Rethinking Clinical Trials In Rare Neurodegenerative Diseases: Lessons From Alterity's MSA Trial
By David Stamler, CEO, Alterity Therapeutics
Multiple system atrophy (MSA) is a rare and devastating neurodegenerative disease that remains largely overlooked despite its high disease burden and rapid progression. Often mistaken for Parkinson’s disease early in its course, MSA is a distinct condition that typically leads to severe disability within a few short years. Today, there are no approved treatments, and patients face a steep decline in independence and quality of life.
In this challenging therapeutic landscape, Alterity Therapeutics has been working to develop the first disease-modifying treatment for MSA. We recently reported positive Phase 2 clinical trial results demonstrating encouraging signs of efficacy for our lead investigational therapy, ATH434. The drug’s mechanism represents an important scientific advance, and crucially, the study’s innovative design may have been vital to demonstrate its potentially safe and efficacious profile in this challenging patient population.
The approach taken to design and conduct Alterity’s Phase 2 study of ATH434 in MSA highlights several important lessons for clinical trial development in rare neurodegenerative diseases, where patient populations are small and diagnosis is difficult. The use of biomarker-informed patient selection demonstrates how more targeted approaches may improve the detection of treatment-related signals in this challenging setting.
The Challenge Of Early And Accurate Diagnosis
A fundamental obstacle in MSA clinical research has been accurate diagnosis at an early stage of the disease. There is no definitive genetic- or biomarker-based diagnostic test that can reliably distinguish MSA from Parkinson’s disease or other neurologic disorders. Diagnosis of MSA is made using clinical criteria, which are quite specific when the disease has fully developed but far less reliable in the early phases. Early MSA symptoms such as imbalance, urinary difficulties, and motor dysfunction can overlap significantly with Parkinson’s disease and other forms of atypical parkinsonism. This overlap contributes to high rates of misdiagnosis and delays in enrollment for clinical trials.
This challenge is more than a logistical inconvenience. It has serious consequences for trial outcomes. Misdiagnosis of early-stage patients may blunt the efficacy signal of an effective treatment and late-stage MSA patients are typically less responsive to intervention. This dynamic may help explain why multiple studies of investigational agents in MSA have failed to show benefit.
A Biomarker-Guided Trial Design
To overcome this diagnostic uncertainty, Alterity designed its Phase 2 study of ATH434 with a deliberate focus on early-stage MSA. Our approach was informed by bioMUSE, a natural history study launched in collaboration with Vanderbilt University Medical Center. bioMUSE tracked individuals with clinically diagnosed early-stage MSA and evaluated a number of biomarkers, including advanced neuroimaging and fluid-based measures.
One of the key findings from bioMUSE was that certain neuroimaging features, such as patterns of iron accumulation and volume loss in MSA-affected brain regions, could help differentiate MSA from other parkinsonian disorders. In addition, levels of neurofilament light chain (NfL) in cerebrospinal fluid and blood provided a sensitive marker of neuronal damage, enabling us to distinguish (and exclude) patients with Parkinson’s disease.
Based on these findings, Alterity incorporated imaging and fluid biomarkers into the eligibility criteria for the Phase 2 trial. This biomarker-guided approach allowed us to enroll a cohort of patients who not only met clinical diagnostic criteria but also showed underlying biological signatures consistent with MSA. By improving diagnostic specificity at enrollment, the study design increased the likelihood of detecting treatment-related signals in a biologically defined patient population.
The trial also benefited from machine learning algorithms that improve the precision of MRI assessments. This state-of-the-art technology, designed and refined in the bioMUSE study, went above and beyond traditional MRI methods for assessing brain volume in patients with MSA. Defined as the MSA Atrophy Index, this novel tool utilizes deep learning methods, a form of AI, to precisely define the neuroanatomy of MSA affected brain regions. The MSA Atrophy Index was then used to track disease progression in MSA patients over one year in bioMUSE and the Phase 2 study. Results from the Phase 2 study showed that ATH434 demonstrated trends in reducing brain atrophy compared to placebo.
This added layer of technological support further enhanced the likelihood of enrolling true MSA patients in our Phase 2 trial at a time when slowing disease progression might still be possible and underscores the importance of utilizing advanced neuroimaging methods and analytical tools in evaluating MSA.
Toward A More Precise And Productive Model
In rare diseases like MSA, every patient enrolled in a clinical trial carries immense value. Optimizing patient selection is essential, not only for ethical reasons but to ensure that signals of efficacy can emerge within the constraints of small trial populations.
Alterity’s experience indicates strategies that incorporate disease-specific biomarkers can improve the detection of treatment-related signals. These lessons extend beyond MSA and may apply to other neurodegenerative conditions where clinical symptoms overlap with other diseases and diagnosis is uncertain.
Moreover, the trial design aligns with FDA efforts to modernize rare disease drug development. Regulators have increasingly encouraged the use of natural history data, predictive biomarkers, and flexible statistical approaches to advance programs where traditional randomized trials may not be feasible. ATH434’s development strategy may serve as a case study in how thoughtful design can help bridge the gap between biological plausibility and clinical relevance.
What Comes Next
Looking ahead to 2026, Alterity is preparing for an end-of-Phase 2 meeting with the FDA, which we expect to occur midyear. We aim to progress toward initiation of a pivotal Phase 3 trial following these regulatory discussions. The results from our Phase 2 study provide not just scientific validation of ATH434’s mechanism but also a blueprint for how to conduct future MSA studies with greater precision and purpose.
As drug development becomes more personalized and data-driven, trials in complex diseases will increasingly rely on integrated strategies that combine clinical observation, biomarker validation, and digital technologies. By investing in this approach from the outset, Alterity hopes to offer both a new therapeutic option for MSA and a more effective pathway for rare disease innovation.
For companies developing therapies in rare and neurologically complex conditions, the takeaway is clear: Identifying the right patient population, at the right time, with the right tools, can make all the difference.
About the Author:
David Stamler, MD, is CEO and managing director of Alterity Therapeutics. With more than two decades of drug development experience, Dr. Stamler has held leadership positions at major pharmaceutical and biotechnology companies, including Teva Pharmaceutical Industries, Auspex Pharmaceuticals, Fujisawa (now Astellas), and Abbott Laboratories (now AbbVie). His expertise spans early-stage research through late-stage clinical trials, with three FDA drug approvals in neurology.