By Thomas Knickelbine, MD. New medication options for people with familial hypercholesteremia and statin intolerance: how they work, effectiveness, case examples and ongoing research. "We're getting to the point where we can offer just about anyone tools or treatments that will help reduce their risk of a cardiovascular event."

1. Advanced Lipid Lowering:
New Treatment Approaches
Thomas Knickelbine, MD
Director: Preventive Cardiology
Minneapolis Heart Institute
Minneapolis MN

3. Lova
(Mevacor)
Simva
(Zocor)
Atorva
(Lipitor)
Fluva
(Lescol)
Pitava
(Livalo)
Prava
(Pravachol)
Rosuva
(Crestor)
Solubility
L – Lipophilic
H - Hydrophilic
L L L L L H H
Cytochrome
P-450
3A4 3A4 3A4 2C9 Min 2C9 None 2C9
Renal Excretion 10% 13% Minimal 6% Minimal 20% Minimal
Use in
Renal Failure
Max dose 20 mg
Yes
reduced dose
Yes
Full dose
Max dose 40mg Max dose 2 mg
Yes
reduced dose
Yes
reduced dose
Cost +/- + ++ ++ ++++ +/- +++
LDL
Lowering
40 mg – 31%
80 mg – 42%
20 mg – 38%
40 mg – 41%
80 mg- do not use
40 mg – 50%
80 mg – 60%
40 mg – 25%
80 mg – 35% (XL)
1mg – 32%
4 mg – 43%
40 mg – 34%
80 mg – 37%
20 mg – 51%
40 mg – 63%
Drug
Interactions
More More More Less Minimal Minimal Less
Myalgia
Incidence
Myalgias common
18%
Myalgias common
18%
Myalgias common
15%
Very low myalgias
<5%
Very low myalgias
<5%
Less myalgias
10% at 40 mg
Low myalgias
7 – 14%
Comments •Rarely used
•Similar to Simva &
Atorvastatin
•Modest ↑INR
•FDA black box
warning on doses
& drug interactions
•80 mg best LDL
lowering
•Very effective
•Modestly effective •Low drug
interaction (EES,
CSA and Rifampin)
•Good LDL lowering
 Cheap •Increase INR
•Avoid with
Protease inhibitors
•Less drug
interactions

4. Statin Myalgias RX: Strategies
– Change Statin metabolism pathway/class
• If renal failure, favor Lipitor (no renal clearance)
• If no renal failure, favor CYP2C9 statins (pravastatin,
rosuvastatin, lescol, pitavastatin (Livalo))
– Try reduced dosing or alternate day dosing
– Holiday, treat vitamin D to > 40
– Trial Co-Q 200/day
– Alternate LDL lowering strategies:
• Soluble fiber (portfolio diet): 5-25 % reduciton
• Plant sterols (cholestoff): 2 gms bid 15% reduction

5. Think FH !

6. Patient Wayne
• 60 yo male Referred by Dr. Moe to MHI Lipid
Clinic for “Refractory Hyperlipidemia”
• 3V CABG at age 28
• Redo CABG at 38
• Angina and PCI LCx 2010
• PCI SVG to LAD 2012

7. WH
• Mom, Dad, and both brothers have very high cholesterol
• Underwent Plasmapharesis from 80’s to late 2000s then
lost venous access and fatigued of the therapy
• Has normal LV function, coaches basketball
• Tolerating moderate dose statin (Atorvastatin 40 mg plus
Zetia), intolerant to other statins or higher doses

8. WH
• Lipid profile (on Lipitor 40 mg + Zetia 10 mg)
• Physical exam: Notable for tuberous
xanthomas of the Achilles tendons
What is the Diagnosis: ?
TC: 452
TG: 238
HDL: 43
LDL: 362

9. Familial Hypercholesterolemia
• Homozygous Familial Hypercholesterolemia
– Type II a Hyperlipidemia (Fredrickson Criteria)
• Involvement of both parents and all siblings
indicates homozygous state with extremely high
LDL (treated > 300 mg/dl, untreated LDL > 500)
• Tuberous Xanthoma diagnostic physical finding
of either heterozygous or homozygous FH

10. Familial Hypercholesterolemia (FH)
• Autosomal Dominant Inheritance
• Prevalence 1/500 heterozygous (LDL 250-500)
• Homozygous: often die <20 yo (LDL > 600-1000)
• Gene mutations in LDL receptor and APO B
interaction
• Untreated CHD risk is > 30% by age 40, > 50% by 50 yo
• 125 x the risk of aged matched peer
• Tendonous xanthomas diagnostic
• Not responsive to diet or exercise
Pediatrics;97:619-28

11. WH
• March 2013 began 200 mg Sub q Mipomersen q Wk
• No change in LFTs (monthly 1st year, then q3 month)
452
238
43
362
409
234
120
57.1
153
177
0
50
100
150
200
250
300
350
400
450
500
TC TG HDL LDL Non HDL
3/1/2013
9/12/2013
10/7/2013
12/2/2013
Changes: 48% 49% 33% 58% 57%

12. Mipomersen
• 200 mg injected Sub Q weekly
• Approved for FH patients

13. Mipomersen: Antisense Strand

14. Mipomersen: Kynamro

15. Treatment Options for Severe
Hyperlipidemias
• Plasma Apheresis: FDA approved for FH
• Two new drugs approved 12/2013 for homozygous
(or compound heterozygous) FH
– Lomitapide: Juxtapid
– Mipomersen: Kynamro
• Phase III clinical trials: Not just FH
– PCSK9 Inhibitors: Many vendors, not approved for use
outside clinical trials

16. Pt Angela
• 45 yo female referred by Dr. Hurrell to MHI Lipid
Clinic for severe hyperlipidemia
• CABG and AVR age 35 yo in Georgia
• Both sisters have hyperlipidemia, Dad with
hyperlipidemia
• Angiogram 2007: Occluded SVG to OM, stent in
LCx, Occluded SVG RCA Taxus stent to RCA

17. AD
• Started Juxtapid (5, then 10 mg) Aug 2013
• Mild elevation in AST, stable
0
50
100
150
200
250
TC TG HDL LDL non HDL
230
58
70
144
156
166
26
79 82 87
Dec-12
Oct-13
Nov-13
Dec-13
Jan-14
Changes: 28% 55% 11% 43% 44%

18. Juxtapid: Lomitapide
 Oral daily drug
 MTP inhibitor (microsomal transfer protein)
 Approved in pts on Apheresis

20. UBC Site Management for US Sites
Mary
Cresswell
CSS
UBC contact for
questions
Answer questions
Assist with Supplies
Isabelle
Mercier
Lead CRA
Monitor subject
data and generate
queries
Inclusion/Exclusion
Protocol questions
Daniel
Weeks
PM
Process payments
Protocol questions
Any other
questions
Site
5
Study Design
• Multicentre, long-term, prospective, observational study.
• N = at least 300 patients globally
• Patients will be followed for at least 10 years
• No study medication will be provided as part of the registry.
You will make all treatment decisions according to your usual
practices and will provide prescriptions for your patients, as
appropriate
• Available data will be collected at the Enrolment Visit and
Follow-up Visits (standard of care visits); visits are estimated
to occur monthly during the first year and ~ every 3 months
thereafter, consistent with the prescribing information.
REMS= Risk Evaluation and Mitigation Strategy

21. New Options for Hyperlipidemia
……PCSK9 Inhibitors

22. Human Loss of Function Mutations of PCSK9
Cohen JC et al. N Engl J Med 2006;354:1264-1272.
These two nonsense mutations are associated with a 28
percent reduction in mean LDL cholesterol and 88% reduction
in CV events in the ARIC database

23. PCSK9: Targets LDL receptor for
degradation
pcsk9

24. PCSK9 Inhibitors
• Amgen: Evolocumab
• Regeneron/Sanofi: Alirocumab
• Pfizer: Bococizumab
• All injectable Monoclonal Antibodies to PCSK9
• Other drugs in early testing to inhibit the
endogenous production of PCSK9
– RNA i= RNA interference
• Will these drugs simply lower LDL or will they
reduce cardiac events??

25. -70
-60
-50
-40
-30
-20
-10
0
10
20
MeanPercentChangeinUCLDL-C
DESCARTES: % Change in UC LDL-C from Baseline at Week 52
Error bars represent standard error for treatment difference
Treatment difference are least squares mean derived from a repeated measures model
EvolocumabPlacebo Treatment Difference
Overall
Diet
Alone
Atorvastatin
10 mg
Atorvastatin
80 mg
Atorvastatin
80 mg +
Ezetimibe 10 mg

26. DESCARTES: Other Lipids at Week 52
0
6%
-2
0
2
4
6
3%
(-17 to 25)
-9%
(-26 to 13)
2%
ApoB
Lp(a)
HDL-C
ApoA1
Triglycerides
-42%-50
-40
-30
-20
-10
0
10
-1%
2%
-2
-1
0
1
2
3
-6%
(-21 to 1)
-28%
(-49 to -6)
-30
-25
-20
-15
-10
-5
0
Placebo QM
Evolocumab 420 mg QM
PercentChangefrom
Baseline,Mean(%)
PercentChangefrom
Baseline,Median(%)
PercentChangefrom
Baseline,Median(%)
PercentChangefrom
Baseline,Mean(%)
PercentChangefrom
Baseline,Mean(%)-6
-4
-2
0
2
4
6
-10
-8
Error bars represent standard error
Data in parentheses represent Q1 to Q3

27. Lipid/Prevention Clinic Research Studies
Updated 9/2/2014
• Odyssey Outcomes-PI Dr. Knickelbine
– Inclusion Criteria:
• ACS event in past 12 months
• Lipids not at goal on highest tolerated statin (rosuvastatin or
atorvastatin) ~patient can be statin intolerant~
– Study Product:
• PCSK9 inhibitor vs Placebo
– Study Duration:
• About 5 years

28. • Pfizer 1019-Dr. Knickelbine
– Inclusion Criteria:
• High/Very High cardiovascular risk
• Lipids not at goal on max statin treatment (rosuvastatin, simvastatin or atorvastatin)
– Study Product:
• PCSK9 inhibitor vs Placebo
– Study Duration:
• About 18 months
•
• CAMELLIA-Dr. Newell
– Inclusion Criteria:
• High risk cardiovascular disease
• BMI ≥27
– Study Product:
• Placebo vs Belviq (lorcaserin)- FDA approved for weightloss
– Study Duration:
• about 5 years
•
• SPIRE 1030-Dr. Knickelbine
– Inclusion Criteria:
• Hyperlipidemia patients with documented intolerance to statins
– Study Product:
• PCSK9 inhibitor vs Placebo with statin re-challenge arm
– Study Duration:
• About 1 year

29. Contacts
• Contact Research Coordinators:
• Christine Majeski, CRC
• Minneapolis Heart Institute Foundation
• Phone: 612-863-3546
• Pager: 612-654-6444
• Christine.majeski@allina.com
• Laura Uppgaard, CRC
• Minneapolis Heart Institute Foundation
• Phone: 612-863-6120
• Pager: 612-654-9027
• Laura.uppgaard@allina.com
•