3 research outputs found
A caseâstudy of modelâinformed drug development of a novel PCSK9 anti sense oligonucleotide. Part 1: First time in man to phase II
Abstract Here, we show modelâinformed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing firstâinâhuman study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and deârisk a phase IIb study. The focus of the caseâstudy is on the crossâfunctional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD
Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.
This phase Ib study compared the effects of AZD9977, a selective mineralocorticoid receptor modulator with predicted low hyperkalemia risk, with spironolactone on serum potassium (sK+ ) in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (EF; â„40%), and renal impairment. Patients with HF with EF greater than or equal to 40% and estimated glomerular filtration rate of 40-70âml/min/1.73âm2 were randomized to once-daily AZD9977 100âmg or spironolactone 25âmg for 14âdays, up-titrated to AZD9977 200âmg or spironolactone 50âmg for another 14âdays. The primary end point was relative change (%) in sK+ for AZD9977 versus spironolactone (baseline to day 28). Serum/urinary electrolytes, fractional excretion (FE) of Na+ /K+ , plasma aldosterone, cortisol, and renin, and safety were also assessed. Sixty-eight patients were randomized (AZD9977, n = 33; spironolactone, n = 35). Mean (SD) age was 73.0 (8.5) years, 51.5% men. Mean sK+ change from baseline to day 28 was 5.7% (AZD9977) and 4.2% (spironolactone), and 1.5% and 4.2% at day 14. Relative change (95% confidence interval) in sK+ with AZD9977 versus spironolactone was -0.3% (-5.3% to 4.4%; day 28), and 3.4% (-0.8% to 7.5%; day 14). Median increase from baseline in plasma aldosterone at day 28 was 89.8 pmol/L for AZD9977 and 67.4 pmol/L for spironolactone. Median FE of K+ was 12.9% (AZD9977) and 10.1% (spironolactone). AZD9977 was well-tolerated. No discontinuations due to hyperkalemia occurred with either treatment. Evidence of target engagement for AZD9977 with a favorable safety profile, supports further evaluation of AZD9977 in patients with HF and renal impairment
Rapid PROTAC discovery platform: nanomole scale array synthesis and direct screening of reaction mixtures to facilitate the expedited discovery and follow-up of PROTAC hits.
Precise linker length, shape and linker attachment point are all integral components to designing efficacious PROTACs. Due to the increased synthetic complexity of these heterobifunctional degraders and the difficulty of computational modelling to aid PROTAC design, the exploration of structure-activity-relationship (SAR) remains mostly empirical, which requires a significant time and resource investment. To facilitate rapid hit finding we developed capabilities for PROTAC parallel synthesis and purification by harnessing an array of pre-formed E3-ligand linker intermediates. In the next iteration of this approach, we developed a rapid, nanomole-scale PROTAC synthesis methodology using amide coupling that enables direct screening of non-purified reaction mixtures in cell-based degradation assays, as well as logD and EPSA measurements. This approach greatly expands and accelerates PROTAC SAR exploration (5 days instead of several weeks) while using nanomole amounts of reagents. Lastly, it avoids laborious and solvent-demanding purification of the reaction mixtures, thus making it an economical and more sustainable methodology for PROTAC hit finding