Currently, the main medical therapeutic modalities for gastroesophageal reflux disease (GERD) are proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H₂RAs) . The effect of both classes of drugs is mediated through gastric acid suppression, albeit with different potency. Other underlying mechanisms for GERD treatment include neutralizing gastric acidity (antacids), creating a foamy raft in the stomach that prevents or replaces gastric acid reflux (alginate-based formulations), and improving esophageal clearance and gastric emptying (prokinetics) .

The main goals of GERD treatment are to relieve symptoms, heal, and maintain remission of erosive esophagitis (EE) , prevent complications, and improve health-related quality of life (HRQL) [1]. Presently, PPIs provide unsurpassed clinical efficacy in GERD patients, primarily due to their profound inhibitory effect on acid secretion. However, even in patients receiving PPI therapy, the resolution of esophageal mucosal inflammation is much more predictable than resolution of symptoms [2].

The different GERD phenotypes demonstrate varied degrees of response to antireflux treatment. Nonerosive reflux disease (NERD) patients, for example, have a significantly lower response rate to PPI therapy as compared with other GERD groups and consequently constitute the majority of patients with refractory heartburn. Failure of PPI therapy is the most common presentation of GERD in gastroenterology practice [3, 4].

Presently, there are several unmet needs in GERD treatment. Approximately 10–15 % of patients with EE fail to achieve complete healing after 8 weeks of treatment [5]. Moreover, even when the initial healing dose of the PPI is continued, 15–23 % of patients with Los Angeles grades A and B and 24–41 % of those with grades C and D relapse within 6 months of initiating maintenance treatment. In addition, up to 40 % of NERD patients remain symptomatic while on standard dose (once daily) of PPI therapy [6]. Treatment of extraesophageal manifestations of GERD has been clinically disappointing [7]. Most of the randomized controlled trials in patients with pharyngeal, laryngeal, or pulmonary symptoms, which are suspected to be GERD related, demonstrate lack of relief or modest benefit with PPI treatment versus placebo. Other unmet needs in GERD include rapid and more effective control of postprandial heartburn, improved control of volume reflux and acid regurgitation, relief of nighttime heartburn symptoms, acid control in Barretts’s esophagus (BE) patients, and a more flexible schedule of PPI administration [1].

The goal of the present review is to provide an overview of the new and future drug developments for GERD treatment (Table 6.1).

H2RAs reduce gastric acid secretion by competitive inhibition of the interaction between histamine and H₂ receptors that are located on the parietal cells. In addition, H₂RAs reduce pepsin and gastric acid volume [8]. Currently, there are four Food and Drug Administration (FDA)-approved H₂RAs in the USA: cimetidine, famatodine, nizatidine, and ranitidine.

The different H₂RAs are considered equivalent in suppressing gastric acid secretion when administered in equipotent doses. The pharmacokinetic and pharmacodynamic differences among the H₂RAs seem to be clinically nonsignificant [9]. Although H₂RAs are effective in controlling basal acid secretion, they have limited efficacy in suppressing postprandial acid secretion. Presently, H₂RAs are used to control symptoms and heal mild to moderate EE (Los Angeles grades A and B) [10]. In addition, several studies have demonstrated that approximately 30 % of NERD patients report symptom relief after receiving an H2RA twice daily for 4 weeks [11, 12]. H₂RAs are particularly helpful in relieving postprandial heartburn for up to 12 h [13]. They are also effective in preventing postprandial heartburn if given 30 min before a meal [14]. In addition, H₂RA at bedtime significantly reduced the duration of nocturnal acid breakthrough (NAB) [15].

The introduction of the PPIs into the US market in the early 1990s revolutionized the treatment of acid peptic disorders. This class of drugs is currently considered the best therapeutic option for GERD [25]. The high potency of PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and dexlansoprazole) is the result of their ability to inhibit the proton pump (H⁺, K⁺-ATPase), which is the final common pathway of gastric acid secretion. They suppress nocturnal, daytime, and food-stimulated acid secretion [26]. Currently, PPIs are the most successful antisecretory agents for healing inflammation of the esophageal mucosa and relieving GERD-related symptoms because of their profound and sustained acid inhibition [5, 8]. PPIs have made an important therapeutic impact on advanced EE, GERD complications, and atypical manifestations of GERD. Even in BE , PPIs have made a significant impact on symptoms control, mucosal healing, and esophageal acid exposure .

A recent Cochrane review examined 134 therapeutic trials that included 36,978 subjects with EE and concluded that PPIs demonstrated a better healing effect and faster symptom relief than H₂RAs [27]. The study did not find any major difference in efficacy among the currently available PPIs. However, the effect of PPIs on symptoms differs between patients with NERD and those with EE. The symptomatic therapeutic gain of PPIs over placebo in NERD patients is much lower than that observed in patients with EE [28]. In a systematic review, the therapeutic gain for standard-dose PPI in relieving heartburn symptoms compared with placebo ranged from 30 to 35 % for sufficient heartburn control and from 25 to 30 % for complete heartburn control. Pooled response rates to PPIs once daily were significantly higher after 4 weeks of treatment for patients with EE compared with NERD patients (56 vs. 37 %).

Since the introduction of PPIs into the market, refractory GERD has become the main presentation of GERD in clinical practice. Specifically, approximately 10–15 % of patients with EE fail to achieve complete healing after 8 weeks of treatment. This subset of patients usually demonstrates moderate to severe disease (Los Angeles grades C and D) and comprises approximately 25–30 % of all EE patients [5]. Moreover, even when continuing the initial healing dose as maintenance treatment for a period of 6 months, 15–23 % of patients with Los Angeles grades A or B and 24–41 % of those with grades C or D relapse while on treatment. In addition, up to 40 % of NERD patients remain symptomatic while on standard dose (once-daily) PPI therapy [6]. Treatment of extraesophageal manifestations of GERD with a PPI has been relatively disappointing, and many trials showed that the drug does no better than placebo in improving or relieving symptoms [7]. Important shortcomings of PPIs include lack of effective control of postprandial and nighttime heartburn as well as limited effect on esophageal acid exposure in BE patients. In addition, PPIs demonstrate a dependence on food consumption for maximal efficacy .

At present, switching to another PPI or doubling the PPI dose has become the most common therapeutic strategy for GERD patients who symptomatically fail to achieve symptom control on PPI with once-daily dosing [3, 8]. According to a recent Cochrane review, doubling the PPI dose is associated with greater healing of EE, with the number needed to treat of 25. However, there is no clear dose–response relationship for heartburn resolution in either EE or NERD [33]. Although doubling the PPI dose has become the standard of care, there is no evidence to support further escalation of the PPI dose beyond PPI twice daily for either symptom control or healing of EE. When doubling the PPI dose, one dose should be given 30–60 min before breakfast and the other 30–60 min before dinner. The support for splitting the dose originates primarily from physiological studies demonstrating improved control of intragastric pH when one dose is taken in the morning and the other in the evening as compared with both doses being taken before breakfast [29] .

Several approaches have been used to improve the acid suppressive effect of PPIs. They include development of enantiomers that undergo slower hepatic metabolism, incorporation of technology that prolongs drug absorption, and combining PPI’s with compounds that maximize PPI absorption and thus bioavailability.

P-CABs represent a heterogeneous group of drugs that share the same final mechanism of action. This class of drugs inhibits gastric H⁺/K⁺-ATPase in a K⁺competitive but reversible mechanism. Consequently, P-CABs do not require prior proton pump activation to achieve their antisecretory effect. P-CABs exhibit an early onset inhibition of acid secretion due to rapid rise in peak plasma concentration [45]. Given the pharmacokinetic and pharmacodynamic profile of P-CABs, they are likely to be beneficial as an on-demand therapy for symptomatic GERD.

Attempts to develop P-CABs in the past two decades have failed to produce even one compound that reached the market. Comparative trials were unable to demonstrate clinical superiority of P-CABs over currently available PPIs. This is primarily due to common utilization of traditional study designs rather than trials specifically focusing on the unique characteristics of P-CABs . In addition, several P-CABs have been associated with severe adverse effects such as liver toxicity. Thus, despite their promising pharmacokinetics and pharmacodynamics profile, their future in the GERD market remains to be elucidated.

TLESR is the main mechanism of gastroesophageal reflux, both acidic and nonacidic, accounting for all reflux episodes in healthy subjects and the majority (55–80 %) of reflux episodes in GERD patients [53]. A wide range of receptors is involved in triggering TLESR including gamma-aminobutiric acid B (GABA_B), metabotropic glutamate receptor 5 (mGlucR5), cannabinoid (CB), cholecystokinin (CCK), 5-hydroxytryptamine-4, muscarinic, and opioid [54].

Prokinetic agents have been proposed to improve GERD-related symptoms by different potential mechanisms that include improvement in esophageal peristalsis, acceleration of esophageal acid clearance, increase in LES basal pressure, and improved gastric emptying. The clinical benefit of prokinetics as sole treatment for GERD has been modest at best. Moreover, their use has been hampered by many adverse effects .