New Oral Gaucher Drug Demonstrates Effectiveness in Phase II Trial

At the Lysosomal Disease Network WORLD Symposium in Miami, Florida, last week, researchers presented preliminary data from a phase II study of eliglustat tartrate (formerly Genz-112638), an investigational oral therapy for type 1 Gaucher disease. Data showed it produced clinically meaningful response and continued improvement after 2 years of follow-up.

Two-year trial shows Genzyme drug also strengthens bone.

At the Lysosomal Disease Network WORLD Symposium in Miami, Florida, last week, researchers presented preliminary data from a phase II study of eliglustat tartrate (formerly Genz-112638), an investigational oral therapy for type 1 Gaucher disease. Data showed it produced clinically meaningful response and continued improvement after 2 years of follow-up. Eliglustat tartrate is being developed by Genzyme Corporation. Genzyme manufactures the intravenous drug Cerezyme (imiglucerase for injection), the first fully approved FDA treatment for patients with type 1 Gaucher disease.

Gaucher is a rare autosomal recessive disease that occurs in approximately 1 of every 20,000 births. Fewer than 10,000 people in the world have Gaucher disease, with type 1 being the most common manifestation of the disorder. Patients with Gaucher disease make an insufficient amount of β-glucosidase (glucocerebrosidase), an enzyme stored in the lysosomes of macrophages that is required to break down glucocerebroside. Without adequate glucocerebrosidase, these lipids accumulate in various organs, including the spleen, liver, kidneys, lungs, and brain; and in the bone marrow. Type 1 Gaucher disease does not affect the brain or central nervous system but generally causes bone disease and bleeding problems. If left untreated, it can lead to mild to severe morbidity or death. Imiglucerase, an enzyme replacement therapy, is a biosynthetic analog of glucocerebrosidase that allows patients to successfully process glucocerebrosidase. Patients with type 1 Gaucher are also believed to be at greater risk of other diseases, such as multiple myeloma and Parkinson’s.

Data from the open-label, single-arm study were presented by M. Judith Peterschmitt, a researcher with Genzyme, who called the results “exciting.” Peterschmitt said while imiglucerase for injection has been the standard of care for 20 years, “having a safe and effective oral treatment for a broad population can also be advantageous and convenient.”

In total, 26 patients with type 1 Gaucher disease who were not receiving treatment at the time enrolled in the trial. Peterschmitt said 22 completed 1 year of treatment and 20 completed 2 years. Only 6 patients discontinued: 4 in the first year and 2 in the second year. Patients received 50 or 100 mg of eliglustat tartrate twice daily, depending on plasma levels. “We continue to see improvement in all parameters in the second year,” Peterschmitt said. “We saw a reduction in spleen volume of 52% at 2 years, a reduction of 24% in liver volume, an increase of 2.1 g per deciliter in hemoglobin, and an increase of 81.5% for platelets.” For the 17 patients with chitotriosidase at baseline, a biomarker of Gaucher disease burden, levels decreased by a median of 63% after 18 months of follow-up. As Genzyme reported last year, the trial met its primary composite endpoint, which was to show “clinically meaningful response” in at least two of three endpoints.

Peterschmitt also discussed the effect of eliglustat tartrate on bone health. “I would like to highlight an important impact of what skeletal disease can have in Gaucher: nearly all patients have [radiologic] evidence of bone disease at diagnosis,” she explained. According to Peterschmitt, bone disease is the primary cause of morbidity and negatively affects patients’ quality of life. She said the accumulation of Gaucher cells in the bone marrow leads to “osteopenia, osteoporosis, pathological fractures, collapse, and other things that can sometimes be irreversible.”

Preplanned analyses indicated that patients who received 2 years of treatment with eliglustat tartrate demonstrated improvement in some indicators of bone disease. Bone mineral density (BMD) was measured at baseline and again at 1 and 2 years using MRI and dual energy x-ray absorptiometry. At baseline, 18 patients (95%) had dark marrow, an indication that Gaucher cells have infiltrated the bone marrow. “Forty-four percent [of patients] showed improvement after 2 years, most of them after 1 year,” Peterschmitt said, adding that bone health remained stable in the remaining 10 patients, with no new lesions or fractures reported. One patient experienced worsening of osteonecrosis at 1 year and discontinued the study. Peterschmitt said data were excluded for this patient.

At baseline, mean T score for the lumbar spine was -1.69, which Peterschmitt said was in the osteopenia range. “After 1 year of treatment, we saw an improvement of +0.39 and after 2 years a +0.56 improvement, which is meaningful and statistically significant,” she said. Improvements in Z scores (normalized for age and gender) were also meaningful and statistically significant. For the 6 patients with below normal Z scores at baseline, Z score improved a median of +0.60; 4 of the patients demonstrated normal Z scores at 2 years.

“Eliglustat tartrate was well tolerated and appeared to be safe after 2 years [of therapy],” Peterschmitt said. She noted that there were 106 adverse events, but most were mild and only 8 were determined to be related to therapy. The most common adverse events—reported in >10% of patients—included viral infections (n = 6), urinary tract infections (n = 3), increased blood pressure (n = 3), and abdominal pain (n = 3). The only serious treatment-related AE was a case of peripheral neuropathy, which developed in a 41-year-old man who previously experienced symptomatic peripheral neuropathy while taking GlucoStat. The remaining treatment-related AEs were considered mild.

Peterschmitt concluded, “Eliglustat tartrate has shown promising outcomes as an oral therapy for patients with Gaucher disease type 1, with continued improvement in hematological volume biomarkers and continued improvement in both bone marrow measures—decreased bone marrow infiltration…and increased bone marrow density.” A total of 19 patients are continuing with a third year of therapy. Peterschmitt said based on the positive outcomes seen with the phase II trial, investigators were enrolling patients for two global, multi-center phase III trials of eliglustat tartrate. ENCORE will compare the oral drug to imiglucerase in adults who have reached therapeutic goals after at least 3 years of therapy with imiglucerase. ENGAGE will randomize patients who have been off treatment for at least 1 year to eliglustat tartrate or placebo. In addition, Genzyme will be initiating a trial that compares the safety and efficacy of a once-daily dose of eliglustat tartrate to a twice-daily dose.