Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease.

Methods

We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated.

Results

Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses.

Conclusion

Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.

Aleena A. Khan MBBS, Laura E. Case PT, DPT, Mrudu Herbert MD, MPH, Stephanie DeArmey MHS, PA-C, Harrison Jones PhD, Kelly Crisp CCC-SLP, MA, Kanecia Zimmerman MD, Mai K. ElMallah MD, Sarah P. Young PhD & Priya S. Kishnani MD

Genetics in Medicine volume 22, pages898–907(2020)

Five patients were cross‐reactive immunologic material (CRIM)‐negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator‐free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)‐naïve setting.

Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator‐free survival was 50% and 92%. Both CRIM‐negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk.

Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM‐negative also received immunomodulation. B‐cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B‐cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250‐1:800 000 and 1:250‐1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator‐free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.

Esther PoelmanJan J. A. van den DorpelMarianne Hoogeveen‐WesterveldJohanna M. P. van den HoutLianne J. van der GiessenNadine A. M. E. van der BeekW. W. M. Pim PijnappelAns T. van der Ploeg

First published: 07 June 2020

https://doi.org/10.1002/jimd.12268

• Data from Pompe Registry
• 396 patients
• All on Enzyme Replacement Therapy (ERT)
• Examined upright FVC
• Median FVC (forced vital capacity) was 66.9%
  • FVC stable at 5 years -> Decline ~ 0.17%/yr
• Baseline FVC lower among some groups
  • Males
  • Older at ERT initiation
  • Longer duration from symptom onset to ERT initiation
  • More advanced disease
• Age of onset NOT associated with baseline degree of dysfunction
• Shorter time from diagnosis to ERT initiation associated with higher FVC after 5 years.
  • Cutoff of 1.7 years used in study
  • Neither short nor long groups’ declines were significantly different from 0.
    • Shorter-Time: − 0.07% predicted/year, p = 0.72;
    • Longer-Time: − 0.25% predicted/ year, p = 0.16

My take:

As a father of a newly diagnosed LOPD infant patient, this is a promising result. As I’m sure is the case with most of you reading, one of my greatest fears is that she (or you or your child) will deteriorate before more effective treatments can be found. The most fascinating finding was that respiratory function (measured with FVC) while on ERT was largely stable over five years. Similarly, although it is potentially better to have begun treatment within 1.7 years of diagnosis, even the group of patients that began ERT later than one year after diagnosis did not have a respiratory function decline significantly different than “no decline”.

With the improved treatments (hopefully) arriving in the not too distant future, a minimal degradation of FVC over five years is encouraging. With the two novel ERT treatments in phase 3 testing and now two current ongoing gene therapy trials [trial 1 and 2], there is certainly hope.

On the less positive side, Upright FVC is just one of many aspects of respiratory function. This result isn’t especially surprising, as most literature that I have read seems to suggest the same thing (while other performance measurements may experience more considerable declines). I guess it makes sense, however, as these patients were pulled from the Pompe Registry, it’s likely they were written about other previous studies.

Overall, this paper’s results is encouraging for those Pompe Disease to know that over five years it is likely that their upright breathing will not suffer significantly while on ERT.

Abstract

Objective

To examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation.

Methods

Longitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models.

Results

Among 396 eligible patients, median baseline FVC was 66.9% (range 9.3–126.0). FVC remained stable during the 5-year follow-up (slope = − 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years.

Conclusion

FVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.

Mol Ther Methods Clin Dev. 2020 Sep 11; 18: 199–214. Published online 2020 Jun 10.
doi: 10.1016/j.omtm.2020.05.026

PMCID: PMC7334420

PMID:  32671132

Naresh Kumar Meena,¹Evelyn Ralston,²Nina Raben,^1,∗ and  Rosa Puertollano^1,∗∗

²Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA

¹Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA