An Overview of Pompe Disease Treatments and Outcomes

Pompe disease (glycogen storage disease type II) spans infantile-onset (IOPD) and late-onset (LOPD) phenotypes. Over the past two decades, enzyme replacement therapy (ERT) has transformed survival and function, while immunomodulation, supportive respiratory care, and new agents have refined outcomes. Below is a synthesis of pivotal trials, registry/real‑world series, consensus guidance, and early investigational approaches, with practical takeaways.

Established disease-modifying therapy: ERT

Three ERT options are now available globally, with differing uptake characteristics, safety profiles, and evidence in IOPD and LOPD.

Table 1. Approved ERTs, dosing, and LOPD efficacy/safety highlights

Long‑term extensions underscore stabilization rather than cure: in LOPD, FVC decline slows versus natural history, and initial 6MWT gains tend to plateau with gradual decline over years; earlier initiation and switching in suboptimal responders may slow progression 21.

IOPD: survival, cardiac remodeling, and the critical value of timing and immunomodulation

Pivotal alglucosidase trials demonstrated dramatic survival gains in infants:

• IOPD <6 months at start: 18‑month survival 100% (vs 2% historical); universal LV mass index (LVMI) improvement; motor gains in most 21.
• IOPD 6–36 months: 79% reduction in death risk vs historical; LVMI improved in 81%; motor gains in 62% despite later initiation 21.

Earlier ERT further improves cardiac remodeling. A longitudinal analysis shows earlier start shortens time to normal LVMI and improves interventricular septum and posterior wall thickness; initiation ≤1 month is associated with faster normalization 5. Newborn screening–enabled treatment ≤4 weeks combined with immune tolerance induction (ITI) and high‑dose ERT (median lifelong 2.76× label) yielded excellent long‑term outcomes: 16/17 alive, ambulatory, orally feeding, ventilator‑free at 3.1–18.4 years; LVMI reduction in 16/17; biomarker reductions (Glc4 in all) despite persistent risks of high‑sustained antibody titers (HSAT) in some CRIM‑positive cases 10.

Dosing strategies in IOPD are evolving. Real‑world series report that initiating high‑dose alglucosidase (up to 40 mg/kg/week) is associated with CK normalization and may reduce HSAT development in some patients; survival at 5 and 10 years reached 92% in one center using high‑dose ERT and ITI, though ventilator dependence and deaths still occurred in a subset 7. A case report of first‑line avalglucosidase 40 mg/kg q2w showed rapid LVMI regression and sustained normalization through 36 months in an atypical IOPD case 11.

CRIM status and immunogenicity are central to IOPD outcomes. Prescribing information and systematic reviews highlight that high, sustained anti‑GAA IgG titers reduce clinical efficacy and require proactive monitoring. Recommendations include early CRIM status assessment, baseline ADA testing, and regular monitoring (especially in the first year) with specialist oversight for ITI 16. A systematic review shows a shift toward genotype‑based CRIM prediction; ITI (often rituximab + methotrexate ± IVIG) is commonly used prophylactically in CRIM‑negative and select CRIM‑positive infants at ERT start, and as rescue in ERT‑experienced patients with HSAT. CRIM‑negative infants receiving ITI with ERT had better outcomes than those without ITI; early, and sometimes higher‑than‑label dosing, are favorable prognostic signals 6. In a newborn‑screened cohort, all CRIM‑negative infants achieved immune tolerance with rituximab/methotrexate/IVIG; among CRIM‑positive infants, some developed HSAT but achieved tolerance after bortezomib‑based ITI 10. For patients with hypersensitivity, structured desensitization protocols can enable continued ERT even in very young infants 8.

Real‑world pediatric data reinforce benefit but also the vulnerability of classic IOPD: ERT improved cardiac function and prolonged survival; the ERT group had fewer clinical events (HR 0.06, p<0.005), yet overall mortality remained high (56%; all IOPD) reflecting baseline severity and late presentation in many cases 18.

