AMX0114 for ALS

(LUMINA Trial)

Overseen By Medical Director, Amylyx

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Amylyx Pharmaceuticals Inc.

Must be taking: Riluzole, Edaravone

Must not be taking: ASO, Gene therapy

Disqualifiers: Tracheostomy, Liver dysfunction, others

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

48 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a placebo-controlled Phase I study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the antisense oligonucleotide (ASO) AMX0114 in adult participants with amyotrophic lateral sclerosis (ALS).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on riluzole or edaravone, you must have been on a stable dose for at least 30 days before starting the study and continue it throughout the trial.

What data supports the effectiveness of the drug AMX0114 for ALS?

Research on a similar drug, AMX0035, showed it could slow down the progression of ALS in a small group of patients, which suggests that AMX0114 might also be effective. ^{1 2 3 4 5}

How does the drug AMX0114 differ from other ALS treatments?

AMX0114 is unique because it may involve gene therapy approaches, similar to those used in treating other neurodegenerative diseases like spinal muscular atrophy (SMA), offering hope for ALS patients where no effective therapy currently exists. ^{6 7 8 9 10}

Research Team

Medical Director, Amylyx

Principal Investigator

Medical Monitor

Eligibility Criteria

Adults diagnosed with ALS within the last 24 months can join this trial. They must understand the study, agree to follow its rules, and give informed consent. Women who could get pregnant and men must use birth control during the trial and for some time after. Participants already on certain ALS medications need a stable dose for at least 30 days before starting.

Inclusion Criteria

I have been on a stable dose of riluzole and/or edaravone for at least 30 days.

I understand the study's risks and agree to follow its requirements.

I have been diagnosed with ALS by an experienced doctor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AMX0114 or placebo by intrathecal injection every 4 weeks for up to 4 doses

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Treatment Details

Interventions

• AMX0114

Trial Overview The trial is testing AMX0114 against a placebo in people with ALS. It's a Phase I study focusing on how safe it is, how well it's tolerated, what happens to it in the body (pharmacokinetics), and what effects it has (pharmacodynamics).

Participant Groups

Group I: Active Treatment: AMX0114 Experimental Treatment 1 Intervention

AMX0114 will be administered once every 4 weeks by intrathecal bolus injection for a total of up to 4 doses. Treatment will be administered on Day 1, followed by repeat dosing every 4 weeks at approximately Day 29, Day 57 and Day 85.

Group II: Placebo Placebo Group 1 Intervention

Placebo drug will be administered once every 4 weeks by intrathecal bolus injection for a total of up to 4 doses. Treatment will be administered on Day 1, followed by repeat dosing every 4 weeks at approximately Day 29, Day 57 and Day 85.

Who Is Running the Clinical Trial?

Amylyx Pharmaceuticals Inc.

Lead Sponsor

Trials

12

Recruited

1,600+

Findings from Research

The phase 2 trial of AMX0035 demonstrated statistically significant effects in slowing ALS progression in a small sample of 137 patients, with a p-value of 3%, indicating potential efficacy.

Using Bayesian decision analysis, the optimal type I error rate for FDA approval of AMX0035 could be higher than the initial 3% if the therapy is at least 30% likely to be effective, suggesting a flexible approach to evaluating its approval based on patient needs and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incorporating patient preferences and burden-of-disease in evaluating ALS drug candidate AMX0035: a Bayesian decision analysis perspective. Xu, Q., Cho, J., Ben Chaouch, Z., et al.[2023]

Despite two completed clinical trials for ALS yielding negative results, the identification of new ALS-associated genes offers hope for future research and potential treatments.

The discovery of biomarkers in body fluids and imaging techniques suggests progress in understanding ALS, which may lead to improved diagnostic and therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor neuron disease in 2014. Biomarkers for ALS--in search of the Promised Land. Chiò, A., Traynor, BJ.[2019]

Recent clinical trials in amyotrophic lateral sclerosis (ALS) have successfully enrolled more homogeneous patient populations by using specific inclusion criteria, leading to observed efficacy signals in smaller and shorter studies than previously thought possible.

While the ALS Functional Rating Scale-Revised remains the primary outcome measure, blood neurofilament levels show promise as a prognostic indicator, although they are not yet validated for use as a primary outcome in trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers: A Review. Shefner, JM., Bedlack, R., Andrews, JA., et al.[2023]

Long-term mechanical ventilation significantly prolongs survival in patients with amyotrophic lateral sclerosis (ALS), with those receiving invasive ventilation showing a mean survival of 72 months.

