Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease

Abstract

Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20 mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20 mg/kg/week or 40 mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n = 4), infantile-onset (n = 9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.

Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction

“…Therefore, we directly compared the efficacy of intensive ERT with AAV2/8-LSPhGAA gene transfer at the established 12 low dose. GAA-KO mice were assigned (both male and female; Figure 1A; Table 1) to receive either a weekly injection of rhGAA for intensive ERT 15 (20 mg/kg/week; n = 10) or a single injection of AAV2/8-LSPhGAA for low-dose gene therapy (8 × 10 11 vg/kg; n = 10). The primary endpoints included GAA activity and glycogen content in the tissues and anti-GAA antibody formation.…”

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease

“…Early initiation of rhGAA infusion after diagnosis through NBS improves the outcomes of IOPD, but muscle weakness, ptosis, and speech disorders still occurred [7], [17]. An increase in the dosage or frequency of rhGAA infusion appears to provide some benefits to these patients but is not sufficient to prevent residual symptoms [7], [22], [23]. In the current study, we demonstrated that albuterol speeded the climb of patients and selectively improved muscle function and movement quality, but we could not prove its benefit in the 6MWT consistently nor its significant benefit in other measurements.…”

Cardiac response to enzyme replacement therapy in infantile Pompe disease with severe hypertrophic cardiomyopathy

“…Pompe disease (PD), a rare autosomal recessive condition also known as glycogen storage disease type II, is caused by deficiency of the lysosomal enzyme acid α‐glucosidase (GAA). This enzyme deficiency results in glycogen accumulation in various organs, primarily muscle tissue . The clinical severity of the disease depends on the degree of enzyme deficiency.…”

“…The most severe form with predominantly cardiac involvement is classic infantile‐onset PD (IOPD) with an estimated frequency of 1:138 000 . Patients with IOPD typically have marked hypertrophic cardiomyopathy, respiratory distress, feeding problems, motor delay, failure to thrive, muscle weakness, and hypotonia . IOPD is rapidly progressive and used to be considered uniformly lethal with the vast majority of patients dying in the first year due to cardio‐respiratory failure .…”

“…The availability of enzyme replacement therapy (ERT) in 2006 transformed the course of the disease with little side effects . ERT effectively reverses cardiomyopathy, improves motor development, and significantly lengthens survival . Decrease in ventricular hypertrophy and improvement in ventricular function and synchrony have been suggested as proof for efficacy and secondary endpoint of treatment …”