Background
Late-onset Pompe disease (LOPD), a rare genetic neuromuscular disorder, results in severe respiratory dysfunction that often progresses to respiratory failure [
1]. LOPD is caused by a deficiency of the lysosomal enzyme acid alpha glucosidase (GAA) [
2], which prevents enzymatic breakdown of glycogen. As a result, glycogen accumulates in multiple tissues. The most severe pathology in LOPD patients is observed in skeletal muscles [
3,
4]. Myopathy in proximal skeletal muscles, for example, reduces mobility in patients and eventually leads to loss of independent ambulation [
5]. Furthermore, weakness of the respiratory muscles (eg, diaphragm) causes respiratory dysfunction that initially manifests as sleep-disordered breathing and nighttime hypercapnia [
6]. In more than 70% of patients, respiratory dysfunction progresses to respiratory failure, which is the most common cause of mortality in LOPD [
7]. The early onset and progressive nature of the disease highlight the need for safe and highly effective treatments.
Recombinant human GAA (rhGAA), the first enzyme replacement therapy (ERT) for LOPD, became available in 2006 [
8‐
11]. Although treatment with rhGAA reduces mortality in infants with Pompe disease, it provides limited improvements in mobility and respiratory function [
9,
12‐
14]. The uptake of endogenous GAA into tissues is mediated by the binding of bis-mannose 6-phosphorylated moieties on GAA to the cation-independent mannose 6-phosphate receptors (CI-MPR) in tissues [
15]. However, rhGAA binds to the CI-MPR with low affinity [
16‐
18], which reduces uptake of the recombinant enzyme into lysosomes.
To enhance the uptake of GAA into the lysosome, a CI-MPR-targeting peptide—derived from insulin-like growth factor 2 (IGF2)—was fused to GAA to form the novel chimeric enzyme reveglucosidase alfa (glycosylation-independent lysosomal targeting [GILT]-tagged rhGAA). In preclinical models of Pompe disease, reveglucosidase alfa is taken up by skeletal muscle cells with greater efficiency than rhGAA [
15] and is more effective at reducing glycogen in skeletal muscle [
19]. The improved efficacy in nonclinical models prompted an initial evaluation of reveglucosidase alfa in LOPD subjects [
19]. Here we report the results of a first-in-human, phase 1/2, open-label clinical trial that evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of reveglucosidase alfa in ambulatory LOPD subjects who were naïve to prior ERT (ie, previously untreated) and had mild-to-moderate respiratory impairment.
Methods
Study design
This ongoing phase 1/2, international, multicenter, open-label clinical trial of reveglucosidase alfa initially enrolled subjects in a dose-escalation study (
Clinicaltrials.gov identifier: NCT01230801; POM-001) [
20]. Subjects could then continue treatment in a dose-extension study (
Clinicaltrials.gov identifier: NCT01435772; POM-002) [
21]. POM-001 consisted of a 25-day pretreatment screening period, a 3-day baseline and enrollment period, a 24-week treatment period, and a provision to continue participation in the dose-extension study. Following the screening and baseline assessments, subjects were treated every 2 weeks for the 24-week treatment period. After completion of POM-001, eligible subjects continued reveglucosidase alfa treatment in POM-002 for additional 24-week treatment cycles (up to a maximum of twenty 24-week cycles, or 480 weeks). Local review boards, ethics committees, and health authorities at each of the 12 study centers approved the protocol and all amendments. Informed consent was obtained from each subject’s parent/guardian, and assent was obtained from each subject where appropriate.
Subject selection
All eligible subjects had a confirmed diagnosis of LOPD based on 2 GAA gene mutations and endogenous GAA activity <75% of the lower limit of the normal adult range. Additional inclusion criteria included age ≥ 13 years at the time of study enrollment, predicted upright forced vital capacity (FVC) ≥30%, and either predicted upright FVC <80% or a reduction in supine FVC >10% compared with upright FVC. Eligible subjects were naïve to ERT with rhGAA (ie, previously untreated) and must have been able to ambulate at least 40 m on the 6-min walk test (6MWT). Subjects were excluded if they had previously received any experimental or approved therapy for LOPD prior to enrollment and had a medical condition that, in the opinion of investigators, might compromise the subject’s ability to comply with the study protocol requirements.
