This document discusses gastrointestinal reflux disease (GERD) and approaches to treating it. It begins by defining GERD and describing its typical clinical presentations. It notes that lifestyle factors like obesity have only weak evidence of aggravating GERD symptoms. Certain medications are also described as potentially aggravating GERD. The document then discusses the phenotypic classification of GERD and reviews the symptoms. It provides data on the prevalence of GERD worldwide and in particular countries and regions. Reasons for treatment failure with proton pump inhibitors are summarized. New therapies for GERD like vonoprazan, a potassium-competitive acid blocker, are introduced and its advantages over proton pump inhibitors are highlighted. Clinical evidence is presented demonstrating

1. NEW ERA IN PEPTIC ULCER Disease
-
SAJID KHAN PESHAWAR
PAKISTAN
An O ld Disease with New
Approaches

2. What is GERD?
GERD should be defined as symptoms or
complications resulting from the reflux of gastric
contents into the esophagus or beyond, into the
oral cavity (including larynx) or lung.

3. Clinical Presentation of GERD
Typical/
Esophageal
Heartburn
Acid regurgitation
Atypical/
Supra esophageal
Chest pain
Laryngitis
Asthma
Sinusitis
Chronic cough
Aspiration
pneumonia
Tooth decay

4. There is only weak evidence that lifestyle factors
aggravate GERD symptoms
• Obesity:
• severity of esophagitis correlates with weight only when
BMI >30 kg/m 2
• contradictory studies into weight loss indicate no
effect/improvement in GERD.
• Smoking:
• lowers LES pressure and the acid -neutralising effect of
saliva.
• Physical activity:
• running might provoke GERD by increasing TLESRs.
Meining A et al. Am J Gastroentero 2000;95:2692.

5. Medications mayaggravate
GERD symptoms
Impairment of LES function:
• beta-adrenergic agonists
• theophylline
• anticholinergics
• tricyclic antidepressants
• progesterone
• alpha-adrenergic antagonists
• diazepam
• calcium channel blockers.
Damage to the esophageal
mucosa:
• acetylsalicylic acid and other
NSAIDs
• tetracycline
• quinidine
• bisphosphates.

6. Phenotypic Classification of GERD
GERD
NERD*
Erosive
Esophagitis
Barrett’s
Esophagus
Fass et al. Alim Pharm Ther 2005
*NERD: Non - Erosive Reflux Disease
Barrett's esophagus is a condition in which tissue that is
similar to the lining of your intestine replaces the tissue lining
your esophagus. People with Barrett's esophagus may
develop a rare cancer called esophageal adenocarcinoma

7. What are the Symptoms of GERD?
• Heartburn
• Regurgitation
• Chest pain
• Impaired QOL
• Others (burning mouth/tongue)
• Atypical (“supraesophageal”) symptoms
• These are the same symptoms as patients with erosive esophagitis
and Barrett’s esophagus
• The severity of these symptoms CANNOT PREDICT the subtype of
GERD into which a patient falls prior to endoscopic examination

8. Taken from Medscape.com

9. Endoscopic Images
Normal Squama- LA Grade A LA Grade D columnar junction
Esophagitis

10. Indications for additional investigations
• Atypical history.
• Symptoms are frequent and long -standing or do not respond to
therapy.
• Alarm symptoms are present:
• severe dysphagia
• weight loss
• bleeding
• hematemesis
• mass in the upper abdomen
• anemia

11. What are the Symptoms of
Symptomatic GERD?
•
Heartburn
• Regurgitation
• Chest pain
• Impaired QOL
• Others (burning mouth/tongue)
• Atypical (“supra esophageal”) symptoms
• These are the same symptoms as patients with erosive esophagitis
and Barrett’s esophagus
• The severity of these symptoms CANNOT PREDICT the subtype of
GERD into which a patient falls prior to endoscopic examination

12. Prevalence of GERD
Worldwide

13. US
18.1 % to 27.8%
Ref. https://www.ncbi.nlm.nih.gov/books/NBK441938/
EU
8.8 % to 25.9%
Ref. World J Gastroenterology. 2017 Jan 21; 23(3): 525 – 532.
Prevalence of GERD Worldwide

