Torcetrapib
Encyclopedia
Torcetrapib was a drug
being developed to treat hypercholesterolemia
(elevated cholesterol
levels) and prevent cardiovascular disease
. Its development was halted in 2006 when phase III studies showed excessive all cause mortality in the treatment group receiving a combination of atorvastatin and the study drug.
) by inhibiting cholesteryl ester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol
to very low density
or low density lipoprotein
s (VLDL or LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol).
Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.
Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin
, atorvastatin
(Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.
Nine phase III studies were completed.
This was a sudden and unexpected event and as recently as November 30 Jeff Kindler
, Pfizer’s chief executive, was quoted as saying "This will be one of the most important compounds of our generation." In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.
Pfizer recommends that all patients stop taking the drug immediately.
Six studies were terminated early. One of the completed studies found it raised systolic blood pressure and concluded "Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further."
The drug cost $800m+ to bring into Phase III development.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
being developed to treat hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
(elevated cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
levels) and prevent cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. Its development was halted in 2006 when phase III studies showed excessive all cause mortality in the treatment group receiving a combination of atorvastatin and the study drug.
Mechanism
Torcetrapib acts (as a CETP inhibitorCETP inhibitor
A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein . They are intended to reduce the risk of atherosclerosis by improving blood lipid levels.Examples include:...
) by inhibiting cholesteryl ester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
to very low density
Very low density lipoprotein
Very-low-density lipoprotein is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream...
or low density lipoprotein
Low density lipoprotein
Low-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...
s (VLDL or LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol).
Development
The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.
Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
, atorvastatin
Atorvastatin
Atorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...
(Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.
Clinical trials
A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.Nine phase III studies were completed.
Early termination of study
On December 2, 2006 Pfizer cut off torcetrapib's [phase III] trial because of "an imbalance of mortality and cardiovascular events" associated with its use.This was a sudden and unexpected event and as recently as November 30 Jeff Kindler
Jeff Kindler
-Background:Jeffrey Kindler graduated summa cum laude from Tufts University in 1977 and magna cum laude from Harvard Law School in 1980. He subsequently clerked for Supreme Court Justice William J. Brennan Jr. and worked at the law firm Williams & Connolly in Washington, D.C...
, Pfizer’s chief executive, was quoted as saying "This will be one of the most important compounds of our generation." In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.
Pfizer recommends that all patients stop taking the drug immediately.
Six studies were terminated early. One of the completed studies found it raised systolic blood pressure and concluded "Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further."
The drug cost $800m+ to bring into Phase III development.
See also
- CETP inhibitorCETP inhibitorA CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein . They are intended to reduce the risk of atherosclerosis by improving blood lipid levels.Examples include:...
- AnacetrapibAnacetrapibAnacetrapib is a CETP inhibitor being developed to treat hypercholesterolemia and prevent cardiovascular disease.-Clinical trials:...
, another CETP inhibitor currently studied by MerckMerck & Co.Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...