Posted: 23 July 2024
Alterity Therapeutics (ASX: ATH, NASDAQ: ATHE) (“Alterity” or “the Company”), a biotechnology company dedicated to developing disease modifying treatments for neurodegenerative diseases, today announced positive interim data from the ATH434-202 open-label Phase 2 clinical trial in patients with multiple system atrophy (MSA). ATH434 has been shown preclinically to reduce α-synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain.
The interim analysis included clinical and biomarker data on 7 participants treated with ATH434 for 6 months and neuroimaging data on 3 participants who were treated for 12 months. After 6 months of treatment, 43% of participants showed improvement on the UMSARS1, indicating reduced disability on activities of daily living. Over the same period, 29% of participants had stable or improved neurological symptoms (clinical responders) as assessed by both the treating physician and the patient. Importantly, the clinical responders on average had reduced accumulation of iron on MRI in the substantia nigra, putamen and globus pallidus and stable levels of NFL, a marker of axonal injury, when compared to participants who declined.
“I am very encouraged by these positive interim data in advanced MSA patients,” said David Stamler, M.D., Chief Executive Officer of Alterity. “As MSA is a rapidly progressive and unremitting disease, we expected to see decline in all participants. Instead, we saw favorable clinical and biomarker outcomes in some patients suggesting that ATH434 has the potential to modify the course of this devastating condition. We were also very pleased to see that the clinical responders had biomarker evidence of stable disease as this provides an objective indication of potential efficacy.”
Dr. Stamler, continued, “In the ATH434-202 trial, the participants who stabilized or improved with ATH434 treatment had less advanced disease than those who progressed. This is noteworthy as we have enrolled earlier stage MSA patients in our randomized, double-blind clinical trial ATH434-201. Although the number of patients studied thus far is small, the new data reinforces that we have taken the right approach in our randomized trial and increases my overall confidence in the ATH434 development program.”
Daniel Classen, M.D., M.S., Professor of Neurology at Vanderbilt University Medical Center and principal investigator for the ATH434-202 Phase 2 study, commented “I am gratified to see that the work we have done over the last several years is bearing fruit as we enhance our understanding of MSA. This has led to improved patient selection and optimized biomarker endpoints in the Alterity Phase 2 trials. The clinical observations in the ATH434-202 study are supported by the objective biomarkers of brain volume, brain iron, and NfL. These early data increase our confidence that we have chosen the right biomarker and clinical endpoints to evaluate the potential effect of ATH434 in individuals with MSA. I am grateful to the study participants and their family members for their contributions to the study.”
ATH434-202 Interim Results
A total of 10 participants have been enrolled in the trial. The interim data reported today is from the 7 patients who have completed six months of treatment with ATH434, 3 of whom have also completed 12 months of treatment. Only neuroimaging data are available from month 12. The participants in the trial were diagnosed with MSA using a multimodal approach (clinical, neuroimaging, fluid biomarkers) and treated with oral ATH434 75 mg twice daily.
Clinical, biomarker and safety assessments were conducted during the study. While the data are preliminary, the Company sees a positive trend with the current participant patient outcomes.
Clinical Assessments at Month 6
Unified MSA Rating Scale Part I, historical review (UMSARS)
- 43% (3/7) of participants had lower scores (improvement) on the UMSARS that assesses activities of daily living affected in MSA, such as speech, swallowing, walking and urinary/bowel function.
- In the trial, mean (SD) UMSARS scores (N=7) increased from baseline to 6 months by
1.7 (5.1) points. These study data compare favorably to historical data in a similar MSA population that demonstrated an increase of 3.9 (4.6) points over 6 months.2
Global Impression of Change
- 29% (2/7) of participants stabilized or improved on the Clinical Global Impression of
Change (CGIC) scale, which asks the investigator to evaluate overall neurological symptoms as compared to immediately before starting therapy.
- 29% (2/7) of participants also stabilized or improved on the Patient Global Impression of Change (PGIC) scale which asks the patient to evaluate their overall neurological symptoms as compared to immediately before starting therapy.
Safety
- In general, ATH434 was well tolerated by study participants and most adverse events were mild to moderate in severity.
- No serious adverse events related to study drug were reported.
Biomarker Assessments at Month 6 and Month 12 MRI Biomarkers (n=7):
- Brain Volume:
- At Month 6, there were similar declines in brain volume, as assessed by the MSA- atrophy index (MSA-AI)3 in all participants consistent with the nature of MSA.
- However, in the clinical responders, brain volume assessed by the MSA-AI was stable between Month 6 and Month 12.
- Iron content in the substantia nigra was stable over 12 months in the clinical responders.
- Myoinositol is an exploratory biomarker of glial cell pathology in MSA. Treatment with ATH434 led to smaller increases in myoinositol in clinical responders compared to participants who worsened.
Fluid Biomarkers (n=5):
- Neurofilament Light Chain (NfL) is a marker of axonal injury in neurons and has been shown to correlate with disease severity in many neurological diseases. In the trial, clinical responders had stable spinal fluid NfL levels on average whereas those who declined clinically had increased spinal fluid NfL levels.
