NG101 is a potent, selective and peripherally restricted dopamine D2 receptor antagonist currently in Phase 2 clinical development for the treatment of gastroparesis. Neurogastrx has generated preclinical data indicating that in addition to its potent antiemetic properties, NG101 is also expected to significantly increase gastric motility, conferring NG101 an ideal pharmacological profile for the treatment of gastroparesis.
Gastroparesis is a chronic, severe and debilitating disorder that may be associated with dysfunction in the enteric nervous system, causing the movement of food from the stomach to the small intestine to slow or stop, and preventing or disrupting normal digestion. Common symptoms include nausea, vomiting, bloating, early satiety, fullness after eating and abdominal pain. These symptoms are chronic and often constant, significantly impacting the patient’s quality of life. Severe cases result in the inability to digest foods and liquids and lead to malnutrition, weight loss and dehydration, periodically requiring hospitalization.
The only approved therapy for gastroparesis in the US, metoclopramide, is a D2 antagonist developed several decades ago and has significant neurological side effects due to its interactions with a variety of receptors throughout the brain. These CNS toxicities have resulted in a black box warning limiting its use to 12 weeks. Other drugs in the class have shown other adverse events, including cardiovascular problems that have prevented them from being approved in the US. Neurogastrx aims to bring forward a D2 antagonist appropriate for first-line therapy without the side effects that have plagued the class for decades.
NG101 has dual mechanisms of action: central antagonism of D2 receptors in the area postrema, an area of the brain stem outside of the blood brain barrier resulting in its potent antiemetic and anti-nauseant properties, and blockade of D2 receptors in the guts which results in a positive effect on motility.
Also, NG101 and its major metabolite are substrates of P-Glycoprotein, an important protein of the cell membrane that pumps many foreign substances out of cells, including preventing them from crossing the blood-brain barrier. This important characteristic of NG101 makes central nervous system adverse events unexpected.
Preclinical data shows that NG101 has the potential to be an improvement over the current standard of care as it does not cross the blood-brain-barrier and does not alter cardiac rhythm, another concern for products in this class. These features may provide safety and tolerability advantages over existing marketed products.
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