BOSTON (Ivanhoe Newswire) - Do you know your LDL? It's the bad cholesterol in our bodies and the American Heart Association said keeping it under 100 is best to avoid heart attacks and strokes, but for some people no matter what they do their numbers skyrocket. Now, a drug that's just hit the market could help bring it back down to earth.
Wenter Blair is a shutterbug.
"Heaven forbid something does happen to me, my babies have a really good idea of who I am through my photography," Wenter Blair, HoFH patient, told Ivanhoe.
She suffers from an inherited condition called HoFH. Her body cannot remove the bad cholesterol from her blood.
"Every night I go to bed fearful that it might be my last night," Blair said.
Wenter's LDL levels are usually around 350. She had three heart attacks before she was 43.
"I know I don't have it under control and it scares the living crud out of me," Blair said.
Kynamro was recently FDA approved to treat HoFH.
"A technology that's been in development for 30 years and this is the first real breakthrough in that technology," Paula Soteropoulos, general manager for Genzyme Corporation, told Ivanhoe.
Developed in part by Genzyme, general manager Paula Soteropoulos said the once a week injection stops the production of cholesterol. A clinical trial found, on average patients taking Kynamro saw their LDL levels drop 25 percent.
"This is getting them to levels they have never seen before," Soteropoulos said.
Wenter said this and other drugs in the works are giving her a better picture of what her future could be.
"I want to live a really long time and without them I won't see the longevity that I so crave," Blair explained.
Kynamro is not a replacement for a patient's HoFH medications. It's designed to be added to their treatment regimen. The FDA reports the most serious risk of Kynamro is liver toxicity. Other side effects include nausea, headache, and flu-like symptoms.
BACKGROUND: Familial hypercholesterolemia is an inherited condition that causes high levels of LDL (low density lipoprotein) cholesterol levels starting at birth. It can also cause heart attacks at an early age. Cholesterol is found in the cells of the body and can also be found in some foods. The body does need some cholesterol to function properly and it uses cholesterol to produce hormones, vitamin D, and substances that help with food digestion. If there is too much cholesterol in the blood stream, then it can build up in the artery walls and can increase the risk of heart disease. Cholesterol is carried in the blood stream in packages called lipoproteins. They are made up of fat (lipid) on the inside and proteins on the outside. Two kinds of lipoprotein carry cholesterol throughout the body: low density lipoprotein (LDL) and high density lipoprotein (HDL). (Source: http://www.genome.gov/25520184)
LDL vs. HDL: Cholesterol that is carried by LDL is also called the "bad cholesterol." People with familial hypercholesterolemia have high levels of LDL because they cannot remove the LDL from the blood stream. The cholesterol carried by the HDL is called the "good cholesterol." It carries cholesterol from other parts of the body to the liver. The liver then removes cholesterol from the body. High levels of HDL will lower a person's risk for getting heart disease. (Source:http://www.genome.gov/25520184)
HOMOZYGOUS: The gene mutation that is responsible for familial hypercholesterolemia is on chromosome 19 and it contains the information for a protein called LDL receptor. LDL receptor clears up LDL from the blood stream. One out of 500 people carry one altered gene causing familial hypercholesterolemia. These people are called heterozygotes. When a person inherits the gene mutation from both parents, they are called homozygous familial hypercholesterolemia (HoFH). These individuals have a much more severe form of hypercholesterolemia. Heart attacks and death usually occur before the age of 30. (Source:http://www.genome.gov/25520184)
NEW TECHNOLOGY: The goal of treatment is to lower the LDL cholesterol levels in the blood stream. Drug therapy is usually needed combined with weight loss, diet, and exercise. The most effective choice are drugs called "statins." However, those who have homozygous familial hypercholesterolemia need aggressive therapies. Drug therapies are usually not sufficient to lower LDL cholesterol levels. (Source: http://www.genome.gov/25520184) The FDA approval of Kynamro injection, along with diet and lipid-lowering medications is now an option for patients with HoFH. Kynamro helps reduce LDL, total cholesterol, apolipoprotein B, and non-high density lipoprotein-cholesterol. It is injected one a week. The safety of this drug was evaluated in a clinical trial of 51 patients with HoFH. The levels fell in about 25% of patients during the first 26 weeks in those who received the injection. However, there is a Boxed Warning on Kynamro of the serious risk of liver toxicity because it is correlated with liver enzyme abnormalities and accumulation of fat in the liver, which could possibly lead to progressive liver disease with chronic use. (Source:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337195.htm)
Paula Soteropoulos, Vice President and General Manager of Genzyme's Cardiovascular Business, talks about a new drug for patients with HoFH.
