Long-term Pombiliti plus Opfolda safe, effective in LOPD adults

2 long-term clinical trials show therapy improved motor function

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

Share this article:

Share article via email
An illustration shows the words

Long-term treatment with Pombiliti plus Opfolda (cipaglucosidase alfa/miglustat) safely improved motor function and stabilized or enhanced lung function in adults with late-onset Pompe disease (LOPD), according to newly published data from two clinical trials.

Pompe disease is marked by a deficiency in an enzyme called acid alpha-glucosidase (GAA), which breaks down glycogen, a stored form of glucose. Without functional GAA, glycogen builds up to toxic levels and causes damage, particularly to muscle cells that rely on glycogen as a power source.

Pombiliti plus Opfolda, formerly called AT-GAA and developed by Amicus Therapeutics, is a combination therapy that contains two active ingredients: cipaglucosidase alfa, a lab-made GAA enzyme designed to enter muscle cells and break down glycogen, and miglustat, which helps maintain GAA activity over time.

Last year, the U.S. Food and Drug Administration approved both of the therapy’s ingredients for adults with LOPD who weigh at least 40 kg (about 88 pounds) and whose disease is not adequately controlled by standard enzyme replacement therapies (ERT). It’s also approved in Europe and the U.K.

Approvals for the combination therapy were partly supported by data from the Phase 3 PROPEL (NCT03729362) trial and its open-label extension (OLE) study (NCT04138277). PROPEL enrolled 123 adults with Pompe disease who could walk and breathe independently.

Recommended Reading
A magnifying glass highlights various checked off boxes.

Short survey may serve as valid measure of LOPD physical function

77% of trial participants already using alglucosidase alfa

Before the trial, 77% of participants were being treated with alglucosidase alfa (sold as Lumizyme in the U.S. and Myozyme elsewhere), a standard Pompe ERT, while the rest had yet to receive an ERT (ERT naïve). About two-thirds received Pombiliti plus Opfolda for one year during the trial, while the rest were given alglucosidase alpha.

Top-line data showed that the combination therapy significantly improved motor skills better than alglucosidase alfa, but only for those previously treated with an ERT, as measured by the six-minute walking test (6MWT). The therapy also slowed lung function decline and outperformed ERT in other physical measures, as well as reducing biomarkers of muscle damage and glycogen clearance.

Of the 123 PROPEL participants, 118 were treated in the OLE for an additional year, of whom 81 continued Pombiliti plus Opfolda (61 ERT-experienced and 20 ERT-naïve) and 37 switched from alglucosidase alpha to combination treatment (29 ERT-experienced and eight ERT-naïve).

Researchers have now published details of the OLE in the Journal of Neurology in the study, “104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).”

New data showed improved motor function among the ERT-experienced patients who received Pombiliti plus Opfolda for two years throughout PROPEL and the OLE, as indicated by a mean 3.1% increase change in the predicted 6MWD. This finding represented a mean 14.2-meter increase in walking distance (about 46 feet).

In comparison, those who received ERT in PROPEL and then switched to Pombiliti plus Opfolda for one year in the OLE remained stable (a 0.5% decline in predicted 6MWD). According to researchers, “study fatigue, switching from a blinded to an open-label study and the relatively low number of patients in the switch group may have contributed to this result.”

Lung function, as assessed by the forced vital capacity (FVC), remained relatively stable in ERT-experienced patients treated with combination therapy for two years. While patients in the switch group saw their FVC decline with alglucosidase alpha during PROPEL, lung function was maintained after switching to Pombiliti plus Opfolda in in the OLE.

Increases in 6MWD during PROPEL trial

Among ERT-naïve patients, both treatment groups showed increases in predicted 6MWD in PROPEL, which were maintained at similar levels during the OLE. Lung function declined during PROPEL in these patients but remained stable in the OLE, with no further decline.

Across all ERT-experienced and ERT-naïve patients, markers for muscle damage and glycogen clearance improved over two years. No new safety signals were reported, with the most common treatment-related side effects being headache, diarrhea, and fever.

The therapy’s FDA clearance was also backed by positive findings from the Phase 1/2 ATB200-02 trial (NCT02675465). Data from this study were also published in the Journal of Neurology in “Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).”

This trial enrolled 29 adults with Pompe, of whom 23 had previously received ERT. Of them, 23 were ambulatory, or able to walk, and six were not ambulatory.

Data presented at a scientific conference last year showed that up to four years of treatment with Pombiliti plus Opfolda improved the walking ability of ambulatory patients, regardless of prior ERT use. Lung function stabilized in ERT-experienced and improved in ERT-naïve patients. Moreover, the combination therapy stabilized muscle strength, and disease-related biomarkers improved, particularly in ERT-naïve patients.

According to new patient-reported outcome data, all ambulatory patients were significantly impacted by fatigue at the study’s start, which lessened after four years of treatment. Measures of daily activities and social participation, as well as physical independence, mobility, occupation, and social integration, remained stable.

Consistently, the subject global impression of change (SGIC) for overall physical well-being improved in most patients across all groups, while the physician global impression of change (PGIC) was enhanced or stabilized for all patients.

Of the three nonambulatory patients with FVC data who were ERT-experienced, one showed lung function gains at three years, while another declined, and the third remained stable after four years.

Nonambulatory participants had durable reductions in biomarkers for muscle damage and glycogen clearance at four years. Measures of fatigue improved, as did those of daily activities and social participation. Scores for physical independence and mobility also rose in two nonambulatory patients.

One nonambulatory patient reported improved SGIC’s overall physical well-being; the other saw no change. With PGIC, one saw no change, while the other declined.

The most frequently reported side effects included falls, diarrhea, cold-like symptoms, headache, and joint pain. Most of these were mild or moderate in severity but led to study withdrawal in two patients. Infusion-associated reactions were similar between ERT-experienced (48%) and ERT-naïve (50%) groups.

“The durable improvements shown in our study provide further evidence for the benefits of [Pombiliti plus Opfolda] as a long-term treatment option to address the current unmet needs of patients with Pompe disease,” the researchers concluded.