NEW THERAPEUTIC APPROACHES AND THEIR READOUT: O.20Results from ATB200-02: first-in-human, open-label, phase 1/2 study of ATB200 co-administered with AT2221 for Pompe disease

Abstract

Late-onset Pompe disease (LOPD) is caused by impaired lysosomal glycogen clearance due to acid alpha-glucosidase (GAA) deficiency. Accumulation of glycogen in skeletal muscle and diaphragm leads to loss of muscle and respiratory function. Recombinant human GAA enzyme replacement therapy (rhGAA ERT; alglucosidase alfa) is standard treatment for LOPD. ATB200-02 (NCT02675465) is a first-in-human, open-label, Phase 1/2 trial to evaluate ATB200, a next-generation rhGAA ERT, co-administered with AT2221, an oral pharmacological chaperone, in adults with LOPD. Twenty patients (pts) were enrolled: ERT-switch ambulatory (Cohort 1, n=11), ERT-switch nonambulatory (Cohort 2, n=4), and ERT-naive ambulatory (Cohort 3, n=5). Mean±SD 6-minute walk test increased for ambulatory ERT-switch (Month [Mo] 6 [n=10], +23.9±52.2; Mo 9 [n=10], +24.5±40.8; Mo 12 [n=8], +57.4±34.4 m) and ERT-naive pts (Mo 6 [n=5], +41.8±29.4; Mo 9 [n=5], +63.5±23.1; Mo 12 [n=2], +86.8±11.1 m). Other motor function tests were generally consistent with these results. Increases were observed in upper extremity strength in nonambulatory ERT-switch pts at Mo 6 and 9. Forced vital capacity (% predicted) increased in ERT-naive pts (Mo 6 [n=5], +4.2; Mo 9 [n=5], +6.2; Mo 12 [n=2], +6.0) and was generally stable in ambulatory ERT-switch pts (Mo 6 [n=9], -1.3; Mo 9 [n=9], -1.7; Mo 12 [n=7], -3.1). All cohorts demonstrated improvements in the Fatigue Severity Scale. ATB200/AT2221 was associated with reductions in creatine kinase and urine hexose tetrasaccharide. The most common treatment-emergent adverse events were upper and lower abdominal pain (n=8), diarrhea (n=8), and nasopharyngitis (n=6). Three events of infusion-associated reactions occurred in 550+ infusions. Data from this interim analysis show a clinical benefit of ATB200/AT2221 in ERT-naive pts and in pts who have been on ERT for ∼5 years. ATB200/AT2221 has the potential to be a significant treatment alternative for patients with Pompe disease.