‘Holy Grail’ – Alterity Therapeutics aims to slow progression of Parkinson’s disease

Alterity Therapeutics, through its lead drug candidate to treat Parkinson’s disease and related disorders, takes an approach considered ‘the Holy Grail in neurology’. 

Alterity is giving hope in slowing progression of Parkinson’s disease and related disorders. Pic: Getty.

• Alterity Therapeutics is focused on slowing progression of Parkinson’s disease and related disorders

• Approach of slowing progression considered “Holy Grail” in treatment of neurodegenerative diseases

• Interim results of a Phase 2 study of lead drug ATH434 released in July were positive

Special Report: Alterity Therapeutics has its roots in developing drugs for neurodegeneration with its latest focus on Parkinson’s disease and related disorders, in an approach considered “the Holy Grail in neurology” for slowing disease progression.

Speaking to Stockhead from the US, Alterity Therapeutics (ASX:ATH) CEO David Stamler said its lead drug ATH434 targets the underlying pathology of the disease.

“If successful we would modify the course of the disease, which is really the Holy Grail of what people are looking for in the neurology area,” he said.

“It’s not to minimise the importance of symptomatic therapies but the approach we are taking is to try and slow down the disease course, which is very important.”

Stamler said many pharmaceutical companies working on neurodegenerative diseases are now focusing on targeting the pathology to slow progression and give sufferers the best chance of preserving function and living with a better quality of life.

“After Alzheimer’s disease, Parkinson’s is the second most common neurodegenerative disorder,” he noted.

“There is a class of less common diseases that are related to Parkinson’s disease and have the same motor deficits such as not moving well and slowly, shuffling along with arms not swinging normally.”

ATH’s target first indication for ATH434 is a Parkinson’s related disorder called Multiple System Atrophy (MSA).

“What it means is multiple regions of the brain have pathology which cause different symptoms in different parts of the body,” he said.

“Beyond the motor impairment you see in Parkinson’s disease you also have bowel and bladder problems, difficulty maintaining blood pressure, which can obviously have a tremendous impact on quality of life.

“Our therapy is really targeting the underlying neurodegeneration of all these different areas to preserve function.”

Targeting proteins

Stamler said the company’s novel drug candidate targets proteins implicated in neurodegeneration of Parkinson’s and related disorders.

“The short story is it targets excess iron that is elevated in areas of pathology,” he said.

“If you look at brain scans on patients who have Parkinson’s disease or autopsies on the brains of these individuals, the areas with abnormalities that caused their symptoms also had elevated levels of iron.”

He said iron is critical for life and is needed for energy production and for many enzymes to work.

“The way I like to think of iron is it's almost like nuclear fuel in a nuclear reactor, where you need a small amount for a controlled reaction but if you get too much you get meltdown,” he said.

“In the same way if you get too much iron then the systems used to control it get overwhelmed leading to damage of proteins and other important cell components.”

He said damaged proteins can cause neurons to die.

“What we are trying to do with our therapy is bind the excess iron, remove it from the cells and put it back into circulation so it can be used by other systems in the body and put back to good use.

“We want to get the nerves back to good health and hopefully restore function.”

Phase 2 trials of ATH434 underway

The company has achieved orphan drug designation for ATH434 in MSA in the US and EU and has two Phase 2 clinical trials ongoing.

“We’ve done all the necessary Phase 1 studies in healthy volunteers to characterise the absorption and metabolism for the drug,” he said.

ATH now has two ongoing Phase 2 trials including an open-label trial ATH434-202, which the company reported positive interim results on in mid July.

Results showed that, after six months of  treatment, 43% of participants showed improvement on the Unified MSA Rating Scale activities of daily living scale, indicating reduced disability.

Over the same period, 29% of participants had stable or improved neurological symptoms (clinical responders) as assessed by both the treating physician and the patient.

Stamler said advances in technology have also enabled the measurement of iron in the brain in living people.

“We’re very interested in measuring iron in the brain of study patients. Historically, 30 or 40 years ago all you could do was an autopsy on end-stage disease and measure the iron,” he said.

“Very sophisticated techniques have been developed over the last 10 to 15 years and those are advancing rapidly so we can measure iron in specific brain regions affected by MSA to track the change with therapy over time.

“What we saw in this open label study was that for the people who responded clinically, the amount of iron in a key brain region affected in MSA remained stable over 12 months.”

He said furthermore, there was improvement in a key biomarker called NFL indicating ATH-434 was having a biologic effect and engaging the target

“We are seeing objective evidence of stability and improvement with these biomarkers corroborating what we are seeing clinically,” he said.

Stamler said another important finding in the interim results was that the patients who stabilised or improved clinically tended to have earlier stage disease.

He said that’s important because the patients in its larger, main Phase 2 trial ATH434-201, have early-stage MSA.

“We think that bodes well… because we are targeting the right kind of patient in that trial,” he said.

The randomised, double-blind study closed enrolment in November 2023 and is expected to complete in November this year with top-line data forecast in January 2025.

He said ATH434 has also been evaluated in various animal models of Parkinson’s disease.

“Aspirationally, we are very interested in evaluating the drug in Parkinson’s disease,” he said.

Long history in drug development

Alterity Therapeutics was incorporated in Australia in 1997 as Prana Biotechnology and has offices in Melbourne and San Francisco in the US.

The company listed on the ASX in 2000 and became dual listed on the Nasdaq under ticker code ATHE in 2002.

The management team has significant R&D experience including three neurology drug approvals by the US FDA.

Stamler joined Alterity about seven years ago with his focus on developing ATH434 in its target indications.

“Before we did the two treatment studies, we conducted a natural history study with Vanderbilt University in the US designed to characterise the patients we wanted to enrol and to choose endpoints and fine tune protocol,” he said.

“That’s been going on for four years now and we’ve learned a lot from that study that helped us with design and to de-risk our Phase 2 programs.

“We’re at an exciting time for the company with the amount of effort that has been put into ATH434 over the past few years and we have a very important study which is going to read out in January.”

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.

Originally published as ‘Holy Grail’ – Alterity Therapeutics aims to slow progression of Parkinson’s disease