Roche announced it will start Phase III clinical investigations for aleglitazar, its innovative PPAR co-agonist R1439 which is uniquely designed to reduce cardiovascular morbidity and mortality in high risk patients with type 2 diabetes. This decision is supported by data from the Phase II SYNCHRONY study published today in The Lancet(1) and announced at the org/” rel=”nofollow”>American Diabetes Association meeting in New Orleans. The Phase III program is anticipated to start in the second half of 2009.

SYNCHRONY, a placebo-controlled dose ranging study in type 2 diabetes patients, showed that aleglitazar had a balanced synergistic effect on both lipid and glucose control with a good safety and tolerability profile in patients with type 2 diabetes.

Cardiovascular disease is currently the leading cause of death among those with type 2 diabetes, accounting for half of all deaths.(2) Despite guidelines recommending that cardiovascular risk in this patient group should be reduced by controlling factors such as dyslipidemia, blood pressure, body weight and hyperglycemia,(3,4) the majority of patients still do not achieve their treatment goals leaving them vulnerable to both initial and residual cardiovascular events.(3,5) Significantly, one in ten patients with an acute myocardial infarction died within a year.(6)

“Roche is confident that aleglitazar has the potential to reduce cardiovascular morbidity and mortality in this high-risk patient group and is therefore committed to pursuing its rapid development,” said Jean-Jacques Garaud, Global Head of Development Pharmaceuticals Division of Roche.

The focused Phase III outcomes trial will investigate whether once daily 150 micrograms aleglitazar reduces the incidence of cardiovascular mortality, non-fatal myocardial infarction and stroke in patients with type 2 diabetes. The approach in this selected high-risk patient population will be unique as no drug has been demonstrated to reduce cardiovascular risk in type 2 diabetes patients following an ACS event.

Professor Robert Henry, SYNCHRONY Clinical Investigator and Chief VA Endocrinology & Metabolism and Professor of Medicine in Residence at the University of California at San Diego, commented: “The favorable balance in the safety and efficacy profile of aleglitazar seen in the SYNCHRONY study represents encouraging short-term clinical data for this agent and provides good evidence to enter Phase III investigation.”

With the decision to move into Phase III, aleglitazar is Roche’s third Phase III clinical trial program in the area of metabolism. The new Phase III study is a cardiovascular outcomes trial designed to assess the potential of once-daily 150 micrograms aleglitazar to reduce cardiovascular mortality, non-fatal myocardial infarction and stroke in type 2 diabetes patients with a recent ACS.

About the SYNCHRONY Study

SYNCHRONY was a multicenter, randomized, double-blind, placebo-controlled dose ranging study among 332 type 2 diabetes patients (either drug-naive or pre-treated with less than or equal to 2 oral agents). Designed to determine the glucose-lowering and lipid-modifying effects, and safety profile of aleglitazar, the study confirmed the favorable safety and efficacy profile of the once daily 150 microgram aleglitazar dose and supported commencement of the Phase III clinical investigation.

Patients underwent a single-blind 4- to 5-week placebo run-in period, then were randomized to receive 16 weeks treatment with either aleglitazar at one of four once daily doses (50, 150, 300 or 600 micrograms), placebo or 45 mg pioglitazone.

The primary endpoint of dose-dependent reductions from baseline HbA1c versus placebo was met and a range of responses observed from -0.36% (95% CI:0.00 to -0.70, P=0.048) with 50 micrograms aleglitazar, to -1.35% (95% CI: -0.99 to -1.70, p<0.0001) with the 600 microgram dose. Notably, the once daily 150 microgram aleglitazar dose (currently in clinical trials) demonstrated numerically comparable reductions from baseline HbA1c to those observed with pioglitazone (-0.85%, 95% CI: -0.50 to -1.20, P<0.0001 vs.-0.71%, 95% CI: -0.36 to -1.06, P<0.0001).

The study’s secondary clinical endpoints were changed from baseline in fasting plasma glucose and lipid profiles. Notably, significant dose-dependent reductions versus placebo were observed with aleglitazar for fasting plasma glucose (-1.0 mmol/L with 50 micrograms to -3.3 mmol/L with 600 micrograms), triglycerides (-27.8% with 50 micrograms to -51.6% with 600 micrograms), and LDL-C (-9.1% with 50 micrograms to -25.9% with 600 micrograms), as well as a significant dose-dependent increase in HDL-C (8.2% with 50 micrograms to 22.9% with 300 micrograms). Importantly, treatment with the once daily 150 micrograms aleglitazar

dose produced a numerically superior effect on triglycerides, HDL-C, and LDL-C when compared with 45 mg pioglitazone.

Known PPAR-alpha (creatinine increase) and gamma-related effects (edema, haemodilution, and weight gain) were seen in a dose-dependent manner of which the incidence of edema for the 150 microgram aleglitazar dose was similar to placebo and numerically less than with pioglitazone, and body weight gain was numerically less than with pioglitazone.

About Aleglitazar

Aleglitazar is an innovative treatment designed to reduce the incidence and impact of cardiovascular mortality, non-fatal myocardial infarction and stroke in patients with a recent ACS and type 2 diabetes.

It is a rationally designed molecule providing balanced dual PPAR alpha/gamma activation. Specifically, it combines the improvements in peripheral insulin sensitivity (and therefore glycemic control) associated with PPAR gamma activation, with improved management of dyslipidemia, which is commonly associated with PPAR alpha activation.

About Diabetes

Diabetes is a disease characterized by excess blood glucose due to a deficiency in insulin availability and/or resistance to its action. Type 2 diabetes accounts for 90 percent of all diabetes cases worldwide. Complications from diabetes, such as coronary artery and peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness, are resulting in increasing disability, reduced life expectancy and enormous health cost for virtually every society. According to current estimates by the World Health Organization, more than 180 million people worldwide have diabetes. This number is likely to more than double by 2030.

About Roche

Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world’s leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people’s health and quality of life.

All trademarks used or mentioned in this release are protected by law.

References

(1) Henry R et al. The dual peroxisome proliferator-activated receptor alpha/gamma: results from SYNCHRONY, a phase II, randomized, dose-ranging study in patients with type 2 diabetes. The Lancet, online edition, 8 June 2009

(2) World Health Organization. Diabetes Fact Sheet No 312, November 2008.

(3) American Diabetes Association. Standard of medical care in diabetes - 2008. Diabetes Care 2008; 31 Suppl 1: S12-54

(4) Graham I et al. European Guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur heart J 2007; 28: 2375-414

(5) Saydah SH et al. poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004; 291: 335-42

(6) Montalescot G and al. STEMI and NSTEMI: are they so different? 1 year outcomes in acute myocardial infarction as defined by the ESC/ACC definition (the OPERA registry). Eur Heart J 2007; 28: 1409-1417

Source: Roche

Low blood glucose levels do not explain the excess deaths seen in the intensive control group of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, according to a report presented here today at the American Diabetes Association’s 69th Scientific Sessions.

“After the original ACCORD report showed an increased mortality risk in the intensive strategy group aiming to lower Centers for Disease Control and Prevention, provide support substudies.

Source
American Diabetes Association

View drug information on Glucagon.

LITTLE FALLS, N.J., June 11 — The FDA issued an alert regarding the risk of increased mortality in stable liver transplant patients who switch from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus (Rapamune).

The agency noted that a causal relationship has not been established and that it is not recommending discontinuation of the drug, which is indicated for the prevention of organ rejection in kidney transplant recipients older than 12.

The mortality risk was identified after the manufacturer, Wyeth, submitted data from a completed randomized trial to the FDA on March 25.

The trial compared outcomes in stable liver transplant recipients who converted from a calcineurin inhibitor to sirolimus and those who remained on a calcineurin inhibitor.

In addition to the association with higher mortality rates, the switch to sirolimus was linked to higher rates of treatment failure and discontinuation related to adverse events, as well as elevated mean fasting lipid concentrations.

The drug’s label already carries a boxed warning of excess mortality and graft loss associated with the use of sirolimus in combination with tacrolimus (Prograf) in de novo liver and lung transplant recipients.

The label also states that the safety of the drug has not been established in lung and liver transplant recipients and that its use in these patients is not recommended.

The FDA said it “is determining whether a labeling change for sirolimus is needed. In the interim, physicians should continue to use the drug’s professional labeling as a guide to therapy.”