Gaucher's disease, also called Gaucher disease, is a rare, genetic, metabolic disorder caused by a deficiency of the enzyme glucocerebrosidase. Deficiency of glucocerebrosidase causes an accumulation of glucosylceramide, which is highly insoluble, in storage cells of the liver, spleen, bone marrow, and lymph nodes. Disease variants are classified according to the presence or absence of neurologic involvement and the rate of its progression into three major clinical subtypes: Types 1, 2, and 3. Type 1, the most common, is a chronic, nonneuronopathic, or adult form; it is the most prevalent. Although Type 1 Gaucher's disease is sometimes referred to as the adult form, symptoms of Type 1 can manifest at any age. Symptoms include bruising easily; fatigue due to anemia and low blood platelets; an enlarged liver and spleen; skeletal disorders; and, in rare instances, lung and kidney involvement. In Type 2 Gaucher's disease, liver and spleen enlargement are apparent by 3 months of age. It is an acute, neuronopathic, or infantile form, characterized by rapid neurologic deterioration; survival beyond 2 years of age is rare. Type 3 is a subacute, neuronopathic, or juvenile form, with a variable course marked by slowly progressive neurologic involvement and some characteristics of Type 1 and 2. Liver and spleen enlargement is a variable, along with brain involvement, which becomes apparent when marked by seizures.
Based on current published research, systemic manifestations of Type 3 Gaucher’s disease can be reduced in individuals treated with enzyme replacement therapy (ERT), but neurologic manifestations of Gaucher's disease are not affected by ERT. According to the evidence, replacement of the missing enzyme glucocerebrosidase through ERT may improve the health outcome and quality of life in individuals significantly affected by Type 3 Gaucher’s disease. However, treatment with ERT is ineffective for individuals with Type 2 disease, the neuronopathic form, because it does not alter the neurodegenerative course of the Type 2 disease.
In April 1991 the US Food and Drug Administration (FDA) approved alglucerase (Ceredase®) as an orphan drug (a drug used to treat, prevent, or diagnose a rare disease) for use as long-term enzyme replacement therapy (ERT) for children, adolescents, and adult individuals with a confirmed diagnosis of Type 1 Gaucher's disease who have signs and symptoms severe enough to result in one or more of the following conditions:
- moderate-to-severe anemia
- thrombocytopenia with bleeding tendency
- bone disease
- significant hepatomegaly or splenomegaly
Alglucerase (Ceredase®) is a modified form of the human enzyme, beta-glucocerebrosidase, prepared from a large pool of human placental tissue collected from selected donors. The quantity of the drug is based on the amount that is collected from selected donors. Due to this limit, alglucerase (Ceredase®) was phased out and replaced with imiglucerase (Cerezyme®).
In May 1994 the FDA approved imiglucerase (Cerezyme®) as an orphan drug for use as a long-term ERT for pediatric and adult individuals with a confirmed diagnosis of Type 1 Gaucher's disease who have signs and symptoms severe enough to result in one or more of the following conditions:
- anemia
- thrombocytopenia
- bone disease
- hepatomegaly or splenomegaly
Imiglucerase (Cerezyme®) is an analogue of the human enzyme, beta-glucocerebrosidase, produced by recombinant DNA technology. It differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. Imiglucerase (Cerezyme®) is equivalent to alglucerase (Ceredase®). In clinical trials, imiglucerase (Cerezyme®) improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with alglucerase
(Ceredase®).
In February 2010 velaglucerase alfa (VPRIV®) was FDA-approved for long-term ERT for pediatric and adult individuals with Type 1 Gaucher's disease. Velaglucerase alfa (VPRIV®) has the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. The safety and effectiveness of velaglucerase alfa (VPRIV®) was assessed in three clinical studies of naïve individuals to ERT and individuals who switched from imiglucerase (Cerezyme®) to velaglucerase alfa (VPRIV®). Per the FDA-approved prescribing information, individuals switching from imiglucerase (Cerezyme®) to velaglucerase alfa (VPRIV®) can begin treatment with velaglucerase alfa (VPRIV®) at the same stable dose of imiglucerase (Cerezyme®).
In May 2012 taliglucerase alfa (Elelyso®) was FDA-approved for long-tern ERT for adult and pediatric individuals with a confirmed diagnosis of Type 1 Gaucher's disease. Taliglucerase alfa (Elelyso®) is a recombinant active form of the lysosomal enzyme, glucocerebrosidase. Taliglucerase alfa (Elelyso®) is the first FDA-approved plant-cell-based ERT for Gaucher disease derived using genetically engineered carrot cells. The safety and efficacy of taliglucerase alfa (Elelyso®) was established in three studies containing individuals naïve to ERT and individuals switching from imiglucerase (Cerezyme®) to taliglucerase alfa (Elelyso®). Most individuals in the studies showed an improvement in their anemia, thrombocytopenia, and/or a decrease in their liver and spleen size.
On August 27, 2014, FDA approved the use of taliglucerase alfa (Elelyso®) for long-term ERT for pediatric individuals who have a confirmed diagnosis of Type 1 Gaucher's disease. In this clinical trial, the safety of Elelyso was assessed in individuals, 16 years and younger in 9 pediatric treatment-naïve individuals (ages two to 13 years) with Type 1 Gaucher disease in a 12 month randomized clinical trial. The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two individuals had hypersensitivity reactions; one individual experienced severe vomiting and gastrointestinal inflammation, and one experienced mild throat irritation and chest discomfort. Both individuals were treated with antihistamines and continued treatment. In the clinical trial in individuals switching from Imiglucerase Treatment to Elelyso the safety of Elelyso was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving treatment with imiglucerase for a minimum of 2 years. Elelyso was administered for 9 months at the same number of units as each individual's previous imiglucerase dose.
On November 13, 2021, FDA approved the use of taliglucerase alfa (Elelyso®), for long-term ERT for pediatric individuals four years and older who have a confirmed diagnosis of Type 1 Gaucher's disease. The long-term efficacy and safety of Elelyso in pediatric individuals with Type 1 Gaucher disease who were treatment-naïve or previously treated with imiglucerase was evaluated in phase 3, multi-center, extension trial.
This pediatric-specific extension trial included 15 individuals aged two to 18 years from two study cohorts. The first study cohort included 10 previously treatment-naïve pediatric individuals treated with Elelyso (9 who completed) for up to 36 months (the first 24 months of which were conducted in a double-blind fashion) at 30 units per kg or 60 units per kg. The second study cohort included five pediatric individuals who were previously switched from imiglucerase (2 who completed) and administered Elelyso for a total of 33 months at the same dose as each individual's previous imiglucerase dose. At the end of the study, treatment-naïve individuals treated with Elelyso for 36 months demonstrated clinical improvements, as measured by a decrease in spleen and liver volume and an increase in platelet count. In patients previously switched from imiglucerase to Elelyso, mean spleen and liver volume, platelet count and hemoglobin value remained stable through 33 months of Elelyso treatment. The most common adverse events reported were upper respiratory tract infection, cough, headache, abdominal pain, diarrhea, nasopharyngitis, pain in extremity, swollen or enlarged lymph nodes, and fever.
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