Infantile GM1 Gangliosidosis Gene Therapy Demonstrates Safety and Dose-dependent Biomarker Changes


Patients who received the high dose of PBGM01 showed an increase in β-Gal activity in the CSF of 4.7 to 5.2 times baseline.

Passage Bio’s PBGM01, an investigational adeno-associated virus (AAV) vector-based gene therapy currently being evaluated in the phase 1/2 Imagine-01 clinical trial (NCT04713475) for the treatment of infantile GM1 gangliosidosis, was shown to have a favorable safety profile and demonstrated dose-dependent changes in biomarkers. The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

PBGM01 is intended to provide a functional copy of GLB1, the disease-targeted gene, via AAVhu68, and is administered to the central nervous system (CNS) with an intra-cisterna magna (ICM) injection. Imagine-01 has treated 6 patients so far: Patient 1 (P1), a male patient aged 14 months with late onset disease; P2, a male patient aged 31 months with late onset disease; P3, a female patient aged 15 months with early onset disease; P4, a female patient aged 18 months with late onset disease; P5, a male patient aged 6 months with early onset disease; and P6, a male patient aged 17 months with late onset disease. P1-3 and P5 received a low dose of PBGM01 (3.3x1010 GC/g), while P4 and P6 received a higher dose of PBGM01 (1.1x1011 GC/g). Furthermore, P1 and P5 were classified as having a mild-moderate developmental delay at baseline while the other patients were classified as having a marked developmental delay at baseline.

Following treatment with PBGM01, participants in the trial showed stabilization of MRI severity scores, in contrast to increases seen in natural history data from untreated patients. Meanwhile, P1 and P5 showed improved responses on the Vineland-II and Bayley-III longitudinal neurodevelopmental assessments compared to the other patients, indicating that milder developmental delay at baseline may allow for better treatment responses. The patients who received the higher dose of PBGM01 also showed an increase in activity of beta-galactosidase (β-Gal), the enzyme encoded by GLB1, in the cerebrospinal fluid (CSF) of 4.7 to 5.2 times baseline, with P4 maintaining activity at 3.6 times baseline at 180 days of follow-up. Similarly, P4 and P6 showed decreases in levels of CSF GM1 gangliosides, the substrate of β-Gal, with P4 showing a 75% drop from baseline at 180 days of follow-up. Decreased levels of β-Gal substrate Dp5 in the urine following treatment were observed in several patients in both the low dose and higher dose cohorts.

In terms of safety, PBGM01 was well-tolerated with no treatment-related serious adverse events (AEs) reported. Notably, no clinically significant changes in liver function requiring intervention, evidence of dorsal root ganglion toxicity, nor complications related to ICM administration were reported. In addition, PBGM01 was deemed to have a favorable immunological profile and no antibodies against the transgene were detected in the CSF or serum. 

It was noted that the eligibility criteria for the trial may be amended to account for patients' degree of developmental delay. CGTLive recently spoke with Samiah Al-Zaidy, MD, vice president of clinical development and lead on the GM1 Program at Passage Bio, about the results of Imagine-01 that were presented at WORLDSymposium and the company’s future plans for further research.

“Future plans and future directions for the Imagine-01 study are really informed by the encouraging safety profile and the early assessment of the dose-dependent response that we're seeing in the biomarkers...” Al-Zaidy said during the interview. “We are exploring the potential benefit of higher doses of PBGM01 in this dose-ascending phase. We look forward to sharing that in the near future.”

Click here to read more coverage of WORLDSymposium 2023.

Jarnes JR, Hatings CA, Ficicioglu C, et al. Updated interim safety, biomarker, and efficacy data from Imagine-1: A phase 1/2 open-label, multicenter study to assess the safety, tolerability, and efficacy of a single dose, intra-cisterna magna (ICM) administration of PBGM01 in subjects with type I (early onset) and type IIA (late onset). Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #186
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