Prasinezumab missed its main goal in a Parkinson's trial

Prasinezumab, an antibody designed to slow Parkinson's disease by clearing the protein alpha-synuclein, did not significantly delay motor decline in the phase 2b PADOVA trial [s1]. The drug missed its primary endpoint — time to a confirmed worsening of motor signs — leaving another disease-modifying candidate for Parkinson's with an encouraging trend but no clear proof, and a larger phase 3 trial now carrying the question forward [s1].

Parkinson's disease has effective symptomatic drugs, chiefly levodopa, but nothing yet shown to slow the underlying neurodegeneration. Alpha-synuclein, a protein that misfolds and aggregates in affected neurons, has been the field's leading disease-modifying target for a decade, and prasinezumab — a monoclonal antibody against it — is among the most advanced attempts to hit it. An earlier phase 2 study, PASADENA, had hinted at an effect on the motor scale in patients who were untreated or on MAO-B inhibitors [s2]. PADOVA was built to test the drug in a broader, more realistic population already on stable symptomatic medication [s1].

What the trial did

PADOVA was a multicentre, double-blind, placebo-controlled, randomised superiority trial run at 110 centres across nine countries in Europe and North America [s1]. It enrolled people aged 50–85 with early-stage Parkinson's — 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2 — on stable symptomatic treatment, and randomly assigned them 1:1 to intravenous prasinezumab 1500 mg or placebo every 4 weeks for at least 76 weeks [s1]. The primary endpoint was time to a confirmed motor progression event, defined as a 5-point or greater increase in the off-medication MDS-UPDRS Part III score [s1].

Of 787 people screened, 586 were enrolled and randomised, 293 to each group; their mean age was 64·2 years (SD 7·3), and 214 (37%) were female and 372 (63%) male [s1]. In total, 550 completed double-blind treatment — 277 on prasinezumab and 273 on placebo [s1].

The design is worth a note because it shapes how the result should be read. Assignment used permuted blocks stratified by symptomatic medication, participants and assessors were masked, and the trial was event-driven: dosing continued until a target number of confirmed motor progression events had accrued, rather than for a fixed follow-up [s1]. That makes the primary analysis a comparison of how quickly worsening events occurred in each group — a design well suited to detecting a slowing of progression, and one in which a hazard ratio of 0·84 that fails to reach significance is genuinely ambiguous rather than clearly negative [s1].

The result

The primary endpoint was not met. Prasinezumab produced a non-significant delay in motor progression versus placebo, with a hazard ratio of 0·84 (95% CI 0·69–1·01; p=0·066) [s1]. The median time to a confirmed motor progression event was 61·1 weeks (95% CI 52·3–71·9) with prasinezumab, compared with 49·7 weeks (40·1–58·1) with placebo [s1]. The direction favoured the drug, and the confidence interval only just crossed 1·00 — but "just missed" is still missed, and a p-value of 0·066 means the trial did not rule out that the difference was chance [s1].

One design feature does strengthen how far the result travels: unlike the earlier PASADENA study, PADOVA recruited a broader, more representative group — people already on stable symptomatic medication, which is how most patients with early Parkinson's are actually treated [s1][s2]. A trial that enrols the realistic population and still cannot separate its drug from placebo is more informative, not less, because it removes the excuse that an effect was hidden by an unusual sample.

On safety, the two groups looked alike: serious adverse events occurred in 34 (12%) of 292 prasinezumab recipients and 34 (12%) of 290 placebo recipients [s1]. Three deaths were recorded — one (<1%) on prasinezumab and two (1%) on placebo — none related to the study drug [s1]. The trial was funded by F. Hoffmann-La Roche [s1].

What the researchers make of it

The authors are candid that PADOVA did not meet its primary endpoint, while arguing that prespecified exploratory analyses "suggest clinical activity" and support the ongoing phase 3 PARAISO trial [s1]. That is a reasonable position for a sponsor to take, but it is a hypothesis for the next trial to test, not a conclusion this one earned. An accompanying commentary weighs PADOVA against the earlier PASADENA study and asks what, across two trials, has actually been learned about the drug — a sign that the alpha-synuclein hypothesis remains unresolved rather than confirmed [s2].

What it means

For patients, nothing changes today: prasinezumab is not an approved treatment, and no disease-modifying therapy for Parkinson's exists. The value of PADOVA is in what it tells the field about how hard this target is. A near-miss on a hazard ratio can reflect a real but small effect, an underpowered design, or noise, and only PARAISO — powered as a confirmatory phase 3 — can separate those. Readers encountering headlines that the drug "slowed" Parkinson's should note the trial's own verdict: the primary endpoint was not met [s1].

Sources

• [s1] Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA). The Lancet, 28 May 2026. https://doi.org/10.1016/S0140-6736(26)00865-2
• [s2] Prasinezumab: what have we learned from PASADENA and PADOVA? The Lancet, 28 May 2026. https://doi.org/10.1016/S0140-6736(26)00985-2