The U.S. Food and Drug Administration (FDA) in the first quarter of 2010 approved liraglutide (Victoza®), the first once-daily human glucagon-like peptide-1 (GLP-1) analogue for the treatment of type 2 diabetes in adults. Several other compounds in the pipeline may also advance the prevention and treatment of kidney disease. Whether 2010 will be a banner year for drug development is unknown. But if the benchmark is 2009, the GLP-1 analogue already has enabled 2010 to keep pace.
Last year the FDA approved only one drug—saxagliptin (Onglyza)—relevant to diabetes, hypertension, or kidney disease. This DPP-4 inhibitor, which stimulates the pancreas to make more insulin after eating a meal, was one of the 26 new compounds approved by FDA in 2009. Saxagliptin is marketed by AstraZeneca and Bristol-Myers Squibb. The companies also have another potential type 2 diabetes drug in development (see below).
Liraglutide (Victoza®) for type 2 diabetes
Liraglutide (Victoza®) was approved by the FDA on Jan. 25 for the treatment of type 2 diabetes in adults, but only in combination with diet, exercise, and other diabetes medicines. The Novo Nordisk drug was not approved as a first-line treatment because of “safety concerns”; the FDA described clinical trial data suggesting that the drug may be associated with pancreatitis. Laboratory animal data indicated that rare type medullary thyroid cancer may be associated with liraglutide. In addition to requiring additional studies to better understand the risks associated with liraglutide, the FDA called for a Risk Evaluation and Mitigation Strategy to include a patient medication guide and a communication plan.
Novo Nordisk’s phase III clinical trials evaluated liraglutide as monotherapy and in combination with commonly prescribed treatments. According to the company, liraglutide achieved better or equivalent lowering of blood glucose than drugs such as sulphonylureas and thiazolidinediones. Weight gain was not associated with liraglutide use.
GLP-1 analogues stimulate the release of insulin from the pancreatic beta cells only when blood sugar levels are high. Byetta, marketed by Amylin and GlaxoSmithKline, is a member of this family of diabetes medications that requires twice-daily dosing. A longer-acting form of Byetta is under FDA review, with a decision expected later this year.
Dapagliflozin: potential first in class SGLT2 inhibitor
In the pipeline is another type 2 diabetes drug, Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor that targets an insulin-independent pathway. Inhibiting SGLT2 forces the kidneys to put glucose into urine, where it is excreted, thereby lowering blood glucose. If given the green light by FDA, Dapagliflozin will be first in class SGLT2 inhibitor for the treatment of diabetes. AstraZeneca and Bristol-Myers Squibb reportedly are on track to seek the agency’s approval to market the drug.
According to BioCentury, Dapagliflozin is not the only SGLT2 inhibitor in the pipeline for type 2 diabetes therapy. Dapagliflozin, however, is the first SGLT2 inhibitor to reach clinical testing, and is the first for which phase III data have been publicly reported. At the European Association for the Study of Diabetes (EASD) annual meeting last October, scientists said that the drug produced early and substantial reductions in blood glucose and body weight when added to metformin therapy. After 24 weeks of treatment, glycated hemoglobin levels declined 0.7 percent to 0.8 percent with dapagliflozin. In the placebo group, the decline was 0.3 percent (p < 0.05).
According to MedPage Today, Hannele Yki-Jarvinen, MD, of the University of Helsinki in Finland, who co-chaired the EASD session at which the phase III data were presented, commented that Dapagliflozin “looks wonderful, glucose goes down, blood pressure goes down.” But, she added, “I wonder if this degree of decrease in glucose levels actually improves insulin action and insulin secretion. Those are the type of things we would like to influence with the drug.”
Also developing an SGLT2 inhibitor is Lexicon Pharmaceuticals, Inc., which has completed phase II studies of its compound, LX4211. According to BioCentury, Lexicon’s phase II data included the unexpected benefit of reducing triglycerides.
“The impact on triglycerides suggests there is more going on here than just the effects from glucose excretion in the urine,” said Lexicon’s Brian Zambrowicz.
Anti-inflammatory for chronic kidney disease
By the second quarter of 2010, the results of a phase IIb clinical trial of a synthetic triterpenoid for the treatment of chronic kidney disease in patients with type II diabetes may be available. The results will determine whether bardoxolone, an anti-inflammatory drug, will proceed to phase III. In two previous phase II trials, bardoxolone significantly improved kidney function in type 2 diabetic patients with advanced chronic kidney disease (CKD), according to the drug’s developer, Reata Pharmaceuticals, Inc.
Bardoxolone inhibits the transcriptional activity of NF-kappa B (NF-kB) and signal transducer and activator of transcription 3 (STAT3). It activates the Nrf2 gene, which controls the production of over 250 antioxidant and detoxification proteins. Activation of Nrf2 protects tissues by increasing cellular antioxidant content and suppressing the inflammatory signaling pathways that play a role in promoting type 2 diabetes and its complications, including CKD.
In 90 percent of patients in the previous phase II studies, the estimated glomerular filtration rate increased from baseline. According to Reata, significant improvements also occurred in other markers of renal function, glycemic control, and cardiovascular disease. The observed increases in GFR suggest that bardoxolone may be able to delay or prevent the initiation of dialysis in diabetic patients.
In a FierceBiotech article about Bardoxolone, Reata CEO Warren Huff is quoted as saying, “The regulatory agencies recently gave us feedback that they would take IIb as pivotal, particularly if GFR was improved from baseline.” According to the article, Reata soon will launch a confirmatory phase III trial, putting Bardoxolone on track for FDA review in 2011.
