Merck's Cholesterol Pipeline under Spotlight Once Again as Key Experimental Drug Study is Discontinued.

Merck has announced the discontinuation of a study involving its experimental cardiovascular drug MK-0524A. The study, ACHIEVE (Assessment of Coronary Health Using an Intima-Media Thickness Endpoint for Vascular Effects), is an imaging study to evaluate the effects of the drug on cIMT (carotid intima-media thickness) in patients with heterozygous familial hypercholesterolemia (HeHF). The company said that the study was discontinued following the recommendation of its steering committee after evaluation of pooled data from completed cIMT studies found that "the patient population being studied in [the] ACHIEVE [trial] was no longer the correct population to test the primary study hypothesis of IMT progression." Merck has reiterated its commitment to pursuing the development of MK-024A in cIMT in patients with heterozygous familial hypercholesterolemia.

However, there is some concern over the study discontinuation. The Associated Press (AP) quotes Dr Steve Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, as stating that the Merck explanation may not be adequate, suggesting that the termination could be commercial. Furthermore, the ACHIEVE study is similar to the ENHANCE trial, which involved cholesterol drug Vytorin (ezetimibe/simvastatin), in that it has used the same imaging technology cIMT. The ENHANCE study, also involving HeFH patients, showed no efficacy of cardiovascular drug Vytorin on artery plaque build-up (see United States: 31 March 2008: ACC Outcome to Deepen Merck, Schering-Plough's Vytorin and Zetia Troubles).

Outlook and Implications

The decision to terminate the ACHIEVE study will be a temporary setback for Merck in advancing MK-0524A. Although Merck has maintained that the study is not related to the FDA's non-approvable letter, it brings into focus the company's cardiovascular pipeline in the backdrop of the Cordaptive drug FDA rejection and the Vytorin/Zetia issues. The link to the ENHANCE study shows that the committee's latest decision may be related, as the efficacy of the drug may not be clearly demonstrable in HeFH patients using the cIMT imaging technology. Notably, the ACHIEVE study was not part of the clinical findings supporting the MK-0524A FDA application. The product combining niacin and lapropiprant was expected to show reduction in LDL ("bad") cholesterol levels and triglycerides, bringing down related side effects such as flushing. The product was recommended for approval by the European Medicine Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) in April. However, the FDA issued a non-approvable letter requesting more information in order to evaluate the product's risk profile. On the positive side, so far the investigational product has not demonstrated any adverse event episodes that would affect the application. In addition, although the ACHIEVE trial has been terminated, the launch date for the drug expected sometime in 2009 could still be realised. In the short term, Merck is expected to persist with the drug candidate, and the next FDA action will focus on the evaluation of study results, firming up the information requested by the regulatory agency.

Related Articles

• United States: 29 April 2008: FDA Rejects Cordaptive Application
• United States: 12 December 2007: Merck Provides Update on R&D Pipeline; Sets 2010 Targets

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