While PPIs are the current standard of care, they have significant limitations that result in a large unmet medical need due to the slow onset and insufficient duration of acid control which can lead to inadequate symptom relief. 1- PHATHOM PHARMACEUTICALS, INC. For the Year Ended December 31, 2019 Calcium Carbonate Sodium Bicarbonate ANTACIDS Introduced 1n 1930 s Ranitidine Cimetidine Famotidine H2 ATAGONIST Introduced 1n 1970 s PPIS Introduced 1n 1989 Conventional PPIs P-CAB Introduced 1n 2015 in Japan Vonoprazan 2022 Vonseca in Egypt First full rang 20 & 10 mg P-CABS: next generation of acid-control therapeutics. 1 is a novel, orally active P-CAB (potassium-competitive acid blocker) that binds and reversible inhibits H+, K+-ATPase at the final step in the acid secretory pathway in gastric parietal cells. Secretory membrane H+ H+ H+ K + K + (a) Conventional (PPIs) Parietal cell Proton pump (PP,H + ,K + -ATPase) Conventional PPIs Active form of conventional PPI Newly surfaced PP H+ K + H+ K + (b) Vonoprazan Secretory membrane Parietal cell Proton pump (PP,H + ,K + -ATPase) Vonoprazan Newly surfaced PP Difference in Mode of action 2- Oshima el al, J Neuogastroenterol Moti, 2018 is a strong acid blocker that has rapid, stable, and long-lasting effects. 2 The mechanistic and pharmacologic differences of PPI and Vonoprazan are summarized in the table below. 3 3- PHATHOM PHARMACEUTICAL S, INC. For the year ended December 31, 2019 Vonoprazan Activation and stability No activation required and stable in acidic conditions Binding to proton pump Reversibly blocks active and inactive proton pumps with slow dissociation Long ( T 1/2 ) : 7 hours Plasma half life Dosing independent of meal Primary metabolism via CYP3A4/5 PPIs Prodrug that require acid for activation & unstable in acidic conditions Irreversibly blocks active proton pumps Short ( T 1/2 ) : 2 hours Take 4 to 5 days to maximum Generally administered 30 to 60 minutes before a meal Primary metabolism via CYP2C19 Onset of action Dosing restrictions Inter-patient variability Achieved target 24-hour acid suppression within 2 house Rapid onset of action Potent acid control Durable 24-hr activity Fewer side effects/drug-drug interactions ADVANTAGES Slow onset of action Limited potency Limited duration of activity Safety issues/ drug-drug interactions UNMET NEEDS *HTRs: pH holding time ratios 4- Aliment Pharmacol Ther 2015; 42: 719–730 Day 1 Day 7 Day 1 Day 7 Rabeprazole 10 mg 7 days study V vs. R Baseline Period 1 Day 1 Day 7 Day 1 Day 7 Period 2 1 day Rabeprazole 10 mg 7 days Vonoprazan 20 mg 7days Vonoprazan 20 mg 7days Washout at least 7 days Washout at least 7 days Sequence VR Sequence RV 24-h gastric pH monitoring Figure 3 | Time courses of gastric pH over 24 h for (a) vonoprazan and (b) rabeprazole at baseline, on Days 1 and 7 for Study V vs. R: pharmacodynamic analysis set (n = 7). The pH data from Day-2 to Day-1 were used as baseline data for both treatments. All study drugs were administered at time 0 (as a rule, 9:00 AM) on Days 7–1. The triangles indicate the timing of meals. Subjects were given identical meals at these time points The difference in pH 4 HTR between and rabeprazole was 58.2% on Day 1 and 28.8% on Day 7 provide more rapid and sustained acid-inhibitory effect vs. rabeprazole 10 mg. 0 0 2 4 6 8 10 12 14 16 18 20 22 24 1 2 3 4 5 6 7 8 9 (b) Gastric pH Time after administration (h) Rabeprazole Baseline (n=7) Day 1 (n=7) Day 7 (n=7) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 1 2 3 4 5 6 7 8 9 Gastric pH (a) Vonoprazan Time after administration (h) Baseline (n=7) Day 1 (n=7) Day 7 (n=7) was significantly greater in Acid-inhibitory effect (pH4 HTR)* than that of rabeprazole on both Days 1 and 7. 4 5- Aliment Pharmacol Ther. 2019;49:140–146. Heartburn was completely relieved in 31.3% and 12.5% of patients on day 1 with and lansoprazole, respectively. Significantly more patients achieved complete nocturnal heartburn relief with than lansoprazole (P < 0.01). Both regimens were well tolerated 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 10 20 30 40 50 60 70 80 90 100 Day n=32 Day n=32 Patients with complete symptom relief, % Vonoprazan 20 mg Lansoprazole 30 mg Vonoprazan 20 mg Lansoprazole 30 mg Daytime Heartburn Relief Nighttime Heartburn Relief was achieved complete sustained heartburn relief sooner than with lansoprazole during the first week of therapy. 