A Study of Monepantel in Individuals With Motor Neurone Disease

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Tolerability, Safety, Pharmacokinetics and Preliminary Efficacy Study of Oral Monepantel in Individuals With Motor Neurone Disease

Conditions
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Motor Neuron Disease

Intervention / Treatment
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* Drug: Monepantel


Participation Criteria
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Eligibility Criteria
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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: absolute neutrophil count (ANC) ≥1500/µL; platelet count ≥ 100,000/µL; hemoglobin ≥ 9 g/dL; creatinine clearance ≥ 60 mL/min (Cockroft & Gault formula); alanine aminotransferase ALT, SGPT) and/or aspartate aminotransferase (AST, SGOT) ≤ 2 x upper limit of normal (ULN); total bilirubin ≤ 1.5 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 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: drug abuse or alcoholism; unstable cardiac, pulmonary, renal, hepatic, endocrine, or hematologic disease; active infectious disease; AIDS or AIDS-related complex; 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; unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit; 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monepantel treatment arm<br>Monepantel tablets will be administered to participants in this arm daily for 28 days. Dose escalation will occur at the end of each 28 day period according to a modified Fibonacci sequence based upon recommendations from the safety management committee | Drug: Monepantel<br>* Monepantel is provided to individuals living with ALS/MND as a white oval tablet to be administered once a day following meals<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Phase 2 Dose | A recommended phase 2 dose will be determined by the number of participants at each dose level recording dose limiting toxicities | At least 4 weeks | 
| Blood Plasma Pharmacokinetics of Monepantel | Characterise monepantel blood plasma levels following administration to individuals living with ALS/MND | 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing | 
| Blood Plasma Pharmacokinetics of Monepantel Sulfone | Characterise monepantel's major metabolite monepantel sulfone blood plasma levels following administration of monepantel to individuals living with ALS/MND | 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and 2, 8, 15, 22 and 29 days after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related changes in peripheral blood mononuclear cell phosphorylated ribosomal protein S6 kinase B1 (RPS6KB1) levels (pharmacodynamics) | Changes RPS6KB1 phosphorylation levels will assist in determining if the proposed targeted mammalian target of rapamycin (mTOR) pathway is being correctly affected (photostimulated luminescence units) | From admission to discharge, up to 6 months | 
| Treatment related changes in peripheral blood mononuclear cell phosphorylated eukaryotic initiation factor 4 E binding protein 1 (EIF4EBP1) levels (pharmacodynamics) | Changes EIF4EBP1 phosphorylation levels will assist in determining if the proposed targeted mammalian target of rapamycin (mTOR) pathway is being correctly affected (photostimulated luminescence units) | From admission to discharge, up to 6 months | 
| Treatment-related changes from Baseline on the ALS Functional Rating Scale (ALSFRS) at Week 4 | The ALS Functional Rating Scale (ALSFRS) is a validated rating instrument for monitoring the progression of disability in patients with amyotrophic lateral sclerosis (ALS). Measurements include: (1) speech (2) salivation (3) swallowing (4) handwriting (5) cutting food and handling utensils (with or without gastrostomy) (6) dressing and hygiene (7) turning in bed and adjusting bed clothes (8) walking (9) climbing stairs and (10) breathing. Possible scores range from 0 (normal function) to 4 (severe loss of function). Change = (Week 4 score - Baseline score) | From admission to discharge, up to 6 months | 
| Treatment-related changes from Baseline in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) at Week 4 | The ECAS-cognitive screen is a validated screen comprises 16 items organized into two sub-scales. An ALS-specific sub-scale taps into the cognitive domains of language, verbal fluency, and executive and social functions. A non-ALS-specific sub-scale specifically assesses memory and visuospatial function. The sub-scales of the ECAS-cognitive screen range, respectively, from 0 to 100 and from 0 to 36. Low scores indicate a greater deficit. Change = (Week 4 score - Baseline score) | From admission to discharge, up to 6 months | 
| Treatment-related changes from Baseline in slow vital capacity (SVC) | A decline in SVC would indicate a decline in respiratory function and is an important indicator of any clinical progression (L/s) | From admission to discharge, up to 6 months | 
| Treatment-related changes in urinary p75 levels | Urinary p75 level reflect nerve damage and therefore increased levels would act as a proxy to disease progression (ng/mg creatinine) | From admission to discharge, up to 6 months | 
| Treatment-related changes in 3 Tesla magnetic resonance imaging (MRI) | MRI is a method used to investigate and exclude conditions that may mimic motor neuron dysfunction (Tesla) | From admission to discharge, up to 6 months | 
| Treatment-related changes in serum neurofilament light (NfL) chain levels | Serum NfL chain levels correlate with disease progression, so stable NfL levels would correlate with stable disease (pg/ml) | From admission to discharge, up to 6 months | 
| Treatment-related changes in central spinal fluid (CSF) NfL chain levels | CSF NfL chain levels correlate with disease progression. Levels in individuals living with MND are 5 to 10 fold higher than those of healthy individuals (pg/ml) | From admission to discharge, up to 6 months |