Interim Results Suggest Chaperone Drug Enhances Enzyme Treatment in Pompe Disease

Encouraging results have been reported for the first three dosage groups in a phase 2 trial of the 'pharmacological chaperone' AT2220

MDA research grantee Eric Sjoberg at Amicus is examining biological samples from people with and without Pompe disease to see whether AT2220 can reduce the likelihood of an ERT-related immune response.
Article Highlights:
  • AT2220 is an experimental drug developed by Amicus Therapeutics that may enhance the effectiveness of, and reduce the immune response to, enzyme replacement therapy (ERT) for Pompe disease.
  • AT2220 appears to increase the level of ERT-associated enzyme activity in trial participants with Pompe disease. The drug is believed to work by preventing unfolding of the therapeutic enzyme.
  • No drug-related adverse events have occurred so far in this phase 2 trial of AT2220 with ERT.
  • In an MDA-supported study in cells from healthy people, AT2220 reduced the incidence of an immune response to ERT.
  • The phase 2 trial is now closed; final results are expected by the end of 2012.
by Margaret Wahl on October 12, 2012 - 3:21pm

Biopharmaceutical company Amicus Therapeutics presented updated and encouraging results for its experimental Pompe disease (acid maltase deficiency) compound AT2220 this week at the 17th International Congress of the World Muscle Society in Perth, Australia.

AT2220, also known as duvoglustat HCl, is a pharmacological chaperone that is believed to help stabilize the therapeutic enzyme given to treat Pompe disease and thereby enhance the effectiveness of enzyme replacement therapy for this metabolic muscle disorder. The drug may prevent the enzyme from unfolding.

Amicus announced the results in a poster at the meeting and in an Oct. 11, 2012, press release. The results build on its previous update, provided in a June 26, 2012, press release.

The new update includes a report on trial participants receiving AT2220 at three different dosages, and on an MDA-supported study of the effects of the drug on human immune system cells in laboratory dishes. The phase 2 study is ongoing but is now closed to new participants.

AT2220 may enhance effect of ERT

Enzyme replacement therapy (ERT) for Pompe disease is available in the United States and several other countries under the brand names Myozyme and Lumizyme. The therapeutic enzyme used in ERT is known as acid maltase or acid-alpha glucisodase (GAA), and is given by infusion.

ERT has improved the lives of children and adults with Pompe disease. However, the benefits vary among individuals, a phenomenon not entirely understood. One factor in the effectiveness of ERT may be the immune system's tolerance of the therapy, which potentially can be improved by keeping the therapeutic enzyme properly folded. In addition, enhancing the effectiveness of ERT could potentially reduce the dosages needed and the cost of treatment.

Interim results for AT2220 trial

So far, one oral dose of AT2220 has been given to 16 trial participants with Pompe disease, who were divided into three groups. Group 1 received a 50-milligram dose immediately prior to an ERT infusion; group 2 received 100 milligrams; and group 3 received 250 milligrams.

Dosage group 4 is slated to receive a 600-milligram dose. Results are expected during the fourth quarter of 2012.

In its Oct. 11 press release, Amicus said this about its phase 2 study of AT2220 plus ERT:

  • So far, AT2220 appears to be well-tolerated, with no drug-related adverse events.
  • All participants showed a higher enzyme activity level in blood plasma when they received ERT combined with AT2220 than when they received ERT alone.
  • Results from muscle biopsies suggest that, in groups 2 and 3, there was more enzyme taken up into muscle tissue following ERT plus AT2220 than there was with ERT alone. In group 1, there was no consistent change in enzyme activity in muscle.

AT2220 reduced immune response to ERT in cells

In addition to increasing enzyme activity, AT2220 also appears to reduce the chance that ERT will cause an immune response that interferes with the therapy. The company's hypothesis is that, by stabilizing the folded and active form of the GAA enzyme, AT2220 may mitigate an unwanted immune response to the enzyme.

The tendency for the immune system to mount a response against ERT in Pompe disease has been an ongoing challenge to the success of the treatment.

In parallel with the clinical trial of AT2220, Amicus has been conducting an MDA-supported study of the effects of ERT alone and ERT plus AT2220 on human T cells in laboratory containers. T cells are part of the immune system.

To see whether AT2220 can reduce the immune response to ERT, Amicus studied blood samples from 50 healthy donors to see whether their T cells would be less responsive to ERT if they were also exposed to AT2220.

In the Oct. 11 press release, the company said:

  • Myozyme alone elicited an immune response (T cell response) in 36 percent of blood samples; administered with AT2220, it elicited an immune response in 14 percent of samples.
  • Lumizyme alone elicited an immune response in 28 percent of samples; given with AT2220, it elicited an immune response in 10 percent of samples.
  • Blood samples from people with Pompe disease who participated in the phase 2 AT2220 clinical trial are now being studied, with results expected by the end of 2012.

For more information

To learn more about the phase 2 trial, as well as the history of enzyme replacement in Pompe disease, read: 

Your rating: None Average: 4.5 (4 votes)
MDA cannot respond to questions asked in the comments field. For help with questions, contact your local MDA office or clinic or email See comment policy