RELAMORELIN AND OTHER GHRELIN RECEPTOR AGONISTS - FUTURE OPTIONS FOR GASTROPARESIS, FUNCTIONAL DYSPEPSIA AND PROTON PUMP INHIBITORS-RESISTANT NON-EROSIVE REFLUX DISEASE

Upper gastrointestinal (GI) disorders are amongst others characterized by inadequate and uncoordinated GI muscular motility. These disorders may be caused by endogenous or exogenous factors, but there is usually no evidence of a structural etiology (1). The most common upper GI disorders with the evidence of abnormal motility pattern include gastroparesis, functional dyspepsia (FD) and gastroesophageal reflux (GERD). Patients suffering from upper GI disorders typically present with various symptoms such as early satiety, postprandial fullness, bloating, nausea, vomiting and epigastric pain (1).

This review summarizes the current knowledge on ghrelin receptor (GHSR) agonists (Fig. 1), with the relamorelin in the forefront, which are in preclinical or clinical stages of development in improving delayed gastric emptying and symptoms associated with impaired upper GI motility. Furthermore, the potential new applications of GHSR agonists are discussed.

Fig. 1. Ghrelin and GHSR agonists structures available at www.pubchem.ncbi.nlm.nih.gov.

GASTROPARESIS

Gastroparesis is defined as a delayed gastric emptying with no sign of mechanical obstruction of the stomach. Recent modeling study estimated that delayed gastric emptying affects 1.8% of the population (2). Its prevalence is estimated as 9.6/100,000 persons for men and 37.8/100,000 persons for women (2, 3). The most common causes of gastroparesis are diabetes, postsurgical and idiopathic; less common causes include iatrogenic, extrinsic neuronal (parkinsonism or paraneoplastic disease) and infiltrative (scleroderma) disorders. Currently, treatment in gastroparesis focuses on the management of an underlying cause, if identified, such as optimization of glucose levels in diabetics as well as stimulation of gastric emptying and dietary therapy with restoration of fluid and electrolytes (4).

FUNCTIONAL DYSPEPSIA

FD is an upper GI disorder defined as bothersome postprandial fullness, early satiation, epigastric pain and/or epigastric burning in the absence of any known organic, systemic or metabolic disease that has been present for the last three months with onset more than 6 months prior to the diagnosis (5). FD has been further sub-classified into the postprandial distress syndrome (PDS) characterized by bothersome postprandial fullness or early satiation at least 3 days per week and the epigastric pain syndrome (EPS) characterized by bothersome epigastric pain or burning at least 1 day per week. The cause of FD remains to be established, but recent data suggest that infections, brain-gut disturbances, duodenal perturbations and food may play a crucial role in pathophysiology of FD (6).

PROTON PUMP INHIBITORS-RESISTANT NON-EROSIVE REFLUX DISEASE

Reflux of gastric acid plays a major role in the pathophysiology of GERD (7). Thus, conventional therapeutic strategy for GERD involves the use of proton pomp inhibitors (PPI) to inhibit acid secretion (8). However, in clinical practice, troublesome GERD symptoms persist in 20 – 30% of patients despite daily treatment with a proton pomp inhibitor (PPI). The PPI resistance rate (40 – 50%) in patients without erosion of the esophageal mucosa (non-erosive reflux disease, NERD) is higher when compared to patients with reflux esophagitis (RE). Therefore, the underlying mechanism of development of NERD is indisputably different from that of RE (9, 10). It is widely known that the persistent GERD symptoms e.g. resulting from PPI resistance worsen the quality of life in patients with PPI-refractory NERD. However, such resistance in these patients may be caused by several other factors, including esophageal mucosal hypersensivity, bile acid reflux, abnormal esophageal motility, gastric motility disorders and rather than from acid reflux (10). Consequently, some combinations of prokinetic drugs and PPIs have been tested to alleviate symptoms of disorders associated with gastric emptying and esophageal clearance, which play an important role in the pathophysiology of GERD (11). However, such therapeutic regiments have not been, proven useful for every type of GERD (8). Thus, a suitable and multi-selective therapeutic strategy is needed as soon as possible for such cases.

