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Why you need the Right Drug Trial Participants: GERD
Posted on October 24th, 2016 by Patricia Morgan in Pharma R&D
Gastroesophageal reflux disease (GERD) is best conceptualized as a complex constellation of related syndromes rather than a single disease entity. People tend to lump the various symptoms of GERD together, when in fact the various facets of GERD, such as esophagitis, symptomatic regurgitation, and reflex cough, represent variegate pathology. These separate conditions possess different pathophysiological determinants — i.e., gastroesophageal reflux, mucosal sensitivity, refluxate constituents and refluxate clearance — and thus react differently to different medications and interventions.
The desire to treat all the syndromes of GERD in the same way, and thus test drugs on people with diverse pathophysiological determinants, has led to clinical trial failures. Specifically, although GABA-B (g-aminobutyric acid) agonists should theoretically reduce GERD by interfering with the relaxation or opening of the lower esophageal sphincter, clinical trials have failed to show significant benefit because patient populations are heterogeneous. These heterogeneous samples include participants with persistent weakly acidic reflux, participants with visceral hypersensitivity as well as those with functional heartburn, dyspepsia or chest pain.
Proton-pump inhibitors (PPIs), such as omeprazole (Prilosec) and lansoprazole (Prevacid), are mainstays in the treatment of GERD. These medications inhibit gastric acid secretion in people with GERD. However, gastric acid secretion is often normal in people with GERD and a reduction in gastric acid is likely most beneficial in patients with esophagitis only and less effective in treating other aspects of GERD, such as symptomatic heartburn, chest pain, cough and laryngitis.
A more fundamental approach to the treatment of GERD involves targeting the lower esophageal sphincter. Typically, the lower esophageal sphincter closes to prevent food from being regurgitated into the esophagus. This reflux of stomach contents is the basic mechanism of GERD. GABA-B (g-aminobutyric acid) agonists interfere with the relaxation or opening of the lower esophageal sphincter by reducing the number of transient lower esophageal sphincter relaxations (TLESRs).
During preclinical testing, the GABA-B agonist baclofen reduced TLESRs by 40 percent. Additionally, baclofen reduced postprandial episodes by 60 percent. Based on these findings, researchers hypothesized that the ability of GABA-B receptors to reduce esophageal exposure to acid and nonacidic fluids could treat the various symptoms of GERD. Of note, baclofen is commonly used as a skeletal muscle relaxant.
Three pharmaceutical companies have pursued the development of GABA-B agonists to treat GERD. AstraZeneca tested lesogaberan, Xenoport tested arbaclofen placarbil, and Addex Pharmaceuticals tested ADX10059. Of these efforts, drug development by AstraZeneca was most aggressive. Lesogaberan was tested in two double-blind, randomized control trials. The results of these trials were mixed, with the second study showing insufficient benefit. Consequently, AstraZeneca discontinued development of lesogaberan.
In retrospect, experts suggest that the reason lesogaberan and other GABA-B agonists failed to impress in clinical trials was related to participant selection. Selection of participants was colored by the dominance of PPIs in the treatment of GERD. In an article titled “Failure of reflux inhibitors in clinical trials: bad drugs or wrong patients?, Kahrilas and Boeckxstaens ask:
However, the profound dominance of PPIs in the therapeutic arena of GORD [GERD] greatly complicated the trial design. Should reflux inhibitors be used in the trial as monotherapy or cotherapy along with PPIs? Should clinical response to PPI treatment be an inclusion criterion, an exclusion criterion, or something in between? By what symptom profile should patients be selected for clinical trials? Should patients qualify for clinical trials on the basis of physiological testing implicating TLOSRs as the basis for their symptoms? If so, while taking PPIs or not?”
These researchers concluded that patients who would most likely benefit from GABA-B agonists did not have refractory GERD assessed in a very general sense but rather were those with persistent reflux, which is most commonly manifested as persistent regurgitation, despite treatment with PPIs.
GERDS research is just one example that underlines how critical it is to start with the right participant population to ensure accurate trial results.
For more information on how Pathway Studio can help with clinical trial design and patient stratification, click here.
All opinions shared in this post are the author’s own.
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