).pptx for md and DM GASTROENTEROLOGIST

astroenterology is the branch of medicine focused on the digestive system and its disorders. The digestive system consists of the gastrointestinal tract, sometimes referred to as the GI tract, which includes the esophagus, stomach, small intestine and large intestine as well as the accessory organs of digestion which include the pancreas, gallbladder, and liverastroenterology is the branch of medicine focused on the digestive system and its disorders. The digestive system consists of the gastrointestinal tract, sometimes referred to as the GI tract, which includes the esophagus, stomach, small intestine and large intestine as well as the accessory organs of digestion which include the pancreas, gallbladder, and liverastroenterology is the branch of medicine focused on the digestive system and its disorders. The digestive system consists of the gastrointestinal tract, sometimes referred to as the GI tract, which includes the esophagus, stomach, small intestine and large intestine as well as the accessory organs of digestion which include the pancreas, gallbladder, and liverWhat is a gastroenterologist?
A gastroenterologist is a medical doctor who specializes in conditions affecting your digestive system. Gastroenterologists begin as general physicians. They complete three years of medical residency after medical school, treating all kinds of diseases and conditions. To become gastroenterologists, they complete three years of additional study after that. Then they receive a special certification. This certification designates them as experts in gastrointestinal diseases and conditions. It also qualifies them to perform certain exams and procedures that general physicians don’t, and to interpret the results.

What is a pediatric gastroenterologist?
A pediatric gastroenterologist is a pediatrician first, with extra training in gastroenterology. Pediatricians spend their three years of medical residency practicing general pediatric medicine, treating babies, children and teens for all kinds of conditions. Pediatric gastroenterologists study for three more years after that to earn their certification. They study the gastrointestinal and liver conditions that are most relevant to growing children, with a special emphasis on nutrition. They learn how to interpret children’s signs and symptoms and how to perform exams and minor procedures inside their smaller bodies.

What part of the body does a gastroenterologist focus on?
The name, gastroenterologist, refers to your stomach and intestines. (“Gastro” means stomach, “entero” means intestines and “ologist” means specialist.) These are the organs most commonly involved in gastrointestinal diseases (diseases affecting your digestive tract). But your digestive system also includes your mouth and esophagus, where you swallow your food. And it includes the organs in your biliary system, which supply bile and digestive enzymes to your intestines. These include your gallbladder, pancreas, liver and bile ducts. G

1. Clinical Outcomes of Vonoprazan in GERD and Other Acid Peptic Disorders Dr HP Yadav, MD, DM Asso Director Medanta Institute of Digestive & Hepatobiliary Sciences July 2024

2. Proton Pump Inhibitors Established Use Gastroesophageal reflux disease Erosive esophagitis NERD Barrett’s esophagus Peptic stricture PPI trial for typical symptoms Peptic ulcer disease Bleeding Gastroprotective, erosive disease H pylori eradication MALT lymphoma Eosinophilic esophagitis Acute nonvariceal GI bleeding Stress ulcer bleeding (short term) Chronic pancreatitis and refractory steatorrhea on panc enzyme therapy Hypersecretory states Side Effects Abdominal pain, headache, diarrhea Fundic gland polyps Impaired absorption of certain medications (e.g. ketoconazole) Gastrointestinal infections Idiosyncratic microscopic colitis and interstitial nephritis May impact magnesium homeostasis Gyawali CP. PPI: Friend or Foe. Curr Gastroenterol Rep 2017;19:46

3. Over the counter medications: antacids, alginates Proton pump inhibitors H2 receptor antagonists Gastric Acid is the common target Rogers BD, Gyawali CP. Ind J Gastroenterol 2019 Buffer acid Competitively inhibit histamine stimulated acid secretion Covalently bind and disable activated proton pumps GERD Management

