Clinical Trials

Inclusion Criteria - Part A and B:

• Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2. 
• A forced vital capacity (FVC) ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC < 50% but ≥ 45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator. 
• If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

Exclusion Criteria - Part A and B:

• History of or positive test result for human immunodeficiency virus. 
• History of, or positive test result at Screening, for hepatitis C virus antibody.
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study. 
• Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed. 
• Current enrollment in any other interventional study.
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.

Inclusion Criteria - Part C:

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use PHI in accordance with national and local participant privacy regulations. In the case that a participant is legally incapable of providing informed consent, the participant’s legally authorized representative will be able to provide the informed consent.
• Aged  18 years at the time of informed consent.
• Weakness attributable to ALS and a confirmed SOD1 mutation:
  • SOD1 mutation must be confirmed by the central reader based on the sample obtained during the Screening Visit; participants with an SOD1 mutation interpreted by the central reader to be pathogenic or likely pathogenic will be eligible;
  • Additionally:
  • Prognostic enrichment criteria for rapid disease progression (participants may be eligible based on one of the following SOD1 mutations and a prerandomization ALSFRS-R slope decline of ≥ 0.2 per month (calculated as [48-baseline score]/time since symptom onset):
  • p.Ala5Val, p.Ala5Thr, p.Leu39Val, p.Gly42Ser, p.His44Arg, p.Leu85Val, p.Gly94Ala, p.Leu107Val, and p.Val149Gly; OR
  • SOD1 mutation other than those listed in item ‘a.’ with prerandomization ALSFRS-R slope decline of ≥ 0.9 per month (calculated as [48-baseline score]/time since symptom onset).
  • Criteria for all other eligible participants: SOD1 mutation other than those listed in item ‘a.’ (no ALSFRS-R slope decline requirement).
  • For participants who meet prognostic enrichment criteria for rapid disease progression, SVC ≥ 65% of predicted value as adjusted for sex, age, and height (from the sitting position). For all other eligible participants, SVC ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
    • Note: For SVC testing, at least 3 acceptable tests with the 2 highest acceptable (largest and next largest) efforts within 150 mL of vital capacity should be achieved.
• If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
• Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
• All women of childbearing potential must agree to practice effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment 1 of the following 2 criteria) [Hamidou 2017; Proudfoot 2016]:
  • One of the following SOD1 mutations and a prerandomization ALSFRS-R slope decline of ≥ 0.2 per month (calculated as [48-baseline score]/time since symptom onset): p.Ala5Val, p.Ala5Thr, p.Leu39Val, p.Gly42Ser, p.His44Arg, p.Leu85Val, p.Gly94Ala, p.Leu107Val, and p.Val149Gly; OR
  • SOD1 mutation other than those listed in item ‘a.’ with prerandomization ALSFRS-R slope decline of ≥ 0.9 per month (calculated as [48-baseline score]/time since symptom onset).
• Criteria for all other eligible participants: SOD1 mutation other than those listed in item ‘a.’ (no ALSFRS-R slope decline requirement).
• For participants who meet prognostic enrichment criteria for rapid disease progression, SVC ≥ 65% of predicted value as adjusted for sex, age, and height (from the sitting position). For all other eligible participants, SVC ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
  • Note: For SVC testing, at least 3 acceptable tests with the 2 highest acceptable (largest and next largest) efforts within 150 mL of vital capacity should be achieved. 5. If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
• Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
• All women of childbearing potential must agree to practice effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment.

Exclusion Criteria - Part C:

• History of or positive test result for HIV. 2.
• Current hepatitis C infection (defined as positive HCV Ab and detectable HCV RNA). Participants with positive HCV Ab and undetectable HCV RNA are eligible to participate in the study (United States Centers for Disease Control and Prevention).
• Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
• Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
• Current enrollment in any other interventional study.
• Current or anticipated need, in the opinion of the Investigator, of a DPS during the study period.
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine.
• History of drug abuse or alcoholism within ≤ 6 months of study enrollment that would limit participation in the study, as determined by the Investigator.
• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
• Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that according to the Investigator would interfere with the conduct or assessments of the study.
• Female participants who are pregnant or currently breastfeeding.
• Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression ≤ 90 days, as determined by the Investigator.
• History of allergies to a broad range of anesthetics.
• Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding. These could include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other abnormalities) and underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand’s disease, liver disease).
• Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication that cannot be safely held before and/or after an LP procedure according to local or institutional guidelines and/or Investigator determination.
• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
• Clinically significant abnormalities in hematology or clinical chemistry parameters, as determined by the Investigator, which would render the participant unsuitable for enrollment. For a list of normal, acceptable, and exclusionary ranges, please refer to the study reference guide.
• Clinically significant, as determined by the Investigator, 12-lead ECG abnormalities, including corrected QT interval using Fridericia’s correction method of > 450 ms for males and > 470 ms for females.
• Inability to comply with study requirements.
• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the participant unsuitable for enrollment.

Eligibility last updated 8/19/21. Questions regarding updates should be directed to the study team contact.