Passage Bio, Inc. announced new interim safety, biomarker, and clinical development results from cohorts 1-3 in the Imagine-1 clinical study. Imagine-1 is a Phase 1/2, global, open-label, dose-escalation study of the AAVhu68 gene therapy PBGM01 delivered by intra-cisterna magna (ICM) injection in four cohorts of pediatric subjects with early and late infantile GM1 Gangliosidosis (GM1). GM1 is a rare, fatal lysosomal storage disease in which mutations in the GLB1 gene result in very low activity of the enzyme beta-galactosidase (ß-Gal).

The interim data include six treated patients from the first three cohorts. Cohort 1 (late infantile, low dose), Cohort 2 (late infantile, high dose) and Cohort 3 (early infantile, low dose) each consisted of two patients. Cohort 4 (early infantile, high dose) patients have been dosed and data is expected by mid-2023.

Topline interim results from cohorts 1-3 of the Imagine-1 study: Safety (patient follow-up ranged from three to 20 months): No treatment-related serious adverse events (SAEs); All treatment-related adverse events (AEs) were mild to moderate in severity; No clinically significant changes in liver function requiring intervention; No evidence of dorsal root ganglion (DRG) toxicity in nerve conduction studies; No complications related to ICM administration. Biomarkers: PBGM01 administration resulted in dose-dependent increases in CSF ß-Gal activity, with both patients who received the high dose (Cohort 2, late infantile) exhibiting increases in enzyme activity well above baseline: For the first patient in Cohort 2, enzyme activity increased 4.7-fold and 3.6-fold over baseline at 30 days and six months, respectively; For the second patient in Cohort 2, enzyme activity increased 5.2-fold over baseline at 30 days; Patients treated with the low dose exhibited variable responses in enzyme activity at 30 days, which ranged from 1.2 to 2.8-fold increase over baseline at six months. PBGM01 administration also resulted in dose-dependent decreases in CSF GM1 ganglioside levels, with both patients in Cohort 2 showing decreases in substrate levels from baseline: For the first patient in Cohort 2, levels decreased by 30% and 75% from baseline at 30 days and six months, respectively; For the second patient in Cohort 2, levels decreased by 21% from baseline at 30 days; Patients treated with the low dose exhibited variable levels of response.

Clinical Development: Patients with milder development delay at dosing showed a higher response to PBGM01 treatment, as determined by investigators and caretakers; Patients 1 (late infantile, low dose) and 5 (early infantile, low dose), who both demonstrated modest developmental delay at baseline, showed increases in overall developmental age.