14. Prevalence of GERD,Peptic Ulcer &
H . pylori infection in Pakistan
Ref. Journal of Pakistan Medical Association. Volume 42, Issue 9
Professional Medical Joiurnal. Vol 17 No 03 (2010): Vol. 17 No. 03
Disease Burden in
Pakistan
Pakistan spend nearly 27
Billion PKR annually for acid
related Diseases.
IMS data 2021
The age adjusted rate
of gastric ulcer patients
shows that 0.7 males and 0.3
females/ 10,000 population of
Karachi might be suffering
from gastric ulcer .
( )
Among PUD Patients
Prevalence of infection
with H. pylori varied to
92 % in Pakistani
population
In Pakistan 24 % of the
population is suffering
from GERD
Ref. Journal of the College of Physicians
and Sureons - - Pakistan: JCPSP 15(9):532 -4

15. • Helicobacter pylori ( H. pylori) infection is one
of the most common chronic bacterial infections
in humans affecting approximately 4.4 billion
people worldwide, with a prevalence of 28 % to
84 % in different populations
• Globally Peptic ulcer disease affects
approximately 4.6 million people annually.
Prevalence of H. pylori infection and Peptic
Ulcer Worldwide
Clinical — alimentary tract| volume 153, issue 2, p420 - 429 , august 1, 2017
Peptic ulcer. OMICS International. August 1, 2019

16. Why Do therapies Fail to
Control Symptoms?

17. PPIs have been used for more than a quarter-century as a first-line
treatment for these diseases, it has become clear that there are some
issues in need of improvement.
 It takes several days to show maximal effect.
 Reflux symptoms of GERD are not sufficiently relieved after the first
dose of PPI in 2/3 patients due to slow onset of the action, 1/3 of
patients still have symptoms even after 3 days of treatment.
 Effects of PPI are influenced by cytochrome p450 (CYP) 2C19
polymorphism.
 Unsatisfactory effects at night • Requires an acidic environment for
activation, PPI are unstable in acidic conditions

18.  To overcome the mentioned unmet needs, alternative formulations of
conventional PPIs and new H+K +ATPase inhibitors have been established.
 Immediate-release Omeprazole and Dex lansoprazole modified release (MR),
which improve nocturnal acid breakthrough (NAB)
 Dex lansoprazole MR is a R-enantiomer of lansoprazole and is a PPI with dual
delayed-release formulation Dual release system in the duodenum and small
intestine gives 2 peak concentrations within 2 hours and 5 hours after
administration.
 % time 24-hour intragastric pH › 4 of Dex lansoprazole MR 60 mg and
lansoprazole 30 mg once daily for 5 days administration was 71% and 60%,
respectively

19. Reasons for treatment “Failure”
• Patient non-compliance
• Persistent esophageal acid exposure
• Hypersecretory state
• Large hiatal hernia
• Nocturnal acid breakthrough
• Acid-sensitive esophagus
• Non-acid reflux
• Wrong diagnosis
• Functional heartburn (NOT GERD!!)

20. Survey of Satisfaction Status with PPI’s
Patients dissatisfied
with PPI
Physicians
dissatisfied with PPI
Ref: Digestive Diseases and Sciences volume 55, pages3415 - 3422 (2010)
1000 patients & physicians survey in the US

21. Current Therapies Status

22. Current therapies including
PPIs, have limited response due
to:
1. Slow onset of action
2. Insufficient duration of acid control
Which results in..
Nocturnal
heartburn
Postprandial
heartburn
J.Neurogastroenterol Motil, Vol. 24 No. 3 July,
2018
Which can leads to..

