Gene Therapy for ALS

Recruiting at 11 trial locations

Overseen By Director Clinical Operations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: UniQure Biopharma B.V.

Must not be taking: SOD1 suppression, AAV gene therapy

Disqualifiers: C9orf72 expansion, SOD1 variants, others

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

Compensation: Varies

Number of Visits: 7

Duration: 1 day

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is the study of AMT-162 in Participants with SOD1-ALS and is designed to evaluate the safety, tolerability, and exploratory efficacy of intrathecally administered gene therapy AMT-162. AMT-162-001 is a Phase 1/2, multi-center, single ascending dose study.

Will I have to stop taking my current medications?

The trial allows you to continue taking certain ALS medications like riluzole, edaravone, and sodium phenylbutyrate and taururosdiol if your dose is stable for 30 days before starting the trial. However, you must not start any new ALS treatments for at least 6 months after receiving the gene therapy.

What data supports the effectiveness of the treatment AMT-162 for ALS?

Gene therapy has shown promise in treating motor neuron diseases like spinal muscular atrophy, which shares similarities with ALS. The use of adeno-associated virus (AAV) to deliver therapeutic genes has been successful in other conditions, suggesting potential for ALS treatment. ^{1 2 3 4 5}

What safety data exists for gene therapy treatments similar to AMT-162 for ALS?

There is safety data available for onasemnogene abeparvovec, a gene-replacement therapy used for spinal muscular atrophy, which is a similar type of treatment. This therapy has been evaluated for safety in clinical trials and postmarketing studies, providing insights into the safety of gene therapies for motor neuron disorders. ^{1 4 6 7 8}

How does the treatment AMT-162 for ALS differ from other treatments?

AMT-162 is a gene therapy that uses viral vectors to deliver therapeutic genes directly to motor neurons, potentially offering a more targeted approach compared to existing treatments like Riluzole, which only modestly extends survival. This method aims to address the genetic causes of ALS, which is a novel approach compared to traditional drug therapies. ^{1 3 5 9 10}

Research Team

Executive Director, Clinical Development

Principal Investigator

UniQure Biopharma B.V.

Eligibility Criteria

This trial is for adults with SOD1-ALS, a form of motor neuron disease. Participants should be in the early to mid-stages of the disease, have normal kidney and blood clotting functions, and not have severe respiratory issues. They must be able to consent and follow trial procedures. People with very high levels of certain antibodies or those who are 'fast' progressors may not qualify.

Inclusion Criteria

My lung function test shows at least 65% of the normal value.

My ALS is worsening quickly, losing more than 1 point per month on the ALSFRS-R scale.

I have ALS with signs of lower motor neuron issues, possibly with upper motor neuron symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single ascending dose of AMT-162 via intrathecal infusion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety, tolerability, and exploratory efficacy of AMT-162

5 years

Regular visits (in-person and virtual) over 5 years

Expansion Cohort

Further testing of selected dose from the single ascending dose part in additional participants

1 day

1 visit (in-person)

Treatment Details

Interventions

• AMT-162

Trial Overview The study tests AMT-162, an intrathecal gene therapy for safety, tolerability, and preliminary effectiveness in treating SOD1-ALS. It's a Phase 1/2 trial where participants receive one dose of the treatment at increasing levels to find out what's safe.

Participant Groups

Group I: EXPANSION COHORT Experimental Treatment 1 Intervention

Expansion cohort: To further test selected dose from the SAD part in approximately 6 to 8 participants The study will be open-label. Each Participant will receive a single dose of AMT-162 delivered via an intrathecal (IT) infusion and will be followed for up to 5 years after AMT-162 administration.

Group II: 3 single Ascending Dose Levels Experimental Treatment 1 Intervention

Experimental: 3 single Ascending Dose Levels The study will be open-label with an initial plan to explore 3 dose levels of AMT-162 in approximately 6 to 12 Participants in total. Each Participant will receive a single dose of AMT-162 delivered via an intrathecal (IT) infusion and will be followed for up to 5 years after AMT-162 administration.

Who Is Running the Clinical Trial?

UniQure Biopharma B.V.

Lead Sponsor

Trials

12

Recruited

260+

Findings from Research

Riluzole is currently the only approved drug for ALS in Europe, providing only a modest survival benefit of about 3 months, highlighting the urgent need for more effective treatments.

Recent advancements in genetic therapies, including gene replacement strategies, show promise for treating ALS by targeting specific genetic mutations that contribute to the disease, offering hope for more effective interventions in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospects for gene replacement therapies in amyotrophic lateral sclerosis. Giovannelli, I., Higginbottom, A., Kirby, J., et al.[2023]

Recent advancements in understanding the mechanisms and genetics of ALS have led to the development of six gene modulation therapies targeting key ALS genes, showing promise for future treatments.

