Gene Therapy for Gangliosidosis

(Imagine-1 Trial)

Not currently recruiting at 11 trial locations

Overseen By Physician Inquiries

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Gemma Biotherapeutics

Must not be taking: Miglustat, Enzyme replacement

Disqualifiers: Neurocognitive deficit, Seizures, Cardiomyopathy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy called PBGM01 for GM1 gangliosidosis, a rare genetic condition affecting the brain and nervous system. The goal is to determine if this therapy can safely and effectively deliver a working copy of a crucial gene to improve symptoms in infants with early or late onset of the disease. The study aims to find the best dose and confirm safety and effectiveness. This trial may suit infants diagnosed with GM1 gangliosidosis who show early symptoms and meet specific developmental milestones, such as sitting up independently. As a Phase 1/Phase 2 trial, it offers the opportunity to be among the first to receive this innovative treatment while helping researchers measure its effectiveness in a smaller group.

Will I have to stop taking my current medications?

The trial requires that participants stop using miglustat 48 hours before the study and throughout the study. Additionally, enzyme replacement therapy must be stopped at least 5 half-lives before the study and is not allowed during the study.

Is there any evidence suggesting that PBGM01 is likely to be safe for humans?

Research has shown that PBGM01, a gene therapy for GM1 gangliosidosis, has promising safety results from earlier studies. Safety data up to 28 months indicate that both lower and higher doses of PBGM01 were well tolerated. These studies reported no serious side effects related to the treatment, suggesting it is safe and does not cause immune system problems. Additionally, researchers observed no concerning health issues. This gene therapy aims to provide a working copy of the GLB1 gene to affected areas in the body, which may help manage this condition. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about PBGM01 for treating GM1 Gangliosidosis because it offers a unique gene therapy approach that targets the root cause of the disease. Unlike current treatments that primarily manage symptoms, PBGM01 aims to deliver a corrective gene directly to the brain using an intra cisterna magna injection. This method could potentially halt or reverse disease progression by addressing the underlying genetic defect, offering hope for more effective and long-lasting results.

What evidence suggests that PBGM01 might be an effective treatment for GM1 gangliosidosis?

Research has shown that PBGM01 is designed to treat GM1 gangliosidosis by delivering a healthy version of the GLB1 gene directly to the brain and other parts of the body. Studies have found that increasing β-gal activity can help reduce harmful substances called GM1 gangliosides, which accumulate in the brain and damage nerve cells. Early reports suggest that PBGM01 might lower these toxic buildups and improve symptoms. This trial will test different doses of PBGM01 to identify the optimal dose and confirm its safety and efficacy. Although more remains to be learned, the goal is to reduce the effects of this serious condition. ^{1 6 7 8 9}

Who Is on the Research Team?

May Orfali, MD

Principal Investigator

Gemma Biotherapeutics

Are You a Good Fit for This Trial?

This trial is for children with GM1 gangliosidosis, a genetic disorder. Infants (Type 1) must be 1-12 months old with symptoms starting before 6 months and meet certain developmental milestones. Older infants (Type 2a), aged 6-24 months, should show symptoms between 6-18 months and can sit independently. Participants cannot have had recent vaccines, gene therapy, or certain medical conditions that could affect the study.

Inclusion Criteria

My infant is 1-11 months old with early signs of GM1 gangliosidosis noted before 6 months.

My child is 6-24 months old, showed GM1 gangliosidosis symptoms between 6-18 months, and can sit up alone.

I have GM1 gangliosidosis confirmed by genetic testing and enzyme deficiency.

Exclusion Criteria

Acute illness requiring hospitalization within 30 days of enrollment, the history must be discussed with the sponsor's medical monitor before allowing the subject to be enrolled.

I have nerve damage in my hands or feet.

My heart muscle is weak (high troponin levels).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part 1 of the study involves dose escalation to assess three dose levels of PBGM01 in six independent cohorts

Duration not specified

Multiple visits

Confirmatory Cohorts

Part 2 of the study tests the safety and efficacy of PBGM01 in confirmatory cohorts with a dose chosen based on Part 1 data

2 years

Multiple visits

Safety Extension

A 3-year safety extension to monitor long-term safety of PBGM01

3 years

Multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PBGM01

Trial Overview The trial tests PBGM01, a gene therapy aimed at delivering a functional GLB1 gene to brain and peripheral tissues of kids with Type 1 or Type 2a GM1 gangliosidosis. It's designed in two parts to evaluate safety, tolerability and effectiveness of this treatment.

How Is the Trial Designed?

Group I: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01 Experimental Treatment 1 Intervention

Confirmatory Cohorts: Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1) Assigned Intervention: PBGM01 Single dose of PBGM01, via intra cisterna magna Dose to be determined

Group II: Part 1: Dose III of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01 Experimental Treatment 1 Intervention

Assigned Intervention: PBGM01 Dose III: 2.2 x 10\^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Group III: Part 1: Dose II of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01 Experimental Treatment 1 Intervention

Assigned Intervention: PBGM01 Dose II: 1.1 x 10\^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Group IV: Part 1: Dose I of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01 Experimental Treatment 1 Intervention

Assigned Intervention: PBGM01 Dose I: 3.3 x 10\^10 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Who Is Running the Clinical Trial?

