DR. UNDERBERG: Familial hypercholesterolemia (FH) is a relatively common condition of autosomal codominant inheritance that results in high levels of low-density lipoprotein cholesterol (LDL-C) from birth. Familial hypercholesterolemia is associated with an increased risk of premature cardiovascular disease (CVD), and its prevalence is increased in certain founder populations. Recently, there has been increased awareness regarding this condition.
In 2011, the National Lipid Association (NLA) released clinical guidance and expert panel recommendations regarding the screening and treatment of patients with FH.1 Two US advocacy groups have emerged that promote awareness and screening for this condition, and several new LDL-lowering drugs are in different phases of development. These agents have and will be evaluated in the FH population.
Recent observational data remind us that medication is the current cornerstone therapy for FH. Lipid-lowering therapies reduce the risk of CVD in these patients as compared with those who are not treated. There remain, however, many patients who cannot tolerate therapy or who, despite maximal pharmacologic treatment, do not achieve the recommended LDL targets. For these patients, LDL apheresis is an option available at approximately 35 centers throughout the United States. Finally, with new national cholesterol guidelines underway, there is renewed interest and awareness regarding the identification and treatment of patients with lipid disorders.
I’m Dr. James Underberg, Clinical Assistant Professor of Medicine at the NYU School of Medicine, NYU Center for Cardiovascular Disease. I am also Director of the lipid clinic at Bellevue Hospital in New York. I’m joined today by 3 internationally recognized experts in the field of hypercholesterolemia: Dr. Eliot Brinton, President of the Utah Lipid Center and Director of Atherometabolic Research at the Utah Foundation for Biomedical Research; Dr. Patrick Moriarty of the University of Kansas Medical Center; and Dr. Mary McGowan, Chief Medical Officer of the FH Foundation.
Dr. Brinton, can you briefly review the epidemiology, associated cardiovascular risk, and different diagnostic criteria for FH?
DR. BRINTON: This is among the most commonly occurring, clinically significant, monogenic metabolic disorders. It is codominant, so the clinical picture differs among homozygotes, heterozygotes, and the unaffected.
Heterozygous FH occurs in approximately 1 of 300 to 1 of 500 persons in the general population, although certain populations have a much higher prevalence. In groups such as the French Canadians and Dutch Afrikaners, 1 in 100 individuals are heterozygotes due to a founder effect. FH homozygotes are less common—about 1 in a million—and it is estimated that up to 10 000 homozygous FH patients are present worldwide.
One of the biggest clinical problems that we face with FH is detecting it or finding affected patients in the general population. The disease is treatable, but it is important to start treatment as early as possible. It has been very hard to identify such patients because they tend to be scattered throughout the population. Many of them may have never had even a single lipid panel, much less been referred to a lipidologist for proper care of their cholesterol disorder.
Another enormous challenge that we face in dealing with FH is that the patients have very, very high LDL-C levels—usually in the range of 250 to 500 mg/dL—in heterozygotes and usually above 500 mg/dL in homozygotes. These are untreated levels, and of course, once treatment is started, the levels fall. The underlying cause of FH in most cases is a defect in the LDL receptor.
The action of the LDL receptor in the liver is the major mechanism responsible for clearing LDL particles from the bloodstream, and if one has a defective receptor such that it is either never synthesized or has little or no capacity to bind to the LDL particle, then the LDL levels greatly increase in the blood. Of course, if someone is heterozygous, he/she will have one functioning receptor and one missing or malfunctioning receptor. By definition, homozygotes have defects in both copies of the LDL receptor gene; therefore, they have very little, if any, LDL receptor activity. This is classic FH, but there are other causes of severe hypercholesterolemia too. Although they are genetically and causally distinct, the increase in LDL-C levels may be similar to that in classic FH. When 2 distinct mutations cause the same phenotype, they are said to be phenocopies of each other.
For example, approximately 10% of patients with FH have a defect in apolipoprotein B (apoB), which is the major ligand for the LDL receptor, rather than a defect in the LDL receptor itself. A much smaller number of patients appear to have a defect in proprotein convertase subtilisin/kexin type 9 (PCSK9), which is a factor that helps process the LDL receptor. Because this factor functions to reduce the activity of LDL receptors, it is a rare gain-of-function mutation that reduces LDL receptor activity, thereby causing an increase in LDL-C levels.
Interestingly, even though a defect in the LDL receptor is by far the most common cause of FH, these defects are very heterogeneous in nature; thousands of individual mutations of the LDL receptor have been discovered in genotyping studies of FH patients. However, genetically isolated populations often have a founder effect with more uniform mutations as well as a higher prevalence of FH. Generally, the most striking aspect of FH is that even though the phenotype tends to be quite similar from genotype to genotype, there is incredible genetic heterogeneity.
FH was one of the very first monogenic disorders with important clinical sequelae ever discovered. These patients tend to have premature CVD, which is CVD occurring in men younger than 45 years and women younger than 55 years of age. CVD is quite uncommon among people in these age groups in the general population. The risk ratio of CVD for people with to those without heterozygous FH is very high at these younger ages, and we generally see a 5- to 20-fold increase, even though, in absolute terms, there are few events. The risk ratios and absolute rates of CVD are much higher in FH homozygotes, especially in those younger than 25 years of age.
Past middle age, CVD becomes quite common in the general population, although obviously, FH patients are also at progressively increased risk for developing CVD at older ages. In homozygous FH patients, CVD can occur before the age of 10 years. It’s really very troubling to see a young child have a heart attack, for example. Thankfully, with improved diagnosis and treatment, we’re now seeing homozygous FH patients getting well into their teens and even sometimes into adulthood before they have their first cardiovascular event.
DR. UNDERBERG: So, how would you diagnose the condition?
DR. BRINTON: That’s a great question. The diagnosis usually should be made clinically, in my opinion. In this modern era, it is tempting to jump right ahead to genetic testing, and indeed, genetic testing can help make or confirm a diagnosis of FH; however, in a significant percentage of patients who truly have FH, the genetic abnormality cannot be determined. More importantly, treatment must be guided by the lipid levels, not the genotype; therefore, lipid testing is much more important in patient management.
Screening can start with determining just the total cholesterol level in a non-fasting specimen. If it’s above 200 mg/dL, then FH may be present, and a fasting lipid panel with an LDL-C level is needed. In children or adolescents, if the LDL-C level is above 160 mg/dL or the non-high density lipoprotein (HDL), which is total cholesterol minus HDL cholesterol (HDL-C), is above 190 mg/dL, then FH is strongly suspected.
In adults over the age of 20 years, the cutoffs are higher because the LDL-C level increases with age, and FH is suspected if the LDL-C level is above 190 mg/dL or if the non-HDL-C level is above 220 mg/dL. FH is very likely at higher levels: for individuals aged below 20 years, this level is an LDL-C of above 190 mg/dL; for those aged 20 to 30 years, it’s an LDL-C level of above 220 mg/dL; and for those aged 30 years or older, the LDL-C threshold is 250 mg/dL.
DR. UNDERBERG: Are those numbers are from the Make Early Diagnosis to Prevent Early Deaths (MEDPED) criteria?2
DR. BRINTON: Yes, and they are also from the NLA Expert Panel statement,3 which, as you mentioned, came out in the middle of 2011.
DR. UNDERBERG: That’s US-based. Are there any other criteria that are used globally?
DR. BRINTON: These are non-US criteria, but they’re fairly similar, so I think we should focus on the US-based guidelines. Screening and diagnostic cutoffs are, of course, always a tradeoff between sensitivity and specificity. Lower cutoffs will have greater sensitivity but less specificity. Thus, you’re going to have a larger number of non-FH patients that you think might have FH. If you set the criteria or the cutoffs higher, then you’re much more likely to have a true FH case, but you will miss some patients with FH due to variability in LDL-C levels, even among patients with an identical FH mutation. These LDL-C variations can be due to variability in other genetic factors and environmental influences.
DR. UNDERBERG: Dr. McGowan, we’ve heard a little bit about diagnostic criteria. How are we doing right now with regard to diagnosis both here and globally? What options do we have to improve the diagnosis-making process with respect to screening, awareness, and other factors?
DR. MCGOWAN: Unfortunately, we’re doing fairly poorly, both in the United States and abroad. Roughly 20% of people with FH have received a diagnosis of FH. That doesn’t mean that people who have FH and have not yet been diagnosed are not being treated with lipid lowering agents: they may be. However, they are often not receiving an adequate dose of medication, and the failure to diagnose means a missed opportunity to educate patients and screen relatives; remember, this is an autosomal codominant disorder. Roughly half of the first-degree relatives of a person living with FH will also have FH.
