WASHINGTON – The American Gastroenterological Association, the Food and Drug Administration, pharmaceutical companies, and patient advocacy groups came together for a first-of-its-kind meeting, a program of the AGA Center for Diagnostics and Therapeutics, to discuss new and emerging drugs for the treatment of four key GI diseases, highlighting the promise that these treatments show and the hurdles they face to gain approval.
“If we look at the AGA’s Burden of GI Disease Survey, published a few years ago in Gastroenterology, [you] can see that there are millions of visits to primary care and specialists for a variety of upper gastrointestinal symptoms, so clearly upper GI disorders still pose a major burden to our health care environment,” explained Colin W. Howden, MD, AGAF, chair of the AGA Center for Diagnostics and Therapeutics from the University of Tennessee in Memphis.
Deepak Chitnis/Frontline Medical News
From left: Dr. Michael Camilleri, Dr. Juli Tomaino, Ms. Robyn Carson, Dr. Jessica Lee, Dr. Nimish B. Vakil, Tom McCourt, Dr. Paul Moayyedi, Dr. Colin W. Howden, and Dr. Jan Tack
While proton pump inhibitors (PPIs) continue to be the first line of management for GERD, severe cases often require a stronger approach. Alternatives that are being investigated include potassium-competitive acid blockers, for which there have been clinical trials. However, no advantage over PPIs was demonstrated in any trials. Another alternative is bile salt binders, for which at least one trial is currently underway. Dr. Vela was unable to say when findings are expected to be published.
Another approach to managing GERD is to treat the acid pocket itself by using alginate. A randomized study by Rohof et al. investigated this in 2013, comparing Gaviscon and antacid; although the population size was small (n = 16), investigators concluded that “alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux [making it] an appropriate therapy for postprandial acid reflux.”
Another new drug is lesogaberan, a GABA-B agonist that was examined in a 2010 randomized, double-blind crossover study by Boeckxstaens et al. While also a small trial (n = 21), the findings indicated that the drug is a good option for those with only partial response to PPIs, as it decreased the number of transient lower esophageal sphincter relaxations (TLESRs) and reflux episodes, and increased LES pressure [in] patients with reflux symptoms. Work to inhibit transient LES relaxations also is being done, but so far lesogaberan, arbaclofen, and ADX 10059 (an mGluR5 modulator) programs have all been halted because of side effects or insufficient efficacy findings.
Prokinetics are also being looked at, with drugs such as metoclopramide being examined for efficacy, although to this point, the drug has shown “no improvement in acid exposure or esophageal clearance [when] compared to placebo,” according to Dr. Vela. Other drugs that are available outside the United States include domperidone, itopride, and mosapride, but Dr. Vela, who led a 2014 report on these therapies, stated that benefits offered by these are modest, and studies investigating them are limited in number.
Also being looked at are rebamipide, which can be used a cytoprotective agent that increases prostaglandin production. A 2010 study by Yoshida et al. found that lansoprazole (15 mg/day), combined with 300 mg/day of rebamipide, was significantly better at preventing relapse within a year than was just the former medication taken on its own. Additionally, there are conceptual studies examining topical protection to maintain mucosal integrity, nociceptor blockades, and imipramine.
Regarding trials for GERD, Robyn Carson, director of health economics & outcomes research at Allergan stated that the company recently redefined what constitutes GERD in order to help refocus what its drugs were trying to do.
“I think we’ve operationalized it very recently in terms of exclusion and GERD,” she explained. “The way we define it is ‘active GERD’ with two or more episodes a week of heartburn, so it was very much focused on the heartburn and PPI use was acceptable.”
Following the GERD discussion, panelists talked about what’s coming up in the realm of EoE. Stuart J. Spechler, MD, of the University of Texas Southwestern in Dallas, discussed ongoing research into treating EoE as an antigen-driven disorder, noting that about half of all EoE patients have a history of atopic disease – such as rhinitis, asthma, and atopic dermatitis – and exhibit sensitization to food or other aeroallergens. Furthermore, about 3% of patients who undergo oral immunotherapy to treat a food allergy develop EoE.
But in terms of what to take EoE research forward, Dr. Spechler called for a shift away from trying to distinguish between EoE and GERD, arguing that GERD contributes to EoE pathogenesis, and vice versa. PPIs can and should be used in EoE for the same reasons that they’re used to treat GERD, he explained.
“We need a shift in focus [because] I don’t think it’s likely to be that productive a line of research,” Dr. Spechler said. “The two diseases often coexist.”
To attack gastroparesis, P. Jay Pasricha, MD explained that a number of trials examining several drugs have shown that they are either ineffective or “do not correlate with improvement in gastric emptying.” These drugs include cisapride, tegaserod, botulinum toxin, mitemcinal, camcinal, TZP 102, and relamorelin.
