Blood vessel abnormalities in the brain, including leaks in the blood brain barrier, play a significant role in Alzheimer’s disease. During normal injuries, bleeding causes enzymes to trim the blood plasma protein fibrinogen, forming fibrin. The conversion of fibrinogen to fibrin is essential for blood clot formation, but also changes the structure of the protein, exposing a sequence that activates inflammatory cells. Normally in the presence of high proteolytic activity fibrin in blood clots is degraded as healing progresses and inflammation subsides. However, in AD brains proteolytic activity is perturbed resulting in sustained fibrin deposition. Vascular alterations occur early in dementia and Alzheimer’s disease. The combination of the underlying vascular defect and the subsequent production of fibrin results in chronic neuroinflammation leading to nerve damage and the progressive cognitive decline characteristic of Alzheimer’s disease. The characterization of the underlying disease biology found in Alzheimer’s disease clearly defines an amyloid-independent vascular mediated mechanism. A drug that blocks fibrin mediated inflammation but does not inhibit its capacity for blood clotting would be of high therapeutic value.

THN391 is a humanized monoclonal antibody (mAb) targeting the P2 epitope of fibrin being developed for the treatment of neurological disorders.  The first-in-human study will evaluate the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous (IV) infusion in healthy adults.  The development of sensitive ligand binding assays to evaluate fibrinogen levels in the CSF of patients may allow for prospective selection of patients and can be correlated with known biomarkers for inflammation.  THN391 treatment in the 5XFAD rodent model will be performed to correlate EEG readouts with known behavioral and cognitive endpoints.  Lastly, cGMP drug product manufacturing paves the way to initiation of patient studies based utilizing safety data from healthy volunteers, use of biomarker data to select patients and EEG to monitor outcome.