GHRELIN

Currently, conventional treatment options used to improve functional GI diseases symptoms are of limited efficacy and usually judged as unsatisfactory. Furthermore, the use of medications such as metoclopramide is restricted due to its adverse effects, such as gynecomastia, changes in the affect and involuntary movements to name only a few (12). Taking into consideration their increasing prevalence, difficulties in diagnosis, and patients’ low quality of life, upper GI disorders have become an emerging problem in gastroenterology. Thus, there is an unmet need to introduce new therapeutics in the treatment of upper GI disorders.

Since the discovery in 1999 ghrelin has been seen as a potential therapeutic option in medicine (13). Recent studies suggest that ghrelin may play an important role in the pathogenesis of upper GI functional diseases.

Ghrelin, a 28-amino acid peptide, is the endogenous ligand of the growth hormone secretagogue receptor (GHSR), later renamed as the ghrelin receptor. In humans it is mainly produced in the P/D1-like cells of the oxyntic mucosa of the stomach and accounts for approximately 20% of the endocrine cell population in the stomach (14). Ghrelin is also produced in smaller amounts in other tissues, such as the pituitary, hypothalamus, pancreas, heart and liver (15). GHSR is a G protein-coupled receptor appearing in two alternative splicing variants. The GHR-S1a form is an active 7-transmembrane domain receptor, whereas GHR-S1b form is a truncated 5-transmembrane domain receptor, with no evident psychological function. The activation of GHSR modulates several intracellular signaling pathways and exhibits different endocrine and non-endocrine effects (16). Ghrelin administered either peripherally or centrally stimulates food intake. Peripheral ghrelin is thought to increase food intake via the GHSR in vagal afferents or being transported in the bloodstream to act on appetite centers in the brain (17, 18). Pirnik et al. showed that subcutaneous administration of a GHSR agonist, Dpr-(N-octanyl)-3-ghrelin, stimulated food intake via Fos expression and activation of tyrosine hydroxylase neurons in hypothalamic arcuate nucleus (19). Furthermore, i.p. injection of the ghrelin-O-acyltransferase (GOAT) inhibitor, which blocks a specific enzyme that modifies ghrelin with a medium-chain fatty acid resulted in the reduction of food intake in Sprague-Dawley rats. This anorexigenic effect was mainly due to reduction of meal frequency, whereas meal size was not altered when compared to vehicle (20). Mogami et al. demonstrated that significantly reduced plasma ghrelin levels may be responsible for the decreased food intake after gastric ischemia and reperfusion, which significantly contributes to the gastric mucosal injuries caused by stress, Helicobacter pylori infection and other factors (21). Moreover, ghrelin is known to interact with the reproductive, cardiovascular and immune system (22) as well as oxidative stress defense mechanisms (23).

Ghrelin expression is highest in the stomach and relatively low in the small and large intestines. Recent research showed altered levels of ghrelin in inflammatory diseases of stomach, such as peptic ulcer disease, and its complications, e.g. gastric outlet obstruction (24, 25). The plasma ghrelin levels are significantly higher in the duodenal ulcer rat model induced by oral administration of cysteamine. Importantly, the study performed by Fukuhara et al. showed that an increase in plasma ghrelin levels precedes the formation of duodenal ulcers in rats (24). In another study, performed by Suzuki et al. expression of preproghrelin mRNA and total ghrelin levels were significantly decreased after H. pylori colonization in Mongolian gerbils, suggesting that peptic ulcer development caused by H. pylori infection may be modulated by ghrelin (26). Interestingly, ghrelin production and secretion in the gastric mucosa is increased in mice lacking H2 receptor, suggesting that ghrelin may stimulate acid secretion independently from histamine-dependent pathway (27). Suzuki et al. showed that plasma ghrelin levels were significantly higher in patients with duodenal and gastric ulcer than in those without ulcers, which confirmed findings from the animal model. Nevertheless, elevated plasma levels of ghrelin did not change significantly after the ulcers were healed (28). In a rat model of gastric outlet obstruction mimicking pyloric stricture, seen in clinical settings in conditions like duodenal ulcers or advanced gastric cancer, fasting plasma levels were increased in comparison to control group suggesting that dysregulation of gastric motility may alter ghrelin levels (25). Interestingly, plasma ghrelin levels may also be altered by emotional stress and thus in upper GI functional diseases (29). For instance, in a study performed by Nishizawa et al. on 97 patients the plasma ghrelin levels were significantly higher in patients with functional dyspepsia, particularly in those with dysmotility-like FD, in comparison to healthy individuals (30).

