The Race to Develop the Next Blockbuster: Merck and Roche Fight High Cholesterol.

Cholesteryl ester transfer protein inhibitors (CETP inhibitors) are a novel class of drugs that have the potential to revolutionize treatment of high cholesterol much like the statins (Lipitor, Zocor, and Crestor).  Like other drugs in their earliest stages of development, there has been some concern and adverse effects that raised red flags.  In particular, Pfizer (NYSE: PFE) discontinued the development of torcetrapib after concern of increase blood pressure.  Merck (NYSE: MRK) and Roche (PINK:RHHBY) have continued to develop their respective drugs, anacetrapib and dalcetrapib.  With so promise in raising good cholesterol (HDL) and reducing bad cholesterol (LDL), these drugs can be blockbusters like the statins.  Since this is a new class of drugs, the risks are relatively unknown and can be the deciding factor whether or not CETP inhibitors will ever thrive.

Dalcetrapib:

• It is less potent than the other two drugs and concentrations reached in clinical studies are not high enough to completely inhibit CETP.  This may be a good thing.
• It acts through a slightly different mechanism than the others and does not induce a complex between CETP and HDL. 
• In a Phase II, placebo controlled trial, it was shown to reduce LDL by 7%, increase HDL by 34% after 4 weeks at a dose of 900 mg/day.  No increase in blood pressure was reported.
• Similar results were achieved when dalcetrapib was given with pravastatin (Pravachol).  Pravastatin is not widely used.  A better study should have been performed using Lipitor or Crestor.
• Current studies (dal-PLAQUE and dal-OUTCOMES) will provide a better glimpse into the potential.

 Anacetrapib:

• Works via the same mechanism as torcetrapib by complexing CETP with HDL.  This causes researchers to be more concerned about blood pressure elevation effects.    
• It is much more potent than dalcetrapib.  This is not necessarily a good thing.  A higher potency may translate into higher risk of adverse effects.
• In a Phase I trial, anacetrapib (300 mg/day) increased HDL by a whopping 129%  and lowered LDL by 38% after 28 days of treatment.  
• A separate Phase I trial tested the safety of anacetrapib in helathy patients for 10 days.  There was no reported increase in blood pressure.  
• A recent 8 week study evaluated anacetrapib co-administered with atorvastatin (Lipitor).  The HDL increase was maintained, but the LDL was lowered by 70%.  No increase in blood pressure was reported.
• The DEFINE study is ongoing and will provide a better projection of anacetrapib's potential.

 Potential of CETP Inhibitors:

• High LDL and low HDL are risk factor for atherosclerosis.  CETP inhibitors help in both regards.
• Defective HDL function contributes to atherosclerosis.
• CETP inhibitors may be the preferential drugs to increase HDL.
• Combination therapy with statins, niacin, and fibrates lays in the future of CETP inhibitor therapy.
• CETP inhibitors will play a big role in the treatment of common types of high cholesterol disease states, particularly patients with metabolic syndrome and type 2 diabetes.
• Further research and investigation of CETP inhibition is needed with monotherapy and combination therapy.
• It's still too early to tell the impact on stock prices for MRK and Roche, but this is one thing to monitor for the next two years as the Phase III trials will take approximately 18 months to complete and another couple of months for follow-up study.
• It is interesting to see if these drugs can help MRK and Roche recuperate from the patent cliff of 2011-2012.