Stockhead: Alterity wins key FDA alignment for pivotal neurological trial

• Alterity announces successful end-of-phase II trial meeting with the US FDA

• The regulator ticks off on key elements of a phase III trial, including study population, endpoint selection, dosing regimen and treatment duration

• Alterity’s Multiple System Atrophy (MSA) candidate ATH434 showed a statistically significant 46% slowing of disease progression in the phase II trial

Special Report: Alterity Therapeutics has achieved alignment with the US Food and Drug Administration (FDA), on key elements of the company’s pivotal phase III program for its lead drug candidate to treat multiple system atrophy (MSA).

This results from a successful end-of-phase II meeting, in which the FDA agreed with the company on key elements for Alterity Therapeutics’ (ASX:ATH) proposed phase III MSA trial design.

The agency green-lighted elements including the study population, treatment duration, primary endpoint and dose regimen.

A randomised, double-blind, placebo-controlled study, the trial will enrol around 200 patients with “clinical and biomarker evidence” of MSA. Participants will be randomly assigned to receive either ATH434, twice-daily, or a matching placebo for 12 months.

The regulator agreed on the primary endpoint will be the UMSARS Part I, an 11-item rating scale that measures the activities of daily living affected by MA, such as walking, swallowing, speech, and dressing. 

This is the same measure and dose as the phase 2 in which ATH434 delivered “clinically and statistically significant efficacy”, with a 48% slowing of disease progression compared to placebo.  Having that endpoint carried forward as the phase III primary endpoint means the pivotal trial is built directly on the strength of the phase II data. The phase II study also showed ATH434 was generally safe and well tolerated.

Alterity also carried out a second, open-label phase II biomarker study in patients with more advanced disease. This also showed “clinical efficacy, target engagement and a favourable safety profile”.

The FDA also has agreed that planned key secondary endpoints were suitable to support efficacy measures. These include a swallowing disturbance questionnaire, an orthostatic hypotension symptom assessment and the clinicians’ impression of disease severity. The agency also indicated the company’s anticipated safety database at the conclusion of the phase III was reasonable. 

Targeting an unmet need 

MSA is a rare, rapidly progressive neurodegenerative disease characterised by autonomic dysfunction and impaired movement. It belongs to a broader group of conditions known as Parkinsonian disorders, which share pathological features including abnormal accumulation of α-synuclein.

In MSA, that protein builds up inside the oligodendrocytes, the cells responsible for producing the protective myelin coating around nerves in the central nervous system. The result is the progressive loss of nerve cells in the brain and spinal cord, leading to profound disability.

Symptoms include slowed movement and rigidity. Patients also may have blood pressure and bladder control problems, with impaired balance and coordination that increases the risk of falls.

MSA affects up to 50,000 people in the US.  While some symptoms can be managed with medication, there are currently no approved treatments that slow disease progression and there is no cure.

Delivered orally, ATH434 is designed to redistribute excess iron and inhibit abnormal protein aggregation associated with neurodegeneration. In preclinical models, ATH434 reduced α-synuclein pathology and preserved neuronal function by restoring the brain’s normal iron balance. Alterity believes this novel iron “chaperone” mechanism gives ATH434 the potential to treat MSA and other Parkinsonian disorders.

The FDA has granted ATH434 Fast Track Designation, while the FDA and the European Commission have granted Orphan Drug Designation for the treatment of MSA. 

‘Important de-risking milestone’

For a company entering its pivotal study, the biggest risks are often not about the science, but about the rules of the game: which patients to enrol, how long to treat them for, and how success will be measured. If one of these are wrong, even an effective drug can fail to prove itself. 

The end-of-phase II meeting removes much of that uncertainty. By securing FDA’s agreement on these elements upfront, Alterity enters the final stage of clinical development before it can seek US approval, with a clear, regulator-endorsed path to the finish line. Alterity CEO Dr David Stamler called the outcome an “important de-risking milestone” that reduced substantially the uncertainty around the design of the pivotal trial.

Alterity CEO Dr David Stamler said the development was an “important de-risking milestone” that reduced substantially the uncertainty around the design of the pivotal trial.

“The successful outcome of the meeting … gives us confidence as we finalise the protocol and prepare to initiate trial activities by the end of 2026,” he said.

“I am confident that ATH434 is well positioned to become a disease-modifying therapy for individuals living with MSA.”

For the roughly 50,000 Americans living with MSA today, and the thousands more who may be diagnosed, a treatment that genuinely slows the disease would be the first of its kind. 

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