[Pharmacological characteristics and clinical efficacies of a novel potassium-competitive acid blocker, vonoprazan fumarate].

Proton pump inhibitors (PPIs) inhibit H+, K+-ATPase, an enzyme which is the final step of gastric acid secretion and is selectively located in the gastric parietal cells. PPIs block the enzyme in a covalent and irreversible binding manner, thus providing better efficacy than previous pharmacological agents such as antacids and histamine H2 receptor antagonists. Although PPIs have been the first-line therapeutic option for acid related diseases (ARDs), there are several limitations to their efficacy, i.e. short half-life in blood, insufficient acid suppression especially at night, necessity of repeated dosages for full action, and large variation in efficacy among patients due to CYP2C19 polymorphism. To overcome these shortcomings, we performed a high-throughput random screening using in-house chemical libraries and further lead optimization to look for the most relevant clinical candidate compounds. As the results of these researches, we discovered vonoprazan fumarate, a novel gastric acid antisecretory agent which inhibits H+, K+-ATPase in a reversible and K+-competitive manner. Vonoprazan exerted a more potent and longer lasting inhibitory effect than lansoprazole on gastric acid secretion in preclinical studies, presumably by its high accumulation profile in the gastric parietal cells. It also exhibited a rapid onset of action and prolonged inhibition of intragastric acidity in humans and showed remarkable effects on multiple ARDs including erosive esophagitis and Helicobacter pylori eradication. Vonoprazan fumarate was approved in 2014 for clinical use in Japan. Vonoprazan is a new therapeutic option which can potentially improve outcomes compared with conventional PPI-based treatments for ARDs.

Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion.

With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.

Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers.

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.

Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action.

With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.

Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases.

Acid-related diseases (ARDs), such as peptic ulcers and gastroesophageal reflux disease, represent a major health-care concern. Some major milestones in our understanding of gastric acid secretion and ARD treatment reached during the last 50years include 1) discovery of histamine H2-receptors and development of H2-receptor antagonists, 2) identification of H+,K+-ATPase as the parietal cell proton pump and development of proton pump inhibitors (PPIs), and 3) identification of Helicobacter pylori (H. pylori) as the major cause of peptic ulcers and development of effective eradication regimens. Although PPI treatments have been effective and successful, there are limitations to their efficacy and usage, i.e. short half-life, insufficient acid suppression, slow onset of action, and large variation in efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers (P-CABs) inhibit H+,K+-ATPase in a reversible and K+-competitive manner, and exhibit almost complete inhibition of gastric acid secretion from the first dose. Many pharmaceutical companies have tried to develop P-CABs, but most of their clinical development has been discontinued due to safety concerns or a similar efficacy to PPIs. Revaprazan was developed in Korea and was the first P-CAB approved for sale. Vonoprazan, approved in 2014 in Japan, has a completely different chemical structure and higher pKa value compared to other P-CABs, and exhibits rapid onset of action and prolonged control of intragastric acidity. Vonoprazan is an effective treatment for ARDs that is especially effective in healing reflux esophagitis and for H. pylori eradication. P-CABs, such as vonoprazan, promise to further improve the management of ARDs.

Characteristics of the Novel Potassium-Competitive Acid Blocker Vonoprazan Fumarate (TAK-438).

UNLABELLED: Proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases, such as peptic ulcers and gastro-esophageal reflux disease, and for the eradication of Helicobacter pylori. However, the therapeutic efficacy of conventional PPIs is considered limited because: (1) they are unstable under acidic conditions and require an enteric-coated formulation in clinical use; (2) they show high interindividual variability in pharmacokinetics due to genetic polymorphisms of cytochrome P450 (CYP) 2C19 metabolism; (3) they have a relatively slow onset of pharmacological action and may require several doses to achieve optimal acid suppression and symptom relief; and (4) they often do not provide stable suppression of gastric acid secretion over 24 h. Vonoprazan fumarate (TAK-438, hereinafter referred to as "vonoprazan") is a new potassium-competitive acid blocker (P-CAB) developed to resolve the above limitations of conventional PPIs. Various physicochemical data have shown that vonoprazan has a high solubility and stability over a broad pH range in aqueous conditions. In addition, vonoprazan has a more potent and longer-lasting acid suppression effect than the conventional PPI, lansoprazole. Preclinical pharmacokinetic studies have shown that vonoprazan is accumulated and retained in the stomach for more than 24 h, even after it is eliminated from the plasma. From these findings, we propose that vonoprazan, which possesses a novel mode of action, can improve on the outcomes seen with conventional PPI-based treatments for acid-related diseases. FUNDING: This review project, including the publication of this article, was funded by Takeda Pharmaceutical Company Limited.

Radiographic Localization Study of a Novel Potassium-Competitive Acid Blocker, Vonoprazan, in the Rat Gastric Mucosa.

BACKGROUND: Vonoprazan fumarate (TAK-438) is a novel potassium-competitive acid blocker that appears to exert a longer/more potent antisecretory effect than lansoprazole due to high accumulation/slow clearance from the gastric glands. However, there is no direct evidence that vonoprazan selectively accumulates in gastric parietal cells of gastric glands. AIM: To investigate the distribution of radioactivity in the rat stomach after single intravenous administration of [(3)H]-labeled vonoprazan. METHODS/RESULTS: Autoradioluminography of the stomach revealed that at 5 h after administration, radioactivity levels in the corpus mucosal layer was higher than radioactivity levels in the muscular layer, pylorus, and forestomach. At 24 h, although overall radioactivity was significantly decreased, the highest radioactivity was still observed in the mucosal layer. Accumulation of radioactivity in gastric parietal cells was quantitatively analyzed using microautoradiography. The number of silver granules in parietal cells from vonoprazan-injected rats was higher than in cells from a saline-injected rat. At 24 h, the number of granules was approximately at 20 % of the number of granules at 5 h. There was no clear deposition of granules in other components. At 5 h, radioactivity was measured at 1.799 µg Eq/g in the stomach and 0.172 µg Eq/mL in plasma. After 24 h, radioactivity had decreased to 0.584 µg Eq/g in the stomach and 0.078 µg Eq/mL in plasma. CONCLUSIONS: Vonoprazan selectively accumulates in gastric parietal cells in the mucosal layer of the rat stomach after intravenous administration.

Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs).

On the basis of a series of novel and potent potassium-competitive acid blockers represented by 1-sulfonylpyrrole derivative 7, we prepared several five-membered heterocyclic analogues (8) and evaluated their H(+),K(+)-ATPase activities in vitro. We also assessed the role of the methylaminomethyl side chain by comparison with methylamino and ethylamino derivatives. We observed that the five-membered core ring and its orientation affect inhibitory activity and that the methylaminomethyl moiety is the best side chain. On the basis of potency and ligand-lipophilicity efficiency, compound 7 remains the most drug-like of the compounds studied to date. This study revealed the factors necessary for potent H(+),K(+)-ATPase inhibition, such as differences in electron density, the properties of the lone pair at each apical position of the heteroaromatic ring, and the geometry of the substituents.

Molecular modeling, design, synthesis, and biological activity of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives as potassium-competitive acid blockers.

A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.

Effects of TAK-480, a novel tachykinin NK(2)-receptor antagonist, on visceral hypersensitivity in rabbits and ricinoleic acid-induced defecation in guinea pigs.

TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK(2)-receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK(2) receptors with a marked species difference and a 10,000-fold selectivity versus NK(1) and NK(3) receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK(2) receptor-selective agonist beta-Ala(8)-NKA(4-10) (ßA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT(3)-receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid-induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as ßA-NKA in an isolated human colon. In conclusion, the novel NK(2)-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK(2) receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers.

To discover a gastric antisecretory agent more potent than existing proton pump inhibitors, novel pyrrole derivatives were synthesized, and their H(+),K(+)-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 17a exhibited selective and potent H(+),K(+)-ATPase inhibitory activity through reversible and K(+)-competitive ionic binding; furthermore, compound 17c exhibited potent inhibitory action on histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs.

Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB).

In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.

Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK2 antagonists.

We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK(2) receptor (NK(2)-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK(2)-R agonist, ßAla(8)-neurokinin A(4-10) (ßA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of ßA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK(2)-R antagonists in dose- and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) values calculated in the PD model were highly correlated (r(2) = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK(2)-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK(2)-R with in vivo therapeutic efficacy.

High-throughput screening of potassium-competitive acid blockers.

H(+),K(+)-ATPase is a key enzyme in the process of gastric acid secretion, and proton pump inhibitors (PPIs) have been accepted as one of the most effective treatments for peptic ulcer and gastroesophageal reflux disease. To discover a novel class of PPIs, the authors screened a low-molecular-weight compound library and identified two prospective acid blockers that were pyrrole derivatives. Both compounds inhibited H(+),K(+)-ATPase in a reversible and potassium-competitive manner. These compounds led to the development of TAK-438 (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate), which is currently undergoing clinical trials as a novel potassium-competitive acid blocker for the treatment of acid-related diseases.

Novel 3-phenylpiperidine-4-carboxamides as highly potent and orally long-acting neurokinin-1 receptor antagonists with reduced CYP3A induction.

The synthesis and biological evaluation of a series of novel 3-phenylpiperidine-4-carboxamide derivatives are described. These compounds are generated by hybridization of the substructures from two types of tachykinin NK(1) receptor antagonists. Compound 42 showed high metabolic stability and excellent efficacy in the guinea-pig GR-73637-induced locomotive activity assay at 1 and 24h after oral administration. It also exhibited good pharmacokinetic profiles in four animal species, and a low potential in a pregnane X receptor induction assay.

Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438).

Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P-CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3-yl)acetonitrile (SCH28080), pK(a) 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t(1/2) being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgP(i). However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg(2+). Modeling of the H,K-ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K(+)-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class.

A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands.

TAK-438 is a novel potassium-competitive acid blocker (P-CAB) type antisecretory agent that reversibly inhibits gastric H+, K+-ATPase. Previously, we showed that TAK-438 has superior efficacy compared to lansoprazole, a proton pump inhibitor, in the inhibition of acid secretion in vivo. In this study, we investigated the differences in the mode of actions of the two drugs using primary cultured rabbit gastric glands. TAK-438 and lansoprazole inhibited gastric acid formation in acutely isolated gastric glands (IC50) values, 0.30 and 0.76 µM, respectively). In cultured gastric glands that were preincubated with TAK-438, the inhibitory effect on forskolin-stimulated acid formation was augmented over the incubation period, whereas the inhibitory effect of lansoprazole was not affected by time of incubation. Next, we evaluated the durations of the actions of TAK-438 and lansoprazole after gastric glands were incubated with either drug for 2h followed by washout. Even 8h after the drug washout, TAK-438 at higher concentrations inhibited acid formation, but the inhibitory effect of lansoprazole disappeared immediately after washout. Additionally, only a small amount of [¹4C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 µM of forskolin. In contrast, high levels of [¹4C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [¹4C] TAK-438 from the glands. These findings suggest that TAK-438 exerts a longer and more potent antisecretory effect than lansoprazole as a result of its high accumulation and slow clearance from the gastric glands.

A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals.

Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.

1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases.

Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H(+),K(+)-ATPase activity in porcine gastric microsomes with IC(50) values of 0.019, 0.14, and 7.6 µM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K(+)-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-d-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.