Can you tell us about the product that you guys are working on? Why is it so important to people with FH?
Paula Soteropoulos: Kynamro is a novel breakthrough product for a very rare disease, called homozygous familial hypercholesterolemia. This is a disease where patients die very young. It is very deadly. Patients have extreme levels of cholesterol as early as infancy and may have a heart attack in their teenage years and their 20s. Kynamro blocks the production of cholesterol. It is very different than what is traditionally used for lipid lowering, like statins. It actually attacks the defect that affects familial hypercholesterolemia. The other part of this product is its antisense oligonucleotide, which is a novel class of products. It is a technology that has been in development for 30 years and this is the first real breakthrough in that technology. So, it holds promise for many other diseases if it is successful.
What makes the technology so special?
Paula Soteropoulos: What antisense does is it blocks messenger RNA from transcribing into proteins, which are how proteins are traditionally formed. Most drugs will block the protein downstream and it blocks it upstream before the protein is even formed. So this has potential in so many other diseases, not only in this extreme form of familial hypercholesterolemia.
So, it could be used for other things?
Paula Soteropoulos: Not this drug, the technology.
In the clinical trials, what has the drug done for the patients?
Paula Soteropoulos: The patients, specifically the homozygous familial hypercholesterolemia patients, in our trials were on all forms of lipid-lowering therapy. Many of them were on the highest doses of statins and on triple therapy; even with all of those therapies they still had elevated LDL cholesterol well above 300 mg/deciliter. The normal is below 200. Despite all that, nothing they did could get their cholesterol lower. Kynamro was able to drop their cholesterol on average of another 100 mg/deciliter, which is very significant. Lowering LDL has been shown to actually have long-term benefits for reducing risks for cardiovascular disease and that is what we hope for. This significant lipid-lowering could hopefully reduce further risk for these patients.
Can you give an example of someone who has 350 LDL? What would the drug do for them? What would their number be after taking it?
Paula Soteropoulos: With the 350, they could be anywhere between 75 and 100 mg/deciliter lower; so anywhere from 250 to 275. These are just rough numbers, but it does reduce their risk quite significantly.
What is the cycle? Is it something that you take every day or every month?
Paula Soteropoulos: Kynamro will be taken as a subcutaneous injection once a week, which is actually quite convenient for patients who take several pills per day. There is a problem in general with oral medication where there is a low, relatively low compliance rate. People forget to take their pills. A once a week injection is actually very convenient because it is something that they can actually, routinely take once a week. They usually don't forget it and it is something that they administer themselves at home; it's very easy to teach. We have millions of diabetics who take subcutaneous injections every day.
What does this do to their normal pill regimen or medication regimen? Can they stop taking them?
Paula Soteropoulos: No. These patients are at such lethal levels of LDL, they actually need to continue with their medication. This is getting them to levels they have never seen before. So, no they would continue to take their medication.
How big of a breakthrough or advancement is this for people with FH?
Paula Soteropoulos: For people with FH, there has not been anything new. Actually, there has been nothing new in lipid lowering for a decade since Zetia came out. There has been really nothing to offer these patients. The only thing these patients have been able to do on top of the lipid lowering medication is to go on a mechanical procedure called apheresis, which is somewhat like dialysis. You are hooked up to a machine and that filters out the cholesterol. They have to do it weekly. It takes 3 to 4 hours. There are only 35 centers in the United States. So many people have to drive several hours to get there and many of these patients are young. This is not an elderly population. These are patients in their 20s and their 30s who are either trying to go to college, trying to build a career, or trying to start a family. So, although it is a therapy that works, it is something that many of these patients actually pass on. They actually don't go on it even though it could be life-saving. Hopefully Kynamro will give them that opportunity to get those LDL levels lowered, but they wouldn't have to change their normal course of their daily lives.
