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

• ClinicalTrials.gov Identifier: NCT06177431
• Recruitment Status: Recruiting
• First Posted: December 20, 2023
• Last Update Posted: April 15, 2024
• Sponsor: PharmAust Ltd
• Collaborators: Calvary Health Care Bethlehem; Macquarie University, Australia
• Information provided by (Responsible Party): PharmAust Ltd

Study Description

Brief Summary:

This study is a multicenter, 12-month open label extension study, following Phase 1 Study MON-2021-001, with a single dose of monepantel (MPL) once daily (QD) for the treatment of individuals with MND.

Condition or disease	Intervention/treatment	Phase
Motor Neuron Disease	Drug: Monepantel	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open Label Extension
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Extension Study to Investigate the Long Term Safety, Tolerability And Efficacy of Oral Monepantel in Individuals With Motor Neurone Disease Who Previously Completed Study MON-2021-001
• Actual Study Start Date: February 13, 2024
• Estimated Primary Completion Date: April 1, 2025
• Estimated Study Completion Date: April 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Monepantel treatment arm; Daily dose of 10 mg/kg body weight (QD)	Drug: Monepantel; Monepantel is provided to individuals living with ALS/MND as a white oval tablet to be administered once a day following meals

Outcome Measures

Primary Outcome Measures :

1. Long-term safety and tolerability [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   Assess long-term safety and tolerability of 10 mg/kg body weight (BW) once daily (QD) of monepantel in individuals with Motor Neurone Disease (MND)

Secondary Outcome Measures :

1. Treatment-related changes in serum neurofilament light (NfL) chain levels [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   Serum NfL chain levels correlate with disease progression, so stable NfL levels would correlate with stable disease (pg/ml)
2. Treatment-related changes in urinary p75 levels [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   Urinary p75 level reflect nerve damage and therefore increased levels would act as a proxy to disease progression (ng/mg creatinine)
3. Treatment-related changes on the ALS Functional Rating Scale (ALSFRS) [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   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)
4. Treatment-related changes on the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   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)
5. Treatment-related changes in slow vital capacity (in participants with the capacity to undergo testing) [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   A decline in SVC would indicate a decline in respiratory function and is an important indicator of any clinical progression (L/s)
6. Treatment-related changes in Quality of Life (QOL) Assessment: ALSSQOL-R [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   ALSSQOL-R is a 50-item disease-specific questionnaire. Each item is rated on a 10-point Likert scale, with 0 being the least desirable situation and 10 being the most desirable. The instrument produces a single-item QoL score and six domain scores (negative emotion, interaction with people and environment, intimacy, religiosity, physical symptoms, and bulbar function). The ALSSQOL-R is used as QoL outcomes measure to examine the effects of experimental treatments on individual's QoL.
7. Treatment-related changes in central spinal fluid (CSF) neurofilament light (NfL) chain levels [ Time Frame: From Baseline to End of Treatment, up to 12 months. ]
   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)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed informed consent obtained prior to initiation of any study specific procedures and treatment.
2. Individuals who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Able to swallow study drug tablets.
4. 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.
5. Diagnosis of ALS/MND defined as clinically possible, probable, or definite according to Awaji-shima Consensus Recommendations.
6. 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.
7. 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.

8. 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.
9. 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:

1. Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g., malabsorption) deemed to jeopardize intestinal absorption of study drug.
2. 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.
3. Any other significant illness or condition that in the opinion of the study investigator would interfere with the study conduct.
4. Dementia that may affect either outcome measures or subject understanding and/or compliance with study requirements and procedures.
5. Women and men of childbearing potential not using effective contraception while on study treatment.
6. Women who are breast feeding.
7. Individuals at risk of or are known to carry a SOD1 mutation or VCP mutation.

Contacts and Locations

Contacts

Contact: Michael Thurn; +61 8 9202 6814; michael@pharmaust.com

Contact: John Clark; +61 8 9202 6814; john@pharmaust.com

Locations

Australia, New South Wales

Macquarie University; Recruiting

Sydney, New South Wales, Australia, 2109

Contact: Dominic Rowe, PhD, FRACP, AM

Australia, Victoria

Calvary Health Care Bethlehem; Recruiting

Melbourne, Victoria, Australia, 3195

Contact: Susan Mathers, MB ChB, MRCP(UK), FRACP

Sponsors and Collaborators

PharmAust Ltd

Calvary Health Care Bethlehem

Macquarie University, Australia

Investigators

• Principal Investigator: Susan Mathers, BSc, MB ChB, MRCP(UK), FRACP; Calvary Health Care Bethlehem
• Principal Investigator: Dominic Rowe, AM, BSc(Med), MBBS(Hons), PhD; Macquarie University, Sydney

More Information

• Responsible Party: PharmAust Ltd
• ClinicalTrials.gov Identifier: NCT06177431
• Other Study ID Numbers: MON-2023-001
• First Posted: December 20, 2023
• Last Update Posted: April 15, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases