Open-label extension study following the Late-Onset Treatment Study (LOTS) of alglucosidase alfa

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Abstract

Objective

Late-onset Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid α‐glucosidase. This extension study was conducted to determine the durability of the efficacy and safety of alglucosidase alfa observed over a period of 78 weeks in the Late-Onset Treatment Study (LOTS).

Methods

Patients who completed the LOTS study were eligible for this open-label extension study and received alglucosidase alfa 20 mg/kg biweekly for an additional 26 weeks. The primary efficacy assessments were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity in the upright position. Data are reported as change from patient's original LOTS baseline for each measure.

Results

The benefit of alglucosidase alfa treatment observed in LOTS at Week 78 was, in general, maintained at Week 104. The mean increase in distance walked measured 28.2 ± 66.5 m from LOTS baseline to Week 78 and 21.3 ± 78.0 m from LOTS baseline to Week 104. The mean change from baseline in percentage of predicted forced vital capacity was 1.3% ± 5.7% from LOTS baseline to Week 78 and 0.8% ± 6.7% from LOTS baseline to Week 104. Treatment-related adverse events were mainly infusion-associated reactions observed in 35% of patients. No deaths or anaphylactic reactions were observed during the extension study.

Conclusions

The LOTS Extension study showed that patients treated with alglucosidase alfa for up to 104 weeks maintained the improved walking distance and stabilization in pulmonary function observed in the first 78 weeks of alglucosidase alfa therapy.

Highlights

► This extension study continued Late-Onset Treatment Study (LOTS) out to 104 weeks. ► Patients maintained the improved walking distance at 104 weeks. ► Patients maintained stabilization in pulmonary function at 104 weeks. ► Treatment-related AEs were mainly infusion-associated reactions (35% of patients). ► No deaths or anaphylactic reactions were observed.

Introduction

Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid α-glucosidase. Patients with late-onset Pompe disease present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and a variable progression of respiratory involvement [1], [2], [3], [4]. Eventually, most patients with late-onset Pompe disease become wheelchair-bound, require ventilator support, and ultimately succumb to respiratory failure [1], [3], [5].

Alglucosidase alfa (Myozyme®/Lumizyme®, Genzyme) is the first approved treatment for Pompe disease; it replaces the deficient acid α-glucosidase enzyme, thereby targeting the underlying cause of the disease. The therapy markedly extended survival and prevented or delayed time to invasive-ventilator dependence as compared to an untreated historical cohort in patients with infantile-onset disease [6].

The Late-Onset Treatment Study (LOTS) was the randomized, double-blind, placebo-controlled, multicenter study that demonstrated the safety and efficacy of alglucosidase alfa in 90 children and adults with late-onset Pompe disease [7]. The major findings of the LOTS study were that alglucosidase alfa treatment improved walking distance and stabilized pulmonary function over the 78-week study period, both of which were statistically significant compared to placebo. Treatment with alglucosidase alfa was well tolerated, with an acceptable risk-benefit profile.

All active and placebo patients who completed LOTS transitioned into an open-label extension study (LOTS Extension) and received treatment for a minimum of 26 weeks (104 weeks cumulatively). The objective of LOTS Extension was to determine the durability of the efficacy and safety of alglucosidase alfa treatment initially observed in LOTS.

Section snippets

Material and methods

Patients who completed 78 weeks of either alglucosidase alfa treatment or placebo in LOTS were eligible to continue to receive 20 mg/kg IV infusions of alglucosidase alfa biweekly for up to an additional 26 weeks (to Week 104) (Fig. 1). Patients at the US sites were eligible to continue treatment for another 26 weeks (to Week 130). Patients were included in the study if they were 8 years of age or older, ambulatory, and free of invasive ventilation. The study protocol and amendments were approved by

Results

At LOTS baseline, 60 patients were randomized to receive alglucosidase alfa (Table 1). These patients were mainly male (57%) and Caucasian (95%), with a mean age of 45 years (range, 16–70 years). At the time of enrollment in LOTS, 38% of patients used a walking device and 33% of patients required respiratory support.

Efficacy results are reported on the 55 out of 60 patients from the alglucosidase alfa arm who completed LOTS and LOTS Extension through Week 104 (Fig. 1). Safety results are provided

Discussion

The LOTS Extension study provides evidence that the positive effects of alglucosidase alfa treatment observed at 78 weeks of therapy are maintained over 104 weeks of therapy in patients with late-onset Pompe disease. This is consistent with the evidence of 1‐year and 3-year effectiveness data reported recently [9], [10]. In LOTS, in the total group of 90 patients (60 received alglucosidase alfa and 30 received placebo), the estimated mean changes from baseline to Week 78 in the primary endpoints

Acknowledgments

This study was sponsored by Genzyme, a Sanofi company. All of the authors contributed to this article by drafting/revising the manuscript for content. The authors take full responsibility for the contents of this paper, which do not represent the views of the Department of Veterans Affairs or the United States Government.

We thank the patients and their families for their participation in this study. We also thank the staff at the study sites and the sponsoring organization, who were

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