Indisputably, ghrelin enhances gastric emptying and induces contractile activity in the GI tract. Nevertheless, the short half-life and plasma instability of ghrelin impairs its usefulness (22). Thus, small molecule GHSR agonists with prolonged receptor activity currently represent an attractive therapeutic option for the management of upper GI tract motility disorders. In this review, we summarize the latest preclinical and clinical studies evaluating the potential of relamorelin and other GHSR agonist (Fig. 1) in improving delayed gastric emptying and symptoms associated with impaired upper GI motility.

GHRELIN RECEPTOR AGONISTS

Delayed gastric emptying is considered to play a role in pathogenesis of upper GI motility disorders symptoms and, thus, constitutes a major therapeutic target. Small-molecules, such as relamorelin, ulimorelin, capromorelin, EX-1314, ipamorelin and GHRP-6 stimulate gastric emptying in animals. Only a small number of preclinical animal studies have been performed so far (Table 1).

Table 1. GHSR agonists under investigation in preclinical animal studies.

NP, not provided; i.p., intraperitoneal; s.c., subcutaneous; p.o, per os; POI, postoperative ileus; GHSR, growth hormone secretagogue receptor, ghrelin

RELAMORELIN

Relamorelin is a pentapeptide GHSR agonist with improved stability and longer plasma circulating half-life (31) compared to ghrelin. Relamorelin activates GHSR with approximately 6-fold greater potency than natural ghrelin.

Animal studies

Animal studies showed that relamorelin due to higher potency to GHSR may become a useful therapeutic in upper GI motility disorders (32). Relamorelin exhibited approximately 100-fold more potency than ghrelin and reversed delayed gastric emptying in morphine-induced model of gastroparesis in Spraque-Dawley rats. Additionally, oral administration of relamorelin enhanced GI transit in the proximal and middle part of the small intestine (32).

Interestingly, relamorelin may possess anti-inflammatory properties as it reduces signs of macroscopic colonic inflammation, reverses weight loss and improves survival in rat model of TNBS-induced colonic inflammation (32). Moreover, relamorelin exhibits anti-inflammatory properties in cachexia models by reducing elevated levels of interleukin-1, interleukin-6, interleukin-12, as well as TNF-α, compared to controls (33).

Human studies

Translated into humans, in a randomized, double-blinded, placebo-controlled study of 16 healthy volunteers relamorelin in a dose 30 µg s.c. significantly increased frequency of distal antral motility contractions without significant effect on their amplitude (ClinicalTrials.gov Identifier: NCT02466711) (34).

In another phase I study (ClinicalTrials.gov Identifier: NCT01394055) relamorelin in a single-day treatment with a dose of 100 µg s.c. significantly accelerated gastric emptying of solids and reduced upper GI symptoms such as nausea, vomiting, fullness and pain in patients with type 1 diabetes (35). Interestingly, in patients with type 2 diabetes and documented delayed-gastric emptying relamorelin greatly accelerated the gastric emptying of solids but failed to improve Gastrointestinal Cardinal Symptom Index (GCSI) such as nausea, bloating, early satiety and pain (35).

