The findings of the study, “Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1,” were published in the Orphanet Journal of Rare Diseases.
Gaucher disease, one of the most common lysosomal disorders, is caused by an abnormal production of an enzyme called beta-glucocerebrosidase, which degrades a fat substance called glucocerebroside, due to a genetic mutation in the GBA gene.
Glucocerebroside gradually accumulates inside immune cells called macrophages, which in turn become Gaucher cells that are present in the liver, spleen, bone marrow, and nervous system. As a result, Gaucher patients usually develop anemia, an abnormally large liver and spleen, bone disease, delayed puberty, and delayed growth before the age of 20.
Cerdelga, a drug marketed by Sanofi Genzyme, is the first oral therapy that has been approved for the treatment of patients with type 1 Gaucher disease. It was approved by the U.S. Food and Drug Administration in 2014, and by the European Medicines Agency in 2015.
Cerdelga is a substrate reduction therapy (SRT) that works by reducing the amount of glucocerebroside produced by partially inhibiting the activity of the enzyme that produces it: glucosylceramide synthase. This way, the accumulation of glucosylceramide inside Gaucher cells is significantly slowed.
“Four clinical trials have been completed in adults with Gaucher disease type 1 …. Together, these four clinical trials have demonstrated the efficacy of eliglustat for preventing or ameliorating hematologic, visceral, and bone manifestations of Gaucher disease in previously untreated patients and for maintaining clinical stability in patients switching from ERT [enzyme replacement therapy] to eliglustat,” the researchers wrote.
However, “clinicians and patients want a better understanding of the long-term safety profile of eliglustat, not only with respect to which adverse events are most commonly attributed to the treatment, but also the severity, frequency, and duration of these treatment-related events,” they added.
In this study, researchers performed a pooled analysis of treatment-emergent adverse events based on data obtained from four completed trials assessing the effects of Cerdelga in patients with type 1 Gaucher disease:
- An open-label, single-arm, Phase 2 trial (NCT00358150) in untreated patients.
- The randomized, double-blind, placebo-controlled, ENGAGE Phase 3 trial (NCT00891202) in untreated patients.
- The randomized, open-label, ENCORE Phase 3 trial (NCT00943111) in patients previously treated with ERT.
- And the randomized, double-blind, EDGE Phase 3 trial (NCT01074944) in patients switching from ERT to Cerdelga.
The analysis was performed in a group of 393 type 1 Gaucher disease patients who had been treated with Cerdelga for an average period of 3.6 years, and a maximum of 9.3 years.
The results showed that nine patients (2.3%) were forced to discontinue treatment with Cerdelga due to one or more adverse events related to the medication. However, with the exception of one case, these adverse events were considered mild or moderate in severity.
In general, 97% of all adverse events reported in the trials were either mild or moderate, and 86% were found to be unrelated to the use of Cerdelga.
In addition, the researchers found the overall rate of adverse events decreased gradually over time, and did not increase in patients receiving higher doses of Cerdelga.
Investigators then calculated the frequency, duration, and severity of 14 adverse events that were reported at least once as treatment-related side effects in 2% or more of the patients.
These included: indigestion (5.9%), headache (5.3%), upper abdominal pain (5.1%), dizziness (5.1%), diarrhea (4.6%), nausea (4.6%), joint pain (3.6%), constipation (3.3%), abdominal pain (2.8%), gastroesophageal reflux disease (2.8%), fatigue (2.8%), palpitations (2.8%), abdominal distension (2.5%), and gastritis (2.3%).
These adverse events, with the exception of joint pain and headaches, were reported once per patient in more than 70% of the patients experiencing the side effect. In addition, five of the adverse events (upper abdominal pain, diarrhea, nausea, abdominal pain, and headaches) were rapidly resolved, lasting less than 14 days on average.
“This analysis of adverse event data from four completed clinical trials underscores the favorable safety profile of eliglustat and is consistent with earlier shorter-term data from these trials …. The majority of the most frequently reported treatment-related adverse events were mild or moderate, transient, and occurred only once per patient,” the researchers wrote.
“As with any new drug, it will be important to continue evaluating safety in the post-marketing setting,” they added.