Translational Medicine in Familial Hypercholesterolemia
November 14, 2016
October 17-18, 2016 | Dallas, TX
the Family Heart Foundation’s 2016 FH Global Summit took place a stone’s throw away from the Brown/Goldstein Lab, where the LDL receptor was discovered. In attendance were a group of over 250 committed physicians, scientists, patients and other key stakeholders, all gathered to discuss the most pressing issues facing the global FH community.
FH Pioneer Award
Nobel laureates Drs. Micheal S. Brown and Joseph L. Goldstein were presented with the FH Pioneer award by the Family Heart Foundation for their remarkable research that has led to the understanding of cellular cholesterol metabolism, contributing directly to the discovery and development of therapies that have saved millions of lives worldwide.
A Historical Perspective from Drs. Brown and Goldstein: Discovery of the LDL Receptor“Their lab continues to be a vital contributor to biomedical research and cholesterol metabolism, and an inspiration to scientists around the world well beyond the field of FH.” – Daniel J. Rader, MD
Drs. Brown and Goldstein treated a 6 year old patients in the early 1970’s with a total blood cholesterol level of 1000 mg/dL and several heart attacks during their post-doctoral fellowship at the NIH. Her family’s tragic story and the realization that it was a solvable problems resulted in the partnership and search for the underlying defect.
In their keynote presentation, Dr. Brown recounted their first hypothesis that the overproduction of cholesterol was due to a failure of feedback inhibition of the HMG-CoA Reductase and how, through rigorous experiments, they reached the discovery that a mutation in the LDL receptor gene is responsible for the overproduction of cholesterol. Dr. Goldstein illustrated the pathway to statin development, the trials that proved LDL reduction and results that indicated a decrease in the frequency of heart attacks. He also presented the breakthrough discoveries and studies of Drs. Jay Horton, Jonathan Cohen and Helen Hobbs that led to the development of PCSK9 inhibitors. “Within 10 years after these studies were done, one had approval of PCSK9 inhibitors. It’s the fastest example that I know of translation medicine – from the bench to the bedside – in this modern era of molecular medicine.” – Joseph L. Goldstein, MD “Hundred years from now, when historians write about medicine in the 21st century, hopefully the chapter on atherosclerosis will be titled ‘Heart Attacks: Gone with the Century’ without a question mark.”
– Joseph L. Goldstein, MD UT Southwestern Medical Center
Basic Science of PCSK9
Dr. Cohen’s research illustrates the importance of PCSK9 variants and the reasons for a greater reduction in coronary heart disease. Data indicates that PCSK9 has pro-atherogenic effects that are independent of LDL-C.
“We can show using genetics that PCSK9 should be an efficacious and safe therapeutic target.”
– Jonathan Cohen, PhD UT Southwestern Medical Center
Dr. Jay Horton explained the mechanism of action of PCSK9 and therapeutic approaches to LDL-C reduction through PCSK9 inhibition.
“How and why the targeting and differential movement of LDL receptor occurs is still unknown and is an area of future study.”
– Jay D. Horton, MD UT Southwestern Medical Center
PCSK9 Inhibitors: Current and Future
“If coronary disease is to be ultimately prevented, we need more out-of-the-blue discoveries of the PCSK9 type.” – Joseph L. Goldstein, MD Dr. Jennifer Robinson explained that although PCSK9 monoclonal antibodies can be used as monotherapy, they are more effective with statins due to the up-regulation of PCSK9, allowing for the full effect of statin therapy. Cost-effectiveness analyses are driven by the number of people who have to be treated in order to prevent one event. If the risk can be predicted and a needs to treat (NNT) value that meets the threshold of the payer could be determined, access to therapies could be improved. “There is animal data that shows that if you dramatically lower LDL-C down to about 20 mg/dL, you can completely regress early atherosclerosis and normalize vascular function.”
– Jennifer G. Robinson, MD, MPH University of Iowa
Access to PCSK9 Inhibitors
“With advancements in therapy development and biotechnology, there is unprecedented speed to identify drug targets with genetic data in humans and to develop novel therapies; however, there is much greater cost of goods to develop biologicals and thus an increased cost for consumers and payers.”
– Christie M. Ballantyne, MD The Methodist Hospital
FOCUS, an Family Heart Foundation initiative, shows that out of 26% respondents who were denied coverage for an FH treatment, 74% were for PCSK9 inhibitors. Data indicates that even patients with the greatest potential benefit are frequently denied.
Debate: Genetic Testing
There is an overlap in LDL-C levels between HoFH and HeFH. In order to ensure access to optimal therapies, there is a need for risk stratification as a means of determining therapy approval.
“What really matters most is the LDL – the higher the levels, the greater the risk.” – Raul D. Santos, MD, PhD“What is most important is what genetic testing can do in order to help individuals and families with FH to be better diagnosed and better treated in the future.”
