Clinical drug trial seeks to avoid liver transplant for LAL deficiency

(Image courtesy Ed Neilan)

neilan_edward_dsc9139Second in a two-part series on metabolic liver disease. Read part 1.

According to the American Liver Foundation, about 1 in 10 Americans have some form of liver disease. One rare, under-recognized disorder, lysosomal acid lipase (LAL) deficiency, can fly under the radar until it becomes life-threatening, often requiring a liver transplant. LAL deficiency currently has no specific treatment, but that may change thanks to combined expertise in genetics, metabolism and hepatology.

In recent years, Boston Children’s Hospital’s Director of Hepatology, Maureen Jonas, MD, and the Metabolism Program’s Edward Neilan, MD, PhD, diagnosed three children with LAL deficiency. All three are now enrolled in the first international LAL deficiency clinical trial, with Neilan serving as Boston Children’s principal investigator.

“LAL deficiency is currently under-diagnosed,” Neilan says. “We think the disease is more common than doctors have thought and now, with a treatment in trial, it is of greater importance to identify those patients so they may have better outcomes.”

The clinical trial, launched in January 2013, has enrolled 66 patients in 54 locations, according to the National Institutes of Health. With three patients, Boston Children’s has the highest patient enrollment in North America.

About LAL deficiency


LAL deficiency is an autosomal recessive liver disorder in which the body does not produce enough of the LAL enzyme, which helps break down fats. This deficiency prompts a build-up of fat and cholesterol in the liver, spleen and other parts of the body.

In early-onset LAL deficiency, also recognized as Wolman disease, LAL is completely absent and the fatty accumulation happens quickly. Disease develops during the first few weeks or months of life and is rapidly progressive and often fatal.

Its more subtle counterpart is late-onset LAL deficiency or cholesteryl ester storage disease (CESD), which affects older children and adults. Patients typically have an enlarged liver, abnormal liver function tests and elevated cholesterol levels, and some may also have an enlarged spleen. Often misdiagnosed, CESD can cause cirrhosis and liver failure.

Because there is some residual enzyme activity, “the whole thing unfolds in a milder, slower way,” says Neilan. But eventually, the accumulation of fats and cholesterol provokes scarring of the liver and can lead to liver failure, the need for liver transplant and/or death.

“LAL deficiency, to some degree, begins at birth and slowly damages the liver to the point where patients who were asymptomatic no longer have enough liver function and drop off the edge,” he says.

And symptoms, he adds, “might not appear until you are 30 years old.”

Recognizing LAL deficiency


In 2012, Jonas and Neilan identified two Massachusetts sisters with LAL deficiency.

Younger sister, Lauren Walsh, now 11, was experiencing stomach pain and general fatigue. Testing revealed liver enlargement and elevated cholesterol and liver enzyme (specifically alanine aminotransferase (ALT) levels above normal range.

Further evaluation prompted Jonas to pursue a liver biopsy.

“The biopsy showed two important things: it showed a metabolic picture that looked like a possible metabolic disease or enzyme deficiency. It also showed a lot of scar tissue,” Jonas recalls. “At that point, we knew we had more serious liver disease than anticipated.”

Jonas referred Lauren to Neilan for metabolic and genetic testing. Testing revealed LAL deficiency and the specific gene sequences causing the disease. Lauren’s siblings were also tested, and her sister Maureen, now 14, also tested positive for LAL deficiency. (Her younger brother was found to be a non-symptomatic carrier of the genetic defect.

(Read more on the sisters’ story in our health blog, Thriving.)

Once the LAL deficiency diagnosis was made, the next step, Neilan says, was “to see if there was a way of treating it.”

Precision medicine for the liver

Lauren (L) and Maureen Walsh

Currently, treatment is limited to reducing dietary fat intake and/or using medications to lower blood cholesterol levels. But treatments do not stop the slow but steady progression of the underlying liver disease.

However, the same year the Walsh sisters were diagnosed, Massachusetts-based Synageva BioPharma Corporation initiated a trial of enzyme replacement therapy for LAL deficiency. Synegeva, which was recently acquired by Connecticut-based Alexion Pharmaceuticals, had developed an intravenous therapy using sebelipase alfa, a bioengineered form of the human LAL enzyme.

Neilan got in touch, and is now principal investigator of the phase 3, LAL deficiency clinical trial at Boston Children’s Hospital.

According to the Synegeva website, sebelipase alfa has been granted orphan designation by the U.S. Food and Drug Administration, the European Medicines Agency and the Japanese Ministry of Health, Labour and Welfare. The drug has received the FDA’s Fast Track designation as well as Breakthrough Therapy designation for LAL deficiency presenting in infants. The study is ongoing.

Jonas and Neilan agree that educating physicians about LAL deficiency is key to diagnosis and treatment. Signs of the disease include patients presenting with elevated liver enzymes, high “bad” cholesterol and low “good” cholesterol that can’t be attributed to a poor diet.

“We don’t know how common or rare this condition is, as there are no external signs or symptoms until later when severe complications set in,” says Jonas. “We want to increase LAL deficiency awareness and knowledge especially when this lifesaving therapy is soon to be available.”