Therapeutic Nanocatalysis to Slow Disease Progression of Amyotrophic Lateral Sclerosis (ALS)

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study in Early Symptomatic Amyotrophic Lateral Sclerosis Patients on Stable Background Therapy to Assess Bioenergetic Catalysis With CNM-Au8 to Slow Disease Progression in ALS.

The objective of this trial was to assess the efficacy, safety, and PK/PD effects of CNM-Au8 as a disease-modifying agent for the treatment of ALS by utilizing electrophysiological measures to detect preservation of motor neuron function. The primary endpoint was the mean change in the average difference between active treatment and placebo from Baseline through Week 36 evaluated by electromyography.

This was a multi-centre randomized, double-blind, parallel group, placebo-controlled study of the efficacy, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who are newly symptomatic within 24-months of Screening and with a clinically probable or possible or definite ALS diagnosis per the Awaji-Shima criteria.

Patients were screened over up to a 6-week period. Patients who met the inclusion criteria and none of the exclusionary criteria were enrolled into the clinical study. Patients were randomized 1:1 into one of two groups: either active treatment with CNM-Au8 30 mg or Placebo.

All patients received their randomized oral treatment daily over thirty-six (36) consecutive weeks during the Treatment Period.

There were up to four study periods:

1. Up to a six (6) week screening period (Screening Period);
2. A thirty-six (36) week blinded randomized treatment period (Treatment Period);
3. Up to a forty-eight (48) week optional open-label extension period (Open-Label Period);
4. A four (4) week safety follow-up period following completion of either the Treatment or Open-Label period or in the case of Early Termination (Safety Follow-Up Period).

Per protocol, all patients received their blinded and randomized oral treatment daily over at least 36 consecutive weeks during the Treatment Period.

For those patients not transitioning into the optional OLE period, patients completed a safety follow-up visit 4-weeks following study drug discontinuation.

An independent DSMB was responsible for monitoring the safety of the study on a quarterly basis and ad hoc at the request of the DSMB or the Sponsor (e.g., in the event of unexpected SAEs) to review data throughout the Treatment Period. The DSMB may make recommendations on the conduct of the study, including study termination. Appropriate procedures will be detailed in a DSMB Charter.

Inclusion Criteria:

1. Able to understand and give written informed consent.
2. Male or female patients aged 30 years or greater (inclusive) and less than 80 years of age at the time of Screening.
3. Patients whose conditions are defined as possible or probable or definite ALS per the diagnostic criteria by Awaji-Shima criteria as determined by a neurologist sub- specialising in ALS (e.g., the Principal Investigator by study site).
4. For patients taking riluzole, stable dosing of riluzole over the prior 30-days from Screening.
5. At the time of Screening either disease duration less than or equal to 24-months from symptom onset, or disease duration less than or equal to 12-months from diagnosis.
6. Forced vital capacity (FVC) 60% of predicted value as adjusted for gender, height, and age at the Screening Visit.
7. Patient who has established care with a neurologist at one of the specialized ALS clinics involved in the study and will maintain this clinical care throughout the study. If a patient is referred from a third party (neurologist or a State based ALS organization) they must be willing to transfer care to the neurologist participating in the study.

Following completion of the 36-week randomized placebo controlled treatment period, interested participants must meet the following inclusion criteria to enroll in the open-label extension:

1. Participants must have completed the randomized placebo controlled Treatment Period without compliance issues
2. Able to understand and give written informed consent to participant in the open-label extension.
3. If referred from a third party (neurologist or a State based ALS organization), participant agrees to maintain transfer of care to a neurologist participating in the study.

Exclusion Criteria:

1. Patients will be excluded from the study if they meet any of the following criteria:

2. At Screening patients who utilize, or in the Investigator's judgment will be imminently dependent upon:

   1. Non-invasive ventilation > 22 hours per day, or
   2. Tracheostomy Note: If the patient requires non-invasive ventilation postrandomisation, they will be allowed to continue in the study.

3. Patients with Familial ALS (e.g., 2 or more family members with ALS or motor neuron disease)

4. Patients with a history of carpal tunnel syndrome, polyneuropathy, or in the investigators judgement diseases that could induce polyneuropathy and interfere with electromyography (EMG) recordings.

5. Patients with too severe atrophy of the Abductor Digiti Minimi (ADM), Abductor Pollicis Brevis (APB), Biceps Brachii (BB), or Tibialis Anterior (TA) muscles in the least clinically affected hand and leg, respectively, to allow for reliable EMG recordings.

6. Patient with a history of significant other major medical conditions based on the Investigator's judgment.

7. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures.

8. Patient with clinically significant abnormalities in haematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator can interfere with study participation.

9. Patients with clinically significant hepatic or renal dysfunction or clinical laboratory findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (< 150 x 109 per liter) or eosinophilia (absolute eosinophil count of ≥ 500 eosinophils per microliter) at Screening.

10. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter).

11. Females who are pregnant or nursing or who plan to get pregnant during the course of this clinical trial or within 6 months of the end of this trial.

12. Females of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control.

13. Active inflammatory condition or autoimmune disorder.

14. Positive screen for drugs of abuse.

15. History of gold allergy.

16. Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.

Following completion of the 36-week randomized placebo controlled treatment period, interested participants will be excluded from participating in the open-label extension phase if they meet any of the following criteria:

1. Lack of treatment compliance during the randomized placebo controlled Treatment Period.

2. Positive pregnancy test at the Week 36 visit, or, females who plan to get pregnant during the course of this extension or within 6 months of the end of this extension.

3. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or any study procedures.

4. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or physical examination identified during the W36 visit which according to Investigator may interfere with continued participation.

5. Patients with clinically significant hepatic or renal dysfunction or clinical laboratory.

   findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (< 150 x 109 per liter) or eosinophilia (absolute eosinophil count of ≥ 500 eosinophils per microliter) at the Week 36 visit.

6. Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.