Pompe Disease 'Chaperone' Drug Moving Forward

The experimental drug AT2220 has shown benefit as an enhancer of enzyme replacement therapy for the metabolic muscle disorder Pompe disease (acid maltase deficiency).

The drug, a pharmacological chaperone, is designed to:

  • stabilize the replacement therapeutic enzyme needed to treat this disorder;
  • keep the enzyme properly folded;
  • improve its uptake and activity in muscle tissue; and
  • reduce the likelihood or magnitude of an immune response against it.

Amicus Therapeutics, developer of AT2220, announced positive results from a phase 2 trial of oral AT2220 plus intravenous ERT in a Feb. 14, 2013, press release; at a presentation Feb. 15 at the Lysosomal Disease Network World Symposium in Orlando, Fla.; and during a Feb. 15 conference call and slide presentation.

The company said that AT2220, given by mouth as a single dose just prior to infusing ERT intravenously, safely increased the activity of the therapeutic replacement enzyme in muscle tissue compared to ERT alone. The drug was given to 23 people with Pompe disease who were divided into four groups, each of which received an increasing dosage of AT2220, also known as duvoglustat. A poster presentation from the February conference summarizes the results of this phase 2a study.

MDA is supporting scientist Eric Sjoberg at Amicus to investigate whether AT2220 can reduce the body's immune response to ERT. According to results released in October 2012, it seems to do that.

AT2220 enhanced the activity of Myozyme and Lumizyme

Pompe disease is due to a genetic deficiency of the acid maltaseenzyme. This enzyme, also known as acid-alpha glucosidase, or GAA, normally helps the body break down and utilize glycogen, a stored form of sugar. When acid maltase is deficient, glycogen accumulates in muscle cells, causing weakness and muscle loss and sometimes cardiac muscle degeneration and respiratory impairment.

Myozyme and Lumizyme are commercially available, intravenously administered ERT medications that replace the missing or deficient acid maltase enzyme. They were developed by Genzyme Pharmaceuticals, with supplemental support from MDA, several years ago.

These laboratory-engineered enzymes have been effective in treating Pompe disease. However, they have a tendency to unfold in the bloodstream, which not only limits their effectiveness but also can elicit an immune response against them, further limiting their ability to compensate for the missing GAA enzyme.

AT2220 is a pharmacological chaperonea laboratory-engineered medication designed to keep the therapeutic GAA enzyme stable and properly folded during enzyme replacement therapy, thereby increasing its effectiveness and reducing any immune response the body may mount against it.

Repeat-dose trial using IV formulation planned

Amicus says it has developed a new formulation of AT2220, designed to be given intravenously in combination with currently available ERT therapies. The new formulation, designated AT2220-IV (intravenous), will be given in a repeat-dose study slated to begin in the third quarter of 2013, pending approval from the U.S. Food and Drug Administration (FDA).

The objectives of this 2013 study are to characterize the safety of the new intravenous (IV) formula of AT2220; study its behavior in the body; analyze the activity of the therapeutic enzyme; and evaluate the immune response to the therapeutic enzyme.

Next-generation ERT also being developed

In addition to developing AT2220, Amicus says it is developing a "next-generation" ERT of its own that is designed to work better than existing ERTs and to be mixed with AT2220-IV and given simultaneously with this chaperone/stabilizer.

In a poster presentation at the Lysosomal Disease Network conference, Amicus showed that mice with a disorder mimicking human Pompe disease benefited from the next-generation ERT mixed with AT2220-IV.

The company said the data suggest that intravenous AT2220 directly binds to and stabilizes the therapeutic enzyme, potentially leading to a larger amount of properly folded, active enzyme available for uptake into muscle tissue. In addition, AT2220 co-formulated with ERT may reduce ERT-related immune responses. (Properly folded proteins are less likely to elicit such responses.)

The company also noted that successful development of next-generation ERT with the stabilizing molecule may allow for new routes of ERT administration, such as subcutaneous injection instead of intravenous infusion.

For more information

For more information about AT2220 in Pompe disease:

  • Drug-Drug Interaction Study (listing that contains details of the phase 2 trial of AT2220 plus ERT; it also can be accessed by entering NCT01380743 in the search box at ClinicalTrials.gov);
  • Lysosomal Disease Network World Symposium Data Highlights (webcast and slide presentation given Feb. 15, 2013, by Amicus is available for viewing until March 16, 2013); and
  • A telephone replay of Amicus' Feb. 15 conference call about AT2220 is available until Feb. 22, 2013. To access the replay, dial (855) 859-2056 in the U.S. and Canada, or (404) 537-3406 from other countries.
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