Objective: To develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to assist in the dose and dosing regimen selection of ABBV-0805 for Phase 2 studies.

Background: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein as compared to monomeric α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson’s Disease (PD).  Development of monoclonal antibodies (mAbs) targeting soluble oligomeric α-synuclein is a promising strategy for delaying disease progression.  ABBV-0805 is an IgG4 mAb that selectively targets human oligomeric α-synuclein. It is currently being developed as a novel disease-modifying treatment for PD by AbbVie.  Preliminary human exposure and safety data being gathered in an ongoing Phase 1 first-in-human single ascending dose (FIH-SAD) study supports the Phase 2 development of ABBV-0805. Here we outline the development and verification of a PBPK/PD model for anti- α-synuclein mAbs and their engagement with monomeric and oligomeric species of α-synuclein in serum and cerebrospinal fluid (CSF).

Method: A PBPK/PD model was built using published human α-synuclein concentration data and serum to CSF concentration ratios; observed ABBV-0805 in vitro data on its binding affinity to monomeric and oligomeric α-synuclein species; and clinical PK and in vivo binding affinity data to α-synuclein following administration of single doses of ABBV-0805 from FIH study. Published Phase 1 PK and in vivo α-synuclein binding data for PRX002 and BIIB054 (anti-α-synuclein mAbs) were used to verify the model.

Results: The PBPK/PD model robustly captures PK profile of ABBV-0805 and its engagement with α-synuclein species in serum and CSF. The model performance was further verified using published competitor anti-α-synuclein mAb data and ABBV-0805 PK and pharmacodynamic profile was compared against that of PRX002 and BIIB054.

Conclusion: This PBPK/PD modeling approach was used to identify monthly intravenous Phase 2 doses of ABBV-0805 to maintain ≥ 95% oligomeric α-synuclein binding in CSF at steady state in PD patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluating-engagement-of-abbv-0805-an-anti-alpha-synuclein-monoclonal-antibody-to-physiological-and-pathological-forms-of-alpha-synuclein-for-phase-2-dose-selection-a-pbpk-modeling-and-simulation-ap/