Prothena pushes Roche-partnered Parkinson's drug into phase 2 after initial trial success

brain imaging
Prothena's new drug targets alpha-synuclein, a protein that is garnering increasing attention among Parkinson's researchers.

Protein immunotherapy specialist Prothena is celebrating some positive early-stage data from a Roche-partnered program that aims to find a disease-modifying therapy for Parkinson's disease.

Top-line results from the program were announced last November, but Prothena has now been able to put the results in front of more than 3,200 scientists and clinicians at the International Conference on Alzheimer's and Parkinson's Diseases (AD/PD) in Vienna, and is buoyant about its prospects.

The drug—called PRX002—targets alpha-synuclein, a protein that is garnering increasing attention among Parkinson's disease researchers. Mutations in the alpha-synuclein gene seem to correspond to Parkinson-like diseases in animal models, and the protein is found in higher-than-usual concentrations in Lewy bodies—a type of lesion found in the brains of Parkinson's disease patients. The hypothesis is that it is secreted by diseased neurons and taken up by healthy neurons, contributing to the spread of the pathology.

Prothena's phase 1b multiple ascending dose study represents the first report of an antibody targeting alpha-synuclein in patients with Parkinson's disease and showed that PRX002—also known as RG7935—was able to reduce serum levels of the protein by up to 97% with a single dose.

Armed with the data, Prothena says it will now start a phase 2 trial, using doses most likely to reduce "pathogenic" alpha-synuclein levels, later this quarter.

Parkinson's disease expert Professor Joseph Jankovic, M.D., of Baylor College of Medicine, who presented the data at AD/PD, said the trial met its safety and tolerability objectives up to a dose of 60 mg/kg and suggests that PRX002 may be administered as a once-monthly dose in the upcoming phase 2 trial, dubbed PASADENA.

"One of the most frequently-asked questions by patients is what can we do to slow down the progression of the disease," said Jankovic. "I think this is the first attempt to not only treat the symptoms of Parkinson's disease—which we are doing reasonably well so far—but perhaps also to alter the natural history of the disease."

The antibody appeared to be safe across all doses tested in the phase 1b study, penetrated the cerebrospinal fluid (CSF) and rapidly reduced levels of alpha-synuclein, particularly an aggregated form that is thought to play a role in Parkinson's pathology, said the company's president and CEO, Gene Kinney, Ph.D., on an investor call.

It's worth pointing out that the effect of the drug on the free form of the protein in the periphery is only a surrogate marker of the activity of the drug, as it is thought to have much higher affinity for the aggregated form which is expected to be more prevalent in the CSF.

As such it wasn't expected that the study would be able to show an effect on alpha-synuclein in the CSF and—with no validated assay to measure aggregated alpha-synuclein—the company has to rely on surrogate markers as it selects doses for the phase 2 assessment.

"We are thinking about using a couple of doses … that we would expect to fully saturate that pathological load in patients with Parkinson's disease," said Kinney.

The results are welcome for Roche as well, which bought into the program in 2013 with an undisclosed upfront payment and up to $600 million tied to clinical and commercial milestones.

Prothena is not alone in looking at alpha-synuclein as a target in Parkinson's, and in fact an entire session at AD/PD was devoted to the topic.

Austrian biotech Affiris completed a phase 1 trial of its anti-alpha-synuclein vaccine PD01A last year, while Biogen, AC Immune, Proclara, NeuroPore and BioArctic Neuroscience are among companies with early-stage programs in this area.