AT-GAA (Cipaglucosidase Alfa/Miglustat) for Late-onset Pompe Disease

AT-GAA (cipaglucosidase alfa/miglustat) is a two-part investigational therapy that Amicus Therapeutics is developing for late-onset Pompe disease, known as LOPD. The treatment candidate mainly works to enhance walking ability and improve or stabilize respiratory function.

Amicus has applied for approval of AT-GAA in the U.S., with decisions expected by fall. Applications seeking the therapy’s approval in the European Union also are under review. Eligible patients in the U.K. can receive the therapy prior to approval through an early access program.

AT-GAA has received breakthrough therapy designation from the U.S. Food and Drug Administration. That status speeds the review of medicines that demonstrate substantial improvement over available therapies.

Therapy Snapshot

In Pompe disease, the body is unable to make sufficient amounts of an enzyme called acid alfa-glucosidase (GAA), which is needed to break down glycogen, a complex sugar molecule. Consequently, glycogen builds up to toxic levels and damages cells, especially muscle cells that normally rely on glycogen to power their activities.

AT-GAA is a two-component therapy that consists of cipaglucosidase alfa — a man-made form of the GAA enzyme designed to effectively enter muscle cells — as well as miglustat, a pharmacological compound that stabilizes the active enzyme so it maintains its activity over time.

The therapy is given in two different parts. Cipaglucosidase alfa, the enzyme-replacing component of AT-GAA, is administered via infusion into the bloodstream, while the stabilizing agent miglustat is taken by mouth.

A Phase 1/2 clinical study determined the optimal dosing regimen to be 20 mg/kg cipaglucosidase alfa and 260 mg miglustat, administered every other week. That 20 mg/kg dose is also the approved dosage for Lumizyme (alglucosidase alfa), the first approved enzyme replacement therapy (ERT) for Pompe disease.

A Phase 1/2 clinical trial, called ATB200-02 (NCT02675465) enrolled 29 adults with Pompe, ages 18 to 75. Among the participants, 23 were able to walk and six were not, and all had previously been on  ERT.

The first stage of the study tested increasing doses of cipaglucosidase alfa over six weeks, while the second stage tested two doses of miglustat for 12 weeks, or about three months. Results from these parts of the study indicated that the most effective dosing regimen for AT-GAA is 20 mg/kg cipaglucosidase alfa; 260 mg miglustat is given every two weeks.

In the third phase of the trial, which is still ongoing, participants are being treated at those identified dosages.

Data from participants who had been treated for up to three years showed that AT-GAA led to improvements in the distance participants could walk in six minutes, regardless of whether the patient had been on prior ERT. Lung function, measured by forced vital capacity (FVC) — the total volume of air that can be blown forcefully following a full inhalation — was stable for patients who had been on prior enzyme replacement, and generally improved for patients being treated for the first time.

Phase 3 PROPEL trial

The PROPEL trial (NCT03729362) compared the safety and effectiveness of AT-GAA against Lumizyme. The study enrolled 123 adults at 62 clinical sites worldwide. About three-quarters of the participants had been on Lumizyme prior to entering the study.

For the trial, participants were randomly assigned to treatment with AT-GAA or Lumizyme for about one year. All 117 participants who completed this initial portion of the study then elected to enroll in an open-label extension, wherein all were treated with AT-GAA.

Results showed AT-GAA outperformed Lumizyme at increasing the distance participants could walk in six minutes; however, the difference was only statistically significant in the subset of patients who had been on prior enzyme replacement. Those patients on average walked 16.9 meters (about 55 feet) further after a year on AT-GAA.

In the overall group, the decline in FVC over one year was significantly smaller for patients on AT-GAA than Lumizyme (0.9% vs. 4%), a difference also seen in the subset who had been on ERT prior to PROPEL. Other measures, including tests of strength, coordination, and mobility, as well as biomarkers of muscle damage and glycogen clearance, generally favored AT-GAA, though not all differences reached statistical significance.

Both AT-GAA and Lumizyme showed similar safety profiles in PROPEL, with infusion-associated reactions reported in about one of every four participants given either medication. Just over 2% of patients in both groups discontinued the trial due to side effects. One serious side effect related to AT-GAA, an allergic reaction, was reported.

Phase 3 ZIP study

The ongoing Phase 3 ZIP study (NCT03911505) is testing the safety and pharmacological properties of AT-GAA in approximately 22 children with late-onset Pompe. Participants are being recruited at sites in the U.S., Canada, Japan, and Taiwan; a site in Australia also will be enrolling patients.

Phase 3 Rossella study

Another Phase 3 trial, dubbed the Rossella study (NCT04808505), also is aiming to evaluate the therapy’s safety, efficacy, and pharmacological properties in children. That study, now enrolling at a single site in Florida, will involve children with classic infantile-onset Pompe disease.

The most common side effects reported in clinical trials of AT-GAA include:

• infusion-related reactions such as redness or itching
• common cold
• headache
• muscle or joint pain
• abdominal pain
• diarrhea