Challenges in multinational rare disease clinical studies during COVID-19: regulatory assessment of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease

Pompe disease/glycogen storage disease type II, is a rare, lysosomal storage disorder associated with progressive proximal myopathy, causing a gradual loss of muscular function and respiratory insufficiency. Studies of patients with late-onset Pompe disease have used endpoints such as the 6-minute walking test (6MWT) and forced vital capacity (FVC) to assess muscular and respiratory function during disease progression or treatment. However, the relevance of these markers to late-onset Pompe disease and the minimal clinically important difference (MCID) for these endpoints in late-onset Pompe disease have not yet been established. A literature search was carried out to identify studies reporting the MCID (absolute and relative) for the 6MWT and FVC in other diseases. The MCIDs determined in studies of chronic respiratory diseases were used to analyze the results of clinical studies of enzyme replacement therapy in late-onset Pompe disease. In 9 of the 10 late-onset Pompe disease studies reviewed, changes from baseline in the 6MWT were above or within the MCID established in respiratory diseases. Clinical improvement was perceived by patients in 6 of the 10 studies. In 6 of the 9 late-onset Pompe disease studies that reported FVC, the changes from baseline in percentage predicted FVC were above or within the MCID established in respiratory diseases and the difference was perceived as either an improvement or stabilization by patients. However, applying the 6MWT and FVC MCIDs from studies of chronic respiratory diseases to late-onset Pompe disease has several important limitations. Outcome measures in muscular dystrophies include composite measures of muscle function and gait, as well as Rasch-designed and validated tools to assess disease-related quality of life and activities of daily living. Given that the relevance to patients with late-onset Pompe disease of the 6MWT or FVC MCIDs established for chronic respiratory diseases is unclear, these measures should be evaluated specifically in late-onset Pompe disease and alternative outcome measures more specific to neuromuscular disease considered.

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.

Late-onset Pompe disease (LOPD) is caused by α-glucosidase (GAA) deficiency, leading to glycogen accumulation resulting in progressive muscular weakness and respiratory insufficiency. Glycogen overload, vacuolation, and autophagic accumulation are the histological hallmarks of the disease. However, markers capable of tracking the progression of LOPD across different disease stages remain insufficiently characterized. We performed a comprehensive myopathologic analysis of eleven LOPD muscle biopsies from untreated patients (age range 7-69 years) and compared them to eleven biopsies from histologically normal age-matched controls. The cohort was divided into two groups considering the age at muscle biopsy below or above 33 years: (1) younger LOPD and (2) older LOPD, respectively. We quantified periodic acid-Schiff-positive fibers, vacuolated fibers using a novel vacuolation severity score, autophagic markers, and satellite cell behavior. We observed prominent vacuolization, glycogen overload, and autophagic bodies in younger LOPD. Moreover, this group showed higher regenerative features accompanied by an increase in the percentages of active satellite cells compared to older LOPD. In conclusion, autophagy impairment correlates with enhanced satellite cell activation in muscle biopsies from younger LOPD patients. These findings suggest that stimulating satellite cell activity may hold therapeutic potential for addressing LOPD progression in its early stages.

P.225 - Living with late-onset Pompe disease: the patient and clinician point of view

Cerebral aneurysms and arteropathies causing severe cerebrovascular events have been reported as rare complications in patients with late-onset Pompe disease. We investigated the frequency of cerebrovascular anomalies in six patients with late-onset Pompe disease followed at our institution. Clinical data collection and magnetic resonance angiography were performed as part of routine annual examinations. Four out of six patients had brain vascular anomalies including dolichoectasia of the basilar artery and ectasia of internal carotids. These patients also complained of gastrointestinal symptoms (chronic constipation and gastrointestinal reflux). Two patients had clinical signs related to the arteriopathy, including partial paralysis of the third cranial nerve and transient ischemic attacks. At 1 year follow-up, enzyme replacement therapy did not modify the size of cerebral vessels, but patients reported a marked improvement of intestinal symptoms. In conclusion, neurologists should be aware that intracranial artery abnormalities are not infrequent in patients with late-onset Pompe disease, and they should be specifically investigated in the presence of unexplained CNS symptoms.

