First proof of pharmacology in humans of a novel glucagon receptor antisense drug

Abstract

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.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…This is a seminal observation that was later confirmed by several independent research groups (Gerich et al, 1976;Felig et al, 1978;Butler and Rizza, 1991;Kelley et al, 1994). Subsequent studies showed that somatostatin-induced inhibition of postprandial glucagon secretion ameliorates hyperglycemia in patients with T2D (Gerich et al, 1974;Dinneen et al, 1995;Shah et al, 2000), and more recently that blocking glucagon action decreases hyperglycemia in a variety of species, including rodents (Mu et al, 2011;Kim et al, 2012b;Okamoto et al, 2017), rabbits (Brand et al, 1996), dogs (Rivera et al, 2007), nonhuman primates (Xiong et al, 2012;Okamoto et al, 2015), and humans (Petersen and Sullivan, 2001;Kelly et al, 2015;van Dongen et al, 2015;Kazda et al, 2016;Kostic et al, 2018). The virtues and limitations of antagonizing glucagon signaling for the treatment of diabetes have recently been highlighted in several review articles (Unger and Cherrington, 2012;Farhy and McCall, 2015;Lee et al, 2016b;Müller et al, 2017), with the implication that excess glucagon action can serve a greater role in the pathology of T2D than impaired insulin action (Unger and Cherrington, 2012).…”

Islet α cells and glucagon—critical regulators of energy homeostasis

“…Treatment with a GCGR antisense oligonucleotide over 6 weeks reduced glucagon-stimulated hepatic production of glucose during a glucagon challenge test in healthy, non-obese male adults. 67 Additional studies of several small molecule GCGR antagonists performed over an increased time period have been completed (Table 1), the results of which have demonstrated robust glucose-lowering efficacies, with some GCGR antagonists producing reductions in HbA 1c levels comparable to, or greater than, metformin. The essential contribution of gluca gon to the development of hyperglycaemia in experimental models of T1DM has also been demonstrated, 4,68 which has fostered clinical assessment of the efficacy of GCGR antagonists in the treatment of T1DM (Table 1).…”

Renal Effects of Antisense-Mediated Inhibition of SGLT2

“…In primates, tubular accumulation of oligonucleotides is usually not associated with renal toxicity and tubular functional changes, unless extremely high doses are used (Monteith et al, 1999;Henry et al, 2012;Zanardi et al, 2012 ). In accordance, these compounds are not associated with adverse renal effects in humans during subsequent clinical investigations (Kastelein et al, 2006;van Dongen et al, 2015). However, it is of note that, compared with other 18-to 20-mer second-generation oligonucleotides, the 12-mer chemistry of ISIS 388626 enables more selective distribution to the kidney (Wancewicz, 2008), the result of lower plasma protein binding, higher free fraction, and increased renal filtration.…”

“…Moreover, it makes it improbable that a general membrane dysfunction occurs as a result of knockdown of the SGLT2 receptor. This is further supported by the absence of signs of membrane dysfunction with other oligonucleotides are directed to transmembrane receptors (Limmroth et al, 2014;van Dongen et al, 2015). ISIS 388626 is, however, the first antisense that oligonucleotide targeted to a renal receptor, and it remains uncertain if knockdown interferes with membrane function.…”