5 6- Ashida et al, Aliment Pharmacol Ther 2016; 43: 240–251 10 and 20 mg once daily were shown to result in a low EE recurrence rate. 6 The non-inferiority of vonoprazan to lansoprazole in EE was verified in the comparison study, and vonoprazan was well-tolerated and effective during the long-term maintenance study 0% 10% 20% 30% 40% 2% 1% 5% 5% 13% 39% 3% 17% 11% Patients with recurrence of EE at 6 months % Lansoprazole 15 mg Vonoprazan 10 mg Vonoprazan 20 mg All EE Patients LA Class A/B Patients LA Class C/D Patients Lansoprazole 15 mg Vonoprazan 10 mg Vonoprazan 20 mg Lansoprazole 15 mg Vonoprazan 10 mg Vonoprazan 20 mg 6- Ashida et al, Aliment Pharmacol Ther 2016; 43: 240–251 Table 3 | Proportion of patients with healed erosive oesophagitis (EE) in various subgroups up to week 8 (a) (primary endpoint), and at week 2 (b) and up to week 4 (c) (secondary endpoints) sub grouped according to LA Classification Grades [A/B and C/D] and CYP2C19 metaboliser status following treatment with vonoprazan (VPZ) or lansoprazole (LPZ) 60% 70% 80% 90% 100% 91% 82% Week 2 Week 8 Week 2 Week 8 99% 99% 96% Vonoprazan 20 mg Lansoprazole 30 mg 88% 88% 64% Patients with healed EE,% All EE Patients LA Class C/D Patients was statistically different in the proportion of patients with healed EE to that produced by lansoprazole up to week 8. 6 7- Murakami K, et al. Gut 2016;65:1439–1446. doi:10.1136/gutjnl-2015-311304 The eradication rate was significantly higher with vonoprazan compared with lansoprazole in those patients infected with CLR-resistant strains (82.0% vs 40.0%; p<0.0001) 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. 7 0% 60% 40% 20% 80% 100% 93% 76% 82% 40% N=100 N=115 N=324 N=320 First line H. pylori eradication rate with triple therapy (%) All Patients Patients with Clarithromycin-resistant H. Pylori Infection Vonoprazan 20 mg Lansoprazole 30 mg Vonoprazan 20 mg Lansoprazole 30 mg * EXT : Extension study 8- Mizokami Y, et al. Gut 2018;67:1042–1051. doi:10.1136/gutjnl-2017-314010 Figure 2 Peptic ulcer recurrence at week 24. The proportion of patients in the full analysis set population with endoscopically confirmed recurrent peptic ulcers within 24 weeks was lower for the vonoprazan 10mg and 20mg groups compared with the lansoprazole 15mg group. was effective and well tolerated in EXT* for longer than 1 year for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer. 8 0 2 4 6 8 5.5% 3.3% Lansoprazole 15 mg Vonoprazan 10 mg Vonoprazan 20 mg 3.4% 10 Patients with Recurrent Peptic Ulcer (%) *TEAE: Treatment-emergent adverse event World J Gastroenterol 2018 April 14; 24(14): 1550-1561 demonstrated similar safety profiles to Conventional PPI* during the 24-week maintenance period. 9 Summary of treatment emergent adverse events during maintenance treatment 000% (23/201) (21/202) Drug related TEAE* TEAE leading to study discontinuation Any serious TEAE (21/204) (8/201) (5/202) (8/204) 3.90% Vonoprazan 20 mg Vonoprazan 10 mg PPI* 2% 2% 2.5% 2.50% 4.00% 10.30% 10.40% 11.40% (4/201) (5/202) (4/204) 2.00% 4.00% 6.00% 8.00% 10.00% 12.00% is a novel, orally active P-CAB (potassium-competitive acid blocker) that binds and inhibits H + , K + -ATPase at the final step in the acid secretory pathway in gastric parietal cells. is a strong acid blocker that has rapid, stable and long-lasting effects. was significantly greater in Acid-inhibitory effect than that of conventional (PPIs). was achieved complete sustained heartburn relief sooner than conventional (PPIs) during the first week of therapy. was statistically different in the proportion of patients with healed EE to that produced by conventional (PPIs). 20 and 10 mg once daily were shown to result in a low EE recurrence rate. is effective as part of first-line & second-line triple therapy in H pylori-positive patients with a history of gastric or duodenal ulcer. Indication 4-8 weeks 7 days 10-20 mg once daily After healing reflux esophagitis (Maintenance therapy) Dose Duration Dose Treatment of gastric ulcer Treatment of duodenal ulcer Treatment of reflux esophagitis Once daily Twice daily Helicobacter pylori eradication (Adjuvant to triple therapy) can be taken without regard to food or timing of food. does not require enteric coating as it is acid-stable.