**5.3 Dosing and duration of therapy**

As mentioned above, the two widely used forms of ERT for Fabry disease are agalsidase alfa and agalsidase beta and there have not been any trials comparing these formulations to one another [46].

The formulations of agalsidase alfa and agalsidase beta are structurally very similar to one another [47–49], however, they are not dosed the same. Agalsidase alfa is dosed at 0.2 mg/kg every other week [50],while agalsidase beta is dosed at 1.0 mg/kg every other week [51]. For patients who weigh less than 30 kg, the infusion rate of agalsidase beta should not exceed 15 mg/hr.

There are no clinical trials to determine the duration of ERT [52] in patients that meet the criteria to be treated, however, treatment is generally continued until a reason for stopping therapy arises. The most agreed-upon reasons for stopping therapy are noncompliance with infusions, failure to attend regular follow up visits, end-stage Fabry disease or other co-morbidities leading to a life expectancy of

<1 year, lack of response for 1 year when the sole indication for ERT is neuropathic pain while receiving maximum supportive care, or persistent life-threatening or severe reactions that do not respond to prophylaxis and patient request [44].

The Fabry registry website includes a detailed table resource that can be used as a visual to guide a prescriber on what lab values, imaging, and other studies should be monitored, specifically in the pediatric population. This can be found in the Fabry Registry section entitled "Fabry Registry Recommended Schedule of Assessments." The page can be found using the following web address:

https://www.fabrydisease.org/images/ReferencePDFs/fabry-registry-scheduleof-assessments.pdf

#### **5.4 Side effects and what to monitor in patients receiving ERT**

The side effects of ERT that were mentioned in the early trials included side effects that are common with infusions including fevers and rigors. These infusionassociated reactions are often treated prophylactically with antihistamines, acetaminophen, and pre-infusion steroids sometimes becoming necessary. It is not uncommon that lengthening of infusion times becomes necessary because of these reactions [39, 50]. There have been reported life-threatening infusion-associated reactions, although those are rare [53].

Expert recommendations have been used to determine potential scheduled assessment and monitoring. The patient will undergo the most amount of testing upon initial evaluation including a full medical history (including family history, physical examination, vital signs, and quality of life), basic metabolic panel, urine protein excretion, lipid panels, and other measures for cardiac, cerebrovascular, neurological, ENT, pulmonary, and ophthalmological assessments. Plasma samples for Gb3 testing should be drawn prior to the first infusion, then every 3 months for the first 18 months of treatment, then every 6 months thereafter. It is reasonable to do a monitoring of serum chemistries and a complete blood count every 6–12 months in all patients. In patients with kidney disease, consider monitoring urinary protein excretion every 3 months. All patients regardless of renal involvement should have annual urinary protein measurement. A baseline kidney biopsy can serve as a potential marker to assess disease progression if the patient experiences deterioration of his/her condition and a repeat biopsy is warranted [19].

The formation of neutralizing antidrug antibodies (ADAs) is not uncommon in patients with Fabry disease receiving ERT [50, 54, 55]. These antibodies are associated with increased accumulation of plasma globotriaosylceramide and disease progression [56]. An open cohort study showed ADA titers decreased significantly in all patients with Fabry disease during ERT infusion and that a not saturated ADA status during infusion is associated with progressive loss of eGFR and ongoing cardiac hypertrophy. Dose escalation can result in saturation of ADAs and decreasing Gb3 levels but may lead to increased ADA titers [56]. Immunosuppression may be considered should ADAs develop but it is not clear how much long-term protection it can offer. Serum samples for IgG antibody testing should be drawn prior to the first infusion, then every 3 months for the first 18 months of treatment, then every 6 months until two consecutive negative results are confirmed.

#### **5.5 Creating a protocol in the infusion center**

Patients with Fabry disease need ERT infusions every other week. The information needed for drug administration often comes from the manufacturer. The information we supply here is for agalsidase beta and serves as an example of what kind of resources would be needed to create a protocol and provide this medication at an infusion center.

*Enzyme-Replacement Therapy in Fabry Disease DOI: http://dx.doi.org/10.5772/intechopen.103799*

Agalsidase beta comes in 5 mg and 35 mg vials that are initially injected with sterile water to create a colorless solution. This solution is then further diluted with 0.9% sodium chloride that is diluted to a higher volume, which is supplied by the manufacturer. Once the diluted solution is created, it is recommended that it be used immediately. If that is not possible, the solution can be stored for 24 h at a temperature of 2–8°C. The initial infusion rate of the solution should be no more than 15 mg/h and this can be slowed down further for infusion-associated reactions. For patients that weigh >30 kg and after the infusion is well-tolerated, the infusion rate can be increased by 3–5 mg/h with each infusion. The minimal infusion time for patients >30 kg should be 1.5 h.

Antipyretics are recommended to be administered prior to the enzymatic infusion. If a patient experiences an infusion-associated reaction, options include decreasing the infusion rate, temporarily stopping the infusion, and/or administering additional antipyretics, antihistamines, and/or steroids if needed. Prophylactic antihistamines and/or steroids can be considered in patients who experience infusion-related reactions. Life-threatening anaphylactic reactions can occur and require immediate discontinuation of the infusion as well as a center that is equipped with appropriate medical support measures and the capability to handle such scenarios.

#### **5.6 Cost**

ERT is expensive. The estimated retail cost of therapy with Fabrazyme for 1 year is approximately USD 300,000 in the United States and Europe.

### **6. Summary**

In short, Fabry disease is a multi-systemic disease associated with a high burden of morbidity and mortality.

The clinical outcome of patients with Fabry disease has drastically changed with the introduction of ERT. Timely initiation of ERT and regular assessments of disease progression by a multidisciplinary care team are critical for the long-term management of patients with Fabry disease.