“I’m not going to talk about emerging biomarkers because there isn’t a lot to talk about with biomarkers that hasn’t already been said,” stated Dr. Pasricha of Johns Hopkins University in Baltimore adding that his focus would largely be focused on emerging therapies and treatment targets.
A 2013 study by Parkman et al. investigated the effects of nortriptyline on mitigating idiopathic gastroparesis symptoms, finding that there was no significant difference in symptoms among patients who took the drug, versus those who took a placebo. In terms of using antinauseants to alleviate symptoms, dopamine receptor antagonists continue to be commonly prescribed, but they have their limitations. Metoclopramide, though approved since 1986, can be used for only 12 weeks, has acute and chronic side effects such as mood and irreversible movement disorders, and a black box warning imposed on it by the FDA in 2009 for tardive dyskinesia. One drug approved in India, though not by the FDA, is domperidone, which has no side effects to the central nervous system but does raise cardiovascular concerns in patients with “mild hERG affinity.”
Currently, the APRON trial is investigating the efficacy of aprepitant to relieve chronic nausea and vomiting in gastroparesis patients. Those enrolled in the study are all at least 18 years old, have undergone gastric-emptying scintigraphy, and either a normal upper endoscopy or an upper GI series within the 2 years prior to enrollment, have symptoms of chronic nausea or vomiting consistent with a functional gastric disorder for at least 6 months before enrollment, and nausea defined as “significant” by a visual analog scale score of at least 25 mm.
“Continuing to focus solely on accelerating gastric emptying is a failed strategy,” said Dr. Pasricha, adding that research needs to focus on the unique aspects of the disease’s biology, including pathogenic similarities with functional dyspepsia.
To that end, the final disease covered was functional dyspepsia. In terms of ongoing or planned clinical studies, Jan Tack, MD, from the University of Leuven (Belgium), mentioned three. Two of them are multicenter controlled trials investigating acotiamide, one in Europe and the other in India, for the management of functional dyspepsia and postprandial distress syndrome, while the other is a multicenter study examining rikkunshito, a traditional Japanese medicine. Additionally, ongoing or planned mechanistic studies include single-center controlled trials in Belgium on the efficacy of acotiamide and rikkunshito for intragastric pressure, as well as another Belgian study analyzing the impact of monoacylglycerol lipase inhibitors on intragastric pressure in patients that have functional dyspepsia with “impaired accommodation.”
Meal-related symptoms, nutrient challenge tests, and intragastric pressure measurements should all become short-term pathophysiology and efficacy markers, said Dr. Tack, adding that it’s also important for new therapeutic targets to include gastric emptying, hypersensitivity, and duodenal alterations, if necessary.
Hurdles persist in getting drugs through the approval process, however. Juli Tomaino, MD, of the FDA’s Center for Drug Evaluation and Research, explained where many proposed drugs run into issues in the regulatory process.
“We really have to know what we’re diagnosing, so the regulatory pathway to any of these approvals will really depend on the independent patient population, it will depend on the mechanism of action of the drug, what the drug is able to do and not do, and how you’re going to design that trial to target whatever that drug can do,” Dr. Tomaino said.
The issue of labeling also factors in, according to her. “We know that patients with acid-mediated heartburn do well on PPIs, but if they’re having different symptoms due to different mechanisms of action, then you have to design that drug with that patient population in mind, and that’s what the labeling would look like,” she explained. “So I’m not saying that it would necessarily have to list all the enrollment criteria, all the enrichment techniques that we use in that trial, but it would be a description of the intended patient population and what the drug would do.”
Mrs. Carson also chimed in on the topic of trial difficulties, saying that “[Irritable bowel syndrome] and [chronic idiopathic constipation] became quite an impediment to recruitment, and I think as we get farther away from the complete overlapping conditions, I think that’s where in discussions with the [Qualification Review Team] at FDA, they recognize that [we should] track that and let this evidence drive the next step,” adding that “we’ll have data on that shortly.”
The AGA Center for Diagnostics and Therapeutics will be issuing white papers on each of the four upper GI disorders discussed at the meeting.
Dr. Howden disclosed that he is a consultant for Aralez, Ironwood, Allergan, Otsuka, and SynteractHCR; an expert witness for Allergan; and coeditor of Alimentary Pharmacology & Therapeutics. Dr. Spechler disclosed that he is a consultant for Interpace Diagnostics, Takeda Pharmaceuticals, and Ironwood Pharmaceuticals. Dr. Pasricha disclosed that he is the cofounder of Neurogastrx, OrphoMed, and ETX Pharma, and is a consultant for Vanda and Allergan. Dr. Tack disclosed that he is a consultant for Abide, Allergan, AstraZeneca, Danone, El Pharma, Menarini, Novartis, Ono, Shire, Takeda, Theravance, Tsumura, and Zeria, as well as being on several of their advisory boards and speakers bureaus. Dr. Vela is a consultant for Medtronic and Torax.*
*Additions were made to the story on 11/8/2016 and 11/18/2016.