Clinical Trials

Inclusion Criteria:

• Subjects diagnosed with mutant SOD1-mediated ALS experiencing signs and/or symptoms of lower motor neuron dysfunction (weakness, atrophy, cramps, fasciculations), with or without upper motor neuron symptoms (weakness, brisk reflexes, spasticity).
  • SOD1-mediated is defined by the presence of a SOD1 coding mutation on a gene test conducted by an accredited lab; specifically, the variation/mutation must be listed in the National Center for Biotechnology Information (NCBI ) ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) as Pathogenic, Pathogenic/Likely Pathogenic, or Likely Pathogenic within the SOD1 gene.
• Subjects with rapidly progressing disease (“fast” progressors), defined as average ALSFRS-R decline > 1.0 per month calculated from score at onset of symptoms compared to score at Screening ALSFRS-R • ALSFRS-R score of 48 is assigned at onset of symptoms of weakness unless otherwise documented in medical history.
• Male or female, aged 18 years or older
• Slow vital capacity (SVC) ≥65% of predicted normal value on Screening assessment.
• King’s stage ≤ 3 at Screening.
• Capable of providing informed consent and complying with trial procedures, in the documented opinion of the Investigator, including:
  • Medically able to undergo lumbar puncture for treatment and collection of CSF, in consideration of known medical status (e.g., bleeding diatheses, allergy to local anesthetics, skin infection at or near the lumbar puncture site, indications of possible raised intracranial pressure, abnormal spine skeletal issues);
  • Physically and mentally able to lie in protocol-required position for the duration of the intrathecal infusion;
  • Willing to forego addition of any new FDA-approved treatments for ALS or participation in other clinical studies of treatment for ALS through at least 12 months after initial APB102/placebo treatment in Part 1 or Part 2 of the study;
  • Has a responsible caregiver able to attend all clinic visits with the subject.
• Titer for neutralizing antibodies (NAb) to AAV rh10 > [1:50] at Screening.
• Normal renal clearance at Screening defined as creatinine clearance ≥ 60 milliliters per minute (mL/min) using the Cockroft-Gault equation.
• Normal coagulation function, defined as international normalized ratio (INR) ≤ 1.1 (based on Screening labs prior to enrollment/randomization and Day -7 labs prior to APB-102/placebo treatment).
• Platelet count > 100,000/mL (based on Screening labs prior to enrollment/randomization and Day -7 labs prior to APB-102/placebo treatment).
• For subjects on anticoagulant or antiplatelet therapy:
  • Able to temporarily stop or bridge therapy for the APB-102/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.)
  • Documentation for this criterion must be reviewed and confirmed by the Sponsor.
  • Note: The fast-progressing mutation H43R is excluded from this study because it falls within the MiR targeting region.
• Homozygosity for the D91A (formerly D90A) SOD1 gene mutation.
• History of significant chronic pain or sensory syndrome such as fibromyalgia, complex regional pain syndrome, or peripheral neuropathy that, in the Investigator’s opinion, would preclude enrollment of such subject in the study.
• Presence of unstable psychiatric illness defined as psychosis (hallucinations or delusions) or untreated major depression within 90 days of signing the informed consent form (ICF).
• Columbia Suicide Severity Rating Scale (C-SSRS) score of 4 or greater at Screening.
• Reproductive status that includes any of the following:
  • Women who are pregnant or have positive pregnancy test at Screening or during Leadin 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 including tumors or hyperplasia, Chiari malformation, or high-grade central canal stenosis that, in the Investigator’s opinion, may impact intrathecal infusion or cause difficulty placing the catheter.
• Known allergy or sensitivity to immunosuppression regimens in this protocol.
• Unstable cardiac function including cardiac arrhythmia requiring chronic medication, prolonged QT > 450 milliseconds (ms) as calculated by Fredericia’s formula (QTcF), congenital long QT syndrome, history suggestive of torsades de pointes, heart failure, or other clinically significant abnormalities on electrocardiogram (ECG) performed at Screening.
• 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 mechanical 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 such that they would preclude safely starting immunosuppression, undergoing surgery, or receiving treatment.
• Clinically significant liver function abnormality at Screening [including ALT > 1.5 x upper limit of normal (ULN), Total Bilirubin > ULN].
• 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 ICF;
  • Planned treatment with live vaccines during Lead-in period or at any time after receipt of APB-102/placebo;
  • Warfarin within 30 days prior to Screening labs.
  • Note: 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.
• Known travel issues that would impair compliance with study visits and return to site for adverse events (AE) follow-up as necessary.
• 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.

Eligibility last updated 8/30/21. Questions regarding updates should be directed to the study team contact.