Merck & Co. Inc.'s Januvia (sitagliptin) made headlines last fall as the first FDA-approved dipeptidyl peptidase-IV inhibitor, and the drug since generated worldwide sales of $42 million in the fourth quarter of last year and $87 million in the first quarter of this year.
But while Januvia may have been the first in its class, it's not likely to be the last. Excitement about the ability of DPP-IV inhibitors to provide long-term improvement of glucose control without the accompanying risks of hypoglycemia and weight gain has driven significant interest in the field. At the American Diabetes Association 67th Scientific Sessions, held Friday through today in Chicago, there was no shortage of DPP-IV data from Merck and the competition.
Merck's Januvia data focused primarily on supporting ongoing efforts to expand the drug's label beyond initial use as a monotherapy and subsequent use in combination with metformin or thiazolidinediones. One study demonstrated that 67 percent of patients treated initially with both 50 mg of Januvia and 1,000 mg of metformin twice daily achieved HbA1c levels below 7, compared to 44 percent of those receiving only metformin. Another study showed that adding Januvia decreased HbA1c by a mean difference of 0.9 percent compared to placebo in patients failing treatment with the combination of metformin and the sulfonylurea glimepiride, and 0.6 percent compared to placebo in patients failing treatment with glimepiride alone.
In the wake of safety concerns about GlaxoSmithKline plc's diabetes drug Avandia (rosiglitazone maleate), Merck also presented a meta-analysis of nine late-stage trials in more than 5,000 patients demonstrating that Januvia was well tolerated, with an overall incidence of adverse events similar to comparator drugs and placebo.
Januvia's closest competition comes from big pharma. Novartis AG presented data at ADA from multiple studies of its DPP-IV inhibitor Galvus (vildagliptin), which received an approvable letter earlier this year. Galvus has shown positive results as a monotherapy and in combination with metformin, thiazolidinediones and insulin, and the new data showed that, like Januvia, Galvus decreased HbA1c by a difference of 0.6 percent when added to glimepiride.
Another late-stage competitor is Takeda Pharmaceutical Co. Ltd.'s DPP-IV inhibitor alogliptin, acquired through the 2005 buyout of Syrrx Inc. Alogliptin is now in Phase III, and data from an earlier-stage study presented at ADA showed the drug significantly decreased mean four-hour plasma glucose after each meal and was well tolerated at doses from 25 mg to 400 mg.
Also in Phase III is saxagliptin, from Bristol-Myers Squibb Co. and AstraZeneca plc. Data from a 743-patient trial presented at ADA showed that adding the drug to metformin resulted in significant decreases in HbA1c. Adjusted-mean placebo-subtracted differences with 2.5 mg, 5 mg and 10 mg of once-daily saxagliptin were 0.73 percent, 0.83 percent and 0.71 percent, respectively. Two smaller studies evaluating doses between 2.5 mg and 400 mg showed no dose-related adverse events.
The DPP-IV data from big pharma didn't stop there. Japanese company Sanwa Kagaku Kenkyusho Co. Ltd. presented data showing SK-0403 was well tolerated at doses up to 400 mg and had dose-dependent affects on DPP-IV inhibition in a small clinical trial. Abbott Laboratories presented clinical data showing ABT-279 was well tolerated at doses up to 1,000 mg and also had dose-dependent effects on DPP-IV inhibition.
The German firm Boehringer Ingleheim GmbH presented posters from several clinical trials showing that BI 1356 was well tolerated, decreased HbA1c, increased GLP-1 levels, reduced glucagon concentrations and - for more than 24 hours after dosing - inhibited DPP-IV. And Eli Lilly and Co. presented a preclinical profile of LY 2463665 showing the drug acts as a reversible ligand with a novel binding conformation and has encouraging efficacy, bioavailability, pharmacokinetic and toxicology properties.
Although big pharma is backing most of the late-stage DPP-IV inhibitors, biotech is staking a claim in the space as well. Earlier this month, Amgen Inc. agreed to acquire Alantos Pharmaceuticals Inc. for $300 million in cash to gain access to its Phase IIa DPP-IV inhibitor, ALS 2-0426, as well as earlier-stage assets. Phenomix Corp. also has a DPP-IV inhibitor in Phase II, and a Phase IIa study of the drug met its primary endpoint of improved postprandial glucose as well as secondary endpoints related to HbA1c and GLP-1 levels. (See BioWorld Today, June 6, 2007.)
Earlier-stage DPP-IV programs are in the works at companies such as Arisaph Pharmaceuticals Inc., Point Therapeutics Inc., and partners Santhera Pharmaceuticals AG and Biovitrum AB. Arisaph presented preclinical data at ADA showing that ARI-2243 compared favorably with Januvia in reducing plasma glucose. ARI-2243 also decreased HbA1c by 2.5 percent and 2.2 percent vs. placebo and Galvus, respectively, in a highly refractory diabetic mouse model. Clinical trials are slated for next year.
In other news from the meeting:
• Amylin Pharmaceuticals Inc., of San Diego, said study results showed Symlin (pramlintide acetate) injection used in conjunction with basal insulin improved glucose control and reduced weight without increased hypoglycemia in patients with Type II diabetes inadequately controlled with insulin glargine and oral agents. Study results formed the basis of a supplemental new drug application submitted in the fourth quarter of 2006. Separately, Amylin and Eli Lilly and Co., of Indianapolis, reported open-label trial data showing comparable improvements in blood sugar control between Byetta and insulin glargine therapies, with weight loss and lower incidence of hypoglycemia associated with Byetta (exenatide). And an open-label extension study in 151 Type II diabetics showed Byetta sustained improvements in blood sugar levels and progressive weight loss through three and a half years of therapy. The incretin mimetic also was associated with improvements in cardiovascular risk factors.