Results of the latest double-blinded trial of 204 patients with diabetic gastroparesis with moderate to severe symptoms and delayed gastric emptying published by Lembo et al. (36) successfully demonstrated that relamorelin may be useful therapeutic option for GI motility disorders. Relamorelin in dose 10 µg s.c. administered twice daily significantly accelerated gastric emptying. Of note, relamorelin significantly reduced vomiting frequency and severity in comparison to the placebo group. Nevertheless, relamorelin did not improve other GI symptoms such as abdominal pain and satiety. Importantly, patients with baseline vomiting benefited the most from prokinetic actions of relamorelin (36) (ClinicalTrials.gov Identifier: NCT01571297).

Very recently, results of a phase IIB study (ClinicalTrials.gov Identifier: NCT02357420) were published in patients with diabetic gastroparesis who received twice daily an injection of relamorelin in a dose 10, 30 or 100 µg s.c. (37). Patients who were given relamorelin had a 75% reduction in vomiting frequency compared to baseline, but this difference did not reach the statistical significance. Administration of relamorelin over the 12-week study significantly reduced all 4 symptoms of diabetic gastroparesis (nausea abdominal pain, postprandial fullness and bloating). Moreover, relamorelin significantly accelerated gastric emptying from baseline compared to placebo. Nevertheless, adverse effects of relamorelin administration were also noted. Relamorelin was responsible for glycemic control worsening in 14.5% of patients in a dose-dependent manner. Some patients needed insulin or other diabetic drug dosage modifications (37).

TZP-101 (ULIMORELIN)

TZP-101 is a macrocyclic peptidomimetic GHSR agonist widely investigated in the management of GI motility.

Animal studies

In the study by Venkova et al. (38) systemic administration of TZP-101 (0.03 – 1.0 mg/kg i.v.) in Sprague-Dawley rats was equally effective against the delayed GI transit induced by surgery, morphine or both interventions simultaneously. Importantly, the promotility action of TZP-101 was more pronounced in the stomach compared to the small intestine.

In detail, TZP-101 significantly increased gastric emptying in a dose-dependent manner up to 96.9% of the values in naïve animals in postoperative (POI) model induced by surgery. Additionally, TZP-101 administration accelerated gastric emptying, increased the geometric center and the distance reached by the meal in a model of morphine-induced delay in GI transit (38).

Human studies

In Phase I study Lasseter et al. (39) evaluated safety, pharmacokinetics and pharmacodynamic of TZP-101 in healthy volunteers. Overall, administration of TZP-101 in a single dose ranging from 20 to 600 ug/kg by a 30-minute intravenous infusion was well tolerated. A few adverse effects such as dizziness, headache, lower abdominal pain and diarrhea were reported. Nevertheless, at the highest dose 2 subjects experienced bradycardia. Moreover, at higher doses, mean arterial blood pressure and heart rate decreased form baseline approximately 45 to 60 minutes after the start of the infusion (39). This study suggested that TZP-101 possesses promising pharmacokinetic, pharmacodynamic and safety profiles for use in GI motility disorders.

In another study ten patients with diabetes, 7 with type 1 and 3 with type 2, with moderate to severe gastroparesis symptoms were enrolled. TZP-101 improved solid-meal gastric half-emptying and solid- as well as liquid meal latency time in diabetes patients with gastroparesis compared to placebo. Nevertheless, due to the small number of patients in each dose group, authors could not make any meaningful conclusion regarding dose-effect. Importantly, TZP-101 infusion improved gastric emptying in a similar magnitude to those observed in diabetes patients with gastroparesis following ghrelin infusion. However, reductions in overall postmeal symptom intensity and postprandial fullness following TZP-101 infusion were not statistically significant (40).