General practitioners and even cardiologists often don’t think of FH when they have a young person with a coronary event admitted to their critical care unit. This is very unfortunate. It may occur in part because coronary disease is such a common disorder in the United States. When physicians miss the diagnosis of FH, they miss the opportunity to educate patients about cascade screening. This is the process I just referred to. Cascade screening involves screening all first-degree relatives of an index case and repeating the exercise in the first-degree relatives of the newly identified patients. As Dr. Brinton pointed out, FH is treatable, and the sooner we make the diagnosis, the more likely we are to prevent a cardiac event.
There are certainly some physical findings that we look for in patients with FH, but these are often quite subtle and are frequently missed. We can look for xanthomas in the Achilles tendon or the extensor tendons of the hands. Corneal arcus is not pathognomonic for FH, but when seen in the correct setting, it may help you make a diagnosis.
These physical findings are actually used in some of the FH-screening tools. Dr. Brinton mentioned the MEDPED, which was developed in Utah. Other screening tools include the Simon Broome criteria4 and the Dutch Lipid Clinic Network criteria.5 Both the Simon Broome and the Dutch Lipid Clinic Network criteria evaluate lipid levels in the context of physical findings and determine the probability that a person has FH.
DR. UNDERBERG: Does making the diagnosis of FH alter the way you would treat someone, especially with respect to how aggressively you would treat someone?
DR. MCGOWAN: This is a very important question. When we think about patients with FH, one of the things we know is that they’ve had elevated lipids since birth. In fact, if a person inherits the FH from his/her mother, he/she has been exposed to the mother’s very elevated lipids in utero and may have a greater cardiac risk than somebody who inherited the FH from his/her father. Having elevated lipids from birth is very different from gaining weight at the age of 40 years and developing hyperlipidemia in mid-life. The NLA has specifically pointed out that we should not be using the Framingham Risk Score in patients with FH because, in fact, they should all be considered very high risk. Anyone with FH should be treated very aggressively.
When we compare children with FH to their unaffected siblings, we see a significant difference in terms of carotid intima-media thickness by approximately 12 years of age.6 The vascular trajectory is very different in people with FH as compared to people who develop hyperlipidemia later in life. We should not be satisfied with achieving an LDL-C level of 190, 160, or even 130 mg/dL. We should try to reduce the LDL level as far as possible. Sometimes, this is very difficult because patients with FH don’t respond to lipid-lowering agents as well as patients with polygenic hyperlipidemia.
For example, homozygotes achieve about a 25% reduction in the LDL level at maximum doses of statins in combination with ezetimibe.7 Clearly, homozygous FH patients are at very high risk, and unfortunately, they don’t get the 50% to 60% reduction that we see when we treat other people with high doses of statins.8 Heterozygotes have a better response, but it’s still not the same response that you see in people with polygenic hyperlipidemia. Therefore, the answer to your question is yes, we should treat FH patients differently.
DR. BRINTON: I generally agree with what Dr. McGowan has said, but I am slightly more agnostic. In my view, there isn’t much clinical value in making a genetic diagnosis of FH, and here’s why: For everyone with suspected FH, we need to obtain the best-possible family history. If the person has a family history of CVD, especially before middle age and especially in more than 1 close relative, 2 things should occur: first, aggressive LDL lowering in the patient, and second, aggressive screening in family members. In cases where little or no family history can be obtained—for example, if the patient was adopted—then we can either do genetic testing or simply assume the presence of FH and proceed to aggressive treatment and screening of any blood relatives of the patient. Therefore, a positive family history and a very high LDL-C level will, in fact, lead us to the aggressive treatment that Dr. McGowan mentioned and to family screening as well.
A lipidologist may want to make the diagnosis of FH in a formal genetic manner, and I can think of some scenarios in which this might be useful. I believe that some of the difficulty that we’ve had in the broader physician community is that FH can seem like an arcane entity with many complicated criteria. I fear that, often, primary care doctors may give up in despair and leave patients undiagnosed and untreated, or undertreated, and do not refer them. I think we need to keep our messages about FH very simple—not only for patients but also for general physicians.
Even though I’ve spent much of my career working in genetically oriented academic institutions, I feel that we and our patients are best served by focusing on the phenotype, or lipid levels, rather than on the genotype in cases of severe hypercholesterolemia. By definition, the levels in these cases are far above the LDL-C cutoffs, and we need to be prepared to give such patients high doses of more than one LDL-lowering medication, as Dr. McGowan has said. Given limited resources, I don’t think we should be worrying so much about the finer details of how to diagnose FH. Instead, we should put that effort toward aggressive screening and treatment.
