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The incidence of type 2 diabetes is increasing at an alarming rate, having grown from 5.6 million cases in 1980 to 16.8 million in 2006 in the US alone, according to the US Centers for Disease Control and Prevention. The World Health Organization estimates that more than 180 million people worldwide have diabetes, and this total is anticipated to double by 2030. There remains a significant unmet medical need for better therapies to treat type 2 diabetes. An approach is needed that not only improves and maintains durable glycemic control, but does so with good tolerability and safety. A significant percentage of patients with type 2 diabetes are not achieving their goal of glucose control (a glycated hemoglobin (HbA1c) level of less than 7%, according to the American Diabetes Association). Many existing therapies have been associated with side effects such as weight gain, increased cardiovascular risk, gastrointestinal upset, increased risk of bone fracture, and some are contraindicated for patients with kidney or liver disease.
Glucokinase activators (GKAs) represent a promising new class of drugs for the treatment of type 2 diabetes that act directly on both the pancreas and the liver. Glucokinase (GK) is a key enzyme in glucose-sensing tissues that regulates glucose homeostatasis. GKAs lower glucose levels by enhancing the ability of pancreatic beta cells to “sense glucose” and increase insulin secretion in a glucose-dependent manner. Simultaneously, GKAs increase the uptake and disposal of glucose in the liver, while simultaneously reducing the amount it produces.
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Array BioPharma Inc. (Boulder, Co.) scientists sought to identify a class of GKAs that retained a higher degree of glucose-dependency than had been observed previously. The team’s efforts resulted in ARRY-403, a highly distinct structural class of GKA, as a clinical candidate. ARRY-403 possesses excellent pharmacokinetics across preclinical species, with linear dose-exposure relationships and a low potential for drug-drug interactions. In multiple well-established in vivo models of type 2 diabetes, ARRY-403 was highly efficacious in controlling both fasting and postprandial blood glucose, with rapid onset of effect and maximal efficacy within five to eight days of once-daily dosing. Of note, ARRY-403 did not induce hypoglycemia in these diabetic animal studies. ARRY-403 was combined with existing standard-of-care drugs such as metformin, sitagliptin (a DPP-4 inhibitor), or pioglitazone (a PPAR? agonist) for additional glucose control. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The candidate demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety.
In preclinical efficacy studies, ARRY-403 was better able to control both postprandial and fasting blood glucose after multiple days of dosing compared to a single dose. A single, oral dose of 30 mg/kg in a diabetic ob/ob mouse gave an excellent suppression of the glucose excursion after an oral glucose tolerance test. After 14 days of once-daily oral dosing of 3 mg/kg, ARRY-403 reduced the glucose excursion in an oral glucose tolerance test, and also reduced fasting blood glucose 24 hours post-dose (Figure 1).
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Possible mechanistic rationale for this phenomenon has been reported in the GK literature. GK expression in the liver is driven by insulin signaling and by increasing the insulin/glucagon ratio GKAs would be expected to increase hepatic GK expression. Insulin may also contribute to GK expression in the pancreas as well, and GKAs could enhance pancreatic GK expression. GKAs have been reported to protect the GK protein from degradation in vitro, and could potentially increase GK protein levels in vivo in the same manner. There is evidence that the inactive, super-open form of GK binds to polyubiquitin chains, associated with ubiquitination of the enzyme. GKAs (and high glucose concentration) modify the conformation of the ubiquitin binding site, thus reducing proteosomal degradation of GK through the ubiquitin-proteosome pathway.
Based on these results, ARRY-403 was evaluated in a Phase 1, single-ascending dose study in patients with type 2 diabetes (seven dose cohorts, 41 patients total), receiving either placebo or single doses of ARRY-403 ranging from 25 mg to 400 mg. It was well tolerated at all doses. ARRY-403 was rapidly absorbed, with a maximal drug concentration achieved within 1 hour (Figure 2). The drug exposure increased with dose, with low variability (18% coefficient of variation). The observed pharmacokinetic profile is consistent with once-daily therapeutic dosing.
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The patients in the trial participated in a standardized meal tolerance test the day before receiving study drug, as well as the same meal tolerance test after receiving ARRY-403. In addition to glucose, insulin and C-peptide were measured several times on both days. There was a dose-dependent reduction in glucose excursions in response to the standardized meal, as shown in Figure 3. Significant reductions in the post-meal glucose were observed with doses ? 50 mg. Consistent with the mechanism of a GKA, ARRY-403 induced an increase in C-peptide and insulin during the meal, which preceded the reduction in serum glucose (Figure 4, shown for the 200 mg cohort as a representative example).
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One of the defects in type 2 diabetes is inappropriate glucose production by the liver, which contributes to the HbA1c elevation seen in patients. After a single dose, ARRY-403 at 200, 300, and 400 mg reduced fasted blood glucose 24 hours after the dose (Figure 5). This reduction in fasted blood glucose (FBG) is consistent with activating GK in the liver to reduce hepatic glucose production.
Encouraged by these initial clinical results, Array has initiated a multiple ascending-dose study in patients with type 2 diabetes to evaluate safety, exposure and glucose control over a 10-day period. As noted above, ARRY-403 may have greater glucose control after multiple days of dosing and could show favorable pharmacodynamics at lower doses than observed in the single ascending-dose study. Array plans to report the combined Phase 1 results at an upcoming scientific meeting.
GKAs such as ARRY-403 show promise in controlling both post-meal and fasted blood glucose in patients with type 2 diabetes. They are expected to work well in combination with many existing treatments, particularly with insulin sensitizers and incretin-based therapies. ARRY-403 promises to be an exciting GKA and will be evaluated in longer-term clinical studies, both in terms of durable glycemic control and long-term safety.
Editors Note:
A shortened version of this article appeared in the October 2009 edition of Drug Discovery & Development.
Filed Under: Drug Discovery