Reducing α-Synuclein in Human CSF; An Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEDI1341, an α-Synuclein-specific antibody, in Healthy Volunteers and Parkinson’s Disease Patients (P1-11.007)

Abstract

<h3>Objective:</h3> To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MEDI1341 (TAK-341) in single (SAD; NCT03272165) and multiple ascending dose (MAD; NCT04449484) studies undertaken in healthy volunteers (HVs) and Parkinson’s disease patients, respectively. <h3>Background:</h3> MEDI1341 is a human IgG1λ monoclonal antibody, engineered for selective, high-affinity binding of α-synuclein (ASN) and for reduced effector function. MEDI1341 recognises both monomeric and aggregated forms of human ASN. In rats and cynomolgus monkeys, MEDI1341 decreases free ASN in brain interstitial fluid and cerebrospinal fluid (CSF). In a mouse model, MEDI1341 attenuates ASN axonal propagation and accumulation in the brain. <h3>Design/Methods:</h3> HVs aged 18–80 years were eligible for the SAD study. Subjects eligible for the MAD study were aged 40–85 years with a diagnosis of mild-moderate Parkinson’s disease according to the UK Parkinson’s Disease Society Brain Bank criteria and stage 1–3 on the Hoehn and Yahr scale. In the SAD study, N=49 subjects received placebo or MEDI1341 administered intravenously (IV) across six dose levels. In the MAD study, two dose levels were evaluated in Parkinson’s patients (N=25), administered IV every 4 weeks for 3 infusions. <h3>Results:</h3> Administration of MEDI1341 or placebo to HVs or Parkinson’s patients was not associated with any medically important changes in safety parameters across all doses tested. Dose-dependent changes in serum concentrations for MEDI1341 were observed across cohorts. CSF concentrations demonstrated central nervous system penetration of MEDI1341. PD data showed dose-dependent suppression of free ASN in CSF, consistent with the results seen in preclinical species. <h3>Conclusions:</h3> MEDI1341 was generally well tolerated following IV administration to HVs or Parkinson’s patients after single or repeat doses, respectively. The PK and PD data provide evidence of dose-dependent and selective ASN target engagement by MEDI1341 in the central compartment. Full study design and data from the Phase 1 studies will be presented. <b>Disclosure:</b> Dr. Shering has received personal compensation for serving as an employee of AstraZeneca. An immediate family member of Dr. Shering has received personal compensation for serving as an employee of eResearch Technology Inc. Dr. Shering has stock in AstraZeneca. Dr. Shering has received intellectual property interests from a discovery or technology relating to health care. Michael Pomfret has nothing to disclose. Dr. Kubiak has received personal compensation for serving as an employee of AstraZeneca. Dr. Kubiak has stock in AstraZeneca. Mrs. Pouliquen has received personal compensation for serving as an employee of AstraZeneca. Mrs. Pouliquen has received personal compensation for serving as an employee of GSK. Mrs. Pouliquen has stock in GSK. Mrs. Pouliquen has stock in AstraZeneca. Wei Yin has received personal compensation for serving as an employee of Takeda. Wei Yin has stock in Takeda. Arthur Simen has received personal compensation for serving as an employee of Takeda. Dr. Ratti has received personal compensation for serving as an employee of Takeda. Dr. Ratti has received personal compensation for serving as an employee of Biogen. Dr. Ratti has stock in Takeda. Dr. Ratti has stock in Biogen. Dr. Perkinton has stock in AstraZeneca. Dr. Tan has received personal compensation for serving as an employee of AstaZeneca. An immediate family member of Dr. Tan has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for SOBI. Dr. Tan has stock in AstraZeneca. Dr. Chessell has received personal compensation in the range of $100,000-$499,999 for serving as a Employee with AstraZeneca. Dr. Ostenfeld has received personal compensation for serving as an employee of AstraZeneca. Dr. Ostenfeld has stock in AstraZeneca. Dr. Ostenfeld has received intellectual property interests from a discovery or technology relating to health care.