Risk Factors for and Risk of Peripheral Artery Disease in Swedish Individuals With Type 2 Diabetes: A Nationwide Register-Based Study.

OBJECTIVE: To investigate to what extent having control of peripheral artery disease (PAD) risk factors is associated with the risk of incident PAD in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 148,096 individuals with type 2 diabetes in the Swedish National Diabetes Register between 2005 and 2009 were included and matched with 320,066 control subjects on the basis of age, sex, and county. A few control subjects who developed type 2 diabetes after recruitment, during wash-in (<0.2%), were not censored but instead matched with two new control subjects. Individuals with type 2 diabetes were evaluated according to the number of PAD risk factors beyond recommended guideline levels at baseline, including LDL cholesterol, blood pressure, smoking, glycated hemoglobin, and estimated glomerular filtration rate. Incident PAD events were ascertained from 2006 to 2019. RESULTS: A graded association was observed between the number of PAD risk factors not at target and incident PAD in individuals with type 2 diabetes. The adjusted hazard ratio for PAD was 1.41 (95% CI 1.23-1.63) for those with type 2 diabetes with all PAD risk factors within target compared with control subjects matched for sex, age, and county but not risk factor status, in contrast with 9.28 (95% CI 3.62-23.79) for those with all five PAD risk factors not at target. CONCLUSIONS: A graded association was observed between increasing number of PAD risk factors not at target and incident PAD in individuals with type 2 diabetes.

A case-study of model-informed drug development of a novel PCSK9 anti sense oligonucleotide. Part 1: First time in man to phase II.

Here, we show model-informed 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 first-in-human 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 de-risk a phase IIb study. The focus of the case-study is on the cross-functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.

An oral antisense oligonucleotide for PCSK9 inhibition.

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.