Emerging Therapies for Pompe Disease: What the Latest Literature Means for Neurologists

Pompe disease is a rare, progressive autosomal recessive disorder caused by pathogenic variants in the GAA gene.¹ This genetic disorder leads to reduced acid α-glucosidase activity and accumulation of intralysosomal glycogen, particularly in skeletal, smooth, and cardiac muscle. The clinical spectrum of the condition ranges from infantile-onset disease (IOPD), which is often associated with cardiomyopathy and marked hypotonia, to late-onset disease (LOPD), which presents more heterogeneously with progressive proximal muscle weakness and respiratory involvement.

Enzyme replacement therapy (ERT) led to improved clinical outcomes in Pompe disease following the approval of alglucosidase alfa more than 15 years ago.² However, limitations such as immunogenicity, suboptimal skeletal muscle uptake, and reduced efficacy over time have underscored the need for alternative approaches. Recent research has expanded knowledge in this disease realm, including comparative evaluations of ERT, updated expert consensus recommendations, and proposed frameworks for the development of patient-centered gene therapy programs.

In recognition of International Pompe Day, held April 15, 2026, this NeurologyLive^® feature reviewed 5 recent and clinically relevant publications in Pompe disease management, summarizing key findings and their potential implications for clinical practice.

Patient-Centered Management of Pompe disease in the Era of Gene Therapy

As gene therapies for Pompe disease advance from preclinical development toward clinical application, questions regarding equitable and safe implementation have become increasingly relevant. A recently published European expert consensus in Journal of Neurology, developed by a steering committee of 8 specialists using a structured think-tank methodology, outlined criteria for establishing centers of excellence for Pompe disease gene therapy.³

Led by Benedikt Schoser, MD, senior consultant in neurology at the Friedrich-Baur Institute at Ludwig-Maximilians University of Munich, the framework identifies 4 key components. These components include timely and accurate diagnosis, comprehensive patient assessment, appropriate selection of candidates for gene therapy, and structured post-treatment monitoring. The authors noted that, despite substantial therapeutic promise, gene therapies introduce logistical and clinical complexity, including requirements for specialized infusion infrastructure, immunosuppression management, long-term surveillance, and multidisciplinary coordination.

As a result, not all current Pompe disease treatment centers may be prepared to deliver these therapies. The proposed framework aims to translate emerging clinical evidence into practical, center-level standards to support implementation. The authors suggest that clinicians managing patients with Pompe disease should assess whether their institutions currently meet, or can develop, the infrastructure and processes required to support gene therapy delivery.

Recommendations for the Diagnosis, Treatment, and Long-Term Management of Late-Onset Pompe Disease

A multidisciplinary Spanish expert group published updated clinical guidance for LOPD in Neurología (English), addressing diagnosis, ERT selection, and long-term follow-up.⁴ The recommendations incorporate the availability of next-generation ERT formulations and acknowledge evidence suggesting that long-term ERT efficacy may decline over time, supporting more frequent clinical reassessment than previously recommended.

Led by Cristina Domínguez-González, MD, PhD, a neurologist at the Hospital 12 de Octubre in Madrid, the updated guidance integrated newer therapeutic options, including avalglucosidase alfa and cipaglucosidase alfa, into a structured decision-making framework. It outlined considerations for treatment initiation, as well as criteria for switching therapies or incorporating adjunctive and emerging approaches.

The document also highlighted the importance of ongoing respiratory monitoring and tracking pulmonary function trajectories, given that respiratory failure remains a leading cause of morbidity and mortality in LOPD. Overall, the guidance provides an updated clinical framework for LOPD management, with emphasis on individualized care, including reassessment of treatment strategies and tailoring of respiratory monitoring intervals based on disease progression.

Recent Advances in Pompe Disease: Pathogenesis, Clinical Management, and Emerging Therapeutic Directions

A recent comprehensive review, published in Frontiers in Neurology, summarized recent advances in Pompe disease management, including newborn screening, biomarker development, next-generation biologics, gene therapy approaches, and health policy considerations.⁵ It outlined a potential future care model in which early detection at birth is combined with detailed disease characterization and multimodal treatment strategies tailored to a patient’s genotype, phenotype, immune profile, and stage of life.

Authored by Guangrui Li, MD, associate professor in the Department of Neurology at The First Hospital of Hebei Medical University, the review noted a need for more robust comparative evidence between currently available therapies, particularly a lack of head-to-head data comparing avalglucosidase alfa and cipaglucosidase alfa in LOPD, which may limit fully informed treatment selection. The author also identified emerging biomarkers, such as neurofilament light chain and plasma glial fibrillary acidic protein, as potential tools for monitoring central nervous system (CNS) involvement in IOPD, particularly among long-term survivors.