These therapies utilize innovative techniques like adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs) to address the underlying genetic causes of ALS, potentially transforming treatment options for this severe disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to Gene Modulation Therapy for ALS. Meijboom, KE., Brown, RH.[2023]

Gene therapy, particularly using antisense oligonucleotides delivered via viral vectors like adeno-associated virus (AAV), shows promise in treating genetic forms of ALS, specifically targeting mutations in the SOD1 and C9orf72 genes.

The FDA's recent approval of Zolgensma, an AAV-mediated treatment for spinal muscular atrophy, highlights the potential of AAV vectors in developing safe and effective therapies for motor neuron diseases like ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Therapy for ALS-A Perspective. Cappella, M., Ciotti, C., Cohen-Tannoudji, M., et al.[2023]

Nusinersen, an antisense oligonucleotide approved for spinal muscular atrophy (SMA), highlights the potential for gene therapy in treating similar diseases like amyotrophic lateral sclerosis (ALS), despite the lack of approved ALS gene therapies.

To develop effective ALS gene therapies, it is crucial to carefully consider the type of therapeutic, the target cells and tissues for drug delivery, the specific pathways to be corrected, and the optimal dosing and timing for administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. Tosolini, AP., Sleigh, JN.[2020]

Gene therapy shows promise as a potential treatment for amyotrophic lateral sclerosis (ALS), with various therapeutic transgenes being tested in transgenic rodent models.

The chapter discusses the challenges of targeting the disease effectively and the timing of therapeutic interventions, highlighting the complexity of developing effective treatments for ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for amyotrophic lateral sclerosis. Federici, T., Boulis, NM.[2013]

Onasemnogene abeparvovec, the first approved gene-replacement therapy for spinal muscular atrophy, has been shown to have manageable safety risks, with 101 out of 102 patients experiencing at least one treatment-emergent adverse event (AE) during clinical trials.

Key safety concerns include hepatotoxicity, which resolved with treatment, and transient decreases in platelet counts, while thrombotic microangiopathy (TMA) was noted in postmarketing data, indicating the need for monitoring and potential medical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Day, JW., Mendell, JR., Mercuri, E., et al.[2022]

Sodium phenylbutyrate-taurursodiol (PB-TURSO) has been shown to be safe and effective for treating amyotrophic lateral sclerosis (ALS), leading to its conditional approval in Canada and full approval in the USA after the CENTAUR trial, which was a randomized, double-blind, multicenter study.

The ongoing phase 3 PHOENIX trial will further evaluate the safety and efficacy of AMX0035, a combination of PB and TURSO, but its high annual cost of $158,000 may limit access for patients with ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. Sun, Y., Li, X., Bedlack, R.[2023]

Conjugating antisense oligonucleotides (ASOs) to an antibody targeting the transferrin receptor significantly improved their bioavailability to the brain in mouse models of spinal muscular atrophy (SMA).

The 8D3130-ASO conjugate not only enhanced SMN2 gene splicing in the central nervous system but also extended the survival of severely affected SMA mice, highlighting its potential as a therapeutic strategy for neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy. Hammond, SM., Abendroth, F., Goli, L., et al.[2023]

Gene-specific therapies targeting SOD1 mutations in familial ALS have shown promising results in animal models, with recent studies demonstrating that subpial injections of AAV9 combined with anti-SOD1 antisense oligonucleotides can completely prevent or halt disease progression depending on the timing of the injection.

Alternative strategies, such as modulating microbiota, have shown potential in treating C9ORF72-related ALS models, offering a safer administration route and good safety profile, highlighting the evolving landscape of experimental treatments for ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic tools for familial ALS. Camu, W., De La Cruz, E., Esselin, F.[2023]

Adeno-associated virus (AAV)-mediated delivery of neuron-derived neurotrophic factor (NDNF) significantly improved motor performance and reduced weight loss in SOD1G93A ALS model mice when administered early in the disease progression.

Even when delivered at later stages, AAV-NDNF extended the lifespan of ALS model mice and promoted the survival of spinal motoneurons, suggesting it activates protective signaling pathways that could be beneficial for ALS treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice. Cheng, W., Huang, J., Fu, XQ., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Prospects for gene replacement therapies in amyotrophic lateral sclerosis. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Approaches to Gene Modulation Therapy for ALS. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Gene Therapy for ALS-A Perspective. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Gene therapy for amyotrophic lateral sclerosis. [2013]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Antibody-oligonucleotide conjugate achieves CNS delivery in animal models for spinal muscular atrophy. [2023]

9. France pubmed.ncbi.nlm.nih.gov

Therapeutic tools for familial ALS. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice. [2023]