• Biodel Inc., of Danbury, Conn., presented additional data from a trial of VIAject, a rapid-acting form of injectable human insulin. Interim Phase III data demonstrated statistically significant daily mealtime (prandial) dose reductions in patients with Type I and II diabetes using VIAject. Type I patients receiving VIAject showed a 28 percent reduction in daily prandial dose while Humulin patients showed a non-significant increase of less than 1 percent. Type II diabetes patients using VIAject showed a 49 percent reduction in daily prandial dose, while Humulin patients showed a non-significant increase of 2.3 percent. Also, Phase II data showed faster insulin absorption than regular human insulin and lower insulin levels after three hours.
• DiObex Inc., of San Francisco, said a Phase IIa study of DIO-902, a cortisol synthesis inhibitor for Type II diabetes, demonstrated a trend toward improved glycemic control as measured by HbA1c, fructosamine and fasting blood glucose, as well as significant dose-dependent reductions in total and LDL cholesterol. Mean levels of C-reactive protein also were significantly reduced. Separately, DiObex said a study in six patients demonstrated DIO-901, a very-low-dose glucagon, can delay or prevent nocturnal hypoglycemia and reduce the number and duration of hypoglycemic episodes.
• Elixir Pharmaceuticals Inc., of Cambridge, Mass., presented preclinical data showing that treatment with a small-molecule ghrelin receptor antagonist decreased weight gain and improved glucose control, insulin control and liver function in mice on a high-fat diet. A second preclinical study showed ghrelin's mechanism of action involves acting directly through its receptor on adipocytes to regulate energy homeostasis. Additionally, Elixir published Phase II data in the ADA abstract book demonstrating that the insulin secretagogue Glufast (mitiglinide calcium hydrate) as a monotherapy managed HbA1c better than acarbose, and that the combination of Glufast and metformin was more effective than metformin alone. Glufast is marketed in Japan, and a U.S. Phase III trial is slated to begin this year.
• Genaera Corp., of Plymouth Meeting, Pa., presented preclinical data on the obesity drug trodusquemine (MSI-1436), which inhibits protein tyrosine phosphatase 1B, an enzyme involved in both the insulin and leptin pathways. The drug induced significantly greater weight loss in mice on a high-fat diet vs. lower-fat diets (p=0.001) and also reduced plasma insulin and plasma leptin. Shares of Genaera (NASDAQ:GENR) rose 25 cents Monday, or 10.8 percent, to close at $2.56.
• Isis Pharmaceuticals Inc., of Carlsbad, Calif., presented data from five research studies, which they said demonstrated potent and selective antisense inhibition of multiple gene targets involved in metabolic disorders such as diabetes, obesity and dyslipidemia. Results in various animal models showed positive effects of antisense drugs against a set of targets that included PTP-1B, SGLT2 and PKC-delta for diabetes, and JNK1 and mDIC for obesity.
• Metabasis Therapeutics Inc., of San Diego, said a study in rats showed MB06322 (CS-917) significantly lowered blood glucose by inhibiting gluconeogenesis and endogenous glucose production. While metformin also lowered blood glucose, it did not inhibit gluconeogenesis or endogenous glucose production in that animal model. The product is a prodrug of a selective inhibitor of fructose-1, 6-bisphosphatase. Separately, Metabasis said the hyperlipidemia candidate MB07811 decreased total and LDL cholesterol in a monkey trial with efficacy similar to Lipitor. MB07811 is a liver-targeted, beta-subtype-selective thyroid hormone receptor agonist.
• Orexigen Therapeutics Inc., of San Diego, presented a new subset analysis from a Phase IIb trial with obesity drug Contrave, a fixed-dose combination of sustained-release bupropion and Orexigen's sustained-release naltrexone. After 24 weeks of treatment, Contrave reduced visceral fat by more than 13 percent compared to a 4.6 reduction in the placebo group in the 107-patient analysis. Contrave also improved insulin resistance and levels of triglycerides, cholesterol and blood sugar. Contrave is being studied in two Phase II trials. Shares of Orexigen (NASDAQ:OREX) rose $1.17 Monday, or 8.2 percent, to close at $15.45. (See BioWorld Today, May 23, 2007.)
• Pfizer Inc., of New York, said interim three-year data from two ongoing long-term trials showed that small mean declines in lung function in diabetes patients who took Exubera inhalation powder reversed when Exubera was discontinued. The studies also showed Exubera patients maintained blood sugar control and generally gained less weight over the three-year period than those on an injected insulin regimen. The inhaled insulin product was developed with San Carlos, Calif.-based Nektar Therapeutics Inc.
• Sangamo BioSciences Inc., of Richmond, Calif., presented data from a Phase Ib trial of SB-509 demonstrating statistically significant improvements in subjects with diabetic neuropathy. Data showed SB-509, in addition to a neuroprotective effect, also may possibly have a neuroregenerative effect. SB-509 is a formulation of a zinc finger DNA-binding protein transcription factor designed to up-regulate the expression of the gene encoding vascular endothelial growth factor (VEGF-A). Sangamo is evaluating SB-509 in two ongoing Phase II trials for the treatment of diabetic neuropathy.
• VeroScience LLC, of Tiverton, R.I., and S2 Therapeutics Inc., of Bristol, Tenn., presented Phase IIIb data on Cycloset, a quick-release formulation of bromocriptine mesylate. The 3,000-patient patient was conducted in response to an approvable letter questioning the drug's cardiovascular safety, and the data showed a serious adverse event rate similar to placebo, with fewer cardiovascular events in the Cycloset group than the placebo group. The data also showed that adding Cycloset to metformin and sulfonylurea decreased HbA1c by a mean of 0.69 compared to placebo (p=0.0002). The companies plan to amend their new drug application with the FDA later this year.