T.P.43 Enzyme replacement therapy in late-onset Pompe disease – A systematic literature review

Background: Pompe disease is a rare lysosomal storage disorder, leading to accumulation of glycogen characterized by muscle weakness, fatigue, pain, and, in the longer term, a requirement for ventilatory and ambulatory support, and early mortality if untreated. Clinical evidence suggests that enzyme replacement therapy improves health outcomes for adults with late-onset Pompe disease (LOPD). PROPEL was a Phase 3, double-blind, randomized controlled trial, which evaluated cipaglucosidase alfa plus miglustat, vs alglucosidase alfa plus placebo in 123 adult patients with LOPD (clinicaltrials.gov: NCT03729362). Objectives: To analyze EQ-5D health-related quality of life (HRQoL) utility data from PROPEL. Methods: Multilevel modeling techniques (mixed regression methods) were used to analyze PROPEL EQ-5D-3L estimates and predict utility values for 7 health states previously identified in an economic evaluation for LOPD. In PROPEL, EQ-5D-5L values were assessed at screening and at weeks 12, 26, 38, and 52. EQ-5D-5L utility values were mapped to EQ-5D-3L values using the van Hout algorithm as recommended by the EuroQoL and the National Institute of Health and Care Excellence position statement at time of analysis. UK population tariffs were applied for all EQ-5D utility valuations. Utility values were predicted according to 6-minute walk distance (6MWD) and percent predicted sitting forced vital capacity. Results: The mixed model predicted that EQ-5D-3L utility values for patients who could walk >75 m with LOPD ranged between 0.55 and 0.67 according to patient 6MWD and respiratory function. In this analysis, patients with a 6MWD ≤75 m, consistent with a health state requiring wheelchair support in the economic analysis, had a predicted utility value of 0.49. There were few patients in PROPEL who could walk ≤75 m at any time point in the study, hence, these utility estimates should be interpreted with caution. EQ-5D-3L utility estimates from PROPEL were consistent with previously reported EQ-5D-3L values in LOPD. Conclusions: Overall, the results from our analysis indicate that important HRQoL losses are associated with reductions in mobility and respiratory function for patients with Pompe disease. The study provides important evidence of HRQoL utility values for patients with advanced LOPD, a population for whom published data are limited.

Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): Effects of training and detraining.

Glycogen storage disease type 2, Pompe disease, is a progressive muscle disorder with a wide range of phenotypic presentations, caused by an inherited deficiency of the enzyme acid alpha-glucosidase. Although only a few patients have been treated with recombinant human alpha-glucosidase from rabbit milk since 2004, enzyme replacement therapy (ERT) with alglucosidase alfa has been licensed for the treatment of Pompe disease since 2006. Here, a systematic review [1] evaluates the clinical efficacy and safety of alglucosidase alfa treatment in juvenile and adult patients with late-onset Pompe disease (LOPD). Studies of alglucosidase alfa treatment in patients with LOPD, published up to October 2012, were identified using an electronic search of the EMBASE and MEDLINE databases, and manual searches of the reference lists. Data on ERT outcomes were extracted from the selected papers and analyzed descriptively. No statistical analyses were performed owing to data heterogeneity. Twenty-two studies containing clinical data from 437 LOPD patients were analyzed. Overall, at least two-thirds of patients were stabilized or exhibited improvements in creatine kinase levels, and muscular and/or respiratory function following treatment with alglucosidase alfa. Enzyme replacement therapy was well tolerated; the majority of adverse events were mild or moderate infusion-related reactions. Alglucosidase alfa treatment offers an effective and well tolerated treatment that attenuates the progression of LOPD in the majority of patients. Although first insights are upcoming, further research is required to investigate reliable prognostic factors such as age at treatment start, phenotypic presentation, and genotypic characteristics, of which may enable better clinical and therapeutic management of LOPD patients.