Clinically, the review suggests that clinicians monitor evolving biomarker data, especially in patients with IOPD who are living longer with ERT, as CNS surveillance strategies may require adaptation. It also underscored the importance of patient participation in registries and observational studies to support the development of comparative effectiveness data.

The Triple-S Consensus Framework in the Treatment of Late-Onset Pompe Disease

A narrative review published in the European Journal of Pediatrics summarized the current therapeutic landscape for LOPD, including ERT, substrate reduction therapy, pharmacological chaperone therapy, adjunctive approaches, and gene therapy, and compared available modalities where evidence allowed.⁶ The review also incorporated the updated Triple-S (Start, Switch, Stop) consensus recommendations from the European Pompe Consortium, which provide a structured framework for ERT decision-making across the disease course.

Led by Misha Khan, MBBS, house officer in the Department of Medicine and Surgery at Liaquat National Hospital and Medical College, the study noted that alglucosidase alfa has been associated with improvements in 6-minute walk test performance and forced vital capacity, but its use may be limited by immunogenicity and infusion-related reactions that can affect long-term outcomes. The authors further highlighted that avalglucosidase alfa demonstrates improved mannose-6-phosphate receptor binding; however, comparative data establishing clear clinical superiority of cipaglucosidase alfa over avalglucosidase alfa remain inconclusive.

Overall, the review emphasized the potential utility of the Triple-S framework as a guide for treatment decisions in LOPD, including proactive and periodic reassessment of switching criteria, particularly in patients receiving first-generation ERT who are clinically stable but not demonstrating continued improvement.

Enzyme Replacement Therapy in Pompe Disease: Current Treatment Strategies and Supporting Clinical Evidence

A focused review published in Expert Opinion on Pharmacotherapy examined the evolution of ERT as the cornerstone of treatment for Pompe disease.⁷ The author described the progression from alglucosidase alfa to newer agents, including avalglucosidase alfa and cipaglucosidase alfa, and reviewed the biochemical rationale supporting these formulations alongside the available clinical evidence for each therapy.

Authored by Alberto Corsini, PharmD, PhD, full professor in the Rodolfo Paoletti Department of Pharmacological and Biomolecular Sciences at University of Milan, the analysis incorporated phase 3 trial data, including the COMET trial (NCT02782741) evaluating avalglucosidase alfa in treatment-naïve LOPD and the PROPEL trial (NCT03729362) assessing cipaglucosidase alfa in combination with miglustat. Outcomes included measures of efficacy, safety, immunogenicity, and considerations of real-world use.

The author reported that biochemical modifications to avalglucosidase alfa have been associated with clinical benefit compared with earlier ERT formulations, whereas comparative uncertainty remains regarding the clinical advantage of cipaglucosidase alfa. Overall, the review suggested that although newer ERT options expand therapeutic choice in LOPD, differences in comparative effectiveness remain incompletely defined.

Implications for Clinical Practice

These 5 reviewed publications suggest that Pompe disease management is entering a new phase characterized by increased therapeutic complexity and expanding treatment possibilities. The era of ERT as a single standard of care has shifted, as clinicians now practice in an environment with approved therapies, a growing pipeline of investigational options, and an evolving evidence base that requires continuous engagement with the literature. Overall, the recent literature reflects both the meaningful progress being made in the field and the continued need for evidence generation to guide optimal management in Pompe disease.

REFERENCES
1. Taverna S, Cammarata G, Colomba P, et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). 2020;12(15):15856-15874. doi:10.18632/aging.103794
2. van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010;362(15):1396-1406. doi:10.1056/NEJMoa0909859
3. Schoser B, Domínguez-González C, Laforet P, et al. A roadmap for a patient-centred approach to Pompe disease management. J Neurol. 2026;273(2):145. Published 2026 Feb 14. doi:10.1007/s00415-026-13687-3
4. Domínguez-González C, Barba Romero MÁ, Caballero Eraso C, et al. Recommendations for the diagnosis, treatment, and follow-up of late-onset Pompe disease. Neurologia (Engl Ed). 2026;41(2):501933. doi:10.1016/j.nrleng.2025.501933
5. Li G. Comprehensive review of recent advances in Pompe disease: pathogenesis, management, and future directions. Front Neurol. 2026;17:1756935. Published 2026 Feb 17. doi:10.3389/fneur.2026.1756935
6. Khan M, Awan Z, Ali EA, et al. New advances in treating late-onset Pompe Disease: A narrative review. Eur J Pediatr. 2025;185(1):41. Published 2025 Dec 24. doi:10.1007/s00431-025-06669-6
7. Corsini A. Improving the treatment of Pompe disease with enzyme replacement therapy: current strategies and clinical evidence. Expert Opin Pharmacother. 2025;26(7):835-848. doi:10.1080/14656566.2025.2491508