Programmed pulmonary assessment before initiating non-invasive ventilation (NIV) positively impacts survival rates, highlighting the importance of a multidisciplinary approach in managing ALS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amyotrophic lateral sclerosis: impact of pulmonary follow-up and mechanical ventilation on survival. A study of 114 cases. Sanjuán-López, P., Valiño-López, P., Ricoy-Gabaldón, J., et al.[2022]

The Accurate Test of Limb Isometric Strength (ATLIS) was found to be more sensitive to changes in strength in ALS patients compared to the ALS Functional Rating Scale-Revised (ALSFRS-R) and vital capacity (VC), making it a better measure for tracking disease progression.

Using ATLIS could potentially reduce the sample size needed for clinical trials by about one-third, which is significant for early trials aiming to detect subtle changes in muscle strength before functional decline occurs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed dynamometry is more sensitive than vital capacity or ALS rating scale. Andres, PL., Allred, MP., Stephens, HE., et al.[2017]

ALS is a complex neurodegenerative disease with no effective therapy currently available, but early diagnosis and risk prediction using proteomic biomarkers and microRNAs could help identify individuals at risk before symptoms develop.

Gene therapies, such as antisense oligonucleotides, have shown promise in treating other neurodegenerative diseases and may offer hope for developing effective treatments for ALS in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy. Bagyinszky, E., Hulme, J., An, SSA.[2023]

A novel mutation in the Angiogenin gene (ANG) was identified in a sporadic ALS patient from southern Italy, suggesting a potential genetic link to the disease.

The study also found an association between the ANG gene and a specific single nucleotide polymorphism (rs11701) in familial ALS cases, reinforcing the gene's involvement in ALS pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy. Conforti, FL., Sprovieri, T., Mazzei, R., et al.[2011]

About 10% of amyotrophic lateral sclerosis (ALS) cases are familial, with most mutations found in the SOD1 gene, particularly the A4V mutation, which leads to a severe and rapid disease progression.

Presymptomatic testing for familial ALS is challenging due to uncertainty about the mutation's responsibility for the disease and its age of onset, highlighting the need for careful genetic counseling similar to that used in Huntington's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Where is the role of the genetic investigations in amyotrophic lateral sclerosis?]. Vandenberghe, N.[2009]

A specific mutation (A4V) in the SOD1 gene was identified in a 51-year-old Chinese male with familial amyotrophic lateral sclerosis (ALS), marking the first report of this mutation in a non-Caucasian patient.

The patient exhibited a typical A4V-related ALS phenotype, characterized by rapid disease progression and significant lower motor neuron involvement, indicating that this mutation has similar effects across different ethnic backgrounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of an A4V SOD1 mutation in a Chinese patient with amyotrophic lateral sclerosis without the A4V founder effect common in North America. Tang, L., Ma, Y., Liu, X., et al.[2022]

The Angiogenin (ANG) K17I variant is found to be rare in Caucasian populations, with frequencies of 0.43% in ALS patients and 0.16% in controls, suggesting it is not a common risk factor for the disease.

However, the K17I variant is associated with an increased risk of amyotrophic lateral sclerosis (ALS), particularly familial ALS (FALS), with odds ratios indicating a significant risk, while no such association was found for sporadic ALS (SALS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between the Angiogenin (ANG) K17I variant and amyotrophic lateral sclerosis risk in Caucasian: a meta-analysis. Pan, L., Deng, X., Ding, D., et al.[2022]

References

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

Incorporating patient preferences and burden-of-disease in evaluating ALS drug candidate AMX0035: a Bayesian decision analysis perspective. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Motor neuron disease in 2014. Biomarkers for ALS--in search of the Promised Land. [2019]

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

Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers: A Review. [2023]

4. Spain pubmed.ncbi.nlm.nih.gov

Amyotrophic lateral sclerosis: impact of pulmonary follow-up and mechanical ventilation on survival. A study of 114 cases. [2022]

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

Fixed dynamometry is more sensitive than vital capacity or ALS rating scale. [2017]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Studies of Genetic and Proteomic Risk Factors of Amyotrophic Lateral Sclerosis Inspire Biomarker Development and Gene Therapy. [2023]

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

A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy. [2011]

8. France pubmed.ncbi.nlm.nih.gov

[Where is the role of the genetic investigations in amyotrophic lateral sclerosis?]. [2009]

9. England pubmed.ncbi.nlm.nih.gov

Identification of an A4V SOD1 mutation in a Chinese patient with amyotrophic lateral sclerosis without the A4V founder effect common in North America. [2022]

10. Italy pubmed.ncbi.nlm.nih.gov

Association between the Angiogenin (ANG) K17I variant and amyotrophic lateral sclerosis risk in Caucasian: a meta-analysis. [2022]