Duke Researchers Initiating Phase 1 Trial on New Gene Therapy for Pompe Disease

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by Alice Melao |

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Duke Health researchers are planning to launch a Phase 1 trial to test the safety of a new investigational gene therapy they developed to treat patients with Pompe disease.

They are currently screening (NCT03285126) adults with late-onset Pompe disease to select eligible participants for the upcoming trial.

This preliminary study is expected to enroll 20 adults who have been receiving enzyme replacement therapy (ERT) at a stable dose for at least two years. They will undergo several physical and clinical evaluations, including muscle and lung function testing, blood and urine evaluation, as well as heart rate analysis. The collected data will serve as the basis for eligibility criteria to be used in the future Phase 1 trial, which is expected to begin in fall 2018.

Funding for the trial is being provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, with support from the National Center for Advancing Translational Sciences (NCATS).

Compelling preclinical data supporting the trial demonstrated the therapeutic potential of the investigational gene therapy in mice. Researchers published the results in a study titled, “Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction,” in Molecular Therapy — Methods & Clinical Development.

“We completed experiments demonstrating the advantages of gene therapy for Pompe disease in mouse models and had convincing evidence for its use in patients,” Dwight Koeberl, MD, PhD, a medical geneticist and professor at Duke University and the principal investigator of the study, said in a press release. “A collaboration with NCATS helped overcome therapy development obstacles — including manufacturing a virus supply needed to deliver the healthy gene and navigating the complex regulatory development processes — to make clinical testing possible.”

Alglucosidase alfa, marketed by Genzyme as Myozyme and Lumizyme, is the only approved therapy by the U.S. Food and Drug Administration for the treatment of Pompe disease. It is a gene therapy designed to replace the faulty gene that causes the disorder, and promote the production of the deficient alpha-glucosidase enzyme in patients.

Development and approval of this ERT has significantly improved patients’ outcomes. However, not all patients respond well to the therapy, with many developing antibodies that prevent the treatment from working.

“Some infants still die from Pompe disease. Others have to add immune suppression to their treatment, which can lead to other complications,” Koeberl said in another press release.

The new gene therapy uses a modified gene delivery method that specifically targets the liver, where the missing enzyme is produced. The delivery system has already been used in therapies for hemophilia B and muscular dystrophy, among others, Koeberl said.

Tested in mice, the therapy effectively prevented the accumulation of glycogen in the muscles, which is caused by a lack of the GAA enzyme and characterizes the disease. A single administration of the gene therapy triggered the liver to continuously produce the enzyme, without requiring additional administrations.

Unlike other ERTs, the new therapy did not promote an immune response. In fact, it was actually found to reverse any immune responses previously developed in response to ERT.

“We would like to see this promising new therapy added to the ‘medicine chest’ for physicians to help treat and manage all patients with Pompe disease,” said Nora Yang, PhD, director of portfolio management and strategic operations at the Division of Pre-Clinical Innovation in NCATS.

“If the concept of using gene therapy to build immune tolerance works, there is the potential that we can apply the same principle to other diseases that involve problems with immune system intolerance for ERT to help many more patients who suffer from debilitating diseases,” she said.