Patients in Trial of Potential DMT Ably Capture Early Parkinson’s, Roche Says
Roche presented initial data from an ongoing Phase 2 clinical trial evaluating prasinezumab (PRX002/RG7935) — an antibody against the alpha-synuclein protein — in more than 300 people with early stage Parkinson’s disease.
Data highlighted that the trial’s participants, including those on MAO-B inhibitors, represent a wider population of patients and one appropriate to studying the effects of disease modifying therapies, such as prasinezumab, on Parkinson’s progression.
Given at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually on April 2–5, the oral presentation is titled “A Phase 2 study to evaluate the safety and efficacy of prasinezumab in early Parkinson’s disease (PASADENA): Rationale, design and baseline data.”
Alpha-synuclein is a protein found mainly in nerve cells (neurons) and thought to be involved in neuronal communication.
In Parkinson’s disease, toxic forms of alpha-synuclein form clumps — known as amyloid, or Lewy bodies — that contribute to the disease onset and progression. Evidence also suggests that these toxic aggregates can propagate, spreading to nearby neurons and resulting in progressive neurodegeneration.
Treatments able to lessen alpha-synuclein accumulation are likely to beneficially alter the course of Parkinson’s disease.
Prasinezumab, developed by Prothena in collaboration with Roche, is an injectable monoclonal antibody designed to selectively bind to alpha-synuclein aggregates, promoting an immune reaction against them.
By clearing alpha-synuclein clumps, prasinezumab is thought to slow neurodegeneration associated with the protein’s toxic accumulation and its transmission to neighboring neurons.
In animal models of alpha-synuclein-related disease, prasinezumab reduced the accumulation of the protein’s toxic clumps, protected neuronal communication, and halted a worsening in behavioral symptoms.
A multiple-ascending dose Phase 1b study (NCT02157714) in 80 Parkinson’s patients showed that the therapy was safe and well-tolerated, and that it sustainably lowered blood levels of alpha-synuclein by up to 97% after a single injection.
These results supported the start of the current Roche-sponsored, two-part Phase 2 study, called PASADENA (NCT03100149). The trial is evaluating the safety and effectiveness of prasinezumab in 316 patients with early stage Parkinson’s (two or fewer years since diagnosis).
Participants — who had no prior disease modifying treatment or were being treated with MAO-B inhibitors — were recruited at 65 clinical sites across the U.S., France, Germany, Austria, and Spain.
In the first part, patients were randomly assigned to an intravenous (into the vein) infusion of one of two doses of prasinezumab (1500 mg or 4500/3500 mg, depending on body weight), or of a placebo, once every four weeks for one year.
Those finishing this first part were eligible to enter the trial’s ongoing second part, a one-year extension in which all are either continuing treatment or switching to one of the two treatment doses from placebo. Doses given in this second part remained blinded, and treatment will be followed by 12 weeks of follow-up.
PASADENA’s main goal is to assess whether prasinezumab is superior to a placebo in lessening motor and non-motor symptoms — measured by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score — after one year (at the completion of part one).
Secondary goals include clinical and patient-based effectiveness measures, as well as safety measures. The level of neurodegeneration of dopamine-producing neurons will also be evaluated using a brain imaging tool called Dopamine Transporter Single Photon Emission Computed Tomography (DaT SPECT).
Roche’s PD Mobile Application v2. — a smartphone app that includes several motor function tests, to be performed every other day, and passive monitoring — is also being used as an exploratory measure of patients’ motor abilities.
Roche in its online session presented baseline (study’s start) data on PASADENA’s participants, compared to data of a reference patient population — the Parkinson’s Progression Markers Initiative (PPMI), an observational, international clinical study to establish Parkinson’s biomarkers.
In PASADENA, participants’ mean age was 59.9 years and all had lived with the disease for a mean of 10.1 months. Most were men (67.4%) and were treatment-naive (63.6 %), meaning they had no prior treatments.
Those using MAO-B inhibitors were slightly younger and had been diagnosed with Parkinson’s for a slightly longer time than treatment-naive patients.
Overall, the patients in PASADENA were mostly classified as stage two (75.3%) on the Hoehn and Yahr scale, with only 24.7% of participants classified as stage one. This scale measures disease progression, with stage one being the earliest, with mild symptoms evident on one side of the body, and associated with minimal or no functional impairment. Stage two, while still early, represents symptoms like rigidity or slowness evident on both body sides or at midline, and can includes changes in speech. Stage five is an advanced disease state.
Compared with the PPMI study population, patients enrolled in PASADENA have a longer mean disease duration (by about three to six months), a higher proportion are classified as stage two on the Hoehn and Yahr scale, similar motor symptom severity, and slightly milder non-motor symptoms.
They also showed a less pronounced loss of dopamine-producing neurons than those in the PPMI study.
“The PASADENA population can be considered representative of a wider [Parkinson’s disease] population and therefore suitable for testing the potential beneficial effect of [therapies] acting on disease progression, such as prasinezumab,” the researchers wrote.