LOPD: motor/respiratory trajectories and therapy selection

In LOPD, ERT improves or stabilizes 6MWT and FVC in the short term; over years, gradual decline typically ensues. Comparative data indicate:

• Alglucosidase improves 6MWT and FVC vs placebo (LOTS) 21.
• Avalglucosidase yields non‑inferior and likely superior FVC change vs alglucosidase and similar or better 6MWT gains with fewer IARs (COMET) 21.
• Cipaglucosidase alfa + miglustat preserves FVC better than alglucosidase overall, with significant benefits in ERT‑experienced patients on both 6MWT and FVC, and greater biomarker improvements (Hex4, CK). Post hoc analyses show higher odds of clinically meaningful motor/respiratory improvements than alglucosidase 213.

Guideline updates and consensus statements reflect this evolution. Spanish experts note ERT has changed disease course for >15 years, effectiveness may wane over time, and newer enzymes offer opportunities; switching between ERTs is recommended for suboptimal response or intolerance to optimize care 1720. UK guidelines provide standardized diagnostic, monitoring, and management approaches across ages 19. The Austrian Delphi consensus specifies a minimum follow‑up set including 6MWT, timed functional tests, dynamometry, patient‑reported outcomes, FVC (sitting and supine), muscle imaging, and antibody titers, among others 9.

Gastrointestinal involvement is increasingly recognized in LOPD; a cross‑sectional analysis summarized real‑world manifestations and ERT outcomes, though specific metrics were not detailed in the retrieved summary 2.

Safety and immunogenicity across ERTs

All ERTs carry risks of hypersensitivity and IARs, with boxed warnings underlining the need for infusion vigilance, premedication as appropriate, and readiness to slow/stop infusions or provide advanced support. Alglucosidase also includes guidance on immune‑mediated reactions and cardiorespiratory risk in fragile IOPD 1. Avalglucosidase and cipaglucosidase+miglustat carry similar boxed warnings; cipaglucosidase+miglustat is contraindicated in pregnancy, with contraception guidance and lactation not recommended 394342. Home infusion of cipaglucosidase+miglustat appears feasible with IAR rates comparable to clinic settings in pooled analyses (1.3% vs 1.8% per infusion) 4.

Immunogenicity matters most in IOPD. High, sustained ADA titers correlate with reduced efficacy, particularly in CRIM‑negative infants; early CRIM assessment and ADA monitoring (baseline, regularly in year 1, then as clinically warranted) are recommended, with referral to teams experienced in ITI 16. In LOPD, immunogenicity is less clearly tied to clinical outcomes in available summaries, but antibody monitoring is part of consensus assessment batteries 9.

ERT in pregnancy and lactation appears feasible in LOPD based on a small case series: breastmilk GAA activity was comparable to healthy controls, and offspring had age‑appropriate growth/development; limited case-series data suggest ERT can be continued during pregnancy and lactation in selected LOPD patients with specialist oversight, but breastfeeding recommendations vary by label/region. 16.

Supportive and symptomatic care

Respiratory management is central in both IOPD survivors and LOPD. International consensus recommends:

• Serial assessments: FVC upright and supine, MIP/MEP; a ≥10% drop supine suggests diaphragmatic weakness (≥30% severe). Sleep-disordered breathing may precede severe FVC decline; overnight oximetry/capnography and polysomnography as indicated 35.
• NIV initiation can be considered if any of: daytime PCO₂ ≥45 mm Hg, supine FVC <50% predicted, MIP <60 cm H₂O, or sleep SaO₂/SpO₂ <90% for ≥5 min; broader criteria include FVC <50% predicted without symptoms or <80% with symptoms, MIP <−40 cm H₂O, and documented nocturnal hypoventilation 3537. Volume‑assured modes (AVAPS/iVAPS) help in progressive weakness, with tidal volume targets 6–8 mL/kg ideal body weight; EPAP as low as tolerated and Ti >1.2 s are often used 38.
• Airway clearance: aim for peak cough flow >160 L/min; consider mechanical insufflation–exsufflation (typical pressures +40/−40 cm H₂O), manually assisted cough, breath stacking, and high‑frequency oscillatory techniques; adjust MI‑E pressures in bulbar involvement to avoid laryngospasm 3738.
• Infection prevention and early treatment are emphasized 35.

Multidisciplinary care encompasses cardiac monitoring (echocardiography/LVMI), swallowing evaluation (videofluoroscopy), dietetics, musculoskeletal rehabilitation (functional scales such as 6MWT, GMFM-88, Pompe‑PEDI), and psychosocial support; Austrian consensus provides a prioritized follow‑up battery, including biomarkers and imaging 369. UK and Spanish guidelines converge on standardized diagnostic and long‑term management frameworks 1917.

Investigational and adjunctive approaches

• Next-generation ERTs now approved (avalglucosidase; cipaglucosidase+miglustat) are considered therapeutic alternatives rather than adjuncts; consensus supports switching when needed to individualize care. A narrative review suggests avalglucosidase may offer superior 6MWT/FVC with fewer adverse effects compared with alglucosidase, while cipaglucosidase+miglustat shows favorable motor/respiratory outcomes but with higher AE incidence. Clenbuterol adjunct to ERT has been associated with motor/respiratory improvement but carries cardiovascular risk. Pharmacological chaperone therapy and substrate reduction therapy show mild improvements in limited studies; gene therapy is early with uncertain long‑term efficacy/safety 20.
• AAV gene therapy (AT845) in adults with LOPD (FORTIS) experienced an FDA clinical hold in June 2022 after a grade 2 peripheral sensory polyneuropathy; the hold was lifted in January 2023 and the trial resumed with reported two‑year safety and exploratory efficacy presentations, though detailed outcomes are limited in public summaries retrieved here 252331.
• Preclinical AAV9 vectors leveraging a muscle enhancer (MyoG6PC) achieved higher skeletal/heart GAA activity, glycogen clearance, and grip strength improvements in male Gaa‑knockout mice without detectable anti‑GAA antibodies, supporting promoter engineering for efficacy and immune evasion; female mice showed attenuated responses in this model 12.
• Biomarkers: Plasma GFAP outperformed NfL in reflecting CNS burden in pediatric Pompe cohorts and differentiated severe vs attenuated neurologic involvement in IOPD, while LOPD without CNS involvement had GFAP levels similar to controls (AUCs 0.886 for IOPD vs controls; 0.801 for severe vs attenuated) 13.
• Pharmaceutical considerations such as alglucosidase stability in saline and early diagnostic integration (DBS enzyme + molecular testing) can support reliable administration and timely diagnosis in diverse settings 1514.

Practical clinical takeaways

• Initiate ERT as early as possible in IOPD (ideally ≤1 month; ≤4 weeks via newborn screening), pair with CRIM‑guided ITI, and consider higher‑than‑label dosing in select cases with careful monitoring; expect major survival and cardiac benefits 56710.
• In LOPD, start ERT upon functional involvement; consider avalglucosidase or cipaglucosidase+miglustat when response to alglucosidase is suboptimal or adverse effects occur. Switching is now a standard strategy to optimize motor/respiratory outcomes 1720213.
• Monitor for and manage hypersensitivity and IARs across all ERTs; plan for premedication, infusion adjustments, and emergency support. Home infusion may be feasible with appropriate protocols for selected adults on cipaglucosidase+miglustat 3940434.
• Embed serial respiratory assessments (upright/supine FVC, MIP/MEP), early sleep evaluations, and timely initiation of NIV per thresholds; integrate airway clearance and cough augmentation to maintain peak cough flow 353738.
• Use a standardized follow‑up battery (6MWT, functional tests, dynamometry, FVC sitting/supine, imaging, antibody titers, QoL/pain) and multidisciplinary supports (cardiac, nutrition/swallowing, rehabilitation, psychosocial) to sustain outcomes 93619.
• Discuss reproductive plans: alglucosidase has supportive data for use during pregnancy/breastfeeding; cipaglucosidase+miglustat is contraindicated in pregnancy and not recommended during lactation 164342.
• Stay alert to investigational advances (gene therapy, promoter engineering, adjunctive agents) and emerging biomarkers (GFAP) while recognizing that clinical evidence remains limited in retrieved materials 12312013.

Overall, ERT remains the cornerstone of Pompe disease management, with earlier initiation, immunomodulation, optimized agent selection, and robust supportive care as key levers to improve survival and functional trajectories from infancy through adulthood.