DR. UNDERBERG: Dr. McGowan, there are some criteria elucidated by the NLA that might create subsets of FH patients that we should target for LDL-C lowering. Do you want to point some of these out?
DR. MCGOWAN: Yes, FH patients with additional risk factors need to be treated more aggressively. This includes patients who have already had CVD, patients who have a family history of very early cardiac disease, and patients who also have elevated lipoprotein(a) (Lp[a]). Additionally, FH patients who smoke, have diabetes or hypertension, or are obese deserve aggressive treatment.
Notably, once diagnosed with FH, many patients feel somewhat at a loss. They feel like they’re all by themselves with this genetic disorder. Certainly, they are likely to have family members with the same diagnosis, but they may still feel alone and different. I would encourage health care providers to refer their patients to the website of the FH Foundation. This foundation is very unique because it was started by a group of patients with FH, and their specific stated mission is to raise awareness of FH through education, advocacy, and research. The goal of the foundation is to save lives by increasing the rate of early diagnosis and encouraging proactive treatment.
Patients who would like to learn more about FH would really be well served by going on the FH website: www.thefhfoundation.com. The NLA also has a wonderful patient page at www.lipidfoundation.org, and this too will give patients some very valuable information about FH.
DR. UNDERBERG: So, Dr. Moriarty, we’ve been talking about the epidemiology and diagnosis rates, but let’s talk about the current treatment paradigms. Where are we now, and how would you proceed in the management of a patient with FH?
DR. MORIARTY: To start with, because this is a genetic disorder, lifestyle changes do not have a major effect on the treatment or prevention of the disease. Pharmacotherapy has been the major treatment for FH patients, but it has had little success, particularly in the homozygote population.
The primary defect of most FH patients involves their LDL receptors, which are either dysfunctional or lacking in number, and the statins are somewhat ineffective due to their inability to alter the receptors in this patient population. Resins, which inhibit bile acid reabsorption in the gut, are also unable to significantly change LDL-C levels in the FH population, and the same can be said for niacin. Alternate nonpharmacological therapies include liver transplant and ileal bypass surgery, both of which are rarely used. Presently, lipid apheresis is the most common therapy for FH patients who are resistant to lipid-lowering therapy.
DR. UNDERBERG: Dr. Moriarty, you have quite a lot of experience with apheresis. From your perspective, how widely accessible is it for the patients, and what has your experience been with it?
DR. MORIARTY: Despite the large number of individuals diagnosed with FH, there are only 500 patients receiving regular apheresis treatments in North America. I believe the cause of this low number is multifactorial: There are only about 50 sites that offer this therapy, and team effort is required including that from the patient, the medical staff, and the healthcare provider. Patients must commit to twice monthly or once weekly 3-hour sessions, and they must understand that a shunt/fistula may be needed for venous access. A week of training is mandatory for the nursing staff, and at least 10 to 20 treatments must be performed before they will be fully confident in the procedure. Clinic space will be needed for machines, beds, and supplies. The cost of kits for one treatment ($1 000 to $1 500) can be daunting, and healthcare providers must understand the investment for the therapy.
Finally, another reason for the low number of patients receiving apheresis treatments is that many patients in this country do not know that they have FH. Dr. McGowan talked about the FH Foundation expanding the knowledge and understanding of FH to both the lay population and to medical personnel.
DR. UNDERBERG: Dr. McGowan had mentioned patients with elevated apolipoprotein(a) (Lp(a)). What has been your experience with them?
DR. MORIARTY: Lp(a) is a very interesting lipoprotein that can be elevated in both the FH and general population. Basically, Lp(a) is an LDL-like particle that is linked to apolipoprotein(a) (apo[a]). It promotes atherosclerosis, inflammation, and thrombosis. Plasma levels of Lp(a) are primarily genetically determined and generally resistant to diet and pharmacotherapy with the exception of some inconsistent and small reductions with niacin.
Lipid apheresis can lower Lp(a) by 80%. The European Atherosclerosis Society recently approved lipid apheresis for patients with progressive coronary disease and markedly elevated plasma Lp(a).9
DR. UNDERBERG: Are there any data regarding either symptoms or outcomes?
DR. MORIARTY: Yes. In a longitudinal cohort study performed in Germany,10 involving 120 patients with elevated Lp(a) levels and coronary artery disease (CAD), the risk of major adverse coronary events was significantly reduced with lipid apheresis irrespective of their baseline LDL-C levels. The important point was that elevated plasma levels of Lp(a) can place a patient at risk, and lowering these levels will reduce adverse events.
Now, interestingly, the German government wanted these lipidologists and apheresis centers to perform a double-blinded placebo-controlled study on these patients despite the data that was already published. These scientists and clinicians refused and said that it was unethical for them to even attempt to perform blinded, sham therapy on patients who had a known CAD risk and elevated Lp(a).
Presently, we still do not have a placebo-controlled trial to demonstrate the benefits of pharmacotherapy for treating Lp(a). Hopefully, the 2 classes of drugs (mipomersen and PCSK9 inhibitors) that lower Lp(a) in addition to LDL-C will demonstrate a reduction of CAD based on lower Lp(a) levels.
DR. UNDERBERG: As another director of a lipid center, Dr. Brinton, I think you’re probably deeply aware of the large gap in treatment efficacy that we see in these difficult-to-manage patients and getting them to their targeted LDL levels—either with pharmacologic treatment or just complacency with apheresis.
So, where are we with regards to new drugs in development? Would you start us off with the antisense apoB therapies that are in development?
DR. BRINTON: Yes. Let me first comment on what Dr. Moriarty said. In addition to the prothrombotic, procoagulant effect of Lp(a), there’s quite a bit of research showing a prooxidative effect.
Apo(a), the protein that turns an LDL particle into Lp(a), seems to be a free radical scavenger but also tends to spread those free radicals around, and so, it actually tends to promote oxidation. Another interesting aspect of Lp(a) in the context of FH is its decreased ability to bind to the LDL receptor. Familial hypercholesterolemia patients have impaired receptor activity, while patients with high Lp(a) levels have impaired ligand activity. Somehow, apo(a) makes the apoB less accessible to the LDL receptor. This effect adds to the atherogenicity of Lp(a) and is likely worsened by any underlying abnormality of the LDL receptor such as FH.
Thus, the finding of elevated Lp(a) level in FH is actually expected to some degree, and certainly, as Dr. Moriarty mentioned, it exacerbates the situation clinically.
I’d like to add that at least 1 of the cholesterylester transfer protein (CETP) inhibitors, anacetrapib, appears to lower the Lp(a) level significantly. We’re not focusing on this class of drugs in this conversation because none have been approved for clinical use, and their effects on LDL-C levels are fairly modest. Two CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing phase III testing to see if they will reduce cardiovascular events.
Development of 1 CETP inhibitor, dalcetrapib, was recently stopped due to lack of a reduction in cardiovascular events. But, dalcetrapib did not lower Lp(a) or LDL-C levels, and that maybe another reason for anacetrapib and evacetrapib to succeed where dalcetrapib could not.
DR. UNDERBERG: Interestingly, there are some data published on FH patients with abnormal HDL function, and specifically in that group, the CETP inhibitors could potentially be a therapeutic option, especially the 2 remaining ones because they seem to be the 2 drugs that had better LDL-lowering effects than the other 2 drugs that have already failed. So, if you combine that with the Lp(a) effect, it does represent a potential fourth drug class that we could consider. That’s actually fascinating.
DR. BRINTON: Yes, that is very interesting, and I’m glad you pointed that out. So, back to drugs more clearly focused on LDL lowering. There is a new antisense oligonucleotide for apoB that has been developed by Isis and Genzyme called mipomersen. It consists of a single-stranded nucleotide that matches the messenger RNA (mRNA) for apoB.
So, the apoB gene produces mRNA, and the mRNA goes to the endoplasmic reticulum where the apoB protein is produced. The antisense apoB oligonucleotide binds to the apoB mRNA, prevents it from producing protein, and sets it up for catabolism.
The reason for this is that double-stranded mRNA, such as that which is created by the binding of single-stranded mipomersen to single-stranded apoB mRNA, is very susceptible to degradation. This greatly reduces the production of apoB. Some of the details of its mechanisms and effects are yet to be determined, in human subjects in particular, but we do know that it blocks the production of apoB. This, in turn, blocks the production and secretion of very low-density lipoprotein (VLDL), which is the precursor of LDL. In this way, LDL levels are reduced.
Mipomersen has been studied now in several different populations starting with homozygous FH patients, where it caused a decent LDL cholesterol reduction of about 25% to 35%. Interestingly, it lowers the apoB levels by approximately the same percentage. This is in contrast to the statins, which tend to lower LDL cholesterol to a greater degree than apoB. So, the use of mipomersen is fairly beneficial for homozygous FH patients, and this is in addition to aggressive therapy that we’ve been discussing with the currently available agents.11
DR. UNDERBERG: Do we see an effect on Lp(a)?
DR. BRINTON: Mipomersen has resulted in an Lp(a) reduction of somewhere between 20% and 30%. This is very exciting because we have so few drugs that can lower Lp(a), and so, anything that can help us in that regard is potentially useful.
In addition to the potential clinical benefits, this provides a clue regarding the metabolism of Lp(a). It is interesting to know that reducing the production of VLDL—which then is later catabolized to LDL—can also reduce Lp(a) levels. It suggests that we can address high Lp(a) levels on the production side.
Mipomersen appears to be very useful for homozygous FH, but it’s too early to know if it actually reduces cardiovascular events. It should do so because it lowers LDL-C and Lp(a) levels. All this, however, remains to be proven.
In addition to homozygous FH patients, heterozygotes have been studied. They tend to achieve an approximate 20% to 40% decrease in LDL-C and apoB levels. Some very interesting recent studies have looked at statin-intolerant patients who don’t have FH. Their LDL-C levels are not high enough to meet the criteria for FH, and yet, they are in trouble clinically because they can’t tolerate our best class of drugs for LDL-lowering. This means that their LDL-C level is generally far above the recommended goals, and it appears that mipomersen works well in these patients too, but it does not have a Food and Drug Administration (FDA)-approved indication for heterozygous FH patients.
DR. UNDERBERG: Do you see this drug being used in addition to statins, in place of statins, or before statins?
DR. BRINTON: Even assuming that mipomersen is proven to reduce CVD events, I think it’s unlikely that it will be used before statins. Mipomersen is cumbersome to use because it is a subcutaneous injection, and although it only needs to be given once a week, this is generally harder to do than taking a pill each day.
There are also some side effects including site reactions, which are quite common and in some cases, can be really bothersome. These can recur later at a previously injected site, and they have been bad enough to cause some patients to drop out of clinical trials.
Another concern is the elevation of transaminases and increases in liver fat content. This may be an on-target effect because the liver gets rid of triglycerides by making apoB and a VLDL particle. So, if we inhibit apoB synthesis sufficiently, the liver may be unable to get rid of triglycerides efficiently and may fill with fat, which may drive the transaminase levels up and cause other undesirable effects such as long-term hepatic inflammation.
Given these 2 concerns in terms of side effects and the far greater cost, I don’t think that mipomersen will replace statins as a first-line treatment any time soon. However, it could be considered as an adjunct to statins and other established treatments for homozygous and potentially heterozygous FH patients who have not achieved their goals with older treatments. Additionally, it might be used in place of statins to treat someone who does not tolerate statins. In this regard, however, we do have drug classes that are already approved and have been studied more extensively than mipomersen.
DR. UNDERBERG: Dr. McGowan, moving from an injectable to oral medication, there have been some issues and concerns with regard to fatty liver as well as steatorrhea with the use of microsomal triglyceride transfer protein (MTP) inhibitors.
DR. MCGOWAN: Yes. The MTP inhibitors are now under evaluation in homozygous FH patients.
DR. UNDERBERG: Can you tell us more about this new medication ?
DR. MCGOWAN: The only MTP inhibitor that is being evaluated at the present is lomitapide. Lomitapide was originally evaluated and then discarded by Bayer. Bayer gave the drug to Dan Rader’s group at the University of Pennsylvania, and now Aegerion Pharmaceuticals has in-licensed it.
There have been previous early phase studies with lomitapide. The current evaluation is in a population of 29 homozygous FH patients. Microsomal triglyceride transfer protein is necessary for both the secretion and assembly of VLDL and chylomicrons. Lomitapide inhibits MTP, and by doing so, it can decrease LDL quite substantially—by about 40%.
