Alterity sets sights on first disease-modifying therapy for MSA

Alterity Therapeutics is aiming to shift the narrative for patients with Multiple System Atrophy with its lead drug ATH434.

Alterity is providing hope in treating MSA with its lead drug ATH434. Pic via Getty Images

Special Report: In a field where treatment options are limited and rapid disease progression remains difficult to manage, Alterity Therapeutics is aiming to shift the narrative for patients with Multiple System Atrophy. 

• Alterity’s phase II drug candidate ATH434 showed promise in treating Multiple System Atrophy 
• ATH434 granted fast track designation and orphan drug status by the US FDA as well orphan drug status in EU
• Upcoming catalysts include final data from phase II trial and open-label results 

There are no approved disease-modifying treatments for the rare and aggressive parkinsonian disorder, with Alterity Therapeutics (ASX:ATH) showing promise with its lead drug ATH434.

Alterity’s drug takes a novel approach to MSA by addressing iron imbalance and protein aggregation  – two central drivers of neurodegeneration – offering what could be the first disease-modifying therapy. 

ATH434 has been granted both Fast Track Designation and Orphan Drug Status by the US Food and Drug Administration (FDA), as well as Orphan Drug Status in the EU.

Backed by promising phase II results, Alterity is now chasing a market opportunity well exceeding US$1.1 billion with ATH434 and preparing for the next stage of development. 

Iron chaperone

Many of Alterity’s competitors are trialling antibodies in MSA, large molecules that can only act outside a cell – not ideal when it comes to tackling brain chemistry.

These antibodies must also be given by intravenous infusion, something neither patients nor their doctors like.

That’s where ATH434 is different, Alterity’s US-based CEO Dr David Stamler said.

It’s a small molecule, which has two important advantages: 1) it can be orally administered and 2) it is able to penetrate the blood brain barrier.

Given ATH434’s small size and ability to work inside the cell, Stamler says it attacks the core of the problem – the imbalance of iron and toxicity of aggregated proteins that drive the pathology in MSA patients.

“Rather than simply trying to reduce the spread of aggregated proteins moving between cells (extracellularly like antibodies), ATH434 addresses the ongoing pathology inside the cell,” he said. 

Stamler, Alterity’s CEO since 2021, said ATH434 is effectively an “iron chaperone” that redistributes excess reactive iron, which is damaging to cells in the central nervous system (CNS). 

“Rather than removing it from the body, ATH434 redistributes the iron so it can be utilised for vital cellular functions or stored for future use,” he said. 

“This is important given we don’t want to deplete iron from the body, because it is essential for energy production, enzymatic functioning, and neurotransmitter synthesis.”

Stamler said, by restoring iron balance in the brain, ATH434 helps reduce harmful protein build-up and cell damage, in turn preserving neurons and stabilising or improving patient function.

“This is why we believe we demonstrated a treatment effect up to 48% on a functional endpoint in our positive phase II trial,” he said. 

Stamler said it was also unusual to see such a good safety profile with a CNS active drug.

“Most CNS drugs typically target receptors, transporters, ion channels, etc., which can cause frequent CNS side effects,” he said. 

“In addition, we saw no adverse effects on haemoglobin or iron storage parameters.”

Providing hope for MSA 

Alterity’s lead indication MSA is a highly debilitating and rapidly progressive neurodegenerative disease with up to 50,000 patients in the US, driven by excess iron and aggregation of a protein called alpha-synuclein in the CNS.

“MSA patients present with various neurologic symptoms such as tremors and slow movements typically seen in Parkinson’s disease.  They also have unsteady gait leading to falls,” Stamler said. “That is why MSA is referred to as a ‘Parkinsonian disorder’”. 

“A key source of impairment in MSA results from failure of the part of the  nervous system that maintains blood pressure and controls bladder function. As a result, patients often develop debilitating lightheadedness when standing and urinary retention that typically leads to catheterisation requirements.” 

Due to the aggressive nature of MSA, average survival for patients is 7.5 years after symptom onset with more than 50% of patients requiring a wheelchair after five years.

“Our company mission is to provide an alternate future for patients who are battling debilitating neurodegenerative disorders that have no effective treatment,” he said. 

“We are determined to change the current narrative for patients and families and offer them hope by developing new treatments with potential to slow the course of this terrible disease.”

Future commercial potential – market size, beyond ATH434

Alterity is re-running its commercial market assessment with an external party, based on input from over 100 neurologists, both general and movement disorder specialists. This forecast is expected to be released in coming months. 

“Our last commercial assessment, run in 2023 using a target product profile with a modest assumption of efficacy in MSA, generated a peak sales number of US$1.1bn for the US alone,” Stamler said. 

“The updated peak sales projection with the robust efficacy we saw in phase II is anticipated to exceed this current estimate.”

Stamler said given Alterity was focused on neurodegenerative diseases driven by iron imbalance at the core of the disease pathogenesis including Parkinsons, MSA and Friedrich Ataxia, its target market is substantial. 

It is estimated that there are roughly one million Parkinson’s disease patients in the US. 

Experienced team committed to patient outcomes

Stamler said the experienced Alterity team understood complexities of drug development from trial design, patient selection to trial execution and commercialisation.

“We are a close-knit team with many of us having worked together for over 15 years in neurology drug development,” he said. 

Stamler said the team came from both large and small pharmaceutical companies, and had successfully led the approval of three neurology drugs through the FDA. 

“I continually pride myself on the quality of our team members, specifically our functional heads of non-clinical development, clinical operations and chemistry and manufacturing,” he said. 

“They were integral to the execution of the successful phase II trial and are trusted professionals to take this drug successfully to the next phase of development andimportantly, into the patient’s hands.”

Several upcoming catalysts

Alterity is preparing for its end-of-phase II meeting with the FDA, a key milestone to align on the design and regulatory path for a phase III trial of ATH434. 

The company’s priorities are focused on completing chemistry, manufacturing, and non-clinical studies to support the next phase of ATH434’s development. 

Alterity is also growing its team to prepare for future clinical and commercial milestones.

Key upcoming catalysts include final data from the phase II trial and open-label trial results. 

To support investor engagement in Australia, Alterity will host a non-deal roadshow from July 31 to August 6. 

Stamler and US-based movement disorder expert Dr Daniel Claassen will meet with institutional, wholesale, and high-net-worth investors.

Stamler will also present at the 19th annual Bioshares conference in Hobart on August 7-8. 

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.