Late-onset Pompe disease is a rare autosomal recessive lysosomal storage disorder caused by acid α-glucosidase deficiency, resulting in progressive skeletal muscle weakness and respiratory failure. We present the case of a 43-year-old African American woman who was admitted to the intensive care unit with acute-on-chronic hypoxemic and hypercarbic respiratory failure, alteration of consciousness, and progressive weakness. Her recent medical history included respiratory distress and aspiration pneumonia, which had not fully resolved despite supplemental oxygen therapy. On admission, initial evaluations including imaging and laboratory tests did not reveal a diagnosis. Muscle biopsy showed a vacuolar myopathy with excess glycogen suggestive of glycogen storage disease. Enzyme testing was obtained through the dried blood spot testing and was low. Molecular genetic testing identified two pathogenic variants in the GAA gene, confirming the diagnosis of late-onset Pompe disease. This diagnosis enabled the prompt initiation of enzyme replacement therapy (ERT) with alglucosidase alpha. The early initiation of ERT in this patient was pivotal in managing her condition, given the progressive nature of late-onset Pompe disease and the potential for improved outcome when treatment is started early. This case highlights the importance of considering late-onset Pompe disease in adults presenting with unexplained progressive respiratory and neuromuscular symptoms. It also demonstrates the critical role of biochemical and molecular genetic testing, as early intervention can significantly impact treatment outcomes and quality of life.

Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease. Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

Pompe disease is an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) enzyme deficiency, resulting in muscle and neuron intralysosomal glycogen storage. Clinical symptoms vary from the severe, infantile-onset form with hypertrophic cardiomyopathy, gross motor delay, and early death from respiratory insufficiency; to a late-onset form with variable onset of proximal muscle weakness and progressive respiratory insufficiency. Newborn screening programs have been instituted to presymptomatically identify neonates with infantile-onset Pompe disease for early initiation of treatment. However, infants with late-onset Pompe disease are also identified, leaving families and physicians in a state of uncertainty regarding prognosis, necessity, and timing of treatment initiation. This report presents a 31 5/7 weeks’ gestational age premature infant flagged positive for Pompe disease with low dried blood spot GAA activity; sequencing identified biparental c.-32-13T>G/c.29delA GAA variants predicting late-onset Pompe disease. The infant’s parents’ initial reactions to the positive newborn screen, subsequent experience during confirmatory testing, and post-confirmation reflections are also reported. While uncertainties regarding natural history and prognosis of presymptomatically-identified late-onset Pompe disease infants will be elucidated with additional experience, suggestions for education of first-line providers are provided to accurately communicate results and compassionately counsel families regarding anxiety-provoking positive newborn screen results.

Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial

Late-onset Pompe disease (LOPD) is a rare neuromuscular disorder, where delays in diagnosis can result in inconsistent patient management and suboptimal use of effective treatments, thereby increasing patient burden. We conducted an exploratory, cross-sectional survey of 20 adults with LOPD in the UK and USA, recruited via patient advocacy groups and vetted databases. Our results showed that patients with LOPD experienced substantial delays from symptom onset to diagnosis. Interactions with healthcare professionals (HCPs) were inconsistent, and LOPD awareness among HCPs was insufficient. Patients were generally satisfied with their treatment, with 90% of patients reporting mild to no discomfort with enzyme replacement therapy or other treatments. However, 60% of patients implemented various nonpharmacological therapies to manage pain or other aspects of LOPD. These exploratory findings highlight persistent gaps in diagnosis and care, emphasizing the need for improved HCP education and integrated support services.

Aerobic exercise, training to sustain motor ability, and respiratory rehabilitation may improve general functioning and quality of life (QoL) in neuromuscular disorders. Patients with late-onset Pompe disease (LOPD) typically show progressive muscle weakness, respiratory dysfunction and minor cardiac involvement. Characteristics and modalities of motor and respiratory rehabilitation in LOPD are not well defined and specific guidelines are lacking. Therefore, we evaluated the role of physical activity, therapeutic exercise, and pulmonary rehabilitation programs in order to promote an appropriate management of motor and respiratory dysfunctions and improve QoL in patients with LOPD. We propose two operational protocols: one for an adapted physical activity (APA) plan and the other for an individual rehabilitation plan, particularly focused on therapeutic exercise (TE) and respiratory rehabilitation.