Roche’s Phase IIb Study of Prasinezumab Missed Primary Endpoint, But Suggests Possible Clinical Benefit in Early-Stage Parkinson’s Disease

Rhea-AI Summary

Prothena (NASDAQ:PRTA) announced results from Roche's Phase IIb PADOVA study of prasinezumab in early-stage Parkinson's disease. The study, involving 586 patients treated for 18+ months, missed its primary endpoint but showed potential clinical benefits. The drug demonstrated a HR=0.84 [0.69-1.01] (p=0.0657) in motor progression delay, with stronger effects in levodopa-treated patients (HR=0.79 [0.63-0.99], p=0.0431).

Covariate-adjusted analyses showed nominally significant effects on the primary endpoint (HR=0.81, p=0.0334) and in the levodopa subgroup (HR=0.76, p=0.0175). The drug was well-tolerated with no new safety concerns. The Phase II PASADENA and Phase IIb PADOVA open-label extension studies will continue while Roche evaluates next steps with health authorities.

Positive

• Stronger efficacy demonstrated in levodopa-treated patients (75% of participants)
• Favorable safety profile with no new safety signals
• Positive trends across multiple secondary and exploratory endpoints
• Covariate-adjusted analyses showed nominally significant effects

Negative

• Missed primary endpoint of confirmed motor progression (p=0.0657)
• Uncertain regulatory path forward pending health authority discussions

Insights

Clinical Research Analyst

The Phase IIb PADOVA study results for prasinezumab present a complex picture that requires careful interpretation. While missing the primary endpoint's statistical significance threshold (p=0.0657), the data reveals promising signals, particularly in the levodopa subgroup analysis. The hazard ratio of 0.84 in the overall population and 0.79 in the levodopa subgroup suggests a potential 16% and 21% reduction in motor progression risk, respectively.

The covariate-adjusted analyses reaching nominal significance (p=0.0334 for primary endpoint) strengthen the evidence for prasinezumab's potential efficacy. For investors, these results position prasinezumab in a challenging but potentially viable space - while not a clear success, the consistent positive trends across multiple endpoints and favorable safety profile maintain its potential as a first-in-class disease-modifying treatment for Parkinson's.

In simple terms: Think of this like a race where prasinezumab didn't quite cross the finish line first, but showed enough promise to suggest it could win with some adjustments to its training program, especially when running alongside levodopa.

Market Research Analyst

From a market perspective, these results create a complex scenario for Prothena (PRTA). The 634.5M market cap company faces a pivotal moment as Roche evaluates next steps. The Parkinson's disease market, valued at approximately 5.3B globally, represents a substantial opportunity, but the path forward requires careful navigation with regulatory authorities.

The continued development program and potential positioning as a first-in-class disease-modifying treatment could maintain investor interest, despite the mixed results. However, the timeline to market may be extended as additional studies or analyses might be required. This creates near-term uncertainty but preserves long-term potential, particularly given the unmet need in Parkinson's disease treatment.

Biostatistician

The statistical nuances in this trial deserve careful attention. The primary analysis produced a hazard ratio of 0.84 with a confidence interval of [0.69-1.01], narrowly missing statistical significance. However, the pre-specified subgroup and covariate-adjusted analyses reaching nominal significance provide important context. The levodopa subgroup's HR=0.79 [0.63-0.99] with nominal p=0.0431 suggests a potentially meaningful treatment effect in this population.

For the general reader: Think of statistical significance like a photo finish in a race - prasinezumab came very close to winning outright and when we look at certain groups of participants (those on levodopa), it actually did show a meaningful benefit. While not a home run, these results suggest the drug is doing something beneficial, particularly in specific patient populations.

