NEW LIPID DRUGS

Henry R. Black, MD: Hi. I'm Dr. Henry Black. I'm an Adjunct Clinical Professor of Medicine at the Langone NYU School of Medicine, and I'm here with my friend and colleague, Dr. Howard Weintraub.

Howard S. Weintraub, MD: Hi, Henry. I'm Howard Weintraub. I'm the Clinical Director of the NYU Center for the Prevention of Cardiovascular Disease, and a Clinical Professor of Medicine at the NYU Langone School of Medicine.

Dr. Black: There is a low buzz going on in the lipid business these days for new treatments. Bring us up to date. What is going on?

Dr. Weintraub: Everybody is aware of the statins, but there is a drug called an antisense drug, which prevents the formation of lipoprotein Apo-B. For those who are not aware, there is one Apo-B for every atherogenic lipoprotein, which means very low-density lipoprotein (VLDL), intermediate low-density lipoprotein (IDL), and low-density lipoprotein (LDL). Each has one. It's felt to be a more sensitive and specific marker than LDL is. There has never been a head-to-head primary trial, but in retrospective studies they find that the predictive accuracy is better.

Dr. Black: How do you mean?

Dr. Weintraub: Well, when they look at which one predicted the events better, it would be Apo-B vs LDL.

Dr. Black: But no comparison directly?

Dr. Weintraub: No; they have never done a study that says, "We are going to take 1000 people and we are going to treat them, and we are going to see which one prospectively is a better risk modifier."

Dr. Black: What are the names of these drugs?

Dr. Weintraub: One is called mipomersen. It's an injectable drug that is currently given once a week. It has been explored in different regimens. Its dosage goes up to 200 mg and it blocks the genes that allow one to make Apo-B. The other drug is a microsomal triglyceride protein (MTP) inhibitor called lomitapide. (I'm not going into trade names.) This is an oral drug that prevents the assembly of lipoproteins. So, one of the drugs prevents Apo-B and the other prevents assembly.

The MTP inhibitor -- obviously from its name -- would be useful for people with very elevated triglycerides, which is almost an orphan area within cardiology and one that I see in a lot of patients, and which is very frustrating to treat. But the drug has also been used as an add-on or a monotherapy in people with hypercholesterolemia.

The problem is that both of them are indicated only for familial hypercholesterolemia (FH) and for homozygous FH, of which it is estimated that there is one in a million. If you look around, you don't have a lot [of this disease] in this country, but the definition of homozygous FH has been left up to the clinician. In other words, there has been no specified criterion by which the company has to insist that the doctor establish a diagnosis of FH.

There has been, to my understanding, a little bit of usage in individuals with heterozygous FH -- people with LDLs that would probably fit the criteria that we would use for apheresis, which would be an LDL of more than 200 with established cardiovascular disease, stroke, myocardial infarction, and peripheral vascular disease.

Dr. Black: Are these people who failed statins?

Dr. Weintraub: It's used either [when a patient doesn't respond to a statin] or in addition to whatever your background therapy is, because at the end of the day, if your LDL is over 200 with disease or over 300 in the absence of disease, you qualify for apheresis.

Dr. Black: So these are powerful drugs.

Dr. Weintraub: Yes.

Dr. Black: It's a very small number of individuals. How do we pick them out from the population?

Dr. Weintraub: LDL is a discriminator. You would be surprised, because obviously the incidence of heterozygous FH is 1 in 500. FH is defined as an LDL in excess of 190 in an adult. And most of the people obviously are going to cluster under 300 to start with before therapy. With drugs like statins, ezetimibe, the bioelastic resins like colesevelam, and even other drugs like fibrates and niacin, you can usually get the numbers down to at least 50%.