Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial

Volc, Dieter; Poewe, Werner; Kutzelnigg, Alexandra; Lührs, Petra; Thun-Hohenstein, Caroline; Schneeberger, Achim; Galabova, Gergana; Majbour, Nour K.; Vaikath, Nishant N.; El‐Agnaf, Omar M. A.; Winter, Dorian; Mihailovska, Eva; Mairhofer, Andreas; Schwenke, Carsten; Staffler, Günther; Medori, Rossella

doi:10.1016/s1474-4422(20)30136-8

Cited by 97 publications

(100 citation statements)

References 27 publications

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“…Initial studies in PD, DLB, and MSA mouse models demonstrated the efficacy of another α-syn AFFITOPE®, PD01, which triggered specific antibody generation with CNS penetration and lowered α-syn aggregates and oligomers, leading to neuroprotection and improvement of locomotor behavior [ 38 , 39 ]. The first-in-human application of PD01 in PD patients has demonstrated safety and immunogenicity [ 40 ]. The recent findings of variable α-syn filaments in different α-synucleinpathies [ 28 , 41 ] suggest that vaccines may show different efficacies in these disorders depending on the epitope binding.…”

Section: Discussionmentioning

confidence: 99%

Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Lemos¹,

Venezia²,

Refolo³

et al. 2020

Transl Neurodegener

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Background Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE® immunotherapy approach, either alone or in combination with Anle138b, in a PLP-α-syn mouse model. Methods The PLP-α-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and α-synuclein pathology. Results The PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03. Conclusions PD03 and Anle138b can selectively target oligomeric α-synuclein, resulting in attenuation of neurodegeneration in the PLP-α-syn mice. Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.

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Section: Discussionmentioning

confidence: 99%

Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Lemos¹,

Venezia²,

Refolo³

et al. 2020

Transl Neurodegener

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“…Following these results, phase I clinical trials of the two AFFITOPE ® vaccines PD01A, and PD03A, which ended in February 2015, and August 2016, respectively, assessed the safety and tolerability in early PD patients with no serious adverse effects. The treatment resulted in a robust humoral response with target engagement [126]. This allowed the development of a phase II trial.…”

Section: Active Immunizationmentioning

confidence: 98%

Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

Castonguay

Gravel

Lévesque

2021

JPD

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Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

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“…Other types of target activation biomarkers may be used for different classes of investigational drugs (see Table 2). For example, in the case of immunotherapy, target activation could be demonstrated by the formation of antibody titers in plasma [156], and in the case of an antisense oligonucleotide, target activation may be demonstrated by a reduction in target protein levels [33,167]. For other types of drugs such as monoclonal antibodies against amyloid β [53][54][55][56][57][58][59][60][61][62][63], it may not be possible to demonstrate target activation, as the goal of these treatments is to clear the molecular target either by macrophage phagocytosis and complement activation or by altering the equilibrium of amyloid across the blood-brain barrier in favor of efflux from the brain to the blood [185].…”

Section: Target Activationmentioning

confidence: 99%

Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders

Vissers

Heuberger

Groeneveld

2021

IJMS

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The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

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Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial

Cited by 97 publications

References 27 publications

Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders

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