Alterity delivers encouraging phase II data in MSA trial

• Alterity presents promising phase II trial data of lead compound ATH434 in multiple system atrophy at international symposium 
• Data highlights symptom stability and enhanced efficacy signals in higher dose group 
• Analysis of phase II trial offers valuable insights to guide ongoing development and planning of phase III trial 

Special Report: Alterity Therapeutics’ phase II study of its lead compound ATH434 in multiple system atrophy (MSA) has been featured in an oral presentation at the American Autonomic Society (AAS) 36th International Symposium on the Autonomic Nervous System in Florida, USA. 

Alterity Therapeutics (ASX:ATH) said the presentation focused on analysis of baseline characteristics related to orthostatic hypotension (OH), a common and debilitating symptom of MSA, and its impact on the efficacy of ATH434.

OH is a form of low blood pressure that occurs when a person moves from a sitting or lying position to standing, causing symptoms such as dizziness, light-headedness, or fainting. 

It’s one of the most disabling symptoms in MSA and is associated with faster disease progression. In the study, ATH434 showed promise in treating OH. 

Lead author on the presentation was Professor of Neurology at the Vanderbilt University Medical Center in the US and coordinating investigator for the phase II trial Dr Daniel Claassen. 

Assistant professor in the Movement Disorders Department of Neurology at Vanderbilt University Medical Center Dr Amy E. Brown delivered the presentation. 

READ: ‘Tough nut to crack’, but expert tips Alterity’s MSA drug as potential game changer

The presentation highlighted data from ATH434-201 trial showing symptom stability and enhanced efficacy signals in the higher dose group. 

ATH434 stabilises orthostatic hypotension in MSA patients

In the phase II, double-blind, randomised trial, severe OH was defined as a sustained fall in systolic blood pressure of ≥30 mm Hg after three minutes of standing. 

Baseline data revealed that severe OH was much higher in the 75 mg dose group, affecting 29.2% of participants, compared with 4% in the 50 mg group and 4.5% in the placebo group. 

Alterity noted that this difference at baseline largely explains the variation in treatment responses between the dose groups.

When these blood pressure changes were included as a covariate in the analysis of the Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, the efficacy signal for the 75 mg dose strengthened from –2.4 to -2.8 points, improving the relative treatment effect from 30% to 35%.  UMSARS Part I measures functional disability in daily activities. 

Importantly, ATH434 maintained consistent efficacy across both doses when assessed using the OH Symptom Assessment, a patient-reported outcome previously accepted by the FDA for OH therapies. 

Over 52 weeks, placebo participants worsened by an average of six points on the OH Symptom Assessment, while participants receiving ATH434 remained stable.

These results suggest that ATH434 is potentially effective in stabilising both functional ability and OH symptoms in MSA patients, highlighting its potential as a disease-modifying therapy in this rare and rapidly progressive neurodegenerative disorder.

Targeting iron accumulation associated with MSA progression

ATH434 is Alterity’s lead clinical candidate and an oral iron chaperone designed to inhibit the aggregation of pathological proteins implicated in neurodegeneration. 

It has received Fast Track Designation by the US Food and Drug Administration (FDA) and Orphan Drug Designation by both the FDA and the European Commission for the treatment of MSA.

Preclinical studies have shown that ATH434 reduces α-synuclein pathology and preserves neuronal function by restoring normal iron balance in the brain. 

These properties position ATH434 as a potential disease modifying therapy not only for Parkinson’s disease but also for related Parkinsonian disorders, including MSA.

MSA is a rare, rapidly progressive neurodegenerative disorder characterized by failure of the autonomic nervous system and impaired movement. 

Symptoms result from the progressive loss of various types of nerve cells in the brain and spinal cord and include slowed movement, rigidity, autonomic instability, and impaired balance and coordination. 

A pathological hallmark of MSA is the accumulation of α-synuclein within glial cells and neuron loss in multiple brain regions. 

MSA affects up to 50,000 individuals in the U.S., and while some symptoms can be managed with medications, no therapies currently slow disease progression or provide a cure.

About the phase II trial 

The ATH434-201 phase II trial enrolled 77 adults who were randomised to receive ATH434 50mg or 75mg twice daily or matching placebo for 12 months. 

The study assessed efficacy, safety, and pharmacokinetics, as well as the effects of ATH434 on neuroimaging and protein biomarkers. 

Wearable sensors were employed to monitor motor activity outside of the clinic. 

Results demonstrated clinically and statistically significant improvements on the modified UMSARS part I functional scale.  

Additional efficacy measures, including the Parkinson’s Plus rating scale, the Clinical Global Impression of Severity, and the OH Symptom Assessment, supported these findings.

Wearable sensor data indicated increased activity in outpatient settings among participants treated with ATH434.

Biomarker analyses further showed that both ATH434 dose levels reduced iron accumulation in brain regions affected by MSA, with trends suggesting preservation of brain volume. 

ATH434 was well tolerated, with adverse events similar to placebo and no serious adverse events attributed to the drug.

Alterity has also completed a phase II open-label biomarker study in patients with more advanced MSA, which reinforced the positive results from the randomized trial. 

With this data, the company is actively planning phase III. 

ATH434 has ‘potential to profoundly impact MSA treatment’

Alterity CEO Dr David Stamler said its recent presentation at the AAS emphasised the impact of ATH434 on OH, a key symptom of MSA that strongly influences disease progression. 

“It is clear that future studies will need to control for clinical parameters such as OH, which can significantly affect disease trajectory.” 

He said data from the phase II trial was critical as the company designs its phase III trial protocol and prepares for discussions with the FDA.

“As we continue to closely examine the outcomes from our clinical trials, our confidence grows that ATH434 has the potential to profoundly impact MSA treatment and alter the course of disease progression,” he said.  

“We are actively planning this pivotal stage of our program in order to bring a meaningful treatment option to patients with MSA.”  

This article was developed in collaboration with Alterity Therapeutics, a Stockhead advertiser at the time of publishing. 

This article does not constitute financial product advice. You should consider obtaining independent advice before making any financial decisions.