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

Sponsor

UniQure Biopharma B.V. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06100276

Collaborator

(none)

Enrollment

Arms

99.9

Anticipated Duration (Months)

Study Details

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

Anticipated 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).

Anticipated Study Start Date :

Nov 1, 2023

Anticipated Primary Completion Date :

Jun 30, 2026

Anticipated Study Completion Date :

Feb 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 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 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.

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 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

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

Incidence of Treatment Emergent Adverse Events (TEAEs). [5 years]
Occurrence of TEAEs upon administration of ascending doses of AMT-162 and at 6, 9, 12 months and up to 5 years.
Characterization of Kinetics, Immune Response and Shedding of AMT-162. [5 years]
AMT-162 Vector Bio-distribution and Shedding and B- and T-Cell Immune Response.
Efficacy of AMT-162 compared to placebo [6 months]
Mean Change from Baseline in ALSFRS-R Score

Secondary Outcome Measures

Efficacy of AMT-162 [5 years]
Slope of ALSFRS-R and Mean Change from Baseline in ALSFRS-R Score, SVC and ATLIS score.
Efficacy of AMT-162 compared to placebo [6 months]
Mean Change from Baseline in SVC and ALTIS, and ALS-SURV

Other Outcome Measures

Efficacy of AMT-162 [5 years]
Change from Baseline in CSF SOD1 Levels, Change from Baseline from other CSF and blood biomarkers, Change from Baselines in ALSAQ-40 score and at 6, 9, 12 months and up to 5 years.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects diagnosed with mutant SOD1-mediated ALS experiencing signs and/or symptoms of lower motor neuron dysfunction, with or without upper motor neuron symptoms.
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.
ALSFRS-R score ≥ 25 at Screening.
Slow vital capacity (SVC) ≥65% of predicted normal value.
King's stage ≤3 at Screening
Capable of providing informed consent and complying with trial procedures, in the documented opinion of the Investigator.
Titer for neutralizing antibodies (NAb) to AAV rh10 >[1:50] at Screening
Normal renal clearance at Screening.
Normal coagulation function.
Platelet count >150 10^3/mm3.
For subjects on anticoagulant or antiplatelet therapy: able to temporarily stop or bridge therapy for the AMT-162/placebo administration procedures.

Exclusion Criteria:

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.).
Homozygosity for the D91A (formerly D90A) SOD1 gene mutation.
History of significant chronic pain or sensory syndrome.
Presence of unstable psychiatric illness.
Active suicidal ideation within 6 months prior to screening.
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

History of structural CNS disease, may impact intrathecal infusion or cause difficulty placing the catheter.
Known allergy or sensitivity to immunosuppression regimens in this protocol
Unstable cardiac function.
Uncontrolled blood pressure, defined as systolic ≥ 180 millimeters of mercury (mmHg) or diastolic ≥ 120 mmHG
Malignancy within 5 years prior to first dose of immunosuppression unless treated definitively without evidence of recurrence
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
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
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.
Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
Laboratory test values during Screening or during the Lead-in period that are clinically significant in the opinion of the Investigator.
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 IC.F
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.

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