AAN 2024: Prasinezumab may slow Parkinson’s symptom progression
Analysis compares trial data to observational study, finds treatment benefits
Treatment with prasinezumab — an experimental therapy designed to stop toxic alpha-synuclein protein clumps from spreading through the brain — seems to slow the progression of motor symptoms in people with Parkinson’s disease.
That’s according to the results of a new analysis that compared the findings of a long-term clinical trial of prasinezumab with data from a real-world observational study.
Patrik Brundin, MD, PhD, therapeutic area leader for movement disorders at Roche, which is co-developing the therapy with Prothena Biosciences, presented the analysis’ findings at this year’s American Academy of Neurology (AAN) 2024 Annual Meeting. The AAN meeting is being held April 13-18, in Colorado and online. The talk was titled “Exploratory Analysis of PASADENA Open-label Extension Evaluating the Effect of Prasinezumab on the Progression of Motor Signs and Symptoms.”
Parkinson’s is characterized by the buildup, in nerve cells, of toxic clumps of the protein alpha-synuclein, which are thought to play a central role in driving the disease. Prasinezumab is an antibody-based therapy that seeks to slow disease progression by stopping these toxic clumps from spreading through the brain.
While the clinical trial of prasinezumab failed to meet its goal, its data were compared with those of a landmark study on disease progression being run by The Michael J. Fox Foundation for Parkinson’s Research (MJFF). That analysis showed that the therapy appeared to help slow motor symptoms from progressing.
PASADENA trial tested prasinezumab versus a placebo
Launched in 2017, the Phase 2 PASADENA trial (NCT03100149) tested prasinezumab, given via intravenous or into-the-vein infusion, in 316 adults with early-stage Parkinson’s. The participants were randomly divided into two groups, dubbed early start and delayed start.
In the early-start group, participants were treated with prasinezumab once monthly for the entire two-year trial. Meanwhile, participants in the delayed-start group were given a placebo for the first year of the trial, then started on prasinezumab in the second year.
Two different doses of prasinezumab were used throughout the trial, though Brundin noted that both “behave exactly the same,” so they were analyzed together.
The main goal of the PASADENA study was to evaluate whether prasinezumab slowed the progression of Parkinson’s symptoms relative to the placebo in the first year of the trial. The results, published in 2022, showed it failed to meet this goal.
After the two-year study, there was a break in treatment lasting a few months, and then all participants were permitted to continue receiving prasinezumab in a long-term extension.
A new analysis presented last year indicated that, though most patients experienced a worsening of motor symptoms over three years of follow-up, the likelihood of motor symptom progression was lower in the early-start group.
Those findings led some credence to the notion that long-term prasinezumab may help slow disease progression, though further evidence is needed, according to researchers.
Trial results now compared with MJFF study data
In Brundin’s presentation at the AAN meeting, results from PASADENA and its long-term extension were compared with data from the MJFF’s Parkinson’s Progression Markers Initiative (PPMI), an observational study that’s collecting data on the disease and its progression.
Brundin and colleagues used a technique called propensity score weighting, in which they specifically selected data from individuals in PPMI who were similar to participants in PASADENA — with the notable exception that patients in PASADENA were receiving prasinezumab, while those in PPMI weren’t.
“The bottom line of this is, we ended up with a balanced demographic and clinical characteristic between the PASADENA participants … [and] the PPMI external control arm,” Brundin said.
The researchers specifically compared scores on part three of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which measures the severity of motor symptoms.
In the PPMI group, motor symptoms scores when participants were off medication continually worsened over up to four years of follow-up — which Brundin said reflects the “expected, textbook deterioration in motor function” typically seen in people with Parkinson’s.
However, a different pattern was seen for patients on prasinezumab in the PASADENA study. In both the early- and late-start groups, average scores on part three of the MDS-UPDRS worsened gradually over the first year or two of the trial — but then scores leveled out and were mostly stable for the rest of the follow-up.
As of the latest follow-up, motor symptom severity scores were 65% lower for patients in the early-start group who’d been on prasinezumab for all four years of follow-up, compared with scores in the PPMI group.
An even more dramatic difference between the groups was seen for MDS-UPDRS scores assessed when patients were on symptom-controlling medication such as levodopa.
If we compare PASADENA … with PPMI data on multiple endpoints related to motor progression, we see slowing of progression.
Scores on part two of the MDS-UPDRS, which assesses patients’ ability to function in day-to-day life, also showed significant improvements with prasinezumab after several years of follow-up. After four years on the therapy, scores were on average 40% lower than for patients in the PPMI group.
“If we compare PASADENA … with PPMI data on multiple endpoints related to motor progression, we see slowing of progression,” Brundin concluded.
Overall, the findings from this analysis are promising for prasinezumab as a potential Parkinson’s treatment. But Brundin stressed that this type of analysis has some noteworthy limitations — most importantly that the results are not as reliable as any that would come from a double-blind placebo-controlled clinical trial. In double-blind trials, neither the researchers nor the participants know what treatment is being given to the patient — whether it’s the medication being tested or the placebo.
To collect further data on prasinezumab in Parkinson’s, Roche is running another Phase 2b trial, called PADOVA (NCT04777331), that is expected to conclude in late 2026.
Note: The Parkinson’s News Today team is providing coverage of the American Academy of Neurology (AAN) 2024 Annual Meeting April 13-18. Go here to see the latest stories from the conference.Â
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