Abstract Phase I trials inform on the initial safety profile of a new molecule and impact whether further development is pursued or not. Understanding the effect of non‐pharmacological factors on the variability of routine safety parameters could improve decision making in these early clinical trials, helping to separate signals related to the new molecule from background “noise.” To understand the impact of non‐pharmacological factors on routine safety parameters, we evaluated pooled safety data from over 1000 healthy participants treated with placebo in phase I trials between 2009 and 2018. The phase I participants were predominantly men, less than or equal to 50 years, White, and non‐Hispanic; and approximately an equal proportion had body mass index in the normal and overweight/obese range. Following administration of placebo, vital signs, electrocardiogram, and laboratory parameters remained near predose baseline values. Large changes from baseline were observed for many safety parameters, but these occurred in a relatively small number of participants. At least one adverse event (AE) occurred in 49.7% of participants receiving placebo in single ascending dose (SAD) studies and in 72.4% of participants receiving placebo in multiple ascending dose (MAD) studies, with headache being the most commonly reported AE (18.7% in SAD and 28.3% in MAD studies). Overall, these analyses are consistent with non‐pharmacological factors having a small impact on routine safety parameters in a phase I trial. The provided supplemental data may be used to contextualize the magnitude and frequency of abnormal safety values and AEs observed in phase I trials.

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK -5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV 1 /FVC <0.7; FEV 1 >30% predicted) and PH (mean pulmonary arterial pressure >= 25 mmHg). Participants were randomized 2:1 to MK -5475 or placebo via dry -powder inhaler once daily for 7 days in Part 1 (360 mu g) or 28 days in Part 2 (380 mu g). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part -2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non -informative prior was used to calculate posterior probability (PP) that the betweengroup difference (MK -5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate -to -severe COPD. Incidences of AEs were comparable between MK -5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug -related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK -5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between -group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK -5475 for PH-COPD treatment.

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.