PharmAust announces positive Phase 1 MEND Study Top-Line Results in MND / ALS
Highlights:
- Monepantel displays a superior safety, tolerability to the leading FDA approved drug Relyvrio®
- Preliminary efficacy data shows a 58% reduction in the rate of disease progression for Cohort 2 (High Dose) using the FDA primary efficacy endpoint, ALSFRS-R
- Confirmation that monepantel and its active metabolite, monepantel sulfone, are both detected in cerebrospinal fluid
- Optimal dose identified for the pivotal Phase 2/3 clinical study, due to commence in Q3 CY2024
Study Design
The Phase 1 MEND Study was a multicentre, open label study comprising a 24-hour escalating single-dose PK study and 4-week repeated escalating dose study to establish the safety, tolerability and pharmacokinetic (PK) parameters of MPL administered orally to patients with MND/ALS. Twelve participants were enrolled in cohorts of 6 patients across 2 sites. Cohort 1 was administered 2 and 6 mg/kg/day dose levels, and Cohort 2 was administered 4 and 10 mg/kg/day dose levels. Participants continued to receive MPL treatment until they were offered dose escalation or until the end of treatment.
Safety and Tolerability Endpoints
The safety and tolerability profile of MPL included no treatment‑related deaths, with all 12 patients successfully completing the study, and no dose limiting toxicities experienced. A total of 56 treatment‑emergent Adverse Events (AEs) were reported. Only 3 AEs, graded mild, were considered possibly related to the study drug.
Patients have remained on daily treatment of MPL for 10 to 16 months. Upon completing the study, all participants continued receiving MPL via a special access scheme and opted to enrol on a 12-month open-label extension (OLE) study.
Exploratory Efficacy Endpoints
The study's exploratory clinical efficacy markers included the ALS Functional Rating Scale-Revised ("ALSFRS-R"), ALSSQOL-R Quality of Life Questionnaire, Edinburgh Cognitive and Behavioural ALS Screen ("ECAS") and Slow Vital Capacity ("SVC"), a measure of respiratory function.
ALSFRS-R is the accepted FDA primary efficacy measure to determine ALS disease progression. It assesses for changes in a person's physical abilities over time of 12 specific functions including speech, walking, climbing stairs, dressing/hygiene, handwriting, turning in bed, cutting food, salivation, swallowing and breathing.
There were no significant differences in ALSFRS-R scores between pre-dose and end of treatment for all 12 patients (p=0.78), Cohort 1 (p=0.41), and Cohort 2 (p=0.88) suggesting that treatment with monepantel over 8 – 12 months slowed the rate of disease progression.
A more thorough comparative analysis of the rate of decline in ALSFRS-R scores performed by
For all 12 patients, the estimated rate of decline was -0.74 (p=0.08) in ALSFRS-R points per month or a 39% slowing in ALSFRS-R decline. For Cohort 1 the estimated rate of decline was -0.83 (p=0.40) in ALSFRS-R points per month or a 23% slowing in ALSFRS-R decline. For Cohort 2 the estimated rate of decline was -0.60 (p=0.11) in ALSFRS-R points per month or a 58% slowing in ALSFRS-R decline indicating a dose response.
Using the prognostic predictor model described in Elamin et al., 2015,[1]depending on the current severity of the disease, a 0.48 slope change as calculated for all 12 patients could provide patients with an additional 13.5- 56.5 months in median survival. Currently approved treatments for ALS/MND provide approximately 2 – 9 months in additional life expectancy.
|
Estimated Rate of Decline (points per month) * |
Slowing in ALSFRS-R Decline * |
Additional Life Expectancy ** |
Combined Cohort 1 + 2 |
- 0.74 |
39 % |
13.5 – 56.5 months [1] |
Cohort 1 (Low Dose) |
- 0.83 |
23 % |
|
Cohort 2 (High Dose) |
- 0.60 |
58 % |
|
Relyvrio ® |
- 1.24 |
25 % |
9 months |
*
The results of the additional exploratory efficacy measures of ALSSQOL-R (p=0.11), ECAS (p=0.21), and SVC (p=0.93) further supported slowing in disease progression. In addition, the analysis of biomarkers provided supplemental supporting evidence that MPL slows disease progression with a large reduction in cerebrospinal fluid neurofilament light chain (NfL), which is a measure of neuronal damage, amongst consenting patients (n=3).
Pharmacokinetics
Concentrations of MPL sulfone, the active metabolite of MPL, increased proportionally with the higher doses of MPL. MPLS was found in the cerebrospinal fluid indicating that both MPL and MPLS have the ability to cross the blood brain barrier.
Target Engagement (mTOR Pathway)
Target engagement of the mTOR pathway (p-EIF4EBP1 and p-RPS6KB1) in the peripheral mononuclear blood cells was confirmed at all dose levels.
MEND participant, S-W, commented:
"The Monepantel phase 1 study has been a very positive experience for me with no ill effects at all. At Calvary I have been treated with the most kind, caring and considerate doctors, nursing & administration staff and I know I am receiving the best care possible. I am more than happy to participate in this trial with the knowledge that MND patients may be helped in the future."
MEND participant, L-G, commented:
"I feel that the Monepantel may have slowed my neurological deterioration. Increasing dosage from 3 per day to 4 may also have been beneficial. My dosage was increased to 6 several days ago. There appears to be no side effects with it."
Associate Professor
"This study has shown oral Monepantel to be safe and well tolerated by people with MND. Given the promising findings on preliminary efficacy markers, I look forward to progressing a phase 2 study as soon as possible"
"The release of the top-line Phase 1 MEND study results is an exciting milestone for
About FightMND
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About
MPL is a potent and safe inhibitor of the mTOR pathway. This pathway plays a central role in cell growth and proliferation of cancer cells and degenerating neurons. The mTOR pathway regulates the cellular "cleaning process", where toxic protein is broken down into macromolecules to be reused. This autophagic process is disrupted in most neurodegenerative diseases, including motor neurone disease (MND/ALS).
PAA's lead MPL program is for the treatment of MND/ALS, a rare, incurable disease. The company is currently completing a Phase 1 study in patients with MND/ALS. Top-line results are expected to be announced in Q1 CY2024. PAA anticipates starting an adaptive Phase 2/3 clinical study in H2 CY 2024 that could lead to accelerated approval with the
[1]Elamin M, Bede P, Montuschi A, Pender N, Chio A, Hardiman O. Predicting prognosis in amyotrophic lateral sclerosis: a simple algorithm. J Neurol. 2015 Jun;262(6):1447-54. doi: 10.1007/s00415-015-7731-6. Epub 2015 Apr 11. PMID: 25860344; PMCID: PMC4469087. |
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