In another double-blinded, randomized, placebo-controlled study (ClinicalTrials.gov Identifier: NCT 00612014) the TZP-101 dose of 80 ug/kg was identified as the most effective. At the end of the study there was a statistically significant improvement in severity of GCSI Loss of Appetite and Vomiting Scores for that dose group. Moreover, in patients group receiving a dose of TZP-101 80 ug/kg meal related Gastroparesis Symptoms Assessment (GSA) scores for postprandial fullness were significantly improved compared to placebo group (41).

In two phase III studies (ClinicalTrials.gov Identifier: NCT01285570 and NCT01296620) involving patients undergoing partial bowel resection, ulimorelin failed to demonstrate its effectiveness. There were no differences between groups receiving ulimorelin and placebo in the study endpoints, which included postsurgical time to first bowel movement, tolerance of solid food and discharge eligibility (42).

Yet, there are no clinical trials evaluating the effect of this ghrelin agonist in patients with upper GI motility disorders.

TZP-102

TZP-102 is an oral low molecular weight synthetic macrocyclic compound with a substantially longer half-life, thereby allowing more sustained action as a potent GHSR agonist compared to parenteral ghrelin agonists (16).

Animal studies

Prokinetic activity of TZP-102 was evaluated in a rat model of gastric emptying, in which TZP-102 in a dose-dependent manner increased gastric emptying up to 51% in comparison to vehicle. Of note, TZP produced promotility effect comparable to metoclopramide, which administered p.o. in a dose 30 mg/kg increased gastric emptying in 35 – 57% (43).

Human studies

In a multicenter, randomized, double-blinded, placebo controlled phase II study (ClinicalTrials.gov Identifier: NCT00889486) oral administration of TZP-102 once daily for 28-days demonstrated significant improvements in the most prevalent symptoms of gastroparesis in diabetic patients (43). Nevertheless, no significant change in gastric emptying after administration of TZP-102 was observed in this study. The average improvement in GCSI total score was greater than in placebo group (43).

In another phase II study the primary outcome was to investigate the effect of TZP-102 in a dose 10 mg on symptoms associated with diabetic gastroparesis. Nevertheless, the study was terminated due to insufficient efficacy in planned interim futility analysis (ClinicalTrials.gov Identifier: NCT01664637).

ELIXIR (EX-1314) AND EX-1315

Animal studies

Intraperitoneal administration of 500 ug/kg of the small-molecule GHSR agonists, EX-1314 and EX-1315 resulted in a significant increase in gastric emptying compared to vehicle-treated mice. Furthermore, rats treated with EX-1314 either intraperitoneally or by oral gavage had a significant increase in gastric emptying relative to the vehicle group. After intraperitoneal injection, gastric emptying was significantly increased in rats given EX-1314 at 5-, 10- and 20-min time points, whereas oral gavage of GHSR agonist produced a significant difference only at the 5-min time point. In addition, administration of EX-1314 improved small intestinal transit, fecal output as well as stimulated food intake (44).

To our knowledge, this compound had never been tested on humans and currently there is no research concerning usefulness of this drug in therapy of GI tract motility disorders.

IPAMORELIN

There is limited data available on possible role of ipamorelin in upper GI motility disorders. Recent studies focused on constipation-related disorders, however those studies are out of scope of this review. More detailed information can be found in Mosinska et al. (22).

Animal studies

In rats undergoing laparotomy and intestinal manipulation intravenous administration of ipamorelin in a dose ranging from 0.014 to 0.14 µmol/kg resulted in significant acceleration of gastric emptying compared to vehicle-treated animals. In the tissue isolated from the gastric fundus, ipamorelin normalized the contractile response to cholinergic neural stimulation. These results suggest that ipamorelin improves delayed gastric emptying by stimulating gastric contractility via a GHSR receptor mediated mechanism located on cholinergic neurons (45).

Human studies

Currently, results of one study concerning prokinetic effect of ipamorelin for the management of postoperative ileus in bowel resection patients are available (ClinicalTrials.gov Identifier: NCT00672074) (44). Administration of ipamorelin in a dose 0.03 mg/kg twice daily did not shorten time to first tolerated meal compared to control (44).

