RARE Daily

Passage Bio Reports Positive Interim Clinical Data from Study of First Eight Patients with GM1 Gangliosidosis

August 8, 2023

Rare Daily Staff

Passage Bio reported new interim safety, biomarker, and survival data from cohorts 1-4 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 six 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 (β-Gal). Reduced β-gal activity results in the accumulation of toxic levels of GM1 gangliosides in neurons throughout the brain, causing rapidly progressive neurodegeneration. GM1 accumulation also results in progressive damage to other tissues including the heart, liver, and bones and manifests with hypotonia (reduced muscle tone), progressive CNS dysfunction, seizures, and rapid developmental regression. Life expectancy for infants with GM1 ranges from 2-10 years, and infantile GM1 represents approximately 60 percent of the global GM1 incidence of 0.5 to 1 in 100,000 live births.

“We are highly encouraged by the compelling data emerging from our Imagine-1 study, with results underscoring the potential of PBGM01 to be a transformative therapy for GM1 patients,” said William Chou, president and CEO of Passage Bio. “Updated data from the first eight treated patients show that PGBM01 continues to have a favorable safety profile, is well tolerated, and shows initial evidence of improved survival relative to what is predicted by the natural history of the disease. Furthermore, Dose 2 of PBGM01 has shown the ability to achieve healthy control levels of β-Gal activity and GM1 gangliosides in CSF, with durability up to 12 months after treatment.”

Topline interim results from cohorts 1-4 of the Imagine-1 study with safety follow-up ranging from 8 to 28 months has resulted in no treatment-related serious adverse events, 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, and a favorable immunological profile with no clinically significant immune response.

Imagine-1 study patients showed initial evidence of improved survival relative to natural history data, which comes from a meta-analysis of 154 GM1 infants with symptom onset <12 months of age indicates mean survival for infantile GM1 of 18.9 months and no survival beyond 35 months. Infantile GM1 patients receiving PBGM01 showed a survival benefit, with one hundred percent survival beyond 20 months of age.

Dose 2 of PBGM01 resulted in robust and durable increases in CSF β-Gal biomarker activity. In three of four children, Dose 2 of PBGM01 resulted in a 4.7-16.1x increase in CSF β-Gal activity at 30 days post-treatment relative to baseline, exceeding average levels seen in healthy adults and GM1 Natural History Study. The increased CSF β-Gal activity was able to be sustained for up to 12 months. Dose 2 of PBGM01 also decreased CSF GM1 ganglioside levels and demonstrated the ability to achieve normal adult levels at one-year post-dose. GM1 ganglioside levels continued to decline over time in all patients treated with Dose 2. The effects on CSF β-Gal activity and GM1 gangliosides were dose-dependent, with Dose 1 of PBGM01 exhibiting modest effects.

The company has treated the first patient at Dose 3 and is actively recruiting additional patients in the Imagine-1 study for Cohort 5 (late infantile) and Cohort 6 (early infantile). The amended study protocol has been approved at several clinical trial sites, including in Brazil, Canada, Turkey, and the United States. Dosing of patients in Cohorts 5 and 6 may occur concurrently, and the company expects to report initial safety and biomarker data from Dose 3 by mid-2024.

The U.S. Food and Drug Administration has granted PBGM01 Fast Track, Orphan Drug, and Rare Pediatric Disease designations. PBGM01 has also received an Orphan designation from the European Commission.

Photo: William Chou, president and CEO of Passage Bio

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