MDA 2025: Possible benefits seen with Pombiliti + Opfolda in LOPD
Combination therapy may help overcome limitations of standard ERT
The combination therapy Pombiliti + Opfolda (cipaglucosidase alfa/miglustat) may help overcome some of the limitations of standard enzyme replacement therapies (ERT) for treating late-onset Pompe disease (LOPD), according to a recent presentation.
Like other ERTs, Pombiliti + Opfolda contains a lab-made version of the enzyme that LOPD patients lack (Pombiliti) with a molecule — Opfolda — to stabilize the enzyme and help it stay active in the bloodstream.
At this week’s Muscular Dystrophy Association’s (MDA) Clinical & Scientific Conference, Jon Brudvig, PhD, discussed preclinical and clinical data that show that adding Opfolda may enhance the therapeutic benefits of ERT without compromising its safety. Brudvig is director of discovery research and gene therapy for Amicus Therapeutics, the developer of Pombiliti + Opfolda. His talk was titled, “Miglustat: a first-in-class enzyme stabilizer for late-onset Pompe disease.”
LOPD patients have a deficiency in acid alpha-glucosidase (GAA), an enzyme responsible for breaking down the large sugar molecule glycogen within cellular compartments called lysosomes. As a result, glycogen accumulates to toxic levels and causes damage, with especially profound effects in muscles, which rely heavily on glycogen as a main energy source.
The cornerstone of LOPD care is ERT, which provides patients with a functional version of the deficient enzyme to ease Pompe symptoms such as muscle weakness and breathing problems. But ERT has difficulty getting it to target cells and there are issues with the enzyme’s stability in the bloodstream. “It’s not as easy as it is for some other disorders that can be treated with an enzyme,” Brudvig said.
Potential benefits of combination treatment
Sanofi markets two ERTs: the first-generation Lumizyme (alglucosidase alfa) and the next-generation Nexviazyme (avalglucosidase alfa), which is designed for better muscle cell uptake than its predecessor. Still, both are limited by how easily the enzyme is made inactive in the blood before being delivered to its target cells.
Pombiliti + Opfolda is composed of cipaglucosidase alfa, a next-generation GAA enzyme modified for better cellular uptake, and the oral small molecule miglustat, which stabilizes the enzyme to help it stay active in the blood longer.
The combination is used for certain adults with LOPD in the U.S. and Europe. Miglustat is also used in other diseases where substances accumulate in lysosomes, namely Gaucher and Niemann-Pick diseases, though it works through a different mechanism and is used at much higher cumulative doses in these diseases.
In his talk, Brudvig reviewed preclinical and clinical data that support adding an enzyme stabilizer to ERT for treating LOPD and noted that the main reason GAA enzymes become inactive so easily in the blood is because they aren’t as stable in its relatively higher pH compared with the acidic environment of lysosomes.
“When you take a lysosomal enzyme that’s evolved to function in the low pH environment of a lysosome, and now you’re putting it into the blood of a patient to deliver it as a drug, that’s a very unnatural environment … for that enzyme,” Brudvig said. “And as you can imagine, lysosomal enzymes are not very stable at neutral pH. So that’s the problem that we’re solving with an enzyme stabilizer.”
Brudvig also showed data from experiments demonstrating that Opfolda indeed helps the enzyme remain stable at blood’s neutral pH, to levels similar to its stability in the lysosomal environment. This was observed for the enzymes in both Pombility and Lumizyme.
Results from studies
In a mouse model of Pompe disease, Lumizyme somewhat reduced muscle glycogen buildup and improved muscle strength over untreated mice, but gains were greater with the next-generation enzyme in Pombiliti.
The greatest benefits, however, were observed when Opfolda and Pombiliti were used together. Glycogen levels in certain muscle groups and muscle strength approached what’s seen in healthy mice.
“You can see the added benefit of having this stabilizer on top of a next-generation enzyme,” Brudvig said.
Data from the first in-human study showed that adding Opfolda helped prolong Pombiliti exposure in the blood, with an even greater impact in humans than what was seen in mice.
In clinical testing, Pombiliti alone was also associated with some reduction in biomarkers of glycogen storage and muscle damage relative to Lumizyme, but even greater benefits were observed once the clinical dose of Opfolda was added.
The safety profile of the Pombiliti + Opfolda combination was similar to that of Lumizyme, “which suggests that adding that small molecule stabilizer didn’t change the safety profile of enzyme replacement in LOPD,” said Brudvig, who noted the combination, “results in improved delivery of rhGAA [lab-made enzyme], further reduced biomarker levels, and was well tolerated in adults with LOPD.”
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