• PADOVA study showed numerical delay in motor progression and positive trends on multiple secondary and exploratory endpoints
• Prasinezumab continues to be well tolerated and no new safety signals were observed
• Roche is further evaluating the data and will work together with health authorities to determine next steps

DUBLIN--(BUSINESS WIRE)-- Prothena Corporation plc (NASDAQ:PRTA), today announced results from the Phase IIb PADOVA study conducted by partner Roche investigating prasinezumab in 586 people with early-stage Parkinson’s disease, treated for a minimum of 18 months while on stable symptomatic treatment. Prasinezumab showed potential clinical effect in the primary endpoint of time to confirmed motor progression with a HR=0.84 [0.69-1.01] and p=0.0657. The effect of prasinezumab was more pronounced in a pre-specified analysis in the population treated with levodopa (75% of participants), HR=0.79 [0.63-0.99] and nominal p=0.0431. Pre-specified supplementary covariate-adjusted* analyses of these endpoints demonstrated nominally significant effects on the primary endpoint (HR=0.81 [0.67-0.98]; nominal p=0.0334) and in the levodopa subgroup (HR=0.76 [0.61-0.95]; nominal p=0.0175). Consistent positive trends across multiple secondary and exploratory endpoints were also observed. Prasinezumab continues to be well tolerated and no new safety signals were observed in the study.

The Phase IIb PADOVA results along with prior clinical study results will inform future clinical development, including study design, statistical analysis, and appropriate evaluation of patient sub-groups, of prasinezumab as a potential first-in-class disease-modifying treatment for patients with Parkinson’s disease.

“The results from the Phase 2b PADOVA study are a significant step forward to potentially bring the first disease-modifying treatment option to the millions of individuals living with Parkinson’s disease and their families,” stated Gene Kinney, Ph.D., President and Chief Executive Officer, Prothena. “As pioneers in developing the first anti-alpha synuclein targeting antibody, we look forward to Roche presenting the results from the PADOVA study at an upcoming medical conference and sharing with health authorities to determine the most appropriate path forward.”

The Phase II PASADENA and Phase IIb PADOVA open-label extension studies will continue in order to explore the observed effects in both studies. Roche will continue to evaluate the data and work together with health authorities to determine next steps.

Full results from the PADOVA study will be presented at an upcoming medical meeting.

About prasinezumab

Prasinezumab is an investigational monoclonal antibody designed to selectively bind aggregated α-syn and reduce neuronal toxicity. By targeting the build-up of α-syn protein in the brain, prasinezumab can potentially prevent further accumulation and spreading between cells, thereby slowing down the progression of the disease. The evidence supporting targeting α-syn aggregates as a mechanism of action in Parkinson’s disease is based on a wide range of scientific evidence in the field.

Prasinezumab is currently being assessed in ongoing open-label extensions of the Phase II PASADENA and Phase IIb PADOVA studies. Four-year data from the PASADENA study showed potential evidence of sustained slowing of motor progression compared to a matched PPMI natural history study cohort, published in the October 2024 edition of Nature Medicine. The PASADENA delayed-start (n = 94) and early-start (n = 177) groups showed a slower decline (a smaller increase in score) in MDS–UPDRS Part III scores in the OFF state (delayed start, −51%; early start, −65%) than did the PPMI external comparator (n = 303). The safety database for prasinezumab consists of data from more than 900 Parkinson’s disease study participants that have been treated with the investigational medicine, including more than 500 who were treated over 1.5-5 years.

Roche entered into a Licensing, Development, and Commercialization agreement with Prothena in December 2013 to develop and commercialize monoclonal antibodies targeting α-syn, such as prasinezumab, for the potential treatment of Parkinson’s disease.

About the PADOVA study

PADOVA is a Phase IIb multicenter, randomized, double-blind trial evaluating the efficacy and safety of prasinezumab compared with placebo in 586 randomized patients with early-stage Parkinson’s disease who were on stable symptomatic treatment (stable doses of levodopa or monoamine oxidase-B inhibitor as monotherapy for more than three months at baseline). Patients receive monthly intravenous doses of prasinezumab 1500 mg or placebo every four weeks for at least 76 weeks. This is followed by a two-year open-label extension phase in which all participants receive active treatment, which is currently ongoing.