23. Unmet need ,limitations of ppi’s
Molecule % Time pH>4 a No. Hours pH>4 b Mean pH
Esomeprazole 58.43 % 14 hours 4.04
Rabeprazole 50.53 % hours
12.1 3.70
Omeprazole 49.16 % hours
11.8 3.54
Lansoprazole 47.98 % hours
11.5 3.56
Pantoprazole %
41.94 10.1 hours 3.33
Ref: Current Diagnosis & Treatment 2020 (Gastro)
3rd
edition 2020
Chapter 11 ,Page 163 Table 11-5
a. Percentage of time that intragastric pH was 4.0
b. Mean 24-Hour intragastric pH on Day 5 by treatment group
PPI’s are unable to maintain pH>4

24. Reflux symptoms persist after 1 st
dose
Symptoms persist after 3 days
Heartburn & regurgitation not relieved
Patients used twice daily PPI
Addition of another antacid required with PPI
Unmet needs of Patients with PPI
treatments
66 %
50 %
40 %
22 %
42 %
J.Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018

25. REVOLUTION
In The Management of Acid Peptic Diseases

26. Mode of Action
Vonoprazan is a Potassium
Competitive Acid Blocker
(P -CAB) and Inhibits acid
secretion by Competitively
Blocking availability of
potassium to hydrogen -
potassium ATPase.
J.Neurogastroenterol Motil, Vol. 24 No. 3 July, 2018

27. Advantages of P -CAB
VS
Activated drug needs no
(
activation also stable in acid)
hours half
>7 -life
No dependency on meal
Limitations of PPIs
Prodrug need acid for activation
(
but active drug is unstable in acid)
<2 hours half -life
Meal required for activation
(one hour before meal recommended )
Comparison PPI V/S P -CAB

28. Indication and Uses
https://newdrugapprovals.org/2016/04/24/vonoprazan -fumarate/
• Gastro -esophageal reflux/ reflux esophagitis/
erosive esophagitis
• Peptic ulcer /gastric ulcer/ duodenal ulcer
• Helicobacter pylori eradication

29. Clinical Evidences

30. Acid - inhibitory effects of Vonoprazan 20 mg compared with
esomeprazole 20 mg
Ref. Sakurai et al, Alimentary Pharmacology and Theraputics,2015
Method:
Randomized, open -label study, vonoprazan 20 mg and esomeprazole 20 mg (Study
V vs. E) were orally administered daily for 7 days.
Result:
• Acid -inhibitory effect (pH4 HTR) of vonoprazan was significantly greater than
that of esomeprazole on both Days 1 and 7; Day 7 difference in pH4 HTR for
vonoprazan vs. esomeprazole was 24.6 % .
• The Day 1 to Day 7 ratio of 24 -h pH4 HTRs was >0.8 for vonoprazan ,
compared with 0.370 for esomeprazole.
pH above 4 maintenance Study

31. Rapid and Potent acid control
Ref. Sakurai et al, Alimentary Pharmacology and Theraputics,2015
pH above 4 maintenance Study

32. Vonoprazan versus lansoprazole for the initial relief of
heartburn in patients with Erosive esophagitis
Ref. Oshima et al.AP&T 2018. Aliment Pharmacol Ther.2019;49:140 -146
Methods:
Patients (n = 32) with erosive esophagitis who experienced heartburn at least
once a week were randomized in a double -blind manner to receive either daily
vonoprazan (20 mg) or lansoprazole (30 mg) before breakfast for 14 days.
Results:
• Heartburn was relieved sooner with vonoprazan than with lansoprazole ( P <
0.05 ).
• Heartburn was completely relieved in Vonoprazan (31.3 % ) than
lansoprazole (12.5%) of patients on day 1, respectively.
• Significantly more patients achieved complete nocturnal heartburn relief with
vonoprazan than lansoprazole ( P < 0.01 ).
Vonoprazan efficacy in Nocturnal
Heart burn

33. Vonoprazan demonstrated a faster time to complete heart burn
relief than Lansoprazole, and this complete relief was most
pronounced for night time heart burn.
Ref. Oshima et al.AP&T 2018. Aliment Pharmacol Ther.2019;49:140 -146
Better Heart burn relief with Vonoprazan Vs PPI
Vonoprazan efficacy in Nocturnal
Heart burn

34. Vonoprazan, a novel potassium competitive acid blocker,
vs. lansoprazole for the healing of Erosive oesophagitis
Ref. Ashida et al, Aliment Pharmacol ther 2016
Method:
In this multicenter, randomized, double -blind, parallel-group comparison study,
patients with endoscopically confirmed EE (LA Classification Grades A–D) were
randomly allocated to receive vonoprazan 20 mg or lansoprazole 30 mg once daily
after breakfast
Result
The proportion of patients with healed EE up to week 8 was 99.0% for vonoprazan
and 95.5% for lansoprazole, thus verifying the non-inferiority of vonoprazan (P <
0.0001).
Erosive Esophagitis Study

