Amyotrophic lateral sclerosis/ Motor Neurone Disease (ALS/MND) is a rare and invariably fatal neurological disease. ALS/MND has a terribly high burden on patients, family and carers, and carries great socioeconomic burden. Current best treatment options are expensive and attempt to control disease progression and manage symptoms while offering no cure. Better treatments are wanting.

Monepantel is a well-known veterinary drug, registered as a livestock wormicide in 39 countries. The industry collaborator, PharmAust Ltd, has found that monepantel shows off-target activity, inhibiting a cellular signaling system controlled by mammalian target of rapamycin (mTOR). This stops cancer growth and reduces protein accumulation in diseased cells. PharmAust has already tested monepantel in humans and pet dogs in Phase I and II anti-cancer clinical trials, respectively, in Australia. Data from these trials show that monepantel treatment associates with an exceptionally high safety profile, mTOR signaling inhibition and anticancer activity.

Abnormal protein accumulation within motor neurons of the brain associates with the cause of ALS/MND. Inhibition of the mTOR signaling pathway slows disease progression in certain preclinical models of ALS/MND and is suggested to provide synergy with the ALS/MND standard-of-care drug, riluzole. An alternative mTOR inhibitor, rapamycin, is currently the subject of an ALS/MND clinical trial in humans investigating control of disease progression. Monepantel has a different structure to rapamycin and an apparently better safety profile.

This Phase I Clinical Trial hypothesis is that monepantel administration to individuals living with ALS/MND will safely reduce disease associated protein accumulation in motor neurons and provide therapeutic benefit. To test this hypothesis, the safety and tolerability of oral monepantel administration and markers of efficacy will be tested in individuals living with ALS/MND in a dose escalating Phase I/II Clinical Trial. To mitigate risk, only patients with sporadic and certain known familial types of ALS will be eligible. To further mitigate risk, the monepantel starting dose will be reduced a calculated five-fold compared to that already used in human cancer patients and already demonstrated to be safe and effective as an mTOR inhibitor. Dependent upon incremental outcomes, three higher doses may then be tested, each for minimally 28 days with a duration at the optimal dose of at least six months.

Inclusion Criteria:

• Signed informed consent obtained prior to initiation of any study-specific procedures and treatment

• Familial or sporadic ALS/MND diagnosed as clinically possible, probable, or definite according to Awaji-shima Consensus Recommendations

• Seated slow vital capacity (SVC) ≥ 3L in males and ≥ 2.5L in females at screening

• Not taking riluzole or on a stable dose of riluzole for at least 4 weeks prior to the screening visit. While on study, subjects are not allowed to start taking riluzole during the study

• Patient has a competent caregiver who can support the patient's involvement in the study, including assisting the administration of study drug

• Adequate bone marrow reserve, renal and liver function:

  1. absolute neutrophil count (ANC) ≥1500/µL;
  2. platelet count ≥ 100,000/µL;
  3. hemoglobin ≥ 9 g/dL;
  4. creatinine clearance ≥ 60 mL/min (Cockroft & Gault formula);
  5. alanine aminotransferase ALT, SGPT) and/or aspartate aminotransferase (AST, SGOT)
  6. ≤ 2 x upper limit of normal (ULN);
  7. total bilirubin ≤ 1.5 x ULN;
  8. serum albumin ≥ 2.8 g/dL

• Women and men with partners of childbearing potential must use effective contraception while on study treatment and women of childbearing potential must have a negative pregnancy test at screening

Exclusion Criteria:

• Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g., malabsorption) deemed to jeopardize intestinal absorption of study drug

• Dependence on mechanical ventilation (invasive or non-invasive, including Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP) for any part of day or night prior to the screening visit. Dependence on mechanical ventilation is defined as being unable to lie flat (supine) without it, unable to sleep without it, or daytime use

• Exposure to any other investigational agent within 3 months prior to the screening visit

• Active gastrointestinal disease within 30 days of the screening visit. Gastro-esophageal reflux disease (GERD) is not considered active gastrointestinal disease and is not exclusionary

• Known immune compromising illness or treatment

• Presence of any of the following clinical conditions:

  1. drug abuse or alcoholism;
  2. unstable cardiac, pulmonary, renal, hepatic, endocrine, or hematologic disease;
  3. active infectious disease;
  4. AIDS or AIDS-related complex;
  5. diagnosis of malignancy within 2 years of screening (adequately treated basal cell or squamous cell carcinoma of skin or non-invasive bladder cancer or carcinoma in situ of the bladder, breast or cervix are allowed;
  6. unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit;
  7. neuromuscular disease other than ALS/MND

• Dementia that may affect either outcome measures or patient understanding and/or compliance with study requirements and procedures

• Women and men of childbearing potential not using effective contraception while on study treatment

• Women who are breast-feeding

• Patients at risk of or known to carry a SOD1 mutation or VCP mutation