This is the classic website, which will be retired eventually. Please visit the modernized instead.
Working… Menu

Safety, Tolerability, and Efficacy Study of Intrathecally Administered Gene Therapy AMT-162 in Amyotrophic Lateral Sclerosis (ALS) Patients With SOD1 Mutations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT06100276
Recruitment Status : Not yet recruiting
First Posted : October 25, 2023
Last Update Posted : November 14, 2023
Information provided by (Responsible Party):
UniQure Biopharma B.V.

Brief Summary:
This is the study of AMT-162 in rapidly progressive ALS Patients with SOD1 Mutations and is designed to evaluate the Safety, Tolerability, and Efficacy of Intrathecally Administered Gene Therapy AMT-162. AMT-162-001 is a Phase 1/2, Multi-center, Three-part Study : Part I Single Ascending Dose, Part II Randomized, Double-blind, Placebo-controlled, and Part III Extended Follow-up.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: AMT-162 Phase 1 Phase 2

Detailed Description:
AMT-162 is an investigational gene therapy that encodes an artificial micro-ribonucleic acid (microRNA or miRNA) targeting the SOD1 gene. This clinical study will test the safety of AMT-162 and explore the hypothesis that it will silence expression of mutant cytosolic SOD1 and thereby ameliorate the course of ALS cause by this mutant gene.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Part 1 of the study is open label. Part 2 of the study is blinded to the participant, care provider, investigator and outcomes assessor.
Primary Purpose: Treatment
Official Title: A Phase 1/2, Multicenter, Three-part Study to Evaluate the Safety, Tolerability, and Efficacy of Intrathecally Administered Gene Therapy AMT-162 in Patients With SOD1 Amyotrophic Lateral Sclerosis (SOD1-ALS).
Estimated Study Start Date : February 1, 2024
Estimated Primary Completion Date : June 30, 2026
Estimated Study Completion Date : February 27, 2032

Arm Intervention/treatment
Experimental: Part 1 (Open-Label Single Ascending Dose)
Part 1 will be open-label with an initial plan to explore 3 dose levels of AMT-162 in approximately 6 to 12 subjects (2 to 4 per dose level). Each subject in Part 1 will receive a single treatment delivered via an intrathecal (IT) infusion. All subjects in Part 1 will receive active immunosuppression (IS).
Drug: AMT-162
AMT-162, the investigational product (IP), is a non-replicating, rep/cap-deleted, self-complementary Recombinant adeno-associated virus (rAAV) vector based on adeno-associated virus (AAV) serotype rh10 and contains complementary deoxyribonucleic acid (cDNA) encoding an artificial miRNA targeting the SOD1 gene.

Placebo Comparator: Part 2 (Randomized, Double-blind, Placebo-controlled)

Approximately 30 subjects will be randomly assigned in a 1:1 ratio to treatment Arm A or Arm B:

  • Arm A ("Treatment"): Active treatment with AMT-162 and active IS
  • Arm B ("Control"): Placebo treatment via control procedure and placebo IS

In addition, if preliminary signs of efficacy were observed in Part 1, subjects from the Part 2 control group (Arm B) will be offered AMT-162 treatment.

Blinded adverse event (AE) raters and blinded efficacy assessors will be used in Part 2, and the blind will be maintained for each subject until they complete Month 6 in Part 2.

Drug: AMT-162
AMT-162, the investigational product (IP), is a non-replicating, rep/cap-deleted, self-complementary Recombinant adeno-associated virus (rAAV) vector based on adeno-associated virus (AAV) serotype rh10 and contains complementary deoxyribonucleic acid (cDNA) encoding an artificial miRNA targeting the SOD1 gene.

No Intervention: Part 3 (Extended Follow-up)
Upon completing Part 1 or Part 2, subjects will enter Part 3 to be followed for up to 5 years after AMT-162/placebo administration.

Primary Outcome Measures :
  1. Incidence of Treatment Emergent Adverse Events (TEAEs). [ Time Frame: 5 years ]
    Occurrence of TEAEs upon administration of ascending doses of AMT-162 and at 6, 9, 12 months and up to 5 years.