– Børge G. Nordestgaard, MD, PhD Copenhagen University Hospital, Denmark
Joep C. Defesche, PhDOpportunities:
Genetic cascade screening
Molecular geography
Risk prediction
Transmission
DNA diagnostic finetuning
Pre- and post-genetic test counseling
Accuracy
Improved adherence and compliance
Sergio Fazio, MD, PhDChallenges:
Patient reluctance
Access to clinical geneticists and specialized labs
Accuracy of results and interpretation
Insurance coverage and burden of cost on the patient
Influence on therapeutic decisions
Life insurance discrimination
Statement on Clinical Genetic Testing for FH
“This is an opportunity to make the case that the time is right for genetic testing for FH in the US.”
– Daniel J. Rader, MD Chief Scientific Advisor, the Family Heart Foundation
Community and Patient Concerns
Stacey Lane and Scott Radabaugh voiced the concerns of FH patients and the community:
Discrimination
Privacy
The right not to know
Accuracy
Semantics
Burden of the cost
Access to therapies
Results not being actionable
“We believe genetic testing for FH should become the standard of care worldwide but we must thoughtfully address the potential issues so we can ensure that patients have access to the therapies they need and are not financially burdened by the additional costs.”
– Stacey R. Lane, JD, MBE Vice Chair, the Family Heart Foundation
Statement co-chair, Dr. David Ledbetter, discussed the evidence for clinical genetic testing: technical validity, clinical validity, clinical utility, personal utility and cost-effectiveness. “For every disease, earlier diagnosis, earlier intervention, and earlier treatment lead to better outcomes. This is the perfect disease for that but if we don’t find all the families soon, we’re not going to have that opportunity in the kids today.”
– David H. Ledbetter, PhD Geisinger Health System
Thank You to our 2016 FH Summit Sponsors:
FH Global Summit 2017
the Family Heart Foundation’s FH Global Summit convenes distinguished leaders in diverse fields to change the status quo for FH. With experts in cardiology, lipidology, biochemistry, health economics, and public health, we are working toward a common goal – to translate FH research into every day clinical practice that prevents premature cardiovascular disease. “We are gathered here to address the glaring divide between what we know about FH and what we do about FH.”
– Katherine A. Wilemon Founder & CEO, the Family Heart Foundation
FIND FH®: Progress
Healthcare providers will be engaged by the Family Heart Foundation Scientific Advisory Board, CASCADE FHâ„¢ Registry clinical site PIs and other experts to identify and diagnose patients in their practice who are flagged through the FIND FH® algorithm to have profiles consistent with FH. “Data from the CASCADE FHâ„¢ Registry shows that in the US, individuals with FH are being diagnosed with high cholesterol a decade before a specialty clinic makes an accurate FH diagnosis, as indicated by statin initiation.” – Kelly MyersKelly D. MyersChief Technology Officer, the Family Heart Foundationthe Family Heart Foundation is deeply committed to identifying and engaging individuals with FH now.
Prospective data from the Family Heart Foundation’s CASCADE FHâ„¢ Registry
Since its launch in 2013, the CASCADE FHâ„¢ Registry has enrolled over 4000 individuals with FH. Joshua W. Knowles, MD, PhD Chief Medical Advisor, the Family Heart Foundation
Average Registry Participant Results: Data from the CASCADE FHâ„¢ Registry
Prospective Data: High prevalence of CAD: Treated LDL-C suboptimal even with combination therapy: Thank you to our CASCADE FH Registry â„¢ Sponsors:
Current Environment
Data from NHANES and other sources shows prevalence of FH more consistent with Northern European data: 1 in 250 in the US have FH. Dr. Sarah de Ferranti presented the relative risk and CHD mortality. “At age 30, estimated CHD mortality for FH is 80 times that of the general population.”
– Sarah de Ferranti, MD, MPH Harvard Medical School
FH Screening
Existing cholesterol guidelines do not adequately address FH and the evidence base for specific recommendations is limited. However, the incorporation of newer types of research, such as registries and big data, into evidence algorithms has the potential to benefit FH-specific cholesterol guidelines. “Children treated with statins have lower event rates than their affected parents.”
– Samuel S. Gidding, MD Nemours Cardiac Center
Primary Prevention
Muin J. Khoury, MD, PhD Director, Office of Public Health Genomics, CDC
Opportunistic Population Genetic Screening
Identify opportunities for genomics to improve health and prevent disease
Inform and communicate with various audience
Integrate evidence-based applications into practice and programs
FH is a significant missed opportunity for public health prevention. A Tier 1 genomic application, there are effective interventions coupled with evidence-based recommendations that can reduce morbidity and mortality of FH.
A Look Toward the Future
Early initiation of cholesterol-lowering therapy is shown to be more effective by population and genetic epidemiology; more LDL cholesterol reduction, as shown by 5-year clinical trials, is more effective for primary prevention of CHD. “Data shows that a 1% reduction in LDL cholesterol translates to a 3% lifetime reduction in risk. The goal of therapy should be modified by the absolute risk; how to translate that into guidelines is a challenge for us but it is an approach we need to take, and the sooner the better.”
