Agalsidase α
The pharmaceutical company Shire manufactures agalsidase alfa (INN) under the trade name Replagal as a treatment for Fabry disease, and was granted marketing approval in the EU in 2001. FDA approval was applied for the United States. However, in 2012, Shire withdrew their application for approval in the United States citing that the agency will require additional clinical trials before approval. Agalsidase β
The pharmaceutical company Genzyme produces synthetic agalsidase β (INN) under the trade name Fabrazyme for treatment of Fabry disease. In 2009, contamination at Genzymes Allston, Massachusetts plant caused a worldwide shortage of Fabrazyme, and supplies were rationed to patients at one-third the recommended dose. Some patients have petitioned to break the companys patent on the drug under the "march-in" provisions of the Bayh–Dole Act. Pharmacological chaperone therapy
Fabry patients who display neurological symptoms cannot receive RERT because recombinant enzymes cannot normally pass the blood-brain barrier. Thus, a more suitable alternative treatment is used: pharmacological chaperone therapy. It has been shown that more potent competitive inhibitors of an enzyme can act as a more powerful chemical chaperone for the corresponding mutant enzyme that fails to maintain proper folding and conformation, despite its intact active site. These chemical chaperones bind to the active site of the mutant enzyme, which can help promote proper folding and stabilize the mutant enzyme. Thus, this results in functional mutant enzymes that will not be degraded via the ubiquitin-proteasome pathway.
Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in magnetic resonance imaging of the brain in patients with Alzheimers disease. ARIA is associated with amyloid-modifying therapies, particularly human monoclonal antibodies such as aducanumab. There are two types of ARIA: ARIA-E and ARIA-H. The phenomenon was first seen in trials of bapineuzumab. ARIA-E
ARIA-E refers to cerebral edema, involving the breakdown of the tight endothelial junctions of the blood-brain barrier and subsequent accumulation of fluid. In a double-blind trial of the humanised monoclonal antibody solanezumab (n = 2042), sixteen patients (11 taking the drug, 5 taking a placebo), or 0.78% developed ARIA-E. A further 7 patients developed ARIA-E during an open-label extension of the trial.The effect of ARIA-E depends on the severity and location of the edema. Symptoms may include headache, changes in mental state, confusion, vomiting, nausea, tremor and gait disturbances. ARIA-H
ARIA-H refers to cerebral microhaemorrhages (mH), small haemorrhages on the brain, often accompanied by hemosiderosis. mH are usually seen as small, round and low intensity lesions and are small haemosiderin deposits. Some studies define mH as being less than or equal to 10mm, while others define the cut-off as ≤ 5mm. The prevalence of mH in healthy elderly people is approximately 6%, but this value increases to between 50% and 80% in elderly people with cerebrovascular disease. ARIA MRI Classification Criteria
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