35. Superior healing rate in Erosive
Esophagitis
Ref. Ashida et al, Aliment Pharmacol ther 2016

36. Maintenance for healed erosive esophagitis: Phase - 3
comparison of vonoprazan with lansoprazole
Ref. Ashida et al,Aliment Pharmacol Ther 2018
Methods
•607 patients aged ≥ 20 years.
•All patients in whom endoscopic healing of EE was confirmed 2, 4, or 8 wk
after the start of the study medication were immediately stratified by
baseline endoscopic LA Classification grade (A/B or C/D).
•Subsequently randomized in a 1:1:1 ratio to receive maintenance therapy
with vonoprazan 10 mg (n = 202), vonoprazan 20 mg (n = 204), or
lansoprazole 15 mg (n = 201) given once daily after breakfast for 24 wk.
Maintenance Study

37. Minimal recurrence of Erosive
Esophagitis
Ref. Ashida et al,Aliment Pharmacol Ther 2018
Lansoprazole 15mg

38. Results
• Rates of EE recurrence during the 24 - wks.maintenance period were 16.8%
(lansoprazole 15 mg), )
5.1 % (vonoprazan 20 mg , and 2.0 %
( vonoprazan 10 mg) , respectively. Vonoprazan was shown to be non -
inferior to lansoprazole 15 mg ( P < 0.0001 for both doses).
• Recurrence rates in patients with baseline LA grade C/D EE were significantly
reduced with vonoprazan 10 mg (13.2%) and 20 mg (4.7%) vs
lansoprazole 15 mg (39.0%) ( P = 0.0114 and P = 0.0001 , respectively).
Conclusion
Vonoprazan was shown to be non -inferior to lansoprazole 15 mg at both
investigated doses.
Maintenance for healed erosive esophagitis: Phase - 3
comparison of vonoprazan with lansoprazole
Ref. Ashida et al,Aliment Pharmacol Ther 2018
Minimal recurrence of Erosive
Esophagitis

39. Vonoprazan, a novel potassium - competitive acid blocker,
as a component of 1 st
and 2 nd
line triple therapy for
Helicobacter pylori eradication
Ref. Murakami K, et al. Gut 2016;65:1439 – . doi:10.1136/gutjnl
1446 - 2015 - 311304
Method:
Randomized, double -blind, multicenter, parallel -group study
was conducted to verify the noninferiority of vonoprazan 20 mg
to lansoprazole 30 mg as part of first -line triple therapy (with
amoxicillin 750 mg and clarithromycin 200 or 400 mg) in H
pylori positive patients with gastric or duodenal ulcer history.
Eradication of H. pylori infection

40. Better eradication of H. pylori
infection
Ref. Murakami K, et al. Gut 2016;65:1439 – 1446 . doi:10.1136/gutjnl - 2015 - 311304

41. Vonoprazan, a novel potassium - competitive acid blocker,
as a component of 1 st
and 2 nd
line triple therapy for
Helicobacter pylori eradication
Ref. Murakami K, et al. Gut 2016;65:1439 – 1446 . doi:10.1136/gutjnl - 2015 - 311304
Conclusion
Vonoprazan is effective as part of first - line triple therapy and as
part of second - line triple therapy in H pylori - positive patients
with a history of gastric or duodenal ulcer.
Better eradication of H. pylori
infection

42. • Rapid Onset of action
• Potent Acid control
• Durable 24 - Hrs activity (Controls nocturnal heartburn
and breakthrough)
• Can be taken with or without food
• Better safety profile
Summary Features

43. Disease Dose Duration
Reflux esophagitis (EE) 20 mg Once a day 4 to 8 weeks
Maintenance of Healing
Esophagitis
10 mg Once a day
-
Gastric Ulcer 20 mg Once a Day 8 weeks
Duodenal Ulcer 20 mg Once a Day
6 weeks
Prevention of NSAID induce
Ulcer
10 mg Once a Day -
H. pylori Eradication
20 mg Twice daily with triple
drug regimen
01 week
Dosage

44. 10MG/20MG