Pombiliti-Opfolda combo may overcome challenges of older ERTs
Analysis shows potential benefits, but more evidence needed, researchers say
Pombiliti plus Opfolda (cipaglucosidase alfa/miglustat) may offer significant advantages over earlier forms of enzyme replacement therapy (ERT) for Pompe disease, according to an analysis of preclinical and clinical data.
Researchers reviewed all available data about the combination therapy’s mechanism and therapeutic effects and determined that it can overcome challenges that other types of ERTs face.
The researchers noted that there haven’t been any head-to-head trials to directly compare the combination therapy to the ERT Nexviazyme (avalglucosidase alfa), and indirect comparisons have had conflicting results. Ultimately, “more clinical experience and real-world evidence will be necessary to fully demonstrate the strengths and limitations of each Pompe ERT,” they wrote.
The article, “Cipaglucosidase alfa plus miglustat: linking mechanism of action to clinical outcomes in late-onset Pompe disease,” was published in Frontiers in Neurology. It was funded by Amicus Therapeutics, Pombiliti + Opfolda’s developer, and some of the study authors are employed by Amicus.
Pompe disease patients are lacking in functional alpha-glucosidase (GAA), an enzyme needed to break down the complex sugar molecule glycogen. In turn, glycogen toxically accumulates and damages tissues, especially the muscle cells that normally store glycogen as an energy source.
Limitations of older ERTs
Standard Pompe care involves ERT to supply the body with the missing enzyme. Lumizyme (alglucosidase alfa; sold as Myozyme outside the U.S.), from Sanofi, can be used in people with all types of Pompe disease, whereas Nexviazyme (sold as Nexviadyme in Europe), also from Sanofi, is approved for people with late-onset Pompe disease (LOPD) ages 1 and older.
Pombiliti + Opfolda, approved for certain adults with LOPD, contains an enhanced ERT that’s infused into the bloodstream (Pombiliti) and an oral stabilizer molecule (Opfolda).
The scientists reviewed all available published data related to the mechanism of this treatment combination, including preclinical and clinical data, to establish whether it truly does address the key challenges faced by other ERTs for treating Pompe disease.
Lumizyme can effectively slow muscle degeneration for patients, but it doesn’t have strong uptake into its target tissues and can lose effectiveness over time.
Nexviazyme was designed to overcome that challenge and have more efficient muscle delivery by attaching to its surface more of a molecule called M6P that facilitates entry into cells. But those added molecules need to be removed from the enzyme once it is in the cell in order for GAA to be fully activated. The lab-made linker molecules used to attach MP6 are not easily broken down by natural enzymes in the body, and thus, enzyme activation may be limited, according to the authors.
To overcome that limitation, Pombiliti + Opfolda’s version of GAA (Pombiliti) is generated from hamster cells that naturally express high levels of M6P and therefore don’t require a synthetic linker to attach the molecule.
Both preclinical and clinical data show that Pombiliti leads to better cellular uptake of the enzyme relative to Lumizyme, according to the authors. Moreover, the ERT was completely activated once taken up by cells and M6P cleavage was not impeded as has been observed for Nexviazyme.
Another limitation of ERT is that it runs the risk of being inactivated after being infused in the bloodstream. GAA works best in the acidic environment of cells’ lysosomes, where it normally works to break down glycogen. It’s easily inactivated in the almost neutral pH of blood.
Opfolda, the second component of Amicus’ treatment combination, is designed to help stabilize the enzyme while it makes its way through the bloodstream to lysosomes. This stabilization has been demonstrated across preclinical studies, with Opfolda helping to prolong GAA enzyme exposure in the bloodstream, according to the researchers.
These mechanistic benefits have shown to translate to clinical gains across a number of studies in mouse models and Pompe patients.
For example, data from the Phase 3Â PROPEL trial (NCT03729362), which compared Pombiliti + Opfolda against Lumizyme in adults with LOPD, showed the treatment combination was associated with greater reductions in markers of muscle damage and glycogen clearance, favorable effects on measures of motor function, and slower declines in respiratory function relative to Lumizyme, although not all findings reached statistical significance.
Additional analyses from the study’s extension phase have indicated that the benefits of treatment are sustained over the long term.
“An extensive collection of in vitro [in the lab], preclinical, and clinical data supports the hypothesis that treatment with [Pombiliti + Opfolda] addresses the three key challenges of ERT for Pompe disease,” the investigators wrote.
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