Regulatory news: Cipaglucosidase alfa-atga (Pombiliti) coadministered with Miglustat (Opfolda) for adults with late-onset Pompe disease

Pompe disease (PD), also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II, is a rare and serious lysosomal disease caused by autosomal recessive variants in the acid alpha-glucosidase (GAA) gene. The resulting enzyme deficiency of GAA results in intra-lysosomal accumulation of glycogen in various tissues. The two forms of PD present differently: infantile-onset PD (IOPD) is a rapidly progressive disease associated with severe left ventricular hypertrophy and high mortality within the first year of life, whereas late-onset PD (LOPD) is a slower progressive disease associated with motor impairment and respiratory muscle weakness; respiratory failure is the most common cause of death.¹ Currently, the approved therapies for PD are recombinant human acid alpha-glucosidases, alglucosidase alfa and avalglucosidase alfa-ngpt. Although alglucosidase alfa results in stabilization or improvement of symptoms for many patients, some patients continue to decline during treatment. For other patients, the improvement in muscle weakness is not sustained, and thus, patients tend to develop progressive disease, which can lead to respiratory failure.^2-4 Therefore, treatment and cure of PD continue to represent unmet needs.

Cipaglucosidase alfa-atga provides an exogenous source of GAA. Cipaglucosidase alfa-atga has the same amino acid sequence as the endogenous GAA enzyme but contains complex-type N-glycan structures with two mannose-6-phosphate (M6P) moieties on the same glycan which mediates binding to M6P receptors on the cell surface. Miglustat, which is coadministered with cipaglucosidase alfa-atga, is an N-alkylated iminosugar (a synthetic analog of D-glucose) and is the active ingredient in Zavesca, which is approved for the treatment of adult patients with mild/moderate Type 1 Gaucher disease for whom ERT is not a therapeutic option. Miglustat binds with, stabilizes, and reduces the inactivation of cipaglucosidase alfa-atga in the blood after infusion. The bound miglustat is dissociated from cipaglucosidase alfa-atga after it is internalized and transported into lysosomes.

In this article, we provide the summary of FDA's review of the biologics license application (BLA) for cipaglucosidase alfa-atga and the new drug application (NDA) for miglustat, which were approved to be coadministered for the treatment of adult patients with LOPD who are not improving on their current enzyme replacement therapy (ERT).

Substantial evidence of effectiveness for cipaglucosidase alfa-atga coadministered with miglustat in subjects with LOPD was established using data from one adequate and well-controlled trial with confirmatory evidence (CE). A single trial in subjects 18 years of age and older with LOPD showed a clinically meaningful numerical improvement in motor and lung function compared with treatment with a non-US-approved alglucosidase alfa product coadministered with placebo. The well-established etiology of the disease, the mechanism of action of the therapy, and data from Gaa knockout mice showing reduced glycogen in tissues and improved muscle function provided strong mechanistic support for CE. While these data are adequate to establish substantial evidence of effectiveness for treatment-experienced subjects who are not improving on their current ERT, the data were not adequate to support use as first-line therapy given the lack of statistical significance for superiority and the inherent increased risk of two products over one.

The observed safety profile of cipaglucosidase alfa-atga coadministered with miglustat as assessed in 151 subjects with LOPD appears to be similar to that of the currently available therapies: alglucosidase alfa, avalglucosidase alfa, and miglustat. The most important safety concerns are known risks with ERTs: hypersensitivity reactions (including anaphylaxis) and infusion-associated reactions.

In summary, the FDA concluded that the benefits of cipaglucosidase alfa-atga coadministered with miglustat on lung function, an important target for drug treatment for patients with LOPD, outweigh its risks when used according to the agreed-upon labeling. The availability of cipaglucosidase alfa-atga coadministered with miglustat provides a second-line ERT for adult patients with LOPD weighing ≥40 kg who are not improving on their current ERT.

Daniela V. Luquetti and Linda J. B. Jeng contributed to the planning and writing of the manuscript. Kathleen M. Donohue and Janet W. Maynard supervised the planning and writing of the manuscript. All authors contributed to the final version of the manuscript.

The authors declare no funding.

Daniela V. Luquetti, Linda J. B. Jeng, Kathleen M. Donohue, and Janet W. Maynard declare that they have conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.