Treatment
During the dose-escalation study (POM-001), subjects were sequentially enrolled in 1 of 3 dosing regimens of reveglucosidase alfa (5 mg/kg [n = 3], 10 mg/kg [n = 3], and 20 mg/kg [n = 20] administered as an intravenous infusion (of approximately 1.5–4 h’s duration) every 2 weeks during the 24-week treatment cycle. Interim safety assessments were completed by an independent review board prior to any dose escalation. POM-002, the extension phase, enrolled subjects from POM-001 who continued treatment at 5 mg/kg, 10 mg/kg, or 20 mg/kg levels for additional treatment cycles. Treatment of patients was completed, and the analysis included data for three 24-week treatment cycles (ie, 72 weeks of total exposure to reveglucosidase alfa).
Pharmacokinetic analyses
Reveglucosidase alfa PK was evaluated (at day 1, week 12, and week 24) in all 3 dosing cohorts, using blood samples taken before, during, and after infusions at predose, 1 h into infusion, 2 h into infusion, end of infusion (EOI; time 0 for PK), and 0.25, 0.5, 1.0, 2.0, 3.0, 6.0, 12, 18, and 24 h post EOI.
Safety assessment
Infusion-related reactions were defined as adverse events (AEs) occurring within 1 day after infusion. Assessments included physical examinations and vital sign assessments, pulse oximetry and blood glucose monitoring before, during, and after infusions, AE recordings (including signs of hypersensitivity and hypoglycemia), chest X-rays, 12-lead echocardiograms, clinical laboratory assessments, and antibody testing (anti-reveglucosidase alfa, anti-GAA, anti-insulin-like growth factor 1 [IGF1], and anti-IGF2). Serum IGF analytes (IGF1, IGF2, and insulin-like growth factor-binding protein-3) were measured to assess the effect of reveglucosidase alfa on serum IGF levels. A subject who was clinically symptomatic or whose blood glucose level was <60 mg/dL was treated as appropriate (oral and intravenous [IV] dextrose). Subjects were measured every 15 min after treatment for hypoglycemia until their blood glucose reached >100 mg/dL.
Efficacy evaluation
The efficacy of reveglucosidase alfa was evaluated at baseline and following 24 and 72 weeks of treatment. Evaluations included mobility/endurance (6MWT), respiratory muscle strength (maximum inspiratory pressure [MIP], maximum expiratory pressure [MEP]), and lung function tests (FVC-upright, FVC-supine, maximum voluntary ventilation [MVV]). Efficacy from the 20 mg/kg group is presented in this manuscript.
Data analysis
The extension phase (POM-002) has recently been completed. The data presented are from the 72-week interim analysis. The efficacy analysis population consisted of all subjects who were dosed with 20 mg/kg reveglucosidase alfa. The safety analysis population consisted of all subjects who enrolled into POM-001 and were dosed. Safety analyses included a summary of AEs and immunogenicity. The statistical significance of treatment effects was not determined as no pre-planned statistical analyses were conducted for this study. Graphical displays were provided for efficacy endpoints.
Discussion
LOPD is a rare genetic neuromuscular disorder caused by GAA deficiency, ultimately resulting in the loss of mobility and respiratory failure. Current ERT with rhGAA has limited efficacy in LOPD subjects partly because of inefficient delivery of rhGAA to skeletal muscle lysosomes and the impact of GAA deficiency in the CNS [
22]. Reveglucosidase alfa is a novel rhGAA analogue with both improved lysosomal uptake [
23] and glycogen reduction in skeletal muscle [
19]. In this phase 1/2 study, we evaluated the PK, safety, tolerability, and efficacy of reveglucosidase alfa in ambulatory LOPD subjects who were previously untreated with rhGAA. Our results show that reveglucosidase alfa infusions were reasonably tolerated and resulted in improvement of respiratory muscle strength, and ventilatory function, however there was a limited effect on walking endurance.