GHRP-6

Animal studies

GHRP-6 is a peptide GHSR agonist tested for potential usefulness in the treatment of motility disorders associated with delayed gastric emptying (46, 47). In a study performed by Kitazawa et al. (47) GHRP-6 improved gastric emptying of solids. In another study GHRP-6 stimulated gastric emptying and small intestinal transit, but not colonic transit in vivo. In both studies atropine blocked the effect of GHRP-6 on gastric emptying, thereby suggesting that these effects may be mediated through potentiation of peripheral cholinergic pathways (46, 47).

To our knowledge, this compound had never been tested on humans and currently there is no research concerning usefulness of this drug in therapy of GI tract motility disorders.

CAPROMORELIN

Animal studies

In one study capromorelin, a non-peptide GHSR agonist, accelerated gastric emptying in mice in an equipotent manner with ghrelin. Moreover Kitazawa et al. demonstrated that not only ghrelin but also capromorelin can increase electrically induced cholinergic contractions, masked by nitrergic nerves, without affecting smooth muscle tonus. This suggests the involvement of nitrergic and cholinergic pathways in acceleration of gastric emptying caused by capromorelin (47).

Human studies

To date, pharmacokinetics and safety of capromorelin as a drug with potential to treat constipation were investigated in Phase I study enrolling patients with spinal cord injury (47). Currently there is not enough available data to support a possible clinical application of capromorelin in the management of gastroparesis or other upper GI motility disorders. To our knowledge, there are no ongoing studies registered in ClinicalTrials.gov, thereby suggesting that its development is no longer pursued.

DIRECTIONS FOR FUTURE RESEARCH OF GHRELIN RECEPTOR AGONIST AND POTENTIAL THERAPY LIMITATIONS:

Potential use of relamorelin and other agonists in FD and NERD refractory to PPI

Indisputably, the majority of studies presented in this paper support the notion that the small molecule ghrelin and GRLR-R agonists may offer a well-integrated therapeutic option for the management of various hypomotility disorders, especially gastroparesis (Table 2).

Table 2. GHSR agonists under investigation on different phases of clinical trials.

NP, not provided; i.v., intravenous; s.c., subcutaneous; p.o, per os; GCSI, Gastrointestinal Cardinal Symptom Index; GSA, Gastroparesis Symptoms Assessment; GHSR, Growth Hormone secretagogue receptor, ghrelin receptor.

Several consistent results from both animal studies and clinical trials, provide strong evidence for great and sustainable effects of relamorelin in improving gastroparesis-related symptoms and gastric emptying without causing severe adverse effects. Nevertheless, despite holding a great promise, further studies are still needed to establish the chronic effect of relamorelin on gastric motility.

Gastroparesis, FD and NERD have some similarities and some degree of clinical overlap between those disorders would appear inevitable. In a cohort of 198 gastroparesis patients Parkman et al. studied the presence of PDS symptoms. Importantly, severe or very severe early satiety and postprandial fullness symptoms were presented in more than 50% of patients. Furthermore, increasing severity of aforementioned was associated with slower gastric emptying, higher scores for other symptoms as well as greater impairment of quality of life (48). Of note, acyl-ghrelin levels have been associated with gastric emptying (49, 50) and delayed gastric emptying has been associated with postprandial fullness and severe early satiety in patients with FD (51). Recent research demonstrated that ghrelin and acyl-ghrelin levels are changed in patients with FD, however results are conflicting (6). Nevertheless, in a study performed by Akamizu et al. repeated i.v. infusions of acyl-ghrelin in dose 3 µg/kg twice daily to patients with FD for 2 weeks tended to increase daily intake and hunger sensation (52).

