Amicus Updates Data from AT-GAA Phase 3 PROPEL Trial

Treatment with AT-GAA, an investigational therapy for late-onset Pompe disease, led to improvements in measures of physical and lung function in the Phase 3 clinical trial PROPEL, top-line data show.

“Data from the PROPEL study demonstrate the potential to further improve motor and respiratory functions in patients with Pompe disease. Given the unmet need in this population, the data from the PROPEL study are very encouraging and will provide an important alternative treatment option for patients living with Pompe disease,” Priya Kishnani, MD, of Duke University School of Medicine (one of the trial sites), said in a press release.

Pompe disease is caused by mutations that lead to deficiency of the enzyme acid alpha-glucosidase (GAA). Amicus Therapeutics‘ AT-GAA is a two-component therapy comprised of a lab-made form of GAA, called cipaglucosidase alfa, given in combination with miglustat to increase its stability. Miglustat is used to treat Gaucher disease, for which it is sold under the brand name Zavesca.

The PROPEL trial (NCT03729362) compared the safety and effectiveness of AT-GAA to that of the enzyme replacement therapy alglucosidase alfa (marketed as Lumizyme in the U.S.), the current standard Pompe treatment.

PROPEL enrolled 123 adults with Pompe disease who were able to walk and  breathe independently. About two-thirds of participants received AT-GAA for one year, while the rest were given alglucosidase alpha. PROPEL was conducted at 62 clinical sites in 24 countries on five continents. According to Amicus, it was the largest clinical study including a control group ever conducted in lysosomal disorders, which include Pompe and are characterized by impaired function of cellular structures called lysosomes.

Prior to enrolling in PROPEL, 77% of participants in the trial were being treated with alglucosidase alfa, while the rest had never been treated with the ERT.

A total of 117 participants completed the trial. All of the participants have enrolled voluntarily in a long-term extension study and are now being treated solely with AT-GAA.

The study’s main measurement of effectiveness was mean change in the six-minute walk test (6MWT) after one year. As the name suggests, 6MWT is the distance a person can walk in six minutes; this measurement is commonly used to assess physical function in ambulatory people.

Among all the trial participants, mean 6MWT distances increased by more in those given AT-GAA than those treated with alglucosidase alfa; however, the difference did not reach statistical significance, meaning that mathematically it could be attributable to random chance.

Among just those participants who had been on alglucosidase alfa before the trial, those who switched to AT-GAA walked on average 16.9 meters (about 18 yards) farther after one year, compared to the trial’s start. In turn, those who continued on alglucosidase alfa showed no changes in 6MWT distance. The difference between the two treatments was statistically significant in this group.

Changes in 6MWT scores were not significantly different between AT-GAA and alglucosidase alfa among participants who had never been treated with an ERT.

Another measurement used in PROPEL was forced vital capacity (FVC), an assessment of lung function based on how much air a person can exhale in a breath. Among all participants, those given AT-GAA experienced a decrease in FVC of 0.9% over the study period. Those given alglucosidase alfa experienced a significantly greater decline of 4%.

A similar significant difference favoring AT-GAA was found in comparisons among participants who had been on ERT prior to PROPEL, with those given AT-GAA actually showing a 0.1% FVC increase. However, no such difference was seen among those who had not been on ERT before the trial.

Other measurements also generally favored AT-GAA, though not all differences were statistically significant. Those that did included assessments of strength, coordination and mobility, as well as biomarkers of muscle damage and glycogen clearance. Notably, glycogen is a large sugar molecule that accumulates inside cells of Pompe patients.

Broadly, the two medications had similar safety profiles. Injection-associated reactions were reported in about a quarter of participants for either treatment.

“The data for patients treated with AT-GAA in this PROPEL study show clinically meaningful and positive changes in the key manifestations of this disease. Particularly impressive are the clinically significant improvements in musculoskeletal and respiratory endpoints [goals] for patients switching from ERT standard of care to AT-GAA,” said Benedikt Schoser, MD, a professor at Ludwig-Maximillians-University of Munich, Germany.

Amicus recently began a rolling submission seeking approval of AT-GAA in the U.S., which the company is planning to complete in the next few months. Regulatory submissions in Europe and elsewhere also are expected this year.

“Based on these data and the entire compelling body of data that we have accumulated over nearly a decade of pre-clinical and clinical studies, we will now advance our plans to obtain regulatory approvals and to bring this medicine to patients worldwide with great urgency,” said John F. Crowley, chairman and CEO of Amicus.

The company is enrolling children with late-onset Pompe, ages 12 to 17, in an additional Phase 3 trial of AT-GAA (NCT03911505). Study locations and contacts are available here.