Evaluating avalglucosidase alfa for the management of late-onset Pompe disease

ABSTRACT

Introduction

Glycogenosis type II (GSDII) is a rare autosomal disorder that is caused by the deficiency of alpha-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose. Autophagy dysregulation plays a critical role. Importantly, since 2006, both patients with infantile (classic Pompe disease) and adult GSDII (late-onset Pompe disease or LOPD) have been treated with enzyme replacement therapy (ERT). To support this use, several double-blind and observational studies including large cohorts of GSDII patients have been undertaken and have shown ERT to be effective in modifying the natural course of disease. Indeed, most LOPD cases improve in the first 20 months of treatment in a six-minute walk test (6MWT), while those who are untreated do not; instead, their response declines over time.

Areas covered

The author reviews avalglucosidase alpha, a therapy approved by both the FDA and European regulatory agencies. Herein, the author considers the pathophysiological approaches such as the role of enzyme entry, autophagy, and the response to ERT treatment of motor and respiratory components.

Expert opinion

There has been a notable drive toward the research of various aspects of this disease regarding the role of new enzyme penetration and immune adverse events. Consequently, avalglucosidase alpha might be a further step forward.

KEYWORDS:

• Pompe disease
• glycogenosis type 2
• enzyme replacement therapy
• autophagy
• acid alpha-glucosidase

Article highlights

• In observational studies in adult GSD II, maximal efficacy with rhGAA was found in the first 24–36 months, and then it declined.

• Adverse events are relatively mild, and a rechallenge needs careful evaluation.

• Prospects of enzyme replacement therapy (ERT) include the improved enzyme preparation NeoGAA with larger tissue penetration.

• An evaluation of NeoGAA (avalglucosidase alfa) clinical trials is favorable regarding safety and has a positive outcome.

• Measurement of pulmonary capacity, as FVC percent, was chosen as the primary endpoint in the COMET 3 trial, rather than the 6MWT, and additional motor outcome measures such as GSGC or time-up-and-go are needed.

• The complexity of GSD II suggests that also combining multiple interventions, such as autophagy modifiers, diet, and exercise, might be an available winning strategy.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.