What is the subset of the population that can use it? What kind of numbers is it? Who can benefit from this?
Paula Soteropoulos: The first indication for Kynamro is in this small population homozygous FH. There is about 1 in a million in the average population, which would be about 300. We do know that there are pockets of populations that have a much greater frequency. It is highly prevalent in French Canadians, Christian Lebanese, and Ashkenazi Jews, for example, and there would be more patients that would have this disease in those populations. So, it could be upwards of perhaps 1,000, but we only know of the 1 in a million from studies.
Is that the real number? Do people have it and don't even know it? Is that the ones that have been identified?
Paula Soteropoulos: So, that is homozygous FH. We think about FH as a disease in general, actually it is a highly prevalent disease. It is one of the most prevalent diseases, 1 in 500 people have FH. The difference with general FH is you have the genetic defect from one of your parents. Homozygotes have it from both. That is why it is so rare. If you think about 1 in 500, that is about 600,000 people in the United States. Most of those people don't know that they have this disease and so they might go through life without actually ever caring about their diet. Some people find out by accident because they get a lipid, a cholesterol test. It is not until they are much older. Many of these patients unfortunately have a heart attack very young and that is when they find out they have the disease. If they had parents, aunts, and uncles who had early heart attacks, they might think that this runs in their family and should get checked out. The majority of people do not know that they have the disease. For the homozygote FH, almost most of them do because it manifests very young. Those patients will develop lipid deposits called xanthomas on their skin and most children are brought to a dermatologist first. Once they understand that they are cholesterol deposits, that's usually when they get sent to a specialist. So, the rare population that was targeted for Kynamro, are aware they have the disease. Those that could still have severe disease, but don't manifest young, are the ones that are at risk of having a heart attack without ever knowing they are carrying a disease.
Why does it help the people who have the homozygous versus the heterozygous? Is it just the way that the disease develops in them?
Paula Soteropoulos: Well, the drug will work in heterozygous. It is just that our approval is for the rare homozygous form. The product is more suited for the ultra-rare population. Most of the broad heterozygotes actually would do very well on a statin. Then you have a group in between that, severe heterozygous FH patients who may only have one defect, but the defect is severe enough that the disease is similar to a homozygote; it just manifests 2 decades later. We hope that in a few years, we can offer this product to them as well. Specifically we are conducting a clinical study to expand the population to severe heterogygous FH.
You offer them to the severe?
Paula Soteropoulos: Yes, to the severe.
How many do you think are affected by that?
Paula Soteropoulos: Probably about 12,000 to 15,000 people in the United States.
Can you tell us about Genzyme's history?
Paula Soteropoulos: Genzyme's history dates back 30 years ago. We began the foundation of Genzyme focusing on orphan diseases; those diseases with a huge unmet need and ones we could bring forward breakthroughs that could transform lives. Homozygous familial hypercholesterolemia is no different. It is a population that is truly underserved and has not had a treatment breakthrough in a very long time. Something that Genzyme does very well, is that we can bring not only the product that can help solve their problem, but also the approach that we take in helping partner with the community, whether it be the physicians or the patients to raise awareness. We try to help people understand what this disease is about, that there is an unmet need that requires urgent care, and how patients and their families can learn more about their disease. So, we have developed a lot of materials that really will help connect patients, families, and physicians to understand more about the disease even if they do not take our product. It is important for people to understand and be armed with information about their disease. That is just something Genzyme has done throughout its heritage.
How long did it take to develop Kynamro?
Paula Soteropoulos: I actually don't know officially. Kynamro is a product that was developed by Isis Pharmaceuticals, who was our partner, and they have been working on antisense technology for about 30 years. So, it has at least been almost a decade.
What does Kynamro do differently than other products?
Paula Soteropoulos: Kynamro is different than other lipid lowering therapies because it actually reduces all atherogenic lipoprotein. So, it is not just LDL that causes atherosclerosis. There are other ones; a specific one is called Lp(a). One thing that is very different than the current lipid lowering therapies would be important for these patients and specifically patients with FH have higher levels of all of these lipoproteins.
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