Gene Therapy May Eliminate Need for ERT in Late-Onset Pompe Disease


All study participants met criteria to remain off enzyme replacement therapy through 104 weeks after treatment.

The gene therapy AAV8-LSPhGAA (Asklepios Biopharmaceutical) has demonstrated safety and the potential to eliminate the need for enzyme replacement therapy (ERT) in patients with late-onset Pompe disease (LOPD).

These results, from a phase 1/2 study (NCT03533673), were presented at the American Society of Gene & Cell Therapy 25th Annual Meeting (ASGCT), held in Washington, DC, and virtually May 16-19, 2022by Edward C. Smith, MD, pediatric neurologist and professor of pediatrics at Duke University School of Medicine.

“Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for ERT by creating a liver depot for acid-alpha glucosidase (GAA) production,” Smith and colleagues wrote.

Three participants with LOPD have been dosed in the low-dose cohort of the phase 1/2 study so far, which is primarily assessing the incidence and severity of adverse events (AEs) as well as clinical laboratory abnormalities. Secondary outcomes include measures of efficacy such as 6-minute walk test distance (6MWT), forced vital capacity (FVC), serum GAA activity, and muscle GAA activity and glycogen content.

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Participants had no detectable anti-AAV8 neutralizing antibodies, had received at least 12 months of stable ERT dosing, and were able to walk at least 100 meters on the 6MWT. These participants went through ERT withdrawal at week 26 based on quantifiable serum GAA activity and the absence of clinically significant declines in FVC or 6MWT performance. They then received 60 mg per day of prednisone as immunoprophylaxis through Week 4, followed by an 11-week taper.

Investigators found that 2 weeks after treatment with AAV8-LSPhGAA, all participants demonstrated sustained serum GAA levels from 101% to 235% of baseline trough activity. All participants met criteria for ERT withdrawal at week 24 and continued to meet criteria to remain off ERT at weeks 52 and 104, although 1 participant chose to resume ERT at week 97.

Smith and colleagues evaluated muscle biopsies and found that 1 participant had around a 40% decrease in muscle GAA activity at week 24, although muscle GAA activity significantly increased from baseline in the cohort as a whole at week 52 (P <.05). One participant had a 10-fold increase from 2.8% to 28% of normal, the second increased from 19% to 44%, and the third increased from 56% to 94% of normal.

Thew gene therapy was well-tolerated, with no treatment-related serious AEs. Laboratory assessments supported the safety of AAV8-LSPhGAA, with no evidence of elevated serum alanine aminotransferase or ELISPOT signals. One participant experienced 2 headaches classified as moderate severity treatment-related AEs.

“Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease,” Smith and colleagues concluded.

To read more coverage of ASGCT 2022, click here.

Smith EC, Hopkins S, Case LE, et al. Phase 1 Study of Gene Therapy in Late-onset Pompe Disease: Initial 104-Week Experience. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022, Washington DC. Abstract #1211
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