Gemma Biotherapeutics

Lead Sponsor

Passage Bio, Inc.

Lead Sponsor

Trials

6

Recruited

112,000+

Published Research Related to This Trial

Two pentasaccharide biomarkers, H3N2a and H3N2b, were identified as significantly elevated in patients with GM1 gangliosidosis, with H3N2b being detectable in a cat model and correlating negatively with β-galactosidase activity.

After AAV9 gene therapy treatment, levels of H3N2b decreased in both the cat model and a patient, indicating that this biomarker can effectively reflect the therapeutic efficacy of gene therapy for GM1 gangliosidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pentasaccharide for monitoring pharmacodynamic response to gene therapy in GM1 gangliosidosis. Kell, P., Sidhu, R., Qian, M., et al.[2023]

LYS-GM101, a gene therapy vector designed to deliver the human GLB1 gene, showed promising efficacy in animal models of GM1 gangliosidosis, correcting the toxic accumulation of GM1 ganglioside in the central nervous system without observable adverse effects.

In nonhuman primates, LYS-GM101 led to a significant increase in β-galactosidase activity in the brain, indicating effective delivery and potential therapeutic benefit, although some asymptomatic adverse changes were noted in sensory pathways, warranting further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates. Hocquemiller, M., Giersch, L., Mei, X., et al.[2022]

Intrathecal delivery of scAAV9 carrying a functional GM2 activator protein gene effectively prevents GM2 ganglioside accumulation in GM2AP-deficient mice, demonstrating its potential as a treatment for AB-variant GM2 gangliosidosis.

The treatment was found to be safe and well-tolerated, with no severe adverse events reported, and it showed dose-dependent efficacy in correcting GM2 accumulation in the central nervous system over a long duration (up to 104 weeks).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis. Deschenes, NM., Cheng, C., Ryckman, AE., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04713475

NCT04713475 | Study of Safety, Tolerability and Efficacy ... Part 2 of the study will test the safety and efficacy of PBGM01 in confirmatory cohorts for Types 1 and Type 2a GM1 gangliosidosis with a dose chosen based on ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11082364/

Therapeutic developments for neurodegenerative GM1 ... The most promising treatments for GM1, include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy and gene editing.

3. passagebio.com passagebio.com/investors-and-news/press-releases-and-statements/news-details/2023/Passage-Bio-to-Present-Updated-Interim-Data-from-Imagine-1-Study-for-GM1-Gangliosidosis-at-19th-Annual-WORLDSymposium-2023/default.aspx

Press Releases and Statements By increasing β-gal activity, PBGM01 has the potential to reduce accumulation of toxic GM1 gangliosides and reverse neuronal toxicity, thereby ...

4. scge.mcw.edu scge.mcw.edu/platform/data/clinicalTrials/report/NCT04713475

Gene Therapy Trial Report PBGM01 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the brain and peripheral tissues.

5. cgtlive.com cgtlive.com/view/imagine-01-aiming-evaluate-safety-efficacy-gm1-gangliosidosis-gene-therapy

Imagine-01 Aiming to Evaluate Safety and Efficacy of GM1 ... The trial includes both patients with early onset infantile GM1 gangliosidosis (type 1) and late onset infantile GM1 gangliosidosis (type 2a).

6. passagebio.com passagebio.com/investors-and-news/press-releases-and-statements/news-details/2023/Passage-Bio-Announces-Promising-Interim-Clinical-Data-from-First-Eight-Patients-with-GM1-Gangliosidosis-in-Imagine-1-Study/default.aspx

Press Releases and Statements Interim safety data up to 28 months showed Dose 1 and 2 of PBGM01 were well tolerated and had a favorable safety and immunological profile

7. passagebio.com passagebio.com/investors-and-news/press-releases-and-statements/news-details/2022/Passage-Bio-Announces-Positive-Interim-Clinical-Data-from-First-Six-Patients-with-GM1-Gangliosidosis-in-Imagine-1-Study/default.aspx

Press Releases and Statements Interim safety data up to 20 months showed the low and high dose of PBGM01 were well tolerated and had a favorable safety profile ...

8. frontiersin.org frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1392683/full

Therapeutic developments for neurodegenerative GM1 ... In the second study, an AAVhu68 serotype delivery mechanism for GLB1 gene, PBGM01, is being investigated for safety, tolerability, and efficacy ...

9. cgtlive.com cgtlive.com/view/infantile-gm1-gangliosidosis-gene-therapy-demonstrates-safety-dose-dependent-biomarker-changes

Infantile GM1 Gangliosidosis Gene Therapy Demonstrates ... In terms of safety, PBGM01 was well-tolerated with no treatment-related serious adverse events (AEs) reported. Notably, no clinically ...