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

• Expert involved in development of Alterity’s ATH434 sees major potential for treating MSA patients
• ATH434 targets excess iron believed to drive the toxic protein build-up and neuronal damage in MSA
• The small molecule has delivered positive top line results in phase II trials 

A leading neurologist involved in the clinical development of Alterity Therapeutic’s lead compound ATH434 believes it could be a game changer for sufferers of Multiple System Atrophy (MSA) and other neurodegenerative conditions.

Professor of Neurology at the Vanderbilt University Medical Center in the US, Dr Daniel Claassen, was principal investigator of the Alterity Therapeutics’ (ASX:ATH) biomarkers of progression in multiple system atrophy (bioMUSE) natural history study.

Claassen was also co-ordinating investigator of Alterity’s phase II trial ATH434-201, a double-blind study in patients with early-stage disease that has delivered positive top-line results.

Patients taking ATH434 showed up to 48% slower worsening of symptoms, as measured by Modified Unified MSA Rating Scale Part I (UMSARS I), a functional rating scale that assesses disability on activities of daily living affected in MSA.

The key MRI biomarker also showed iron stabilisation in MSA-affected brain regions.

Claassen designed the open-label ATH434-202 trial in patients with more advanced disease, which in July also reported positive topline results.

Targeting iron implicated in MSA progression

ATH434 is a small molecule drug candidate which has been granted US Food and Drug Administration (FDA) fast track designation along with orphan drug designation (ODD) in the US and Europe for the treatment of MSA.

The rare and aggressive Parkinsonian disorder, which affects up to 50,000 patients in the US, is driven by excess iron and aggregation of a protein called alpha-synuclein in the central nervous system (CNS).

ATH434 takes a novel approach to MSA by addressing iron imbalance and protein aggregation, offering what could be the first disease-modifying therapy.

“I was approached by Alterity about six years ago to help them understand positioning of a drug which might change iron concentrations,” Claassen said.

“We recognised there was a missing data set and that was how to diagnose patients early with MSA and see how these assessments track over time.”

Alterity worked with Claassen and his team at Vanderbilt to fill this missing data set through the bioMUSE study, which tracked progression of individuals with MSA.

“We called the study bioMUSE because it focused on understanding biomarkers of early MSA and we recruited about 25 patients who had presented to our clinics with possible symptoms of the disease,” he said.

“It was important that we weren’t entirely sure of a definitive MSA diagnosis and we followed them for a year assessing blood samples, cerebral spinal fluid, brain imaging, clinical measures and skin biopsies to understand what changes over time and how we can improve our positive predictive value for MSA diagnosis.”

Claassen said the bioMUSE study provided rich data for optimising design of the phase II trials and continued to provide critical insights into early-stage MSA, helping select the right patient, define which biomarkers are useful and track disease progression.

“We have been following those patients for five or six years now,” he said.

“The bioMUSE work has been pivotal in development of the clinical trials for ATH434 because MSA is a challenging disease and by the time you confirm the diagnosis the patient is very impacted.

“As this disease progresses, gait and mobility might be so bad they can’t walk without assistance or their blood pressure is so low that they can’t stay upright.”

He said trials for the disease had talked about looking at early MSA but it was defined more on a time basis, leading to complications with definitive inclusion criteria.

“Most studies approach inclusion criteria based on verbiage like “if you haven’t had symptoms for longer than three or five years” but we took a different multimodal approach,” he said.

Claassen said the BioMUSE study was designed to capture patients in the earlier stages of MSA, while also incorporating biomarkers and imaging to improve diagnostic accuracy.

This approach, he explained, increased confidence that participants truly had the disease, which was critical for evaluating a potential therapy versus a placebo group.

“If you include a patient with Parkinson’s in a study, for example, they’re going to progress much slower than a person with MSA and that is very unhelpful.”

Novel approach to MSA treatment

Claassen said many of Alterity’s competitors in MSA were testing synuclein related approaches, like antibodies – large proteins that act only outside cells and require IV infusions – making them less convenient and limited in effect.

In contrast ATH434 is taken orally, has been proven to cross the blood-brain barrier and enters neurons to target toxic protein aggregates and the underlying iron imbalance driving MSA, rather than just slowing protein spread.

“The safety profile is impeccable and it doesn’t compete with a lot of the other mechanisms being studied so it’s a big opportunity,”Claassen said.

He said the novel approach in tackling the disease meant there was strong support among the MSA community and clinicians to be involved in the phase II trials of ATH434.

While the mechanism of action wasn’t top of mind for clinicians in treating MSA, the clinical program using the multi-biomarker approach for diagnosis and progression was very interesting to investigators.

“The 201 results were very encouraging and a clear signal we should go forward in a larger phase III study,” Claassen said.

“We saw clear differences between treated patients and placebo patients favouring treated patients and improvements in various assessments and imaging outcomes with a similar story for the 202 trial.”

‘Tough nut to crack’ but ATH434 shows promise

Claassen describes ATH434 as an “iron chaperone”, explaining that it redirects excess reactive iron to helps protect neurons, curb protein accumulation and maintain or enhance neuronal function.

He said iron was dysfunctional in MSA with excessive iron build up in parts of the brain seen through MRI imaging and pathology studies.

“Iron is a problem and what this drug does is redistributes excess iron in the cell and ultimately slows the pathologic progression of MSA but also preserves cellular function to keeps cells going,” he said.

“There is a large body of literature linking iron to neurodegeneration and that is through cellular and models along with autopsy.

“Neurodegeneration is a tough nut to crack, and this really moves the needle.”

He said many Parkinsonian disorders, and even, to some extent, Alzheimer’s, were linked to iron dysregulation, making them potential targets for exploration with ATH434.

Methodical drug development

Claassen said for investors it was worth noting Alterity’s methodical development approach with ATH434, which had been heavily supported by academic research and collaboration.

Along with Vanderbilt University, Melbourne’s Monash University has played a significant role in its R&D.

Monash has collaborated with Alterity on various preclinical and clinical studies, contributing expertise in neuroscience and protein research.

“The drug development for this compound has been very methodical,” Claassen said.

“You can’t fast track this process and you must do the hard work, and it has been done with ATH434.

“Drug development is a tedious process and the work has been done here in a very systematic, rigorous process to get where we want to go.”

At Stockhead, we tell it like it is. While Alterity Therapeutics is a Stockhead advertiser, the company did not sponsor this article.