Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial

Schöser, Benedikt; Roberts, Mark; Byrne, Barry J.; Sitaraman, Sheela; Jiang, Hai; Laforêt, Pascal; Toscano, Antonio; Castelli, J.; Díaz‐Manera, Jordi; Goldman, Mitchell; Ploeg, Ans T. van der; Bratkovic, Drago; Kuchipudi, Suresh V.; Mozaffar, Tahseen; Kishnani, Priya S.; Sebök, Ágnes; Pestronk, Alan; Dominović-Kovačević, Aleksandra; Khan, Aneal; Koritnik, Blaž; Tard, Céline; Lindberg, Christopher; Quinn, Colin; Eldridge, Crystal; Bodkin, Cynthia; Reyes‐Leiva, David; Hughes, Derralynn; Stefanescu, Ela; Salort‐Campana, Emmanuelle; Butler, Ernest; Bouhour, Françoise; Kim, Gee; Papadimas, George K.; Parenti, Giancarlo; Bartosik-Psujek, Halina; Kushlaf, Hani; Hashiguchi, Akihiro; Lau, Heather; Pedro, Hélio; Andersen, Henning; Amartino, Hernán; Shiraishi, Hiroaki; Kobayashi, Hiroshi; Tarnev, Ivaylo; Vengoechea, Jaime; Avelar, Jennifer; Shin, Jin‐Hong; Cauci, Jonathan; Alonso‐Pérez, Jorge; Jánszky, J.; Berthy, Julie; Kornblum, Cornelia; Gutschmidt, Kristina; Claeys, Kristl; Molnár, Mária Judit; Wencel, Marie; Tarnopolsky, Mark A.; Dimachkie, Mazen M.; Tchan, Michel; Freimer, Miriam; Longo, Nicola; Vidal-Fernandez, Nuria; Musumeci, Olimpia; Göker-Alpan, Özlem; Deegan, Patrick; Clemens, Paula R.; Roxburgh, Richard; Henderson, Robert A.; Hopkin, Robert J.; Sacconi, Sabrina; Fecarotta, Simona; Attarian, Shahram; Wenninger, Stephan; DeArmey, Stephanie; Hiwot, Tarekegn; Burrow, T.; Ruck, Tobias; Sawada, Tomo; Laszlo, Vescei; Löscher, Wolfgang N.; Chien, Yin‐Hsiu

doi:10.1016/s1474-4422(21)00331-8

Cited by 72 publications

(104 citation statements)

References 26 publications

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“…The antibody titer decreased to 1:6400, but clinical benefit remained partial; therefore, at age 2.5 years he started therapy with cipaglucosidase alfa/miglustat (Amicus Therapeutics). Cipaglucosidase alfa is a novel rhGAA, enriched with cellularly derived bis-phosphorylated N-glycans to improve cellular uptake that was administered with miglustat, a pharmacological chaperone that stabilizes the GAA enzyme [ 48 ]. A clinical trial in adult patients was ongoing, but the drug had not been approved yet; therefore, it was provided under compassionate use.…”

Section: Resultsmentioning

confidence: 99%

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Gragnaniello¹,

Pijnappel²,

Groen³

et al. 2022

Molecular Genetics and Metabolism Reports

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Section: Resultsmentioning

confidence: 99%

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Gragnaniello¹,

Pijnappel²,

Groen³

et al. 2022

Molecular Genetics and Metabolism Reports

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“…These chaperones can be given in tandem with conventional ERT [ 20 ], or in the context of a novel rhGAA with higher M6P levels [ 21 ]. In addition to the correction of the glycogen buildup in skeletal muscle in a preclinical Pompe mouse model, the combination of the novel rhGAA (ATB200) co-administered with the small molecule chaperone AT2221 (miglustat, N-butyl-deoxynojirimycin [NB-DNJ]) was able to decrease autophagic accumulation in skeletal muscle and improve both wire hang and grip test function in a preclinical mouse model, however, clinical trial results failed to show superiority over the existing standard of care and suggest further long-term studies are needed (NCT03729362) [ 22 ].…”

Section: Current Standard Of Care For Pompe Diseasementioning

confidence: 99%

Gene Therapy Developments for Pompe Disease

et al. 2022

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Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles. Despite recent advancements in enzyme replacement therapy management several limitations remain using this therapeutic approach, including risks of immunogenicity complications, inability to penetrate CNS tissue, and the need for life-long therapy. The next wave of promising single therapy interventions involves gene therapies, which are entering into a clinical translational stage. Both adeno-associated virus (AAV) vectors and lentiviral vector (LV)-mediated hematopoietic stem and progenitor (HSPC) gene therapy have the potential to provide effective therapy for this multisystemic disorder. Optimization of viral vector designs, providing tissue-specific expression and GAA protein modifications to enhance secretion and uptake has resulted in improved preclinical efficacy and safety data. In this review, we highlight gene therapy developments, in particular, AAV and LV HSPC-mediated gene therapy technologies, to potentially address all components of the neuromuscular associated Pompe disease pathology.

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“…In the case of IOPD, avalglucosidase is also being tested in a phase II 59 and a phase III 60 clinical trial, although so far to our knowledge data on efficacy in these cohorts has not been published. Cipaglucosidase has been tested in one phase I/II 61 and one phase III (PROPEL) 55 ( Table 3 ) clinical trial in LOPD patients. This drug has shown to improve muscle function safely in treated patients.…”

Section: New Therapiesmentioning

confidence: 99%

“… Achieved non-inferiority on upright FVC% change but not superiority. (For more details go to Table 3 ) Schoser B et al 55 2021 Cipaglucosidase alfa + miglustat (vs rhGAA + placebo) (treatment-naive and non-naive patients) 20 mg/k eow (CPA) 195 mg or 260 mg (MG) IV (CPA) Oral (MG) Phase III (RCT) 123 46.8 yo 52 Change in 6MWT. 6MWT: Mean diff between groups 13.6m (p=0.07), not statistically significant.…”

Section: Introduction To Pompe Diseasementioning

confidence: 99%

Therapeutic Options for the Management of Pompe Disease: Current Challenges and Clinical Evidence in Therapeutics and Clinical Risk Management

Bolano-Diaz¹,

Díaz‐Manera²

2022

TCRM

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Pompe disease is a genetic disorder produced by mutations in the GAA gene leading to absence or reduced expression of acid alpha-glucosidase, an enzyme that metabolizes the breakdown of glycogen into glucose. There are two main phenotypes, the infantile consisting of early onset severe weakness and cardiomyopathy, and the adult which is characterized by slowly progressive skeletal and respiratory muscle weakness. Enzymatic replacement therapy (ERT) has been available for Pompe disease for more than 15 years. Although the treatment has improved many aspects of the disease, such as prolonged survival through improved cardiomyopathy and acquisition of motor milestones in infants and slower progression rate in adults, ERT is far from being a cure as both infantile and adult patients continue to progress. This fact has prompted the development of improved or new enzymes and other treatments such as gene therapy or substrate reduction strategies. Here, we review the data obtained from randomized clinical trials but also from open-label studies published so far that have assessed the advantages and limitations of this therapy. Moreover, we also review the new therapeutic strategies that are under development and provide our opinion on which are the unmet needs for patients with this disease.

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Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial

Cited by 72 publications

References 26 publications

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Gene Therapy Developments for Pompe Disease

Therapeutic Options for the Management of Pompe Disease: Current Challenges and Clinical Evidence in Therapeutics and Clinical Risk Management

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