The primary endpoint of PADOVA is the time to confirmed motor progression of Parkinson’s disease (≥5-point increase in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] Part III score assessed in OFF medication state). A 5-point increase in MDS-UPDRS Part III represents a clinically meaningful motor progression event (Trundell et al., in press).

About Parkinson’s disease

Parkinson's disease is a chronic, progressive and debilitating neurodegenerative disease that has a devastating impact on patients and families. Parkinson's disease is characterized by the gradual loss of neurons that make dopamine and other nerve cells, and the development of motor and non-motor symptoms that may appear years before diagnosis. Symptoms can vary widely between individuals and disease progression is not predictable, in which symptoms can develop gradually over time or suddenly. Clinical diagnosis of Parkinson’s disease is late in the disease course and currently based only on motor symptoms, with non-motor symptoms often preceding diagnosis by up to 20 years.

About Prothena

Prothena Corporation plc is a late-stage clinical biotechnology company with expertise in protein dysregulation and a pipeline of investigational therapeutics with the potential to change the course of devastating neurodegenerative and rare peripheral amyloid diseases. Fueled by its deep scientific expertise built over decades of research, Prothena is advancing a pipeline of therapeutic candidates for a number of indications and novel targets for which its ability to integrate scientific insights around neurological dysfunction and the biology of misfolded proteins can be leveraged. Prothena’s pipeline includes both wholly-owned and partnered programs being developed for the potential treatment of diseases including AL amyloidosis, ATTR amyloidosis with cardiomyopathy, Alzheimer’s disease, Parkinson’s disease and a number of other neurodegenerative diseases. For more information, please visit the Company’s website at www.prothena.com and follow the Company on Twitter @ProthenaCorp.

Forward-Looking Statements

This press release contains forward-looking statements. These statements relate to, among other things, the treatment potential, design, and proposed mechanism of action prasinezumab; plans for ongoing and future clinical trials of prasinezumab; plans to work with health authorities to determine next steps for prasinezumab; and the expected reporting data from the PADOVA clinical trials. These statements are based on estimates, projections and assumptions that may prove not to be accurate, and actual results could differ materially from those anticipated due to known and unknown risks, uncertainties and other factors, including but not limited to those described in the “Risk Factors” sections of our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 12, 2024, and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the SEC. We undertake no obligation to update publicly any forward-looking statements contained in this press release as a result of new information, future events, or changes in our expectations.

*Covariates used for adjustment: Medication at baseline, H&Y stage, DaT-SPECT, Age, Sex, Baseline dependent parameter

View source version on businesswire.com: https://www.businesswire.com/news/home/20241218381145/en/

Media

Michael Bachner, Senior Director, Corporate Communications

609-664-7308, michael.bachner@prothena.com

Investors

Mark Johnson, CFA, Vice President, Investor Relations

650-417-1974, mark.johnson@prothena.com

Source: Prothena Corporation plc

FAQ

What were the main results of Roche's Phase IIb PADOVA study for PRTA's prasinezumab?

The study missed its primary endpoint but showed potential clinical benefit with HR=0.84 [0.69-1.01] (p=0.0657) in motor progression delay, with better results in levodopa-treated patients.

How did prasinezumab perform in levodopa-treated patients in the PRTA PADOVA study?

In levodopa-treated patients (75% of participants), prasinezumab showed stronger effects with HR=0.79 [0.63-0.99] and nominal p=0.0431.

What is the safety profile of PRTA's prasinezumab in the Phase IIb PADOVA trial?

Prasinezumab continued to be well tolerated with no new safety signals observed during the study.

What are the next steps for PRTA's prasinezumab after the PADOVA study results?

Roche will evaluate the data and work with health authorities to determine next steps, while continuing the Phase II PASADENA and Phase IIb PADOVA open-label extension studies.

How many patients were involved in PRTA's Phase IIb PADOVA study?

The study included 586 people with early-stage Parkinson's disease, treated for a minimum of 18 months while on stable symptomatic treatment.