An Open Label Extension Study of Monepantel in Individuals With Motor Neurone Disease

ALS/MND is a progressive, fatal neurodegenerative disease; characterized by motor neuron loss resulting in muscle weakness and atrophy, disability, and eventually death from failure of the ventilatory muscles. The median age of onset is 55 years and average survival is 3-5 years after onset of the first symptoms. The only FDA-approved disease modifying medications confer only a modest survival benefit. Given the poor prognosis and dearth of effective treatments, clinical studies are of primary importance for people with ALS/MND.

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. PharmAust has shown that MPL and its major metabolite MPL sulfone (MPLS) have activity against mTOR signaling pathways in humans; based on published data, the inhibition of mTOR may be relevant to the treatment of ALS/MND.

This Phase I Open Label Extension will further test the hypotheses that MPL administration to individuals living with ALS/MND will safely reduce disease associated protein accumulation in motor neurons and provide therapeutic benefit. The safety and tolerability of oral monepantel administration and markers of efficacy will continue to be tested in the same participants that completed the Phase I Study (MON-2021-001).

A daily dose of 10 mg/kg monepantel (QD) will be studied in the Open Label Extension Study (MON-2023-001) to further evaluate long-term safety and efficacy in participants with MND/ALS that completed the Phase I Study (MON-2021-001). Based on the previous pre-clinical efficacy data and clinical safety data, a dose of 10 mg/kg QD is estimated to produce the most robust mTOR inhibition while still being well tolerated. The 10 mg/kg QD dose was the maximum dose evaluated in the Phase 1 Study.

Inclusion criteria

• Signed informed consent obtained prior to initiation of any study specific procedures and treatment.
• Individuals who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Able to swallow study drug tablets.
• Individuals must have completed Study MON-2021-001 and, in the opinion of the investigator, have been compliant with the study procedures and study treatment.
• Diagnosis of ALS/MND defined as clinically possible, probable, or definite according to Awaji-shima Consensus Recommendations.
• Not taking riluzole or on a stable dose of riluzole for at least 4 weeks prior to the screening visit; subjects are not allowed to start taking riluzole during the study.
• Individual has a competent caregiver/support person who can and will be able to support the individual's participation in the study, including assisting with the administration of study drug.
• Adequate bone marrow reserve, renal and liver function:

• absolute neutrophil count ≥ 1500/µl.
• platelet count ≥ 120,000/µl.
• hemoglobin ≥ 11 g/dL.
• creatinine clearance ≥ 60 mL/min (Cockroft & Gault formula).
• alanine aminotransferase and/or aspartate aminotransferase ≤ 3 x upper limit of normal.
• total bilirubin ≤ 2.0 x ULN.
• 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 be non-lactating.

Exclusion criteria

• Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g., malabsorption) deemed to jeopardize intestinal absorption of study drug.
• Participated in another investigational drug research study within 4 weeks (28 days) of the Baseline Visit or five half-lives of the drug, whichever is longer.
• Any other significant illness or condition that in the opinion of the study investigator would interfere with the study conduct.
• Dementia that may affect either outcome measures or subject 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.
• Individuals at risk of or are known to carry a SOD1 mutation or VCP mutation.