– Scott M. Grundy, MD, PhD UT Southwestern Medical Center
| Our Mission | the Family Heart Foundation is a patient-centered nonprofit organization dedicated to research, advocacy, and education of all forms of
familial hypercholesterolemia (FH).
Our mission is to raise awareness and save lives by increasing the rate of early diagnosis and encouraging proactive treatment. If left untreated, FH leads to aggressive and premature heart d isease in women, men and children of all racial and ethnic backgrounds.
Thank you to our Corporate Advisory Council Members for their support of the Family Heart Foundation’s work to contribute to the scientific understanding of FH and increase the rate of early diagnosis and optimal management.
THANK YOU
the Family Heart Foundation would like to take this opportunity to convey our deepest gratitude to all who joined to create an environment of collaboration and stand with us in our commitment to add decades of life to families with familial hypercholesterolemia. “the Family Heart Foundation is committed to thoughtful action that brings about real change in a disease that is so highly under-diagnosed and under-treated.” – Katherine A. Wilemon
the Family Heart Foundation is grateful to our most distinguished hosting co-chairs and international co-chairs, Drs. Christie M. Ballantyne, Børge G. Nordestgaard, Daniel J. Rader, and Raul D. Santos, and all the members of the 2016 FH Global Summit Steering Committee.
“Their lab continues to be a vital contributor to biomedical research and cholesterol metabolism, and an inspiration to scientists around the world well beyond the field of FH.” – Daniel J. Rader, MD 
In their keynote presentation, Dr. Brown recounted their first hypothesis that the overproduction of cholesterol was due to a failure of feedback inhibition of the HMG-CoA Reductase and how, through rigorous experiments, they reached the discovery that a mutation in the LDL receptor gene is responsible for the overproduction of cholesterol. Dr. Goldstein illustrated the pathway to statin development, the trials that proved LDL reduction and results that indicated a decrease in the frequency of heart attacks. He also presented the breakthrough discoveries and studies of Drs. Jay Horton, Jonathan Cohen and Helen Hobbs that led to the development of PCSK9 inhibitors. “Within 10 years after these studies were done, one had approval of PCSK9 inhibitors. It’s the fastest example that I know of translation medicine – from the bench to the bedside – in this modern era of molecular medicine.” – Joseph L. Goldstein, MD 
“Hundred years from now, when historians write about medicine in the 21st century, hopefully the chapter on atherosclerosis will be titled ‘Heart Attacks: Gone with the Century’ without a question mark.” 
“We can show using genetics that PCSK9 should be an efficacious and safe therapeutic target.” 
“How and why the targeting and differential movement of LDL receptor occurs is still unknown and is an area of future study.” 
“There is animal data that shows that if you dramatically lower LDL-C down to about 20 mg/dL, you can completely regress early atherosclerosis and normalize vascular function.” 
“With advancements in therapy development and biotechnology, there is unprecedented speed to identify drug targets with genetic data in humans and to develop novel therapies; however, there is much greater cost of goods to develop biologicals and thus an increased cost for consumers and payers.” 
“What is most important is what genetic testing can do in order to help individuals and families with FH to be better diagnosed and better treated in the future.” 
Joep C. Defesche, PhD Opportunities:
Sergio Fazio, MD, PhD Challenges:
“This is an opportunity to make the case that the time is right for genetic testing for FH in the US.” 
“We believe genetic testing for FH should become the standard of care worldwide but we must thoughtfully address the potential issues so we can ensure that patients have access to the therapies they need and are not financially burdened by the additional costs.” 
“For every disease, earlier diagnosis, earlier intervention, and earlier treatment lead to better outcomes. This is the perfect disease for that but if we don’t find all the families soon, we’re not going to have that opportunity in the kids today.” 
“We are gathered here to address the glaring divide between what we know about FH and what we do about FH.” 
“Data from the CASCADE FHâ„¢ Registry shows that in the US, individuals with FH are being diagnosed with high cholesterol a decade before a specialty clinic makes an accurate FH diagnosis, as indicated by statin initiation.” – Kelly Myers
the Family Heart Foundation is deeply committed to identifying and engaging individuals with FH now. 
High prevalence of CAD: 
Treated LDL-C suboptimal even with combination therapy: 
“At age 30, estimated CHD mortality for FH is 80 times that of the general population.” 
“Children treated with statins have lower event rates than their affected parents.” 
“Data shows that a 1% reduction in LDL cholesterol translates to a 3% lifetime reduction in risk. The goal of therapy should be modified by the absolute risk; how to translate that into guidelines is a challenge for us but it is an approach we need to take, and the sooner the better.” 
Thank you to our Corporate Advisory Council Members for their support of the Family Heart Foundation’s work to contribute to the scientific understanding of FH and increase the rate of early diagnosis and optimal management. 
“the Family Heart Foundation is committed to thoughtful action that brings about real change in a disease that is so highly under-diagnosed and under-treated.” – Katherine A. Wilemon
