Safe and effective intravenous enzyme replacement therapy (ERT) has been available for more than 25 years for patients with Gaucher disease (GD). The safety of the several ERTs for GD has also afforded the possibility of home infusions. Yet, ERT is usually a life-long commitment to infusions and many patients find the every-other-week (EOW) hourly infusions onerous. Previous experience with rapid intravenous infusion of biological materials, in particular monoclonal antibodies, have defined a variable potential for reactions, ranging from mild local irritations at the access site to life-threatening hypersensitivities and anaphylactoid reactions as well as various inflammatory and immunological responses. Particularly in the home environment, these reactions could conceivably occur too quickly for an effective response by a medical team. Thus, we designed a "change in practice" study to assess the safety and efficacy of rapid infusions in adult with type I GD who had already been treated for at least 3 months with velaglucerase alfa. The switch from infusion time of 60 minutes to 10 minutes was done using a step-wise reduction.
Methods: Fifteen patients, (8 female), mean age 32 (range 22-44) years, genotype N370S homozygous (n=7) or heterozygous, stable on treatment for a mean of 9.6 (range: 2.5-17) years at doses of treated at 15-60 units/kg body weight/infusion were recruited. Study was started with three months at the standard infusion time of 60 minutes EOW in the home setting. Next was a rate change with one infusion at 30 minutes, one infusion at 20 minutes, and then four infusions over 10 minutes, all in the hospital clinic setting. The final stage was infusions over 10 minutes at home with every three months study evaluations in the clinic. Safety was determined by adverse events (AEs) during or directly after infusions as monitored by an experienced nurse. Efficacy parameters included hemoglobin concentration and platelet counts, spleen and liver volume estimation by ultrasound, the biomarker LysoGb1 (Centogene, Rostock Germany ) and anti-velaglucerase alfa antibodies formation. Seven visual analogue scales were used to assess disease related impact including  dependence on others;  fatigue;  bone pain;  depression ;  satisfaction with treatment;  family impact  pessimistic/optimistic view of the future. Local investigational review board approval was granted for the study and all participating patients provided written informed consent before commencing study procedures.
Results: Patients were followed for a mean±SD of 60±19 weeks on this study. No serious AEs associated with the 10 minute infusions, in the clinic or at home, were reported. The only mild AE was a single patient who experienced discomfort (feeling cold) in the infused arm during two 10 minute infusions. All patients maintained stability in the key disease features including the hematological parameters and organ volumes. Mean (range) LysoGb1 levels at baseline and last evaluation were 80.8 (11.5-246) ng/mL and 84 (13.8-200) ng/mL, respectively. A single patient showed increased values of LysoGb1, yet her platelet counts were unaffected. On week 36 evaluation - no patient developed antibodies. Twelve patients completed the disease impact questionnaire; mean responses to the specific questions and mean score, ranging from 5.3-9.4 at baseline and 7.6-9.7 on 10 minute infusion, were not altered over the study period. Pharmacokinetics studies are pending.
Discussion: With this study protocol, we established that step-wise shortening of infusion duration, from one hour to 10 minutes in three stages and as home infusions, did not compromise the safety or efficacy of treatment in adult patients with type 1 GD receiving velaglucerase alfa EOW at dosages ranging from 15-60 units/kg body weight. Rapid administration of velaglucerase alfa was generally well tolerated and disease-specific parameters were maintained over the course of the study. Willingness of patients to continue with 10 minute infusion confirms the importance of convenience, specifically decreased infusion duration, to patients for whom ERT infusions are currently envisioned to be a life-long commitment. Moreover, this approach may also have wider implications for healthcare providers and payers because of the possibility of reducing the costs engendered by prolonged intravenous administrations and the reliance on a hospital setting.
Zimran: Shire: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding. Elstein: Shire: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding.
Asterisk with author names denotes non-ASH members.