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Protara Therapeutics, Inc.
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  3. Protara Therapeutics, Inc.
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  5. IV Choline Chloride for IFALD

IV Choline Chloride for IFALD

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IV choline chloride is an investigational, intravenous (IV) phospholipid substrate replacement therapy initially in development for patients receiving parenteral nutrition (PN) who have intestinal failure-associated liver disease (IFALD). Choline is a known important substrate for phospholipids that are critical for healthy liver function. Because PN patients cannot sufficiently absorb adequate levels of choline and no available PN formulations contain sufficient amounts of choline to correct this deficiency, PN patients often experience a prolonged progression to hepatic failure and death, with the only known intervention being a dual small bowel / liver transplant. If approved, IV choline chloride would be the first approved therapy for IFALD. It has been granted Orphan Drug Designations (ODDs) by the FDA for the treatment of IFALD and the prevention of choline deficiency in PN patients.

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Protara had an end of Phase 2 meeting with the FDA in late 2018 and received the FDA’s support to advance IV choline chloride into a registration-enabling study for the treatment of IFALD.
The mechanism for which choline supplementation reverses steatosis and improves cholestasis is not completely understood. However, clinical studies support that exogenous supplementation of choline can restore normal physiologic levels of choline thereby reversing steatosis by playing an important role in the synthesis of very low-density lipoprotein (VLDL), which is necessary to move fat out of the liver. Additionally, choline supplementation plays a critical role in the production of normal, healthy mixed micelles in bile, which protects against cholestatic injury to the biliary system.

Intestinal failure-associated liver disease (IFALD), which occurs in patients dependent on PN support, is characterized by choline deficiency, hepatic steatosis, cholestasis, and rapid progression of liver disease through to hepatic failure and death in the absence of intestine-liver transplant. IFALD carries a relatively poor prognosis, with a 15-34% death rate within 1-4 years. When IFALD presents with symptoms of liver disease in children, mortality is even higher (23–40%).

IFALD is uniquely characterized by the presence of both steatosis (toxic fat accumulation in liver cells) and cholestasis (damage to the biliary system in the liver) in patients who are chronic (greater than six months) PN users. A patient is considered to have IFALD if she/he is dependent on PN for more than six months (e.g., has chronic intestinal failure); has evidence of steatosis, determined by imaging techniques or histologic assessments; has evidence of cholestasis (e.g., elevated alkaline phosphatase (ALP), elevated bilirubin and/or histology); and may have evidence of ongoing, progressive liver injury on the basis of multiple abnormal liver function tests, in conjunction with findings of fibrosis, cirrhosis, and/or end-stage liver disease (ESLD).