It is widely recognized that patients with PPI-resistant NERD have lower quality of life due to persistent symptoms resulting from PPI resistance. This resistance may be caused by several factors, with gastric motility disorders among others (bile acid reflux, esophageal mucosal hypersensitivity, abnormal esophageal motility). Although the symptoms experienced by NERD patients are not as severe as those experienced by patients with GERD, one cannot classify NERD as a milder form of GERD. Moreover, recent studies showed that the pathogenesis of NERD may differ from that of erosive GERD or Barrett’s esophagus (49). In their study Shindo et al. demonstrated that 33% of NERD patients exhibited delayed gastric emptying (49). Furthermore, plasma acylated ghrelin levels in FD patients, especially patients with PDS, and NERD were significantly lower than in healthy volunteers (49). These results demonstrated that ghrelin analogs, especially relamorelin, have great therapeutic potential in the treatment of FD and NERD.

Another piece of evidence supporting a potential use of ghrelin analogs in the treatment of GI motility disorders other than gastroparesis, is Rikkunshito, a representative of Kampo medicines in Japan, with promising results in the treatment of FD and NERD. Rikkunshito, known as a ghrelin enhancer, is prepared from eight crude medications: Atractylodis Lanceae Rhizoma, Ginseng Radix, Pinelliae Tuber, Poria, Zizyphi Fructus, Aurantii Nobilis Pericarpium, Glycyrrhizae Radix, and Zingiberis Rhizoma (53). It has been reported that Rikkunshito elicits a continuously increased acylated ghrelin signal in GHS-R-expressing cells and a decreased afferent activity of the gastric vagus nerve (54). Furthermore, Rikkunshito suppressed cisplatin-induced decrease in plasma acylated-ghrelin and food intake in an anorexia model in rats through 5-HT2 receptor antagonism (55). Flavonoids found in Rikkunshito, such as heptamethoxyflavone, hesperidin and isoliquiritigenin were responsible for the 5-HT2 antagonistic effect of this herbal medication (55). In a randomized trial of gastroprokinetic agents for 27 patients, conducted by Arai et al., Rikkunshito was effective in ameliorating upper GI symptoms, assessed by their scores on the Gastrointestinal Symptoms Rating Scale Questionnaire (56). Furthermore, Tominaga et al. in a randomized, placebo-controlled, double-blind trial of Rikkunshito for 242 patients with NERD refractory to PPI showed that treatment with ghrelin enhancer for 4 weeks significantly improved mental component summary scores in a short-form health survey-8 (SF-8) in patients with low BMI values (under 22) as well as acid-related dysmotility symptoms in females and the elderly assessed by the Frequency Scale for the Symptoms of GERD (57). In another multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial conducted by Suzuki et al. on the effect of Rikkunshito on 247 patients, the 8-week administraton of ghrelin enhancer reduced dyspepsia. In addition, epigastric pain was significantly alleviated and postprandial fullness tended to improve (58). Togawa et al. in a post-hoc analysis of a randomized placebo-controlled trial on the efficiency and safety of rikkunshito for the treatment of FD focused on the differences between responders and non-responders to rikkunshito. Interestingly, a low baseline level of plasma des-acyl ghrelin was associated with an increased treatment efficacy of rikkunshito among FD patients, especially in H. pylori-negative population (59).

Taking into consideration promising effects of ghrelin agonists in alleviating gastroparesis-related symptoms as well as the effect of acyl-ghrelin and Rikkunshito on FD and NERD symptoms, new clinical trials should be designed to evaluate potential therapeutic efficacy of relamorelin in FD and NERD-refractory to PPI.

Advantages of therapy with relamorelin

While there are very limited treatment options in gastroparesis, relamorelin shows promising efficacy of this condition with a significant reduction in core symptoms and the overall composite score of Diabetic Gastroparesis Symptom Severity Diary (DGSSD) as well as acceleration of gastric emptying. Nevertheless, there was no meaningful association between improvement of gastric emptying and symptoms of gastroparesis in the phase IIA and IIB studies (60). This is a common observation in studies concerning prokinetic treatment in gastroparesis (60). Thus, it is possible that beneficial effects of relamorelin result from activation of GHSRs in vagal afferent pathways, with reduction of vagal tone and therefore, reduced sensations expressed as symptoms (61).