4. Acid Manipulation: Why Do We Need New Options? Kinoshita Y, et al. J Neurogastroenterol Motil . 2018;24:182-196. PPIs are vulnerable to degradation by gastric acid Enteric coating protects them from acid but delays absorption PPIs are prodrugs Must be activated by gastric acid to bind covalently to proton pumps Short plasma half-life (2 to 3 hours) Stomach constantly making new proton pumps (25% replaced in 24 hours) Repeated administration required Only actively secreting parietal cells are blocked by PPIs Fasting: only ~ 5% of proton pumps actively secreting With meals: 60% to 70% of proton pumps actively secreting Individual variability in rate of metabolism by CYP2C19

5. Night time acid control Ease of administration Better/faster/more complete healing of advanced esophagitis Better/faster symptom control Safe, without prominent drug-drug interactions Potassium Competitive Acid Blockers: animal studies Inhibitory efficacy 80x that of omeprazole at pH 6.4 Single dose completely inhibits basal acid secretion - Mermelstein J, et al. Drugs Today ( Barc ). 2020;56(11):715-721 , Frontiers in Acid Manipulation

6. Potassium-Competitive Acid Blockers (PCABs) Oshima T, et al. J Neurogastroenterol Motil. 2018;24:334-344. Acid stable Do not require enteric coating Active drugs Not prodrugs like PPIs Not metabolized primarily by CYP2C19 I nhibit H + , K + - ATPase Bind ionically to H + , K + - ATPase Bind active and inactive proton pumps No need to time dose around meals

7. History of PCAB Development 1982 SCH 28080 hepatotoxicity 2007 AZD0865 efficacy similar to esomeprazole concern for hepatotoxicity 2004 YH1885 revaprazan not superior to PPIs 2015 TAK438 vonoprazan 2018 CJ12420 tegoprazan 2020 DWP14012 fexuprazan 2023 JP1366 zastaprazan omeprazole 1979 lansoprazole rabeprazole pantoprazole 1980-86 dexlansoprazole 2009 esomeprazole 1993

8. PCAB: Mechanism of Action Leowattana W, et al. World J Gastroenterol 2022;28:36-8=19. Laine L, et al. Am J Gastroenterol 2022;11158-61 PPIs are prodrugs, activated by acid to sulphenamides that covalently bind to cysteines in the activated proton pump PCABs do not require activation, and bind competitively and ionically to the K + binding site in the proton pump

9. Potassium Acid Channel Blockers vs. PPIs 9 P-CABs PPIs Acts directly on the H + K + ATPase enzyme in both resting and stimulated states Requires transformation to an active sulphenamide Super-concentrates in parietal cell acid spaces ~100,000x greater than in plasma Concentrates in parietal cell acid spaces ~1,000x greater than in plasma P-CABs bind competitively and reversibly to the K + binding site of the H + K + ATPase enzyme PPIs bind irreversibly and covalently to the H + K + ATPase enzyme Duration of effect is related to the half-life of P-CAB in plasma (3.7-5.4 hours) Duration of effect is related to the half-life and regeneration of H + K + ATPase (0.5-2.1 hours) Stimulation of H + K + ATPase (via food intake) not required Stimulation of H + K + ATPase (via food intake) required Full effect is achieved at first dose (1 day) Full effect achieved following multiple doses (4-5 days) (Hunt, et al 2018) 8

10. P-CABs vs. PPIs: Time to Efficacy Scarpignato C et al, Annals of the New York Academy of Sciences 2020;1482:193-212

11. Vonoprazan in Erosive Esophagitis Phase 3 multicenter randomized double-blind parallel group comparative study 409 eligible patients, 401 completed the comparative phase, and 305 entered the maintenance phase Ashida K et al. APT 2016;43:240-51 Vonoprazan may have an advantage in advanced grades of esophagitis

12. Laine L, et al. Gastroenterology. 2023;164:61-71. Vonoprazan in Erosive Esophagitis Phase 3 multicenter randomized double-blind study comparing vonoprazan 20 mg and lansoprazole 30 mg 1024 eligible patients were included in the healing phase, 514 randomized to vonoprazan and 510 to lansoprazole