Lomitapide inhibits MTP in not only the liver, but also the gut; thus, one of the hurdles that needed to be overcome was steatorrhea. The way the investigator overcame this hurdle was by using very low doses of lomitapide and gradually increasing the dose while keeping people on a very low-fat diet. That combination of a gradual increase in the dose and a very low-fat diet allowed some patients to tolerate a dose of 60 mg, which resulted in a substantial reduction in LDL levels. The other major issue with lomitapide is the propensity of this agent to increase transaminases and hepatic fat. Lomitapide was presented at an FDA advisory board in October.
DR. UNDERBERG: Dr. Moriarty, you made a reference to newer drugs when we were discussing Lp(a). The last class of drugs I wanted to discuss today is the PCSK9 inhibitors, which are also injectable agents. What can you tell us about them?
DR. MORIARTY: As Dr. Brinton discussed earlier, the PCSK9 pathway of lipid metabolism was discovered only 10 years ago, and progressing from that discovery to the development of a new PCSK9 inhibitor has been a commendable feat. There are more than 6 pharmaceutical companies investigating PCSK9 inhibitors, and some of them have found a significant benefit in reducing LDL-C levels.
Again, as Dr. Brinton mentioned, the subcutaneous injectable drug mipomersen appears to significantly lower LDL-C levels when added to statin therapy.
Unlike mipomersen, which can cause flu-like symptoms, injection-site reactions, and fatty liver, the side effects of PCSK9 inhibitors appear to be almost non-existent at present. There are some side effects related to injection sites, as Dr. Brinton mentioned, but nothing close to the severity that we find with mipomersen. There’s no sign of liver toxicity such as fatty liver deposits, most likely since the drugs act on LDL receptors rather than within the liver tissue. So, this class of drugs has great potential for future use in the FH population.
Phase III outcome studies have been initiated with PCSK9 inhibitors, which will analyze hard cardiovascular endpoints to validate the effectiveness of the drug. Interestingly, statins actually upregulate PCSK9 production, so this drug could be used synergistically with statins. This would be another added benefit for the FH population.
DR. BRINTON: Dr. Underberg, let me just interject something here to add to what Dr. Moriarty has said. An interesting nuance here is that most of the PCSK9 inhibitors advancing now are monoclonal antibodies, which is a relatively new technology. There are other such drugs that have been approved and are under use for a limited number of conditions, so there is a precedent for injecting monoclonal antibodies to a protein that naturally occurs in the body, but it’s a relatively new approach. I think that’s one problem we should maintain caution about.
One thing that makes this treatment approach more exciting—and this is in agreement with what Dr. Moriarty was saying—is that there are some people in the population who naturally have low PCSK9 activity. These are people with natural mutations in PCSK9 who have had a lifelong reduction in their LDL-C levels simply because PCSK9 is not functional in these patients. The only obvious clinical finding in these patients is fewer cardiovascular events. There doesn’t seem to be any adverse consequence of having low levels of PCSK9 over one’s entire lifespan, so I think that makes the PCSK9 inhibitors more likely to be a safe treatment option.
DR. MORIARTY: You mentioned that Lp(a) does not have a high affinity for the LDL receptor, but it appears that the PCSK9 inhibitors significantly reduce Lp(a) by a mechanism that is not fully understood at present.
DR. UNDERBERG: People often ask about the role of genetic screening. Currently, in the US, it’s not something that we use routinely in the diagnosis of FH, but with targeted therapies such as those focusing on apoB or PCSK9, do you think that genetic testing can play a role in identifying patients who might respond better to one or another of these therapies?
DR. BRINTON: There is clearly potential for this. For example, if we knew that somebody had a gain-of-function mutation in PCSK9, then maybe a PCSK9 inhibitor would work much better. We might target therapy in that way.
In cases of FH that are due to a mutation in the apoB gene that causes apoB to bind poorly to the LDL receptor, the antisense apoB oligonucleotide might confer a greater benefit. Of course, this assumes that the antisense apoB oligo somehow still bound well to the mutated apoB mRNA.
But yes, I think we’re entering an era where the clinical benefit from genetic screening might increase, at least in certain cases. My own personal view—and I’d be interested to hear what the other panelists would say—is that there’s very limited clinical benefit from genetic screening at the moment for any of these disorders. However, if it would help the patient or maybe help the family to understand the disease and cooperate better with screening and treatment, then genetic testing might be warranted.
For now, my primary viewpoint is that routine screening to establish a diagnosis of FH is often difficult because of the many potential mutations, and the genetic cause doesn’t matter as much as the degree of LDL-C elevation at baseline and how well the patient responds to a given treatment.
In other words, we need to treat a patient empirically because it is so hard to predict the lipid response genetically, and CVD risk is largely driven by time-averaged LDL-C levels.
DR. UNDERBERG: Dr. McGowan, have you found that genetic testing is helpful for convincing parents to have their children screened? For example, if you identify an abnormality in a parent, you can also look for it in a child?
DR. MCGOWAN: You know, I think that we are moving to a point where it is going to be more important to do genetic screening, but I would agree with Dr. Brinton that we’re not quite there yet.
I was involved in a situation where I was treating a homozygous child who had 1 parent who very clearly had FH, while the other parent had an elevated LDL level but didn’t really meet the criteria for FH. That family would probably have benefited from knowing what their genetic situation was. I’m not saying that would necessarily change the outcome. However, there is clearly some variation in the LDL levels of heterozygotes. You can imagine 2 heterozygotes having children and not realizing their situation, and this is certainly a situation where genetic testing would potentially be valuable.
I’ve found that genetic screening often helps motivate patients—it helps them feel like they understand their disease better. It’s certainly expensive and not covered by all insurances, but if it’s going to help inform a patient and help patients be more motivated to stick with their treatment plan, I think it’s worthwhile. I also think that ultimately, we will find that certain genetic mutations respond better to certain drugs.
In the United States, things are quite complex because we have such a diverse population, whereas in Canada, for example, there may be very few mutations that lead to FH. The same is true for Spain. It may therefore be more difficult to perform genetic testing in the US. There are many more mutations here than we see elsewhere, although I believe genetic screening will evolve over the next 5 to 10 years.
DR. BRINTON: Dr. Underberg, may I interject something again? Two things that Dr. McGowan mentioned earlier are quite important. One is this concept of cascade screening: If you find somebody who has a very high LDL-C level and/or very premature atherosclerosis, it is critical to screen as many close family members as possible.
We start, of course, with first-degree relatives, but hopefully we go on to second-degree relatives—a group that includes so many people who are otherwise so hard to identify. Of course, there are good arguments in favor of population-wide screening, but cascade screening is much more cost-effective.
Second, I am impressed by Dr. McGowan and all the others who are working on the FH Foundation and the websites and social media magnets where people with very high cholesterol levels can experience a sense of community. I also appreciate their work to help both the general population and physicians recognize FH more easily. The promotion of wider screening and the organization of FH patients are the keys to success when fighting this very serious but treatable disease.
DR. MORIARTY: Speaking of genes, under the direction of Dan Rader and the University of Pennsylvania, we hope to initiate a phase I trial examining the use of gene therapy for homozygous FH patients next year.
Dan and his colleagues at the University of Pennsylvania have developed an LDL receptor genome with adenovirus 8 as the vector. A similar study was successfully executed in patients with hemophilia B and was recently published in the New England Journal of Medicine.12
Our site will be involved with the trial, and if the outcome is anything close to the hemophilia B study, it will be very exciting and hopefully will add another mode of treatment for the FH population.
DR. UNDERBERG: A new gene therapy was recently approved for the management of patients with familial hyperchylomicronemia and recurrent pancreatitis in Europe. So clearly, the path has been laid, and this actually makes it very easy for me to summarize because I feel like we’re at the crest of a wave when it comes to a variety of different forces at play in the field of treating patients with FH.
As Dr. Brinton pointed out, we’re becoming more aware of the cardiovascular risks and better at understanding the epidemiology as well as the pathophysiology of this condition since the past several years. This coincides with more awareness about the disease state, thanks to the foundations that Dr. McGowan brought to our attention: the FH Foundation of the NLA. There’s actually even a Facebook page for patients with FH that doctors can direct their patients to, and very interesting dialogues go on there.13
There are some gaps in our currently available options, but at the same time, we now have several potential new tools that we may be able to use—some of them very soon hopefully—to help in the treatment and management of these patients.
For those of us who treat patients often, it’s an exciting time, but I think it’s also exciting for those who come in contact with these patients but don’t think about them as much, for example, a cardiologist or someone doing any type of cardiovascular risk management or lipid management. We now understand how important it is to identify these patients because of everything we’ve talked about today, and I think it becomes even more evident with every passing day.
I would like to thank all of you for your participation, discussion, and insights, and I look forward to getting together and talking again in the future. Thank you.
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