The PK profile of reveglucosidase alfa is consistent with enhanced uptake of the enzyme into tissue. Reveglucosidase alfa contains a lysosomal-targeting peptide [
23] that binds with high affinity to the CI-MPR, the receptor that mediates uptake of rhGAA into skeletal muscle lysosomes [
9,
12,
13]. The short half-life and high CL of reveglucosidase alfa indicates a rapid distribution and suggests enhanced Cl-MPR–mediated uptake of the enzyme into tissue.
As expected, subjects developed antibodies against reveglucosidase alfa, although no impact on efficacy or safety was observed through 24 weeks. While high therapeutic antibody titers were evident at week 72, less than 20% of subjects were positive for neutralizing antibody at any time point. Moreover, despite the development of anti-IGF-IR neutralizing antibodies, overall changes in IGF-I levels were not detected in the study. Patients treated with the rhGAA alglucosidase alfa (Myozyme®; Genzyme, Cambridge, MA, USA) also develop antibodies [
10,
24‐
27], which can block the delivery of the recombinant enzyme in tissues such as muscle and result in attenuated efficacy of Myozyme [
28,
29]. Subjects treated with reveglucosidase alfa who have persistently high antibody titers would require close monitoring for efficacy and safety until the effects of the antibodies are more fully understood [
13,
30].
To determine the efficacy of reveglucosidase alfa, established measures of respiratory muscle strength (MIP and MEP), lung capacity (FVC and MVV), and mobility (6MWT) were utilized [
10,
27]. In particular, MIP and MEP are sensitive measures of respiratory muscle strength in patients with neuromuscular diseases [
31‐
34] and correlate with more direct measures of diaphragmatic muscle strength. Additionally, a systematic literature review examining 174 patients with LOPD from 34 studies demonstrated that pulmonary function tests predicted ventilator use [
35]. In particular, MIP and upright vital capacity consistently correlated with ventilation and wheelchair use. The current study demonstrated that reveglucosidase alfa improved MIP, MEP, MVV, and 6MWT by 24 weeks of treatment, and these improvements were maintained for >1 year of treatment, with stable lung volumes as assessed by FVC throughout the study duration. The higher gains in MIP compared with FVC may be related to changes in muscle strength occurring prior to gains in volume, in addition to potential limitations in lung volume expansion related to scoliosis and lung elasticity in neuromuscular disease [
36]. The impact of scoliosis, which is common in LOPD [
37], is known to contribute to extrapulmonary restrictive lung disease [
38,
39]. The frequency or degree of spinal abnormalities was not evaluated in the current study.
Evaluation of the long-term benefit of reveglucosidase alfa requires accurate knowledge of the rate of disease progression in untreated patients. The natural history of LOPD suggests that respiratory muscle strength, lung capacity, and walking endurance steadily decrease at rates of 1–4% per year [
1,
5,
10,
40]. van der Beek et al. [
40], for example, reported annual declines in FVC (−1.1%), MIP (−3.2%), and MEP (−3.8%). The fact that reveglucosidase alfa increased respiratory muscle strength, lung capacity, and walking endurance (by as much as 13.9% for up to 72 weeks of treatment) suggests that reveglucosidase alfa has an initial effect on the disease. Longer term studies, however, are needed to determine whether reveglucosidase alfa impacts disease progression in patients with LOPD.
