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Small Molecule Is Promising Drug Target for Multiple System Atrophy

A novel, small molecule that inhibits the aggregation of alpha-synuclein produced encouraging concentrations in the cerebrospinal fluid, boosting hopes as the drug moves forward as a candidate for multiple system atrophy (MSA) treatment.

The findings of the small phase 1 study were described in an abstract featured as part of the AAN 2020 Science Advances.

The molecule, called PBT434, is thought to act on labile iron, said David Stamler, MD, chief medical officer of the manufacturer Alterity Therapeutics. Labile iron is seen in higher concentrations in areas of pathology in Parkinson's disease (PD) and MSA and is thought to contribute to misfolding of alpha-synuclein, leading to its aggregation, while also causing oxidative stress.

"By targeting the labile iron, we bind it and redistribute it and by doing so, we take it out of harm's way, so it doesn't promote alpha-synuclein aggregation," Dr. Stamler said. "Also, by taking the iron out of this state where it's the root cause of oxidative stress, we reduce the cellular damage that it promotes."

The findings appeared promising in a single ascending dose trial—involving four dose levels and 32 healthy volunteers, including those on placebo—and a multiple ascending dose trial—with three dose levels and 30 healthy volunteers, including placebo subjects. In both trials, concentrations of the drug in the CSF were seen at levels that researchers expect will be effective in MSA patients, once the drug moves on to the next research phase, Dr. Stamler said. The highest multiple dose regimen was also evaluated in 10 older adults, at least 65 years old.

At 200 mg or greater twice a day, the CSF concentrations were higher in these healthy volunteers than the concentrations that were linked with efficacy in animal models of PD and MSA.

 "We know that our projected clinical dose is going to give us spinal fluid concentrations that are at or above the efficacious spinal fluid concentrations in these multiple animal models," Dr. Stamler said.

Adverse events were mild to moderate and self-limited, he said, most often including headache and dizziness, he said.

The goal is to treat MSA patients early in their disease course, and Alterity researchers are now studying the natural history of early MSA to get data to help them optimize the phase 2 investigation, expected to start in the early part of next year.

The hope is that the drug will get at the root cause of pathology that could help with MSA's devastating array of symptoms, he said.

"Because we're treating the underlying cause of disease by targeting alpha-synuclein, I think we have the potential to affect all aspects of disease—the motor symptoms, the blood pressure problems, gait and balance, and even bowel and bladder dysfunction."

Wouter Peelaerts, PhD, a post-doctoral fellow at the Van Andel Institute and an expert in degenerative brain diseases, said, compared to iron-chelating treatments being explored for PD, PBT434 has a lower binding affinity for iron, which could mean the potential for fewer side effects and potentially allowing for higher doses.

Dr. Peelaerts said it seems that, based on the researchers' data, the drug can be "dosed at relatively high levels and that it is tolerated quite well, which would be an improvement over existing strategies."

"By preventing the buildup of iron in susceptible brain regions, some of the damage to the striatonigral system could be ameliorated via inhibiting synuclein aggregation or improving mitochondrial oxidative stress—iron is highly concentrated in the striatonigral system of MSA patients," he said.

He noted that MSA is more widespread than just iron-loaded regions such as the basal ganglia, so some regions or symptoms might not be affected as much from the treatment.

Dr. Peelaerts said he'd also be interested to see effects of the drug on iron deposition patterns, which could have implications for the forms of MSA the drug could target as well as it effects on brain inflammation and the immune system, given iron's important role in immune function.

"Iron accumulation might be a true target of disease modification and PTB434 might be a step towards disease modification," Dr. Peelaerts said. "I'll be interested to see what more comes out of this."

Disclosures: Dr. Stamler has received personal compensation for consulting, serving on a scientific advisory bd, speaking, or other activities. He is a former employee of Teva Pharmaceuticals and has received salary and benefits from Auspex Pharmaceuticals. Patents are pending: US20160346270, US20160287574. Dr. Peelaerts has no relevant disclosures.

Link Up for More Information

AAN Abstract 4871: Stamler D, Bradbury M, Wong C, et al. A phase 1 study of PBT434, a novel small molecule inhibitor of alpha-synuclein aggregation, in adult and older adult volunteers.