Fabrazyme Safe, Effective in Japanese Study

Fabrazyme (agalsidase beta) demonstrated an acceptable safety profile and resulted in sustained reductions in globotriaosylceramide (GL-3) levels over seven years among patients with Fabry disease, a large real-world study from in Japan found. 

The study, “Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies,” was published in the journal Expert Opinion on Drug Safety. 

Fabry disease is caused by a lack of alpha-galactosidase A, due to mutations in the GLA gene that provides instructions for making for the enzyme. The loss of this enzyme causes the molecule GL-3 to build up within cells, which causes damage to organs and a number of symptoms.

Fabrazyme is an enzyme replacement therapy (ERT) that contains a modified version of alpha-galactosidase A enzyme, and is designed to reduce GL-3 buildup in cells and the associated damage.

The safety and efficacy of Fabrazyme have been established in several clinical trials, in which the therapy decreased deposition of GL-3. Fabrazyme also reduced the frequency of major clinical events involving the kidneys, heart, and brain. 

However, only 13 patients with the condition were enrolled in clinical trials in Japan.

Now, scientists at Sanofi Genzyme, the therapy’s developer, conducted two studies involving patients in Japan who were not registered in long-term trials to evaluate the safety and efficacy of Fabrazyme in real-world clinical practice.

The Special Drug Use Investigation (SDUI) of Fabrazyme (NCT00233870) analyzed the safety and efficacy of long-term use, while the Drug Use Investigation (DUI, AGAL02904) analyzed the safety profile in those who were not included in the SDUI. Safety data were collected every six months.

A total of 332 patients in the SDUI and 64 patients in the DUI were enrolled. Of these, 307 patients, with a mean age at treatment initiation of 39.5, of whom 65.5% were men, had enough data to participate in the safety analysis. Efficacy data were available for 196 of the patients.

Most participants had not received prior ERT (76.2%) or had a history of allergic reactions to medications in general. Before treatment (baseline), kidney impairment was present in 37.5% of patients, and 40.4% had heart problems. 

The most common reported symptom was pain in the extremities (56.7%), followed by itchy skin blisters (44.6%), and dark spots on the skin (30.9%). The mean GL-3 level in blood samples at baseline was 8.5 micrograms per milliliter (mcg/mL). The upper limit of normal GL-3 is 7.03 mcg/mL.

In the safety analysis, the mean total duration of Fabrazyme administration was 1,363 days (more than 3.5 years), the mean total number of doses was 83.6. The average dose was 0.93 mg/kg.

Overall, adverse events occurred in 171 of participants (55.7%). Slightly more of those who were 15  and younger experienced side effects compared to older participants. Similarly, a higher number of patients with heart and classic disease reported adverse events compared with those who had kidney involvement, and women with one mutated GLA gene copy (heterozygous). 

The most common side effects were general disorders and injection site conditions (20.5%), such as chest discomfort, chills, pain, and fever; nervous system issues (20.2%), and infections (16.9%).

Overall, the incidence of adverse drug reactions occurred in 93 (30.3%) participants. 

“Importantly, no unexpected safety signals or concerns were identified, indicating that the safety profile of [Fabrazyme] was consistent with the established profile of this drug,” the team wrote. 

Similar to general adverse events, adverse reactions to Fabrazyme also were more common in patients 15 or younger, as well as in those with classic disease. A total of 27 (8.8%) discontinued Fabrazyme due to these adverse events. 

Serious adverse treatment reactions were reported in 25 patients (8.1%), with eight deaths (2.6%) occurring during the study that could not be ruled out as caused by Fabrazyme or ERT. Causes included suicide, body weakness, excess fluid in the lungs, cardiac arrest, sudden death, blood coagulation with pneumonia; two were unexplained.

Again, the most common treatment-related adverse events were general disorders and injection site conditions (17.9%), nervous system problems (9.8%), and skin tissue disorders (7.5%). There was a higher number of such adverse events in patients with a blood GL-3 level of 7.2 mcg/mL or greater.

Overall, a significantly higher proportion of participants who experienced adverse drug reactions and injection-related reactions were positive for antibodies that target Fabrazyme. A higher incidence of these reactions also was observed among patients with prior ERT use.

However, a total of 50.5% of patients developed antibodies, which was lower than those reported in earlier studies, the team noted. 

Regarding efficacy, the mean blood GL-3 levels measured throughout the study were reduced from 8.7 mcg/mL at baseline to 5.7 mcg/mL at six months and remained below 6.0 mcg/mL at all subsequent assessments. These reductions occurred regardless of age, accompanying therapies, or the presence of complications.

“Results of this analysis … in over 300 Japanese patients with Fabry Disease, demonstrate the long-term safety and efficacy of [Fabrazyme] over a period of up to 7 years,” the investigators concluded, adding that the safety profile of Fabrazyme in this study “was broadly consistent with that reported in previous global clinical trials.” 

“These findings add to the wealth of data supporting the long-term safety and efficacy of [Fabrazyme] in the treatment of Fabry disease,” they added.