FDA approves CHOLBAM (cholic acid) for treatment of bile acid synthesis disorders

Asklepion Pharmaceuticals, LLC. today announced that the U.S. Food and Drug Administration (FDA) approved CHOLBAM™ (cholic acid) as a once-daily treatment for cholic acid deficiency in bile acid synthesis disorders due to single enzyme defects. This indication is based on CHOLBAM's ability to markedly improve or normalize liver function test values and to improve general health, as measured by weight gain. CHOLBAM was also approved as an adjunct to standard of care for peroxisomal disorders including Zellweger spectrum disorders in patients with evidence of liver disease, based on improvements in liver function.

CHOLBAM is the first medication approved by the FDA to turn off a genetically-damaged bile synthesis pathway and prevent its toxic products from damaging the liver. The approval of CHOLBAM is a testament to the pioneering work of Dr. Kenneth Setchell and Dr. James Heubi of Cincinnati Children's Hospital and Medical Center, who were the first to recognize many of the constituent diseases and develop a safe and effective therapy. The U.S. approval of CHOLBAM was based on two pivotal trials that showed improved liver function test values and restoration of growth assessed by weight gain in comparison to the natural history of untreated patients. Some patients in these trials have been healthy on therapy, exhibiting normal liver function for more than 16 years.

"The FDA approval of CHOLBAM is of vital importance to patients and families who are dealing with bile acid deficiency diseases," said Philip Rosenthal, MD, Director of Pediatric Hepatology at the University of California, San Francisco. "Previously, the patients who rely on this life-saving medicine were only able to receive it through research studies. Making this therapy more widely available is a significant accomplishment of science and collaboration in this rare disease space."

The safety and efficacy of CHOLBAM in patients with bile acid synthesis deficiency disorders were evaluated in a nearly 20-year open label, single arm, investigator-initiated trial at Cincinnati Children's Hospital and Medical Center. FDA noted responses in 28 of 44, or approximately 64 percent, of patients with single enzyme defects and in 11 of 24, or 46% of peroxisomal disorder patients.

"The approval of CHOLBAM is a significant medical advancement for patients with bile acid deficiency disorders and the physicians who treat them," said Gary Pasternack, MD, PhD, Chief Executive Officer of Asklepion Pharmaceuticals.

"Asklepion is committed to developing and bringing to market treatment options for populations with a high unmet need," added Jeff Courtney, Asklepion's Chief Operating Officer.

Bile acid synthesis disorders caused by single enzyme defects are a group of highly symptomatic conditions that prevent the liver from properly producing bile acids that help the intestines absorb essential fats, vitamins and nutrients. The genetically damaged pathway instead produces toxic products that damage the liver. The disease is most commonly diagnosed in infants.

In the U.S., there are at least 500 babies born with bile acid deficiencies each year. Children with bile acid deficiency diseases may present during the neonatal period or during early childhood. If untreated, these deficiencies can cause the buildup of defective bile acids that lead to cholestasis, nutrient malabsorption, liver disease, neurologic disease, and, eventually, liver failure and death. Because many physicians are unfamiliar with these diseases, it is believed that the majority of cases go undiagnosed and untreated.

Zellweger spectrum disorder patients lack peroxisomes and produce abnormally long fatty acids, leading to numerous problems in many organ systems. Occurring in 1 of 50,000 live births, about 80% of people with these disorders will develop liver disease. Patients with Zellweger spectrum disorders are usually recognized at birth as floppy babies, without muscle tone.

CHOLBAM works by down regulating cholesterol 7alpha-hydroxylase, the rate limiting step in bile acid synthesis. In doing so, it inhibits the production and accumulation of hepatotoxic and cholestatic bile acid precursors. It also stimulates bile flow and secretion, and facilitates fat absorption at therapeutic doses. Patients with single enzyme defects cannot make cholic acid, and instead make abnormal, toxic intermediate products. Zellweger spectrum patients make cholic acid, but the lipid side chains that are subsequently added are too long, making the product toxic to the liver.

The main purpose of providing CHOLBAM is to prevent the production of toxic products. CHOLBAM also restores the main functions of cholic acid, including lipid transport in the form of mixed micelles; the activation of co-lipase, and fat digestion and absorption; the absorption of fat-soluble vitamins; and, the induction of bile flow, thus preventing cholestasis. Cholic acid is one of the primary bile acids on which essential physiological functions depend.

The Warnings and Precautions for CHOLBAM include worsening liver disease and biliary obstruction. Adverse reactions include a 2 percent incidence of diarrhea, and 1 percent incidence of abdominal pain, nausea, intestinal polyp, reflux esophagitis, malaise, jaundice, urinary tract infection, peripheral neuropathy and skin lesion.

The recommended dosage for pediatric patients 1 month of age and older and adults is 10 to 15 mg/kg once daily or in two divided doses.

The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis or Zellweger spectrum disorders have not been established.