13. Maintenance of Healing Vonoprazan is Superior in LA C/D Laine L, et al. Gastroenterology. 2023;164:61-71 Randomized, double blind, multicenter trial Mean age 51.3 years, 53% female, 34.3% with LA C/D esophagitis Vonoprazan was non-inferior to lansoprazole overall in esophagitis healing by 8 weeks (92.9% vs. 84.6%, p<0.0001) Vonoprazan was superior to lansoprazole in LA C/D esophagitis healing at 2 weeks and 8 weeks Maintenance 24 weeks 878 patients

14. Vonoprazan in Heartburn Relief in NERD Randomized, double blind, multicenter trial 772 patients with heartburn ≥4 days a week and negative endoscopy randomized to placebo, vonoprazan 10 mg and 20 mg Patients on placebo re-randomized to vonoprazan 10 mg or 20 mg; all patients continued medications for 20 weeks 4 week data 20 week data Laine L, et al. Clin Gastroenterol Hepatol 2024, in press Vonoprazan 10 mg: 8.3% and 11.6% gain over placebo on days 1 and 2 Vonoprazan 20 mg: 18.1% and 23.2% gain over placebo on days 1 and 2 Vonoprazan 10/20 mg: mean % days without heartburn: 61-63% median % days without heartburn: 76-78% % heartburn free days placebo: 27.7% vonoprazan 10 mg: 44.8% vonoprazan 20 mg: 44.4% p<0.0001

15. Phase 3 Trial of Vonoprazan vs. placebo in NERD Heartburn Free Days with 4-week therapy with Vonoprazan 10 mg Kinoshita Y, et al. Clin Translational Gastroenterol. 2019;10 . In Vonoprazan group Early onset of heartburn relief Greater cumulative proportions with heartburn relief Greater proportion with heartburn relief at end of therapy Patients with heartburn and no/low grade esophagitis randomized to placebo (n=245) or vonoprazan 10 mg (n=238) for 4 weeks

16. Vonoprazan On-Demand Treatment for Symptomatic NERD Randomized Phase 4 Study p < 0.0001 for all doses vs placebo Fass R, et al. APT 2023;58:1016-27 . 207 patients with heartburn ≥4 days a week and negative endoscopy with no heartburn for previous 7 days on randomized to vonoprazan 10 mg, 20 mg, 40 mg and placebo on demand on 1:1:1:1 basis for 6 weeks Proportion of heartburn episodes relieved within 3 hours and no further heartburn for 24 hours. Significantly more heartburn episodes were relieved with vonoprazan doses compared to placebo (p≤0.01 compared to placebo) When taken on-demand in NERD, vonoprazan relieves heartburn within 3 hours and benefits last at least 24 hours

17. Refractory Erosive Esophagitis Shirai Y. JSRD 2022;7:57-61 Scleroderma: Switched to vonoprazan PPI refractory esophagitis Vonoprazan 20 mg daily Healing at 4 weeks: 91.7% Healing at 8 weeks: 88.5% Maintenance of healed esophagitis Vonoprazan 10 mg daily 82.6% at week 8 86.0% at week 24 93.8% at week 48 Symptom improvement 74.6% at week 4, 51.9% at week 8 Simadibrata DM et al, J Gastroenterol Hepatol 2024, in press

18. Meta-analysis: PCABs in Acid-Related Diseases 19 studies with 7023 participants Vonoprazan was superior to PPI in healing of erosive esophagitis week 2 (RR 1.09, CI 1.03-1.14) week 4 (RR 1.03, CI 1.00-1.07) week 8 (RR 1.02, CI 1.00-1.05) PCABs non-inferior in improvement of GERD symptoms PCABs non-inferior in healing of gastric and duodenal ulcers Simadibrata DM et al J Gastroenterol Hepatol 2022;12:2217-28 LA C/D erosive esophagitis initial treatment: 9267 participants, 13 RCTs: PCAB failure 6%, PPI 21% maintenance: 1834 participants, 4 RCTs: PCAB failure 21%, PPI 30% Zhuang Q et al Am J Gastroenterol 2024; in press

19. Iwakiri K, et al. J Gastroenterol 2022;57:267-85 Mild Reflux Esophagitis Severe Reflux Esophagitis PCABs in GERD Guidelines Japan

20. PCABs in GERD Guidelines Seoul Consensus Jung HK et al. J Neurogastroenterol Motil 2021; 27(4):453-481 Statement 21: The efficacy of potassium-competitive acid blockers is comparable to proton pump inhibitors; hence they are recommended as an initial treatment of gastroesophageal reflux disease. Potassium-competitive Acid Blockers Level of evidence: moderate Strength of recommendation: strong Experts’ opinions: agree strongly (66.7%), agree with some reservations (33.3%), undecided (0.0%), disagree (0.0%), and disagree strongly (0.0%) Gastroesophageal reflux disease Typical symptoms Atypical symptoms If symptom sustained Symptom resolution Presumptive GERD Reflux esophagitis Barrett’s esophagus Abnormal acid exposure Normal acid exposure (+)Sx-reflux association Normal acid exposure (-)Sx-reflux association Proton pump inhibitors Potassium-competitive acid blockers Prokinetics /baclofen/alginate Anti-reflux surgery Questionnaires Neuromodulators Proven GERD NERD Reflux hypersensitivity Functional heartburn Endoscopy +/- biopsy PPI test Ambulatory pH +/- impedance Unproven GERD (-) (+) ERD

21. Vonoprazan in Helicobacter pylori Eradication Randomized, Controlled, Phase 3 Trial Chey WD et al, Gastroenterology 2022;163:608-19 1046 treatment naïve adults with Helicobacter pylori infection randomized 1:1:1 to open label vonoprazan dual therapy, or double blind vonoprazan vs. lansoprazole triple therapy for 14 days Dual therapy: vonoprazan 20 mg bid, amoxycillin 1 g tid Triple therapy: vonoprazan 20 mg bid OR lansoprazole 30 mg bid; amoxycillin 1 g PLUS clarithromycin 500 mg bid Clarithromycin non-resistant strains Clarithromycin resistant strains All patients Vonoprazan dual and triple therapy is superior to PPI based therapy, particularly in Clarithromycin resistant strains

22. Meta-analysis: PCABs in Helicobacter pylori Eradication 7 RCTs, 7 observational studies, 1 comparative study 8049 patients (4471 PCAB, 3578 PPI) in ITT analysis Vonoprazan was superior to PPI in RCT (RR 1.17, CI 1.11-1.22, p<0.0001) in observational studies (RR 1.13, CI 1.09-1.17, p<0.0001) Kanu JE, Soldera J. World J Gastroenterol 2024;30:1213-23

23. Potential for Hypergastrinemia Ashida K, et al. World J Gastroenterol . 2018;24(14):1550-1561 Vonoprazan 12 16 20 24 4 8 LPZ 15 mg VPZ 10 mg VPZ 20 mg t/wK 1600 1400 1200 1000 800 600 400 200 Serum gastrin (pg/ml) e e e

24. Vonoprazan Safety Phase 3 trial comparing Vonoprazan and Lansoprazole in Erosive Esophagitis Laine L, et al. Gastroenterology. 2023;164:61-71.

25. Other Attributes Acid suppression with PCABs, including nocturnal pH control, is not dependent on CYP2C19 status PCABs are metabolized by CYP3A4, but do not induce or suppress this No significant pharmacokinetic interactions with NSAIDs or agents used for Helicobacter pylori eradication Limited short term side effects reported in clinical trials, consisting of dyspepsia, diarrhea, dizziness and nasopharyngeal infections Risk of hepatotoxicity is very low, cumulatively lower than PPIs No deficiencies of iron, magnesium, Vit B12 or folate over long term Potential for reversible hypergastrinemia Yang E, et al. Br J Clin Pharmacol. 2022;88(7):3288-3296 Moon SJ, et al. Clin Ther . 2022 Jul 1:S0149-2918(22)00214-4 Hwang S, Frontiers Pharmacol 2021;754849

26. PCABs Are an Option for Refractory Acid Peptic Disorders Expert Perspective Severe reflux esophagitis (LA-C or LA-D) who do not heal on optimized double dose PPI Patients who are not good candidates for anti-reflux procedure due to comorbidities Persistent s ymptomatic reflux including ‘on demand’, especially reflux symptoms in proven NERD Patients with motility issues: esophagus and gastric GERD patients with… Other patient categories… Helicobacter pylori eradication, especially with antibiotic resistance Hypersecretory states Barrett’s after ablation?

27. 13 studies included, Effect sizes of vonoprazan for ulcer healing was 33% higher compared to PPIs were at 4 weeks and 48% higher at 8 weeks. The overall risk for the occurrence of delayed bleeding was 34% less with vonoprazan compared to PPI.

28. BMC Gastroenterol 23, 139 (2023). Human gastric biopsy specimens were obtained from 135 patients treated with vonoprazan 10 mg or 20 mg once daily for up to 260 week No neoplastic changes were observed

29. Safety

30. Indications

31. Recommended Dosage

32. Japanese Society of Gastroenterology guidelines (2021) Conditions Recommendation Initial treatment of mild RE Both medications are recommended as a first-line treatment for patients with mild RE. (Strong recommendation, Evidence level B, 100% agreed). Initial treatment of severe RE Vonoprazan at 20 mg once daily for 4 weeks is proposed as the initial treatment of patients with severe RE. (Evidence level: C, 100% a greed) when the effect of a PPI is insufficient at the standard dose If esophageal mucosal breaks do not heal or the patient develops severe symptoms despite standard PPI treatment, a change to the standard dose of PPI twice daily or vonoprazan 20 mg once daily is recommended. (Strong recommendation, Evidence level B, 93% agreed) long-term management of mild RE, P-CAB is proposed for the long-term maintenance of mild RE. (Evidence level C, 86% agreed) long-term management of severe RE? Vonoprazan at 10 mg once daily is proposed for the long-term management of severe RE due to the low endoscopic relapse rate. (Evidence l evel C, 93% agreed) J Neurogastroenterol Motil 2021 Oct 30;27(4):453-481.

33. Is the P-CAB test more useful than the PPI test? The P-CAB test may be more useful than the PPI test. Empirical acid suppression with the ‘‘PPI test’’ or ‘‘P-CAB test’’ is often used in the primary care setting as a simple, non-invasive, and cost-saving ‘diagnostic’ test to evaluate whether upper gastrointestinal symptoms are due to GERD. The pooled sensitivity and specificity of a positive PPI test result were reported to be 0.78 and 0.54, respectively, when an abnormal 24-h pH study was used as the reference standard. P-CAB achieves the rapid and marked suppression of gastric acid secretion in a dose-dependent manner , which results in greater symptom improvements than conventional PPI in patients with RE and NERD Therefore, the P-CAB test may be more useful than the PPI test; however, further investigations are warranted to assess the optimal dosage and duration of P-CAB as well as the appropriate tool for evaluating symptomatic relief.

34. USPs: Vonoprazan Expert Opinion on Pharmacotherapy, 2027 18:11, 1145-1152

35. USPs: Vonoprazan Expert Opinion on Pharmacotherapy, 2027 18:11, 1145-1152,

36. 1- Now you have two class of drugs, what would be your choice of drug for acid related diseases ? 2- What would be the impact of new drug on fundoplication rate ? 3- Is there any place for PPI after introduction of vanoprazan ? 4- Any comment on side effect profile ? 5-