ALECARDIO trial halted for safety

July 10, 2013

July 10, 2013

Basel, Switzerland - Roche has announced the halting of a phase 3 trial of its investigational diabetes drug aleglitazar in type 2 diabetes patients with acute coronary syndrome, due to safety concerns with the agent [1]. All other studies with the drug will also be terminated, the company said.

The decision to halt the study, called ALECARDIO, came after a scheduled meeting of the data safety and monitoring board (DSMB), the lead investigator Dr Michael Lincoff (Cleveland Clinic, OH) said in an interview.

The safety concerns relate to "three things: bone fractures, heart failure, and gastrointestinal bleeding," Lincoff said. These are all known potential adverse effects of this drug class, he noted, but the DSMB had to perform "an analysis to determine if there was benefit to the [primary] cardiovascular end point that would offset the risk. They determined there were criteria for futility: the drug was not reducing the CV end point, so there was no evidence of a benefit to offset the risks, and therefore [they] recommended to us that the trial be stopped."

Patients currently in the study will be called back within four weeks and transitioned off the drug, Lincoff added, noting that an investigator letter to this effect went out today. "On balance, we decided not to tell people to stop the drug emergently because we were afraid that some people's diabetes control would deteriorate, so the letter says that it's not such a safety issue that they have to . . . stop the drug immediately."

To heartwire, Lincoff explained that ALECARDIO was designed not just to establish safety but to also show superiority: hence, the "recent ACS" patient population was chosen in the hopes of demonstrating not just glucose-lowering but a reduction in cardiovascular events in a group of high-risk patients. Another, larger trial, ALEPrevent, had also recently gotten under way based on the assumption of a CV benefit in ALECARDIO. The 17 000-patient trial was enrolling patients with stable coronary artery disease and diabetes or metabolic syndrome. ALEPrevent, as well as other trials testing the drug in the setting of diabetes and retinopathy and nephropathy, in addition to studies looking at combining aleglitazar with other diabetes agents, have all been stopped, he added.

Not much good news for PPAR agonists

This looks likely to sound the death knell for aleglitazar, a dual peroxisome proliferator-activated receptor (PPAR)-alpha/gamma agonist, similar to the thiazolidinediones (TDZs or glitazones), such as rosiglitazone (Avandia, GlaxoSmithKline) and pioglitazone, although rosiglitazone is exclusively a PPAR-gamma agonist and pioglitazone is primarily gamma but has some alpha-agonist properties, Lincoff noted.

Rosiglitazone has had its own well-publicized issues—it was withdrawn from the EU market in 2010 and severely restricted in the US, although there have been calls there recently to ease these restrictions—and pioglitazone has also been the subject of controversy, most recently due to a decision by the Indian government there to suspend the drug.

Other dual PPAR alpha/gamma agonists have also failed to make it to market due to safety concerns, including muraglitazar (Pargluva, Bristol-Myers Squibb/Merck) and tesaglitazar (Galida, AstraZeneca), both of which were discontinued in 2006. Muraglitazar increased the risk for cardiovascular events and tesaglitazar was associated with renal problems.

Roche is now left with little in its cardiometabolic pipeline following this latest development and last year's discontinuation of dalcetrapib—a medicine aimed at boosting levels of high-density cholesterol.

Full details of ALECARDIO will be presented in the future

In the worldwide ALECARDIO trial, 7228 patients with a recent acute coronary syndrome and type 2 diabetes were randomized to aleglitazar 150 µg or placebo daily, in addition to standard medical therapy. Patients were primarily recruited through cardiology clinics, and the primary efficacy end point was time to first event of cardiovascular death, MI, or stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function.

Lincoff said as well as the flags about bone fractures, heart failure, and gastrointestinal bleeding associated with aleglitazar, there was also deterioration in renal function among some patients taking it, "but it was reversible, and we knew that based on other trials."

A full analysis of the trial will now be conducted, with results to be presented at a future cardiology meeting, he said, adding, "We won't know until we analyze the data whether diabetes control is better in the aleglitazar arm."

Lincoff is the study chair for the ALECARDIO trial but does not receive personal honoraria.

 

 

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....