Patients with gastroparesis are at risk of lost weight or nutritional deficiencies (62). Thus, administration of relamorelin, which may increase appetite and reverses weight loss, may be beneficial for these patients. On the other hand, the administration of ghrelin agonist may result in weight gain which may be a potential concern in patients with gastroparesis due to diabetes, who may become more overweight or obese (60). Since data from an available clinical trial did not show significant changes in weight, future studies should focus on the effect of relamorelin on weight changes in patients with diabetic gastroparesis (36).

Another advantage of relamorelin is that compared to presently available therapies for gastroparesis, relamorelin was efficacious and well tolerated (63). Considering adverse effects, relamorelin seems to be superior to other available drugs, such as metoclopramide, domperidone, cisapride, which possess neurological or cardiovascular adverse effects. Whereas domperidon, cisapride and metoclopramide may cause QTc prolongation, safety studies of relamorelin did not report any electrocardiogram changes.

Limitations of therapy with relamorelin

Hyperglycemia is one of the major side effects reported for relamorelin therapy. An increase in gastric emptying may enhance movement of nutrients from stomach to intestine and normal absorption may contribute to hyperglycemia. Thus, proper adjustments in the treatment of diabetes should be implemented during therapy with relamorelin.

Another concern is that ghrelin and its receptor are expressed in a vast number of cancers and cancer cell lines and thus may play a role in cancer development and progression (64). One of the ghrelin agonists, anamorelin, has been studied in patients with cancer cachexia. The administration of anamorelin had no effect on a 1 year survival as compared to placebo, which suggests that ghrelin agonist has no effect on cancer progression (65, 66). Nevertheless, the impact of relamorelin in cancer progression has not been studied so far.

In summary, considering their beneficial effects on gastric emptying, core symptoms and overall symptoms of DGSSD, ghrelin agonists, and relamorelin in particular, show promise as novel and efficient therapies for gastroparesis and other upper GI motility disorders, such as FD and PPI-resistant NERD. Chedid and Camilleri anticipate that relamorelin is likely going to be available on the market within the next 3 years for patients with gastroparesis and will immediately become the treatment of first choice in upper GI motility disorders (60). Nevertheless, further studies are required, particularly Phase III studies and long-term safety studies for relamorelin to become available on the market.

List of abbreviations: DGSSD, Diabetic Gastroparesis Symptom Severity Diary; EPS, epigastric pain syndrome; FD, functional dyspepsia; GCSI, Gastrointestinal Cardinal Symptom Index; GSA, Gastroparesis Symptoms Assessment; GERD, gastroesophageal reflux; GHSR, growth hormone secretagogue receptor, ghrelin receptor; GI, gastrointestinal; GOAT, ghrelin-O-acyltransferase; i.p., intraperitoneally; i.v., intravenously; NERD, non-erosive reflux disease; POI, postoperative ileus; PDS, postprandial distress syndrome; PPI, proton pump inhibitors; RE, reflux esophagitis; s.c., subcutaneously

Author’s contributions: Hubert Zatorski, Paula Mosinska, Martin Storr, and Jakub Fichna provided the overall concept and framework of the manuscript; Hubert Zatorski researched and identified appropriate articles, and wrote the manuscript; Paula Mosinska, Hubert Zatorski, Martin Storr, and Jakub Fichna revised the manuscript; and all authors approved the final version of the manuscript.

Acknowledgements: The study was supported by the Medical University of Lodz (502-03/1-156-04/502-14-339 to HZ, 503/1-156-04/503-11-001 to JF and 502-03/1-156-04/502-14-343 to PM) and National Science Center (2016/21/N/NZ5/01932 to PM). Hubert Zatorski is the recipient of Diamentowy Grant Program of the Polish Ministry of Science and Higher Education (No. 0202/DIA/2015/44).

Conflict of interests: None declared.

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