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DUBLIN, Ireland I December 19, 2024 I 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. SOURCE: Prothena

Roche’s alpha-synuclein-targeting antibody has failed to slow the progression of motor symptoms in a mid-stage Parkinson’s disease test, marking the latest setback in a largely challenging year for the disease pipeline. The pharma company’s prasinezumab missed statistical significance in the Phase 2b PADOVA study’s primary endpoint of time to confirmed motor progression versus placebo (p=0.0657), according to a Thursday release . The trial enrolled 586 people with early-stage Parkinson’s who were taking stable doses of levodopa or a monoamine oxidase-B inhibitor. Roche secured the rights to prasinezumab more than ten years ago, when it inked a global development and commercialization deal with the drug’s creator, Prothena, worth up to $600 million. Prothena’s share price $PRTA was down around 6% premarket Thursday. Prasinezumab seemed to have a stronger effect in the subset of Phase 2b patients taking levodopa, Roche said. There were also “positive trends” in multiple secondary endpoints. Roche plans to present the full Phase 2b data at a future medical meeting. In the meantime, the Swiss drugmaker will carry on with open-label extensions of PADOVA and a separate failed prasinezumab study called PASADENA. The latter trial missed its primary endpoint in 2020. Roche is not the only company to struggle with developing effective treatments for Parkinson’s. On Tuesday, UCB and Novartis reported that minzasolmin, which has the same mechanism as prasinezumab, failed to significantly slow signs of disease progression in a Phase 2a study. In April, Sage Therapeutics axed its Parkinson’s asset , dalzanemdor, on the heels of a Phase 2 disappointment. Two months later, the FDA rejected AbbVie’s 24-hour infusion therapy for Parkinson’s for the second time due to manufacturing concerns. AbbVie has had better luck with tavapadon, the Parkinson’s drug it acquired from Cerevel, which passed its third late-stage test earlier this month.

PADOVA study showed numerical delay in motor progression and positive trends on multiple secondary and exploratory endpointsPrasinezumab 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 Basel, 19 December 2024 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today results from the Phase IIb PADOVA study 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 efficacy in the primary endpoint of time to confirmed motor progression with a HR=0.84 [0.69-1.01] and p=0.0657, missing statistical significance. In a pre-specified analysis, the effect of prasinezumab was more pronounced in the population treated with levodopa (75% of participants), HR=0.79 [0.63-0.99]. 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. “Parkinson’s is complex and devastating with no disease modifying treatment options available for the millions of people impacted,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “We believe the consistent efficacy trends from the Phase IIb study of prasinezumab merit further exploration. We will continue our close collaboration with the Parkinson’s community as we further evaluate the data to determine next steps.” 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 prasinezumabPrasinezumab 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 Commercialisation agreement with Prothena in December 2013 to develop and commercialise monoclonal antibodies targeting α-syn, such as prasinezumab, for the treatment of Parkinson’s disease. About the PADOVA studyPADOVA is a Phase IIb multicentre, randomised, double-blind trial evaluating the efficacy and safety of prasinezumab compared with placebo in 586 randomised 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 diseaseParkinson's disease is a chronic, progressive and debilitating neurodegenerative disease characterised 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. Today, PD affects over 10 million people worldwide. The prevalence of Parkinson’s disease is increasing, and it has become one of the fastest-growing neurological disorders. Currently, symptomatic treatments that effectively alleviate motor symptoms are available today, having a significant impact on people’s quality of life; however, no available symptomatic therapies slow down or stop the clinical progression of Parkinson’s disease and the effects wear off over time as the disease progresses. Roche is evaluating multiple approaches to slow down disease progression and potentially prevent Parkinson’s disease that involve targeting underlying disease processes such as aggregated α-syn production, lysosomal dysfunction and neuroinflammation. About Roche in NeuroscienceNeuroscience is a major focus of research and development at Roche. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases. Roche is investigating more than a dozen medicines for neurological disorders, including neuromuscular diseases: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy and spinal muscular atrophy; neuro immune diseases: multiple sclerosis and neuromyelitis optica spectrum disorder; and neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Together with our partners, we are committed to pushing the boundaries of scientific understanding to solve some of the most difficult challenges in neuroscience today. About Roche Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. For over 125 years, sustainability has been an integral part of Roche’s business. As a science-driven company, our greatest contribution to society is developing innovative medicines and diagnostics that help people live healthier lives. Roche is committed to the Science Based Targets initiative and the Sustainable Markets Initiative to achieve net zero by 2045. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com. All trademarks used or mentioned in this release are protected by law. Roche Global Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com Hans Trees, PhDPhone: +41 79 407 72 58 Sileia UrechPhone: +41 79 935 81 48 Nathalie AltermattPhone: +41 79 771 05 25 Lorena CorfasPhone: +41 79 568 24 95 Simon GoldsboroughPhone: +44 797 32 72 915 Karsten KleinePhone: +41 79 461 86 83 Nina MählitzPhone: +41 79 327 54 74 Kirti PandeyPhone: +49 172 6367262 Yvette PetillonPhone: +41 79 961 92 50 Dr Rebekka SchnellPhone: +41 79 205 27 03 Roche Investor Relations Dr Bruno EschliPhone: +41 61 68-75284e-mail: bruno.eschli@roche.com Dr Sabine BorngräberPhone: +41 61 68-88027e-mail: sabine.borngraeber@roche.com Dr Birgit MasjostPhone: +41 61 68-84814e-mail: birgit.masjost@roche.com Investor Relations North America Loren KalmPhone: +1 650 225 3217e-mail: kalm.loren@gene.com Attachment 19122024_MR_prasinezumab_en