P301S model, AlphaLISA measurements demonstrated a significant decrease of human Tau multimers (HT7/HT7 setup), as well as a significant decrease of a misfolded Tau (MC-1/HT7 setup) in a total brain fraction. A trend to decrease human Tau phosphorylated at pS396 in different brain fractions was also observed. ACI-35 treatment significantly improved the rotarod performance in both the transgenic hTauP301S-Tg model and the AAV-TauP301S spreading model. Conclusions: The study demonstrated that active immunization with ACI-35 significantly decreased human pathological Tau species in different brain fractions and ameliorated the clinical phenotype in two different mouse models of tauopathy.

BackgroundNitric oxide donors are widely used to treat cardiovascular disease, but their major limitation is the development of tolerance, a multifactorial process to which the in vivo release of nitric oxide is thought to contribute. Here we describe the preclinical and clinical results of a translational drug development effort to create a next‐generation nitric oxide donor with improved pharmacokinetic properties and a unique mechanism of nitric oxide release through CYP3A4 metabolism that was designed to circumvent the development of tolerance.Methods and ResultsSingle‐ and multiple‐dose studies in telemetered dogs showed that MK‐8150 induced robust blood‐pressure lowering that was sustained over 14 days. The molecule was safe and well tolerated in humans, and single doses reduced systolic blood pressure by 5 to 20 mm Hg in hypertensive patients. Multiple‐dose studies in hypertensive patients showed that the blood‐pressure–lowering effect diminished after 10 days, and 28‐day studies showed that the hemodynamic effects were completely lost by day 28, even when the dose of MK‐8150 was increased during the dosing period.ConclusionsThe novel nitric oxide donor MK‐8150 induced significant blood‐pressure lowering in dogs and humans for up to 14 days. However, despite a unique mechanism of nitric oxide release mediated by CYP3A4 metabolism, tolerance developed over 28 days, suggesting that tolerance to nitric oxide donors is multifactorial and cannot be overcome solely through altered in vivo release of nitric oxide.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01590810 and NCT01656408.

BackgroundOver 2 million girls and young women are living with HIV, being newly infected at disproportionately high rates. HIV infection adds risks to pregnancy, including vertical transmission and maternal death. Hormonal contraceptives are among the most effective reversible contraceptives, but they have clinically meaningful drug–drug interactions (DDI) with many antiretrovirals (ARV). MK-8591 is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently in Phase 2 clinical development for treatment of HIV. Unlike many ARVs, MK-8591 is not an inhibitor or inducer of major CYP enzymes and is not expected to alter the pharmacokinetics (PK) of hormonal contraceptives. This clinical study evaluated the DDI of MK-8591 with levonorgestrel (LNG) and ethinyl estradiol (EE) to support use of hormonal contraceptives with MK-8591.MethodsThis was an open-label, two-period, fixed-sequence DDI study in 14 healthy, postmenopausal or oopherectomized females aged 50–64. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7-day washout. MK-8591 20 mg was then dosed once weekly for 3 weeks; a single dose of LNG 0.15 mg/EE 0.03 mg was given concomitantly with the third dose of MK-8591. PK samples were collected for evaluation of LNG and EE levels. Individual values of AUC0-inf and Cmax were natural log-transformed prior to analysis and evaluated separately using a linear mixed effects model with a fixed effects term for treatment. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the treatment measurements within each subject.ResultsThe PK of EE and LNG were not meaningfully altered by co-administration with MK-8591. For the comparison of (MK-8591 + LNG/EE) / (LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals (CIs)) for LNG AUC0-inf and Cmax were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE the GMRs (90% CI) for AUC0-inf and Cmax were 1.05 (0.981, 1.11) and 1.02 (0.971, 1.08), respectively. Co-administration of all three drugs was generally well tolerated.ConclusionThe results of this study support use of hormonal contraceptives in HIV-infected patients receiving MK-8591.Disclosures W. Ankrom, Merck & Co, Inc.: Employee and Shareholder, Salary. D. Jonathan, Merck: Employee, Salary. D. Rudd, Merck & Co., INC.: Employee, Salary. S. Zhang, Merck & Co, Inc.: Employee, Salary. K. Fillgrove, Merck & Co., Inc.: Employee, Salary. K. Gravesande, Kezia Gravesande: Research Contractor, Salary. R. Matthews, Merck: Employee, Salary. A. Stoch, Merck & Co, Inc.: Employee and Shareholder, Salary. M. Iwamoto, Merck & Co, Inc.: Employee and Shareholder, Salary.

Background: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson’s disease (PD). Objective: To explore the use of the electronic medical records (EMRs) to identify participants with PD. Methods: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants. Questionnaires were completed to ascertain Ashkenazi Jewish (AJ) ancestry and family history of PD. Results: Among 837 participants with PD, 82% were 65 years and older and 72% had a family history of AJ ancestry. Among those with AJ ancestry, 15.6% reported having relatives with PD. The frequency of observed mutations for LRRK2 and GBA genes combined was approximately 15.4% . The frequency of observed LRRK2 mutation was 6.1% overall and 7.2% from those with AJ ancestry; and for GBA mutation was 9.3% overall and 11.2% from those with AJ ancestry. Conclusion: Although the frequency of observed mutations in this study was lower than anticipated, mutation carriers were enriched among those with a family history of AJ ancestry increasing nearly 2-3-fold, from 3% –7% (LRRK2) and 4% –11% (GBA). The identification (and selection) of PD patients through EMRs prior to genotyping is a viable approach, to establish a genetically defined cohort of patients with PD for clinical research.