Laird Harrison

November 05, 2014

SAN DIEGO — Eliglustat (Cerdelga, Genzyme), a new oral treatment for type 1 Gaucher's disease, works almost as well as intravenous enzyme replacement therapy with imiglucerase, new research shows.

"It provides a new treatment option for our patients," said Thomas Andrew Burrow, MD, assistant professor of human genetics at the University of Cincinnati.

Dr Burrow presented one of four studies on eliglustat here at the American Society of Human Genetics 2014 Annual Meeting.

Gaucher's disease, also known as glucocerebrosidase deficiency, is an autosomal recessive disease that affects about 1 in 20,000 live births. Type 1, the most common form, does not affect the nervous system.

The disease occurs when the lipid glucosylceramide accumulates in the bone marrow, lungs, spleen, liver, and sometimes the brain. If left untreated, it can enlarge the liver and spleen and cause anemia, thrombocytopenia, neurologic damage, and bone disease, among other manifestations.

Although Gaucher's disease is pan-ethnic, type 1 is the most common inherited Jewish genetic disease. It affects about 1 in 450 people of Ashkenazi Jewish heritage.

The US Food and Drug Administration (FDA) approved eliglustat in hard capsule format for adults with type 1 Gaucher's disease in August.

We're looking at five different products that have been approved by the FDA, which is pretty impressive in the grand scheme of genetic diseases.

Imiglucerase is one of three enzymes that can be given intravenously to supplement the patient's glucocerebrosidase and break down accumulated glucosylceramide. Enzyme replacement is very effective, but it takes 1 to 2 hours and must be given every 2 weeks. "Enzyme replacement therapy is by no means fun," said Dr Burrow.

In addition, the enzyme does not reach every cell where it is needed, he said.

In contrast, substrate reduction therapy works by inhibiting glucosylceramide synthase, slowing the production of glucosylceramide. The FDA has approved another agent for substrate reduction, miglustat (Zavesca, Actelion), but only for adults who are not eligible for enzyme replacement therapy.

"We're looking at five different products that have been approved by the FDA, which is pretty impressive in the grand scheme of genetic diseases," said Dr Burrow.

He and his colleagues conducted a comparison of eliglustat and imiglucerase.

They administered eliglustat 2 times a day to 106 patients. On the basis of plasma trough levels, patients received 50, 100, or 150 mg.

They also infused imiglucerase 30 to 50 units/kg every 2 weeks in 53 patients.

The patients, at a mean age of 37.5 years, were in stable condition and had been on enzyme therapy for at least 3 years at the start of the trial. None had a history of heart disease, previous substrate reduction therapy, or splenectomy.

Fewer patients in the eliglustat group than in the imiglucerase met the criteria for hemoglobin level, platelet count, spleen volume, and liver volume indicating stable disease for 12 months (85% vs 94%).

Table 1. Patients Remaining Stable for 12 Months

Outcome Eliglustat Group, % Imiglucerase Group, %
Hemoglobin level 95 100
Platelet count 93 100
Spleen volume 96 100
Liver volume 96 94
Composite 85 94

After a year, the imiglucerase patients were switched to eliglustat. During the second 12-month period, 86% of the patients who switched remained stable, as did 87% of the patients who continued on eliglustat.

Adverse events were more common in the eliglustat group than in the imiglucerase group, but most were mild reactions, such as fatigue, diarrhea, and nausea. However, two patients in the eliglustat group experienced serious drug-related adverse events.

Table 2. Adverse Events at 24 Months

Adverse Event Eliglustat Group, n Imiglucerase + Eliglustat Group, n
Any 95 79
Any drug-related 51 11
Serious 17 0
Serious drug-related 2 0

Results from three other trials were also presented at the meeting.

In one, patients with Gaucher's disease treated for 9 months with eliglustat did much better than those treated for 9 months with placebo.

In another, results were similar for patients treated with eliglustat for 4 years and those treated with imiglucerase for 4 years.

In the last, patient outcomes were similar when dosing regimens were determined on the basis of CYP2D6-genotype-predicted phenotype or on the basis of plasma eliglustat concentrations. Researchers have not yet established the optimum dose of eliglustat, or whether it should be administered once or twice a day, Dr Burrow pointed out.

This study could make a big difference for many people with Gaucher's disease, said Thiago Donizete Da Silva, a geneticist from the University of Guadalajara in Mexico.

"The best part of the oral treatment is that it's not invasive," he told Medscape Medical News.

He said he hopes that such an option will eventually be used to treat people with types 2 and 3 Gaucher's disease. These patients often suffer neurologic damage, and eliglustat does not penetrate the blood–brain barrier. Many of these patients die as children if not treated, he said.

The studies were funded by Genzyme. Dr Burrows reports being on the advisory board and receiving travel funding from Genzyme. Dr Da Silva has disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2014 Annual Meeting: Abstracts 2282M and 2284M, presented October 20, 2014; Abstracts 2281T and 365, presented October 21, 2014.

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