  2. Characterization of Kinetics, Immune Response and Shedding of AMT-162. [ Time Frame: 5 years ]

    The biodistribution of vector DNA and any positive results in shedding samples will be summarized at each timepoint for each study part by treatment group.

    Immunogenicity parameters will be summarized for each study part by treatment group and visit.

    Summary tables will include descriptive statistics for observed values and changes from baseline, or frequencies and percentages, as appropriate.

  3. Efficacy of AMT-162 compared to placebo [ Time Frame: 6 months ]
    Mean Change from Baseline in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) Score

Secondary Outcome Measures :
  1. Efficacy of AMT-162 [ Time Frame: 5 years ]

    Slope of ALSFRS-R and Mean Change from Baseline in ALSFRS-R, Slow Vital Capacity (SVC), and Accurate Test of Limb Isometric Strength (ATLIS).

    The ALSFRS-R uses an ordinal rating scale (0-4) to determine a subject's assessment of their capability and independence in 12 functional areas. This study will enroll subjects with rapidly progressing disease (ALSFRS-R decline ≥ 1.0/month from onset of symptoms to Screening). An ALSFRS-R score of 48 is assigned at onset of symptoms of weakness unless a score is otherwise documented in medical history. A higher score means better independent functioning than a lower score.

    Vital Capacity (% of predicted normal) will be determined using the SVC method. A higher % of predicted normal for VC or SVC means better lung function than a lower % of predicted normal.

    ATLIS is a dynamometer and grip strength device that measures isometric static limb strength in 12 muscle groups in the arms and legs (expressed as a percentage of expected normal

  2. Efficacy of AMT-162 compared to placebo [ Time Frame: 6 months ]
    Mean Change from Baseline in SVC and ALTIS, and ALS Combined Assessment of Function and Survival (ALS-SURV)

Other Outcome Measures:
  1. Efficacy of AMT-162 [ Time Frame: 5 years ]

    Change from Baseline in Cerebrospinal fluid (CSF) SOD1 Levels, Change from Baseline from other CSF and blood biomarkers, Change from Baselines in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) score and at 6, 9, 12 months and up to 5 years.

    The ALSAQ-40 is disease specific patient reported outcome. It contains 40 questions for subjects to answer about their perceived well-being with 5 discrete scales: Physical mobility (10 items), Activities of daily living and independence (10 items), Eating and drinking (3 items), Communication (7 items) and Emotional reactions (10 items).Subjects are asked to think about the difficulties they may have experienced during the last 2 weeks and to indicate the frequency of each event by selecting one of 5 options: never/rarely/sometimes/often/always or cannot do at all.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subjects diagnosed with mutant SOD1-mediated ALS experiencing signs and/or symptoms of lower motor neuron dysfunction, with or without upper motor neuron symptoms.
  2. Subjects with rapidly progressing disease ("fast" progressors), defined as average ALS Functional Rating Scale - Revised decline ≥1.0 per month calculated from score at onset of symptoms compared to score at Screening ALSFRS-R.
  3. ALSFRS-R score ≥ 25 at Screening.
  4. Slow vital capacity (SVC) ≥65% of predicted normal value.
  5. King's stage ≤3 at Screening
  6. Capable of providing informed consent and complying with trial procedures, in the documented opinion of the Investigator.
  7. Titer for neutralizing antibodies (NAb) to AAV rh10 >[1:50] at Screening
  8. Normal renal clearance at Screening.
  9. Normal coagulation function.
  10. Platelet count >150 10^3/mm^3.
  11. For subjects on anticoagulant or antiplatelet therapy: able to temporarily stop or bridge therapy for the AMT-162/placebo administration procedures.

Exclusion Criteria:

  1. SOD1 mutation in positions 2-12 of the MiR targeting sequence, also defined as complementary deoxyribonucleic acid (cDNA) position 128-139, which also corresponds to amino acid regions 43-47. (Position 1 is defined as the start codon ATG.).
  2. Homozygosity for the D91A (formerly D90A) SOD1 gene mutation.
  3. History of significant chronic pain or sensory syndrome.
  4. Presence of unstable psychiatric illness.
  5. Active suicidal ideation within 6 months prior to screening.
  6. Reproductive status that includes any of the following:

    • Women who are pregnant or have positive pregnancy test at Screening or during Lead-in period
    • Women who are breastfeeding
    • Women of childbearing potential (WOCBP) who are unwilling or unable to use birth control to avoid pregnancy for the entire study period
    • Men who are unwilling to use birth control for the entire study period
  7. History of structural Central Nervous System (CNS) disease, may impact intrathecal infusion or cause difficulty placing the catheter.
  8. Known allergy or sensitivity to immunosuppression regimens in this protocol
  9. Unstable cardiac function.
  10. Uncontrolled blood pressure, defined as systolic ≥ 180 millimeters of mercury (mmHg) or diastolic ≥ 120 mmHG
  11. Malignancy within 5 years prior to first dose of immunosuppression unless treated definitively without evidence of recurrence
  12. Known immunocompromised status including individuals who have undergone organ transplantation; who test positive at Screening for the human immunodeficiency virus (HIV), HCV antibody (anti-HCV) or hepatitis B surface antigen (HBsAg); or who have history of active tuberculosis (TB) or a positive tuberculosis blood test during Screening
  13. Anticipated survival, per Investigator judgment, that is shorter than the duration of Screening plus Lead-in plus 6 months after treatment in Part 1 or Part 2
  14. Presence of tracheostomy and/or dependent on mechanically assisted ventilation, defined as being unable to lay supine without it, unable to sleep without it, or continuous daytime use- with exception of continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) for obstructive sleep apnea.
  15. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
  16. Laboratory test values during Screening or during the Lead-in period that are clinically significant in the opinion of the Investigator.
  17. Any of the following prior or concomitant treatments:

    • Change in dose of riluzole (RILUTEK®, TIGLUTIK®) or edaravone (RADICAVA®) within 30 days prior to immunosuppression (i.e., riluzole and/or edaravone are allowed if dose is stable).
    • Concomitant medications contraindicated for use with rituximab or sirolimus, including strong inducers and strong inhibitors of CYP3A4 and P-glycoprotein.
    • Chronic systemic corticosteroid use, defined as >10 mg of prednisone or equivalent systemic corticosteroid taken for more than 2 consecutive weeks within 2 months prior to first dose of immunosuppression.
    • Treatment with stem cells for any indication within 6 months prior to first dose of immunosuppression.
    • Any prior treatment with SOD suppression therapy (viral microRNA or antisense oligonucleotide (ASO) mediators).
    • Any prior administration of an AAV gene therapy.
    • Treatment with any other investigational study medication within 90 days prior to signing Informed Consent (ICF)
    • Planned treatment with live vaccines during Lead-in period or at any time after receipt of AMT-162/placebo.
    • Warfarin within 30 days prior to Screening labs. If a subject switches to a different anticoagulant for the sole purpose of meeting criteria for participation in the study, ICF should be signed before the switch.
  18. Presence of any other condition or clinically significant laboratory values which, in the opinion of the Investigator (by its nature or by being inadequately controlled), might put the subject at significantly higher risk due to participation in the study or might influence the results of the study or the subject's ability to complete the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT06100276

Layout table for location contacts
Contact: Amy Pinette +1 339-999-1508
Contact: Christy Quintana +1 781-879-6442

Sponsors and Collaborators
UniQure Biopharma B.V.
Layout table for additonal information
Responsible Party: UniQure Biopharma B.V. Identifier: NCT06100276    
Other Study ID Numbers: AMT-162-001
First Posted: October 25, 2023    Key Record Dates
Last Update Posted: November 14, 2023
Last Verified: November 2023

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UniQure Biopharma B.V.:
Gene Therapy
AAV (adeno-associated virus)
serotype Rh10 AAV
Additional relevant MeSH terms:
Layout table for MeSH terms
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases