Objective: Phase I study with AFFITOPE® PD01A and PD03A to assess safety and tolerability as well as immunogenicity of this approach in MSA patients.

Background: Multiple system atrophy (MSA) is characterized by the accumulation of aggregated alpha-synuclein (aSyn) in oligondendrocytes forming glial cytoplasmic inclusions. Some symptomatic treatments are available, while disease-modification remains an urgent unmet treatment need in MSA. aSyn-targeting AFFITOPE®-based specific active immunotherapies are a novel approach aimed to achieve disease-modification in synucleinopathies.

Methods: In this 52-week phase I study (AFF009; NCT02270489), 30 early stage MSA patients on stable symptomatic therapy received four s.c. injections at 4-weekly intervals followed by a boost injection at week 36. Subjects were randomized to receive either AFFITOPE® PD01A 75 µg or AFFITOPE® PD03A 75 µg or matching placebo (adjuvant only) in a patient-blinded fashion (random assignment on a 2:2:1 basis). The study was conducted at two centers in France as part of an EU-funded program (FP7, SYMPATH Grant Agreement No. 602999). The objectives were to evaluate the safety and tolerability (primary endpoint) of repeated s.c. injections with PD01A and PD03A, and to explore the immunological response (secondary outcome). Clinical ratings of MSA symptoms were performed as exploratory endpoints.

Results: There was no significant signal in terms of safety and tolerability. Treatment-emergent adverse events (TEAE) were observed in 29 of 30 patients. Serious TEAE were recorded in all treatment groups (7/12 patients for PD01A, 2/12 patients for PD03A and 2/6 patients for placebo). Serious TEAE were mostly due to worsening of MSA symptoms. Two patients died because of worsening of MSA-related symptoms or complications and one from fatal pulmonary embolism. There were no signs on clinical examination or magnetic resonance imaging suggestive of inflammatory responses in the brain in any of the patients. PD01A was able to induce a significant and sustained immune response against aSyn protein and could be reactivated by boost injection. Antibodies induced by PD01A recognized the aSyn target epitope.

Conclusions: AFFITOPE® PD01A and PD03A had a favorable safety and tolerability profile in early MSA patients. The results of this study support further clinical development of this novel treatment approach for MSA, mainly of PD01A which was able to induce a significant and sustained immune response against aSyn.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/specific-active-immunotherapy-sait-against-alpha-synuclein-with-affitope-pd01a-and-pd03a-results-from-the-aff009-phase-i-trial/