Given the serious clinical consequences of progressive LOPD (eg, respiratory failure and mobility loss) and other neuromuscular diseases, the benefit:risk ratio of an ERT is important to consider. In this study, a favorable benefit:risk ratio is suggested by improvements in global respiratory muscle strength and a reasonable AE profile. Although hypersensitivity-type reactions are a serious potential complication of any recombinant human protein [
41], these events were manageable with antihistamines or steroids and did not require hospitalization. Hypoglycemia occurred intermittently, was mostly mild and successfully managed in all subjects using caloric supplementation shortly after each occurrence, and did not result in dose reduction or discontinuation. The reduced plasma glucose in some subjects reflects a pharmacologic effect of IGF2 derived from the GILT tag of reveglucosidase alfa [
23].
Acknowledgments
BioMarin Pharmaceutical Inc. provided funding for medical writing and editorial support in the development of this manuscript. Roger J. Hill, PhD, of Ashfield Healthcare Communications (Middletown, CT, USA) drafted and revised the manuscript based on input from authors, and Dena McWain of Ashfield Healthcare Communications copyedited and styled the manuscript per journal requirements. Additional editorial assistance and data analysis provided by Aji Nair, PhD, Lynn Smith, and Brian Long, PhD, of BioMarin Pharmaceutical Inc. Part of the study was carried at the NIHR/Welcome trust Birmingham clinical research facility. The authors wish to acknowledge the participation of the following POM-001/POM-002 investigators:: Drago Bratkovic, Ian McPhee Chapman, David Bruce Ketteridge, Marni Anne Nenke (SA Pathology, Adelaide, SA, Australia); Seyfullah Gökce, Christoph Kampmann, Nesrin Karabul, Eugen Mengel, Hildegard Nick, Gundula Staatz (Johannes Gutenberg University, Mainz, Germany); Marie Cecile Augeraud, Marie Claire Champagne, Emilien Delmont, Claude Desnuelle, Helen Rocca, Evelyne Rulle, Sabrina Sacconi, Véronique Tanant-Olive (University Hospital of Nice, Pasteur Hospital, Nice, France); Anthony Behin, Aurélie Canal, Pierre Carlier, Jean-Christophe Corvol, Valérie Decostre, Bruno Eymard, Jean-Yves Hogrel, Pascal Laforet, Timothée Lenglet, François Renard, Tanya Stojkovic, Maya Tchikviladze (Paris-Est Neuromuscular Center, Hôpital Pitié-Salpêtrière, Paris, France); Charlotte Dawson, Tarekegn Geberhiwot, Raashda Sulaiman, John Boyle Winer (University Hospital Birmingham, Birmingham, UK); Derralynn A. Hughes, Atul Mehta, Alison Thomas (Royal Free London NHS Foundation & University College London Department of Hematology, London, United Kingdom); Chinonso Stanley Ezeanyika, Christian J. Hendriksz, Ana Jovanovic, Jane Mooney, Adrian Parry-Jones, Mamatha Ramaswamy, Mark Roberts, Reena Sharma, Samuel Joseph Sprakes, Elspeth Louise Twiss, Anne Elina Uutela (Salford Royal NHS Foundation Trust, Salford, United Kingdom); Bruce A. Barshop, Annette Feigenbaum, Richard H. Haas, William L. Nyhan, Zarazuela Zolkipli-Cunningham (University of California, San Diego School of Medicine, La Jolla, CA, United States); Julie A. Bowen Berthy, Barry J. Byrne, Lindsay Falk, Barbara Kellerman Smith, Jenna L. Lammers, Lee Ann Lawson, Michele N. Lossius, Terry M. Sexton (University of Florida, School of Medicine, Gainesville, FL, United States); Heather Anderson, Kristy Anderson, Anne K. Arthur, Richard J. Barohn, Jeffrey Burns, Melissa Cooley, Majed J. Dasouki, Mazen M. Dimachkie, Laura Herbalin, Andra Lahner, Dan K. Lewis, Dawn Lockhart, April L. McVey, Hiwot (Mimi) Michaels, Mamatha Pasnoor, Christian Pearson, Joseph Sibinski, Yodit Teklu, Maureen Walsh, Yunxia Wang (Kansas University Medical Center, Kansas City, KS, United States).