May 7th, 2012

Roche Terminates Development of CETP Inhibitor Dalcetrapib

Roche announced today that it has ended development of dalcetrapib, its entry into the once-promising class of HDL-raising CETP inhibitors. A data and safety monitoring board recommended that the dal-OUTCOMES phase 3 trial be stopped due to a lack of clinically meaningful efficacy. The DSMB found no evidence of safety problems.

4 Responses to “Roche Terminates Development of CETP Inhibitor Dalcetrapib”

  1. The withdrawal of dalcetrapib is an unwelcome blow to the development of additional add-on therapies to reduce residual risk by raising HDL. HDL is a complex, heterogeneous molecule with several functions that change dynamically during health and disease. Unfortunately, although epidemiological and preclinical evidence support HDL-raising, there is no large scale RCT showing its effectiveness. An additional problem is that there is no method to measure macrophage cholesterol efflux in vivo, so that HDL quality, rather than quantity, is unknown.

    In classical large statin studies about 69% of events were not prevented. This persists even when guideline targets are attained. We are reminded by the recent TNT analysis [Mora et al. Circulation. 2012;125:1979-1987] that residual risk is a large problem that still haunts. AIM-HIGH put a dark cloud over niacin, although most of us still have hope for HPS2-THRIVE. Enthusiasm for aggressive statin therapy has also been dampened somewhat by concern about diabetes, especially since dose-response curves for statins are relatively flat. In diabetics, with the greatest residual risk, tight control of glucose, BP, and lipids are also off the table.

    What is left, in addition to statins? Currently, fish oil and behavioral change. Lifestyle improvement is difficult, if not impossible for most patients, and a tough sell, but the truth is that in this venue there is much low-lying fruit to be harvested. This is where the future is. Relatively small changes over a large population will result in impressive reductions in CV risk. Smoking, physical activity, and weight loss are on the top of the list, data from Mora et al imply, since on-treatment lipid and lipoprotein measurements dropped out of their multivariate equation after a year. Surprising, but perhaps non-lipid generated risk is greater than we believe.

    Richard Kones, MD

  2. I agree that there is a lot of low hanging fruit to be picked when it comes to improve the lifestyle of our patients (1 in 5 still smoke, 8 of 10 had a bad diet and just 2 of 10 are active according to recommendations). I also agree that it’s a hard sell! The adherence to lifelong medications also needs to be better adressed than today. Health professionals are good to tell patients what to do, but not how to do it. We need to be better skilled in adressing the behavioral part.

    To save the next generation, we need to take a whole society approach and think health in all policies. IOM has released a new report today on obesity-prevention ( )They point to these different areas for intervention:
    -Integrate physical activity every day in every way
    -Market what matters for a healthy life
    -Make healthy foods and beverages available everywhere
    -Activate employers and health care professionals
    -Strengthen schools as the heart of health
    Health promotion and prevention are important for the future of our kids and everybody is a stakeholder.
    Carina Alm, RN

  3. This is an extraordinary event – I am eager to learn more about the trial and the decision-making by the DSMB. Is it more evidence that modifying risk factors do not necessarily modify patient risk. Seems so.

  4. CTEP inhibition is a bad thing. The fact that the body responds to the CTEP inhibitor making HDL cholesterol ineffective by producing more HDL cholesterol should not lead anyone to assume that CTEP inhibition could reduce heart disease.

    The only circumstance that I can imagine that CTEP inhibition could be of benefit is if the CTIP inhibitor had a much shorter half life than HDL cholesterol and it was dosed in a pulsed fashion.