IONIS-FXI RX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI and has been investigated in healthy volunteers and end-stage renal disease (ESRD) patients. FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI RX but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes. FXI-LICA has been studied in healthy volunteers and is currently investigated in ESRD patients on hemodialysis.We present a model-informed bridging approach that facilitates the extrapolation of the dose-exposure-FXI relationship from IONIS-FXI RX to FXI-LICA in ESRD patients and, thus, supports the selection of FX-LICA doses being investigated in ESRD patients. A two-compartment PK model, with mixed first-and zero-order subcutaneous absorption and first-order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/PD model adequately described the median trends, as well as the inter-individual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS-FXI RX and FXI-LICA, and in ESRD patients of IONIS-FXI RX . The Accepted ArticleThis article is protected by copyright. All rights reserved model was then used to predict dose dependent steady-state FXI activity following repeat once-monthly doses of FXI-LICA in a virtual ESRD patient population.Under the assumption of similar ASGPR expression in ESRD patients and healthy volunteers, doses of 40mg, 80mg, and 120mg FXI-LICA are expected to cover the target range of clinical interest for steadystate FXI activity in the Phase 2b study of FXI-LICA in ESRD patients undergoing hemodialysis.

No abstract

Compared with placebo, IONIS-PTP-1B treatment for 26 weeks produced prolonged reductions in HbA, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.

Fasting and postprandial hyperglucagonemia in type 2 diabetes mellitus (T2DM) patients cause excessive hepatic glucose production (HGP), suggesting that attenuation of hepatic glucagon action could be a therapeutic strategy for T2DM. In this study we evaluated the safety, tolerability, PK, and pharmacodynamics in healthy human volunteers of single and multiple doses (50-400 mg) ISIS 325568, a 2'-O-MOE antisense (ASO) developed to reduce hepatic glucagon receptor (GCGR) mRNA expression. In the multiple dose cohorts, treatment consisted of eight doses of ISIS 325568 or placebo over 6-weeks. Drug effects were assessed using serial fasting glucagon measurements and the glycemic response to a glucagon challenge at baseline and at the end of 6-week treatment. ISIS 325568 was not associated with clinically relevant changes. Dose-dependent predominantly mild injection site reactions were the most common side-effect. Active treatment caused a gradual increase in fasting glucagon levels and, compared to placebo, a significantly blunted glucagon-induced increase in plasma glucose AUC (24%, P < 0.0001) and HGP (13%, P = 0.007) at the 400 mg/week dose. Six weeks treatment with ISIS 325568 in healthy volunteers attenuated glucagon-stimulated HGP and glucose excursions, supporting further evaluation of the GCGR antisense approach in patients with T2DM.

No abstract

To evaluate the safety and efficacy of IONIS-GCGR Rx , a 29-O-methoxyethyl antisense oligonucleotide targeting the glucagon receptor (GCGR), and the underlying mechanism of liver transaminase increases in patients with type 2 diabetes on stable metformin therapy. RESEARCH DESIGN AND METHODS In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGR Rx (50-200 mg) or placebo for 13 or 26 weeks. RESULTS Significant reductions in HbA 1c were observed after IONIS-GCGR Rx treatment versus placebo at week 14 (22.0% 200 mg, 21.4% 100 mg, 20.3% placebo; P < 0.001) or week 27 (21.6% 75 mg, 20.9% 50 mg, 20.2% placebo; P < 0.001). Dose-dependent increases in transaminases were observed with IONIS-GCGR Rx , which were attenuated at lower doses and remained mostly within the normal reference range at the 50-mg dose. There were no other significant safety observations and no symptomatic hypoglycemia or clinically relevant changes in blood pressure, LDL cholesterol, or other vital signs. At week 14, IONIS-GCGR Rx 100 mg did not significantly affect mean hepatic glycogen content compared with placebo (15.1 vs. 220.2 mmol/L, respectively; P = 0.093) but significantly increased hepatic lipid content (4.2 vs. 22.7%, respectively; P = 0.005) in the presence of transaminase increases. CONCLUSIONS IONIS-GCGR Rx is a potent inhibitor of hepatic glucagon receptor expression with a potential to improve glycemic control at low weekly doses in combination with metformin. Significant reductions in HbA 1c occurred across the full-dose range tested, with minimal transaminase elevations at lower doses. Furthermore, novel results suggest that despite inhibition of glycogenolysis after GCGR antagonism, IONIS-GCGR Rx did not increase hepatic glycogen content.

The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy volunteers separated in 2 groups. The first group of 12 volunteers underwent a 5-h glucagon challenge during a pancreatic clamp procedure with infusion of [6,6-2H2]-glucose infusion in combination with heart rate variability measurements. In the second group, 12 other healthy volunteers underwent two 6-h glucagon challenges separated by 6 weeks, and fat biopsies were taken for analysis of glucagon receptor expression. Serum glucose rose rapidly after glucagon infusion, and reached a plateau at 90 min. The time profiles suggested rapid development of tolerance for glucagon-induced hyperglycemia. During the glucagon challenge intra- and inter-individual variabilities for hepatic glucose production, the rate of disappearance of glucose, and plasma glucose were approximately 10-15% for all variables. Hyperglucagonemia did not affect heart rate variability. Human adipose tissue had a low, but variable, expression of glucagon receptor mRNA. This standardized glucagon challenge test has a good reproducibility with only limited variability over 6 weeks. It is a robust tool to explore in detail the contribution of glucagon in normal and altered glucose homeostasis and can also be used to evaluate the effects of drugs antagonizing glucagon action in humans without confounding changes in ANS tone.

No abstract