Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial

Dam, Tien; Boxer, Adam L.; Golbe, Lawrence I.; Höglinger, Günter U.; Morris, Huw R.; Litvan, Irene; Lang, Anthony E.; Corvol, Jean‐Christophe; Aiba, Ikuko; Grundman, Michael; Yang, Lili; Tidemann-Miller, Beth; Kupferman, Joseph; Harper, Kristine D.; Kamisoglu, Kubra; Wald, Michael J.; Graham, Danielle; Gedney, Liz; O’Gorman, John; Haeberlein, Samantha Budd

doi:10.1038/s41591-021-01455-x

Cited by 76 publications

(52 citation statements)

References 62 publications

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“…Gosuranemab is a humanized monoclonal antibody against extracellular N-terminal of tau in the interstitial fluid (ISF) and CSF released by neurons. A phase II trial in progressive supranuclear palsy showed that the unbound N-terminal tau in CSF was decreased by 98% in the gosuranemab group and increased by 11% in the placebo group, but the N-terminal tau neutralization does not translate into clinical efficacy (NCT03068468) [ 72 ]. Recently, Kim and his colleagues examined the brain tissues of three individuals receiving gosuranemab and found that gosuranemab treatment may be associated with glial responses including accumulation of tau within astrocytic lysosomes [ 73 ].…”

Section: Immunotherapies Based On Tau Proteinmentioning

confidence: 99%

Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Song

Shi

Zhang

et al. 2022

Transl Neurodegener

118

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Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly worldwide. However, the complexity of AD pathogenesis leads to discrepancies in the understanding of this disease, and may be the main reason for the failure of AD drug development. Fortunately, many ongoing preclinical and clinical studies will continually open up avenues to unravel disease mechanisms and guide strategies for AD diagnosis and drug development. For example, immunotherapeutic strategies targeting amyloid-β (Aβ) and tau proteins were once deemed almost certainly effective in clinical treatment due to the excellent preclinical results. However, the repeated failures of clinical trials on vaccines and humanized anti-Aβ and anti-tau monoclonal antibodies have resulted in doubts on this strategy. Recently, a new anti-Aβ monoclonal antibody (Aducanumab) has been approved by the US Food and Drug Administration, which brings us back to the realization that immunotherapy strategies targeting Aβ may be still promising. Meanwhile, immunotherapies based on other targets such as tau, microglia and gut-brain axis are also under development. Further research is still needed to clarify the forms and epitopes of targeted proteins to improve the accuracy and effectiveness of immunotherapeutic drugs. In this review, we focus on the immunotherapies based on Aβ, tau and microglia and their mechanisms of action in AD. In addition, we present up-to-date advances and future perspectives on immunotherapeutic strategies for AD.

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Section: Immunotherapies Based On Tau Proteinmentioning

confidence: 99%

Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Song

Shi

Zhang

et al. 2022

Transl Neurodegener

118

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“…Furthermore, subtypes of PD were not considered in most PD trials (Pagano et al 2021 ; Rascol et al 2011 ). Recent trials in PSP enrolled patients according to the previous NINDS-SPSP diagnosis criteria (Höglinger et al 2021 ) or by the presence of postural instability and vertical gaze palsy (Dam et al 2021 ) and thereby de facto only included patients with a Richardson-syndrome without taking into account that these only comprise a quarter of all PSP patients (Respondek and Höglinger 2016 ). In MSA, some trial only included patients with predominant Parkinsonism (Dodel et al 2010 ), whereas other trials included patients with MSA-C and MSA-P (Bensimon et al 2009 ; Levin et al 2016b , 2019 ).…”

Section: Studies With the Aim To Investigate Neuroprotectionmentioning

confidence: 99%

Disease modification in Parkinsonism: obstacles and ways forward

2022

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To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is already advanced. However, disease modification or neuroprotection, is considered to be most effective before marked neurodegeneration has occurred. In recent years, early clinical or prodromal stages of Parkinson syndromes came into focus. Moreover, subtypes of distinct diseases will allow predictions of the individual course of the diseases more precisely. Thereby, patients will be enrolled into clinical trials with more specific disease entities and endpoints. Furthermore, novel fluid and imaging biomarkers that allow biochemical diagnoses are under development. These will lead to earlier diagnoses and earlier therapy in the future as consequence. Furthermore, therapeutic approaches will take the underlying neuropathological process of neurodegenerative Parkinson syndromes more specific into account. Specifically, future therapies will target the aggregation of aggregation-prone proteins such as alpha-synuclein and tau, the degradation of pathological aggregates, and the spreading of pathological protein aggregates throughout the brain. Many of these approaches are already in (pre)clinical development. In addition, anti-inflammatory approaches are in development. Furthermore, drug-repurposing is a feasible approach to shorten the developmental process of new drugs.

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“…There have been several large antibody-based clinical trials for CNS disorders. Dam et al [ 140 ] examined the safety and efficacy of an anti-tau antibody (gosuranemab) for progressive supranuclear palsy (NCT03068468). However, the phase II trial failed to show evidence of neurologic efficacy even though unbound N-terminal tau levels in CSF decreased by 98%.…”

Section: Drug Deliverymentioning

confidence: 99%