Ascentx Medical

G125 Injectable Bulking Agent for GERD

Gastroesophageal Reflux Disease (GERD) is defined as the presence of symptoms such as heartburn and regurgitation, and/or tissue damage (i.e. erosive esophagitis) secondary to reflux of normal gastric contents into the esophagus. GERD affects 10-20% of the Western populations and causes chronic symptoms of mucosal damage by acid coming up from the stomach into the esophagus. It is the third most common disorder of the gastrointestinal tract and an estimated 100 million Americans suffer from GERD every month, and about 20 million Americans battle it at least once a day. Hundreds of millions more suffer from daily GERD globally. There is no data that support sex predominance with regard to GERD and the prevalence rate of GERD is tightly linked with age, with adults 60-70 years old being the most commonly affected. The combination of longer life expectancy and aging populations in developed countries is expected to lead to an increase in GERD prevalence in the years to come.

Chronic GERD can cause progressive injury of the esophagus, which may include:

• Reflux Esophagitis
• Erosive Esophagitis
• Esophageal Strictures (can cause difficulty swallowing)
• Barrett's Esophagus
• Esophageal Adenocarcinoma

The basic cause of GERD has been well characterized. The disease's fundamental defect is a loss of integrity of the gastro-esophageal 'barrier'-- the 'Lower Esophageal Sphincter' (LES), which normally holds the top of the stomach closed. Dysfunction and loosening of the LES results in reflux of gastric acid and occasionally even duodeno-gastric reflux of bile and digestive pancreatic enzymes ('witch's brew').

Years of chronic acid exposure and inflammation (GERD)t can lead to Barrett's esophagus, a pre-cancerous lesion, e.g. a metaplastic change in the distal esophageal lining from the normal squamous epithelium to intestinalized columnar epithelium, which may eventually turn into aggressive and particularly lethal esophageal cancer (adenocarcinoma) with a survival rate of less than 1 year in most patients.

About 12% of GERD sufferers develop Barrett's esophagus, which increases the risk of esophageal cancer by 40-times. The incidence of esophageal adenocarcinoma - the type linked with heartburn - has jumped five-fold in the past 30 years and has become the fastest growing cancer in the U.S and the seventh most common killer among men.

Based on the severity of GERD, three types of treatments exist in progressive order:

• Life Style modifications
• Medications
• Surgery

Proton Pump Inhibitors (PPIs) are among the most commonly used medications used to treat GERD. Brand-name PPIs (Nexium^®, Prevacid^®, Protonix^®) comprise 3 of the top 11 most commonly prescribed medications in the United States and, as a group, are second only to cholesterol lowering statins. With the advent of over-the-counter Omeprazole (Prilosec^®, AstraZeneca), self-directed PPI therapy for GERD is now widely available, which also increases the potential for inappropriate use.

Pharmaceutical treatment of GERD is highly successful in relieving heartburn symptoms with a relief rate among the four different generations of PPIs of 78-92% with once-a-day therapy. However, the fact that medications only provide 'symptomatic' relief and 75-90% of patients will relapse following discontinuation of PPIs explains why they have to be continued lifelong.

It is therefore not surprising that PPIs have evolved into the second most popular drug type with annual U.S. sales reaching >$14 Billion in 2009. The average per-U.S. patient co-pay cost for GERD medication are estimated at approximately $1,300 annually.

'Symptom control' with medication does not equal 'disease control', and GERD patients under medical therapy have shown to develop esophageal cancer at the same rate, nevertheless.

Another challenging problem remains with 10-20% of GERD patients who do not respond to high doses of PPIs (so-called 'refractory patients').

PPIs merely 'mask' GERD symptoms and do not cure the underlying pathophysiology because 'asymptomatic' reflux continues. It was reported that the 'less acidic' refluxate under PPI use is even more damaging to esophageal tissues, as it consists mostly of bile and pancreatic enzymes ('witch's brew'). Long-term use of PPIs is associated with severe side-effects including higher death rates, higher risk of heart attack, higher risk of dementia, stomach cancer, chronic liver disease, chronic kidney disease, increased risk of bone fractures, reduced effects of chemotherapy for cancer- and the list keeps growing. As U.S. patients increasingly find themselves with health insurance that does not or only partially covers prescription drugs, they are seeking alternatives to medication for economic reasons including anti-reflux surgery.

With G125 injectable bulking agent, we aim to restore the physiologic barrier of the Lower Esophageal Sphincter (LES) muscle to 'cure' the underlying cause for GERD, aiming to get patients off lifelong pharmacotherapy.

Available GERD therapies besides pharmacotherapy include invasive surgical procedures that are costly and require anesthesia and hospitalization. These procedures include open or laparoscopic NISSEN fundoplication, Esophyx^® Transoral Incisionless Fundoplication (TIF), and the Linx^® magnetic titanium bead antireflux bracelet. There is currently no safe, cost-effective and minimal-invasive (endoscopic) treatment available for GERD:

Our pre-clinical studies⁽¹⁾ have shown G125 to form a healthy, soft, pliable, and fully vascularized permanent tissue bulk at the LES that completely maintains its location, shape and volume after precise submucosal injection. These are crucial attributes of G125 , as they enable the endoscopist to perform a reliable and predictable 'augmentation' of the Lower Esophageal Sphincter, individually adapted to each patient, without the risk of tissue necrosis, volume loss, migration or dislocation.