Roche Drops Aleglitazar In Another Cardiology/Metabolics Setback

Development of dual PPAR agonist aleglitazar terminated due to fractures, renal impairment and heart failure reported in the AleCardio study, leaving another hole in Roche’s cardiovascular/metabolic pipeline.

Roche’s ambitions in cardiology/metabolics suffered another blow with the discontinuation of Phase III development for the diabetes drug aleglitazar.

An independent safety monitoring board recommended discontinuing the AleCardio study, a prevention trial involving more than 7,000 diabetes patients who had recently had an acute coronary syndrome, due to safety signals and lack of efficacy. All trials with the drug will be terminated, Roche said July 10. Eight Phase III studies are listed on the clinicaltrials.gov website.

Roche explained that there was an increased rate of adverse events in the trial, including fractures, renal impairment and heart failure.

The news on aleglitazar is the latest blow for Roche in cardiology. In May 2012, the company terminated development of the Phase III CETP inhibitor dalcetrapib due to lack of efficacy (Also see "Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol" - Pink Sheet, 14 May, 2012.). And in 2010, it suspended development of the late-stage GLP-1 agonist taspoglutide in light of safety problems (Also see "Roche/Ipsen's Suspended Taspoglutide Could Become Another Diabetes Casualty" - Pink Sheet, 10 Sep, 2010.).

Aleglitazar targets peroxisome proliferator-activated receptors. The drug is a dual PPAR agonist targeting alpha and gamma receptors. It is in the same family as thiazolidinediones, including Takeda Pharmaceutical Co. Ltd.’s Actos (pioglitazone) and GlaxoSmithKline PLC’s Avandia (rosiglitazone).

Dual PPAR agonists have been discontinued in the past – AstraZeneca PLC’s Galida (tesaglitazar) and Bristol-Myers Squibb Co.’s Pargluva (muraglitazar) – and aleglitazar’s failure is likely the end of development for the class in diabetes (Also see "Lilly Halts Trials Of PPAR Alpha Agonist After Preclinical Safety Signal" - Pink Sheet, 2 Oct, 2006.).

The side effects reported in the study would be expected with the class of drugs, but the hypothesis had been that the benefits would outweigh the risks, AleCardio lead investigator Michael Lincoff, Cleveland Clinic, said in an interview. Event rates were also higher than expected, he noted.

The study was intensely monitored and at the time of the recommendation by the safety board, 60% of events had been reported. Based on the data, there was little likelihood of showing sufficient efficacy, Lincoff said.

The rationale for the study was that a more-targeted PPAR agonist like aleglitazar would demonstrate better efficacy. The drug has a number of beneficial effects on patients with diabetes, including anti-inflammatory properties and reduction in blood sugar. Aleglitazar raises HDL, lowers LDL and lowers triglycerides. Big pharmas have been heavily invested in drugs that raise HDL, but their effectiveness for reducing cardiovascular events has come under question with the failure of niacin and dalcetrapib, among others, in large outcomes studies.

The AleCardio failure is yet another example of an HDL-raising effect not translating into event reduction. However, Lincoff points out that aleglitazar raises HDL by 35%, about the same as dalcetrapib, and drugs with a much larger magnitude of effect on HDL – Merck & Co. Inc.’s anacetrapib and Eli Lilly & Co.’s evacetrapib – may still prove effective, said Lincoff, who is principal investigator on the Phase III ACCELERATE study of evacetrapib.

Lincoff expects that following the aleglitazar failure, researchers will conclude that the PPAR agonists are too unpredictable and complicated a class of drugs.

During an R&D day in March 2010, Roche set the goal of establishing itself in metabolic and cardiovascular disease (Also see "With One Foot Firmly Planted In Oncology, Roche Moves The Other Into CV/Metabolic" - Pink Sheet, 18 Mar, 2010.).

At that time, the company was projecting peak sales of CHF 5 billion ($4.7 billion) for dalcetrapib and said that success with this drug would “transform the company.”

Later that year, however, execs noted that requirements for proving cardiovascular safety of diabetes drugs were prompting companies to trim their pipelines. Anders Svensson, head of global clinical development for metabolism, said it was best to kill more projects early to avoid costly Phase III failures (Also see "Glycemic Control Not Enough For New Diabetes Drugs, Roche Exec Says" - Pink Sheet, 18 Oct, 2010.).

The company’s metabolic pipeline is now looking sparse, with one drug in Phase III, the SGLT2 inhibitor tofogliflozin. Roche also has a PCSK9 inhibitor in Phase II (see table).

Roche’s Cardiovascular/Metabolism Pipeline
Drug	Mechanism of Action	Indication
Phase III
Tofogliflozin	SGLT-2 inhibitor	Type 2 diabetes
Phase II
Inclacumab (RG1512)	Monoclonal antibody neutralizes P-selectin, a molecule involved in inflammation and thrombosis	Acute coronary syndrome/cardiovascular disease
RG7652	Monoclonal antibody targeting PCSK9, a protein that regulates LDL-C	Metabolic disease
Phase I
RG7697	Dual agonist peptide analogue of the incretin hormones GIP and GLP-1	Type 2 diabetes