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

• ClinicalTrials.gov Identifier: NCT06100276
• Recruitment Status: Not yet recruiting
• First Posted: October 25, 2023
• Last Update Posted: November 14, 2023
• Sponsor: UniQure Biopharma B.V.
• Information provided by (Responsible Party): UniQure Biopharma B.V.

Study Description

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.

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Amy Pinette; +1 339-999-1508; amt162_clinical_trials@uniqure.com

Contact: Christy Quintana; +1 781-879-6442; amt162_clinical_trials@uniqure.com

Sponsors and Collaborators

UniQure Biopharma B.V.

More Information

• Responsible Party: UniQure Biopharma B.V.
• ClinicalTrials.gov Identifier: NCT06100276
• Other Study ID Numbers: AMT-162-001
• First Posted: October 25, 2023
• Last Update Posted: November 14, 2023
• Last Verified: November 2023

• 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; ALS; SOD1

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases