Pompe Disease Research Articles

Nonclinical studies in non-human primates on ABX1100: A centyrin:Gys1 siRNA conjugate for the treatment of Pompe disease

Nonclinical studies in non-human primates on ABX1100: A centyrin:Gys1 siRNA conjugate for the treatment of Pompe disease

Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS®) physical function questionnaire in late-onset Pompe disease using PROPEL phase 3 data

BackgroundThe construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT).MethodsIn the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers’ maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients’ age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods.Results123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively.ConclusionsPROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD.Trial registrationClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www.clinicaltrials.gov/search?term=NCT03729362.

A novel siRNA targeting and delivery platform inhibits glycogen synthesis and reduces glycogen levels in skeletal and cardiac muscle in a mouse model of Pompe disease

A novel siRNA targeting and delivery platform inhibits glycogen synthesis and reduces glycogen levels in skeletal and cardiac muscle in a mouse model of Pompe disease

Real-world evidence study finds no new-onset diabetes or drug-related hyperglycemia in Pompe disease patients treated with avalglucosidase alfa

Real-world evidence study finds no new-onset diabetes or drug-related hyperglycemia in Pompe disease patients treated with avalglucosidase alfa

Intravital imaging of muscle damage and response to therapy in a model of Pompe disease

Intravital imaging of muscle damage and response to therapy in a model of Pompe disease

NEO1/NEO-EXT studies: Long-term muscle quantitative magnetic resonance imaging and functional efficacy in adults with late-onset Pompe disease (LOPD) on avalglucosidase alfa treatment

NEO1/NEO-EXT studies: Long-term muscle quantitative magnetic resonance imaging and functional efficacy in adults with late-onset Pompe disease (LOPD) on avalglucosidase alfa treatment

Switching treatment to cipaglucosidase alfa plus miglustat positively affects motor function and quality of life in patients with late-onset Pompe disease

Switching treatment to cipaglucosidase alfa plus miglustat positively affects motor function and quality of life in patients with late-onset Pompe disease

COMET post hoc analysis: Efficacy of long-term avalglucosidase alfa in subgroups of participants with late-onset Pompe disease

COMET post hoc analysis: Efficacy of long-term avalglucosidase alfa in subgroups of participants with late-onset Pompe disease

Experience with enzyme replacement therapy in children with late-onset Pompe disease diagnosed via newborn screening in the United States

Experience with enzyme replacement therapy in children with late-onset Pompe disease diagnosed via newborn screening in the United States

Challenges in management of late-onset Pompe disease (LOPD) identified through Indiana newborn screening

Challenges in management of late-onset Pompe disease (LOPD) identified through Indiana newborn screening

Baseline demographics of the UK Early Access to Medicines Scheme registry for cipaglucosidase alfa plus miglustat in enzyme replacement therapy-experienced adults with late-onset Pompe disease

Baseline demographics of the UK Early Access to Medicines Scheme registry for cipaglucosidase alfa plus miglustat in enzyme replacement therapy-experienced adults with late-onset Pompe disease

Rare complication in late-onset Pompe disease: A case report

Rare complication in late-onset Pompe disease: A case report

Restoration of acid-alpha glucosidase expression and function through efficient adenine base editing of Pompe disease variants

Restoration of acid-alpha glucosidase expression and function through efficient adenine base editing of Pompe disease variants

Barriers and facilitators to physical activity and exercise in late-onset Pompe disease (LOPD): A qualitative study exploring patients' perspectives and experiences

Barriers and facilitators to physical activity and exercise in late-onset Pompe disease (LOPD): A qualitative study exploring patients' perspectives and experiences

Minimal clinically important differences in six-minute walking distance in late-onset Pompe disease

Minimal clinically important differences in six-minute walking distance in late-onset Pompe disease

Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa.

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase. Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6months. Results: A total of n = 8/15 patients received alglucosidase for more than 3years prior to switching, and n = 7/15 received it for more than 5years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of -104.8U/L, -3.0mmol/molCr, and -14.7U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch. Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.

Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.

Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease

BackgroundClinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context.MethodsAll possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded.ResultsIn the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018).ConclusionThe win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion.

Primary: Establish a new figure for prevalence at birth for Pompe disease by collecting and analyzing the largest relevant dataset to date and using that result to project population prevalence at birth in a novel way. Secondary: Compare these results to previous analyses to offer a framework for evaluating 'frequency' data that can be applied to other rare, genetic diseases, along with methods to assess quality of estimates.

Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease.

The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800). We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800). Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers. The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies.