Protein Convertase Subtilisn/Kexin (PCSK9) Inhibitors Will they live up to the hype? What do I need to know?

Transcription

1 Protein Convertase Subtilisn/Kexin (PCSK9) Inhibitors Will they live up to the hype? What do I need to know? Adley Lemke, Pharm.D. PGY-1 Pharmacy Resident Hennepin County Medical Center April 27, 2018

2 Objectives 1. Describe the current therapies and guideline based recommendations surrounding cholesterol management. 2. Explain the mechanism by which PCSK9 inhibitors lower LDL cholesterol. 3. Name the different PCSK9 inhibitors. 4. Identify patient characteristics that make them good candidates for PCSK9 inhibitor therapy. 5. Demonstrate how these medications are administered and relevant monitoring. 6. State medication education points for patients before receiving PCSK9 inhibitor therapy.

3 Conflict of Interest Statement I, Adley I. Lemke, certify that I have no affiliations with or involvement in any organization or entity with any financial interest (such an honoraria; educational grants; participation in speakers bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this presentation.

4 GUIDELINES AND THERAPIES

5 Boekholdt et al. J Am Coll Cardiol Aug 5;64(5): Dyslipidemia- Why do we care? 50% decrease LDL-C. ~35% decrease risk of CV event. WOW

6 Which Guideline? Does it Matter? Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B): Jacobson et al. Journal of Clinical Lipidology. 2015;9: Jellinger et al. Endocrine Practice. 2017;23(2):1-87.

7 Guideline Overlap- Staging Risk Very High High ASCVD Diabetes mellitus (type 1 or 2) with 2 other major ASCVD Risk Factor or Evidence of End-Organ Damage 3Major ASCVD Risk Factors Diabetes mellitus (type 1 or 2) with 0-1 other Major ASCVD Risk Factors and no evidence of end organ damage Chronic kidney disease stage 3B or 4 LDL-C 190 mg/dl Quantitative risk score reaching the high-risk threshold ASCVD MAJOR RISK FACTORS - Age - Males 45 years - Females 55 years - Family history of early CHD - Current cigarette smoking - High blood pressure - Low HDL-C Moderate Low 2 Major ASCVD Risk Factors 0-1 Major ASCVD Risk Factors STATIN BENEFIT GROUPS - Clinical ASCVD - LDL-C 190 MG/DL - Diabetes (Type 1 or 2) age years - Estimated 10-year ASCVD Risk >7.5% Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B): Jacobson et al. Journal of Clinical Lipidology. 2015;9:

8 Guideline Differences: Treatment Goals Risk Group Low Moderate High Very High Extremely High Guideline/ Treatment Goals ACC/AHA 2013 NLA 2015 ACCE 2017 Life Style Changes Moderate-Intensity Statin (30-50% LDL Reduction) High-Intensity Statin (>50% LDL Reduction) LDL <100 mg/dl Non-HDL <130 mg/dl Treat if: LDL 160 mg/dl Non-HDL 190 mg/dl LDL <100 mg/dl Non-HDL <130 mg/dl Treat if: LDL 130 mg/dl Non-HDL 160 mg/dl LDL <100 mg/dl Non-HDL <130 mg/dl Treat if: LDL 100 mg/dl Non-HDL 130 mg/dl LDL <60 mg/dl Non-HDL <100 mg/dl Treat if: LDL 70 mg/dl Non-HDL 100 mg/dl LDL <130 mg/dl Non-HDL <160 mg/dl LDL <100 mg/dl Non-HDL <130 mg/dl Apo B <90 mg/dl LDL <70 mg/dl Non-HDL <100 mg/dl Apo B <80 mg/dl LDL <55 mg/dl Non-HDL <80 mg/dl Apo B <70 mg/dl ACC/AHA: American College of Cardiology; NLA: National Lipid Association; ACCE: American Association of Clinical Endocrinologist and American College of Endocrinology Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B): Jacobson et al. Journal of Clinical Lipidology. 2015;9: Jellinger et al. Endocrine Practice. 2017;23(2):1-87.

9 Usefulness of Specific Cholesterol Treatment Goals Goal directed therapy has not been tested in randomized controlled clinical trials. Collectively, trials demonstrate lower ontreatment levels are associated with lower risk of ASCVD. PURPOSE OF SPECIFIC CHOLESTEROL GOAL: To assure aggressive treatment. Jacobson et al. Journal of Clinical Lipidology. 2015;9:

10 Lipid/Lipoprotein Effect (% Change) Comparing Treatment Options LDL-C Non-HDL-C HDL-C TG -60 Statins Bile Acid Sequestrants Nicotinic Acid Fibric Acids Cholesterol Absorption Inhibitor Drug Class Long-Chain Omega-3 Fatty Acid Drugs Adapted from Jacobson et al. Journal of Clinical Lipidology. 2015;9:

11 Therapy Strategy Start with a statin Use risk stratification to choose intensity Contraindications: hypersensitivity, active liver disease, pregnancy, and lactation Verify adherence and efficacy Maximize the statin Consider additional agents to achieve goals in high risk patients Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B): Jacobson et al. Journal of Clinical Lipidology. 2015;9:

12 QUESTION My patient is statin intolerant. Now what?

13 Answer Statin intolerance defined: Adverse symptoms, signs or laboratory abnormalities attributed by the patient or provider to the statin and in most cases perceived by the patient to interfere unacceptably with activities of daily living (such as sleep, work/ housework, leisure-time activity), leading to a decision to stop or reduce statin therapy. -Guyton et al. (2014) Most often intolerance presents as myalgia Some reports of short-term memory impairment Guyton et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol May-Jun;8(3 Suppl):S72-81.

14 Answer cont. Intolerance reported in ~10% of patients Real rates of intolerance unknown Risks for increased adverse effects: Multiple comorbidities History of muscle disorders Unexplained ALT elevations (>3 times the upper limit of normal) Interacting medications >75 years of age Guyton et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol May-Jun;8(3 Suppl):S Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B):

15 Answer cont. Muscle symptoms: Symptoms include pain, tenderness, stiffness, cramping, weakness, or generalized fatigue Severe: Hold the statin and evaluate Mild Moderate: Consider holding statin Restart or lower dose when symptoms resolve or another cause is identified Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B):

16 Answer cont. Of note, it is assumed that the failure to achieve an optimal response to statin therapy is largely due to nonadherance with treatment, also know as pseudoresistance. -Ito & Santos (2017) Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

17 PCSK9 Inhibitors- The Hype BIG CHANGE PCSK9 Inhibitors are included in the 2017 AACE Guidelines. these drugs have the potential to revolutionize the treatment of the highest risk individuals, as well as those individuals unable to reach LDL-C goals with maximally tolerated statin dose Jellinger et al. Endocrine Practice. 2017;23(2):1-87.

18 PCSK9 Inhibitors The Hype This drug class meets a large unmet need for more aggressive lipid-lowering therapy beyond statins in a effort to further reduce residual risk in individuals with clinical ASCVD and diabetes, which up to now has not been possible. - Jellinger (2017) Jellinger et al. Endocrine Practice. 2017;23(2):1-87.

19 PCSK9 INHIBITOR MECHANISM

20 Origins of PCSK9 2 French families with high cholesterol genetically tested No link to LDL-R or Apo B genes found 12.5% of members had mutations at the PCSK9 locus There is a link! PCSK9 shown to play a role in cholesterol homeostasis Abifadel et al. Nat Genet Jun;34(2):154-6.

21 Why PCSK9? Familial hypercholesterolemia genetic disorder associated with defects in LDL degradation 60-90% LDL-R mutations 2-10% Apo B mutations <5% PCSK9 mutations million people affected world wide Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

22 Why PCSK9? Heterozygous Familial Hypercholesteremia (HeFH) Total cholesterol: mg/dl Heart disease develops by age 55 in males, 60 in females Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

23 Why PCSK9? Homozygous Familial Hypercholesteremia (HoFH) More severe and rare Total cholesterol: mg/dl Heart disease and aortic stenosis often developing at a young age Death before age 20 or 30 if not treated Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

24 Why PCSK9? Treatment for HeFH or HoFH: Diet Lifestyle modification Statins BUT. Most patients require multiple cholesterol lowering agents Effective management remains low Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

25 Why PCSK9? Statins Cholesterol synthesis PCSK9 Synthesis LDL Degradation RESULT: Statin efficacy plateaus Marais AD, Kim JB, Wasserman SM, Lambert G. Pharmacol Ther Jan;145:58-66.

26 LDL Regulation 1. Package 5. Degradation & removal 4. Trig loss LDL 2. Distribute 3. Repackage & Distribute Marais AD, Kim JB, Wasserman SM, Lambert G. Pharmacol Ther Jan;145:58-66.

27 Mechanism- PCSK9 3. Complex internalized and destroyed in lysosome. 2. PCSK9 binds LDL and LDL-R to form a complex. 1. PCSK9 synthesized and secreted into plasma. Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

28 Mechanism- PCSK9 Inhibitors 2. LDL and LDL-R internalized 3. LDL-R recycled not destroyed 4. More LDL-R available while LDL is destroyed 1. Inhibitor (mab) captures PCSK9 Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

29 Monoclonal Antibodies Antigen Antigen FAB Domain FC Domain Antibody Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32. FAB = Mouse FC = Human Human Monoclonal Antibody

30 Monoclonal Antibodies Antigen Antigen Receptor Lysozome Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32. Macrophage

31 Monoclonal Antibodies Safety and Efficacy Problems Human immune system can react to mouse segment Suboptimal penetration of target site Diminished efficacy with cytokine release Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

32 PCSK9 INHIBITORS: EVIDENCE

33 Alirocumab ODYSSEY LONG TERM Purpose: to establish the safety and efficacy of alirocumab use Primary outcome: change in calculated LDL from baseline to week 24 Robinson et al. New England Journal of Medicine. 2015;372(16):

34 Alirocumab ODYSSEY LONG TERM Baseline 99.9% on a statin 47% on a high intensity statin Average LDL: 122 mg/dl Average HDL: 50 mg/dl Robinson et al. New England Journal of Medicine. 2015;372(16):

35 Alirocumab ODYSSEY LONG TERM Robinson et al. New England Journal of Medicine. 2015;372(16):

36 Alirocumab ODYSSEY LONG TERM Adverse events: Injection site reactions: 5.9% Myalgia: 5.4% Neurocognitive effects: 1.2% Ophthalmologic events: 2.9% Allergic reaction 10% vs 9.5% in placebo? Robinson et al. New England Journal of Medicine. 2015;372(16):

37 Evolocumab OSLER trial Purpose: Establish long term safety and efficacy Primary outcome: change in LDL, adverse effects Extension on phase 2 and 3 studies Sabatine et al. New England Journal of Medicine. 2015;372(16):

38 Evolocumab OSLER trial Baseline 70% taking a statin 27% on a high intensity statin Average LDL-C: 120 mg/dl Average HDL-C: 51 mg/dl Sabatine et al. New England Journal of Medicine. 2015;372(16):

39 Evolocumab OSLER trial Sabatine et al. New England Journal of Medicine. 2015;372(16):

40 Evolocumab OSLER trial Sabatine et al. New England Journal of Medicine. 2015;372(16):

41 Evolocumab OSLER trial Neurocognitive adverse effects <1% but occurred more often in treatment group Injection site reaction (4.3%), not evaluated in placebo Muscle related 6.4% treatment and 6% placebo Sabatine et al. New England Journal of Medicine. 2015;372(16):

42 Evolocumab FOURIER trial Purpose: Investigate long term outcomes Primary outcome: composite for cardiovascular death, myocardial infarction, stroke, hospitalization of unstable angina or coronary revascularization Sabatine et al. New England Journal of Medicine. 2015;372(16):

43 Evolocumab FOURIER trial Baseline Myocardial infarction: 80% 70% on high intensity statin Median LDL: 92 mg/dl Sabatine et al. New England Journal of Medicine. 2015;372(16):

44 Evolocumab FOURIER trial Sabatine et al. New England Journal of Medicine. 2015;372(16):

45 Evolocumab FOURIER trial Sabatine et al. New England Journal of Medicine. 2015;372(16):

46 NLA PCSK9 Recommendations Populations of interest: Stable ASCVD Progressive ASCVD LDL-C 190 mg/dl Very-high risk patients with a statin response Orringer et all. Journal of Clinical Lipidology (11):

47 BOTTOM LINE: Which patients will be prescribed PCSK9- inhibitors? Familial hypercholesterolemia Clinical ASCVD on maximally-tolerated statin with on-treatment LDL 70 mg/dl or non-hdl 100 mg/dl Very high ASCVD risk with statin intolerance Essentially, PCSK9 inhibitor s role is to facilitate the achievement of LDL goals for patients taking the maximum tolerated statin. Orringer et all. Journal of Clinical Lipidology (11):

48 PRODUCT ADMINISTRATION AND INFORMATION

49 Alirocumab (Praluent ) FDA indication: HeFH ASCVD on max tolerated statin Dose: Start- 75 mg SQ every 2 weeks Max- 150 mg every 2 weeks OR 300 mg SQ monthly Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July 2017.

50 Alirocumab (Praluent ) Dose forms: 75 mg/ml or 150 mg/ml solution in pen or prefilled syringe Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July 2017.

51 Alirocumab (Praluent ) Adverse Reaction Placebo (N=1,276) Praluent (N=2,476) Nasopharyngitis 11.1% 11.3% Injection site reactions 5.1% 7.2% Influenza 4.6% 5.7% Urinary tract infection 4.6% 4.8% Diarrhea 4.4% 4.7% Bronchitis 3.8% 4.3% Myalgia 3.4% 4.2% Muscle spasms 2.4% 3.1% Sinusitis 2.7% 3.0% Cough 2.3% 2.5% Contusion 1.3% 2.1% Musculoskeletal pain 1.6% 2.1% Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July 2017.

52 Alirocumab (Praluent ) Monitoring: Lipids at 4-8 weeks Missed dose: Within 7 days give dose and resume schedule >7 days give dose and start new schedule Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July 2017.

53 Alirocumab (Praluent ) Store: refrigerator or room temp for up to 30 days Inject in thigh, upper arm or abdomen Do not administer to damaged skin Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July 2017.

54 Alirocumab (Praluent ) 1. Check window is clear. 2. Let pen warm to room temp for mins. 3. Clean injection site. 4. Remove safety cap and press pen into injection site at 90 degree angle until yellow safety cover is no longer visible. 5. Push green button and release immediately. You will hear a click. 6. Remove the pen after the window has turned yellow (up to 20 sec). 7. Discard pen in a sharps container. Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July 2017.

55 Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Evolocumab (Repatha ) FDA indication: HeFH HoFH ASCVD on max tolerated statin Dose: 140mg SQ every 2 weeks 420 mg SQ monthly

56 Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Evolocumab (Repatha ) Dosage Forms: 140 mg/ml solution in pen or prefilled syringe 420 mg/3.5 ml Pushtronex system

57 Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Evolocumab (Repatha ) Adverse Reaction Placebo (N=302) Repatha (N=599) Nasopharyngitis 9.6% 10.5% Upper respiratory tract infection 6.3% 9.3% Influenza 6.3% 9.3% Back pain 5.6% 6.2% Injection site reactions 5.0% 5.7% Cough 3.6% 4.5% Urinary tract infection 3.6% 4.5% Sinusitis 3.0% 4.2% Headache 3.6% 4.0% Myalgia 3.0% 4.0% Dizziness 2.6% 3.7% Musculoskeletal pain 3.0% 3.3% Hypertension 2.3% 3.0% Diarrhea 2.6% 3.0% Gastroenteritis 2.0% 3.0%

58 Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Evolocumab (Repatha ) Store: refrigerated or room temp for 30 days Inject in upper arm, abdomen or thigh

59 Evolocumab (Repatha ) Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Check window is clear. 2. Let pen warm to room temp for 30 mins. 3. Clean injection site. 4. Stretch skin over thigh injection site, pinch over stomach or upper arm injection site. 5. Remove safety cap and press pen into injection site at 90 degree angle until skin stops moving. 6. Push gray button and release immediately. You will hear a click. 7. Remove the pen after the window has turned yellow (up to 15 sec). 8. Discard pen in a sharps container.

60 Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Evolocumab (Repatha ) 1. Warm infusor for ~45 mins. 2. Clean injection site. 3. Open cartridge door, clean tip of cartridge and insert. 4. Close cartridge door. 5. Peel away green pull tabs. 6. Blue flashing light means it is on. 7. Place infusor on skin (stretched if stomach placement). 8. Press and release start button. 9. May take 9 mins. Solid green light means it is done. 10. Discard infusor in sharps container.

61 Bococizumab Humanized monoclonal antibody Currently in clinical trials Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32.

62 $$$ COST $$$ Product Evolocumab (Repatha) SureClick autoinjector 140 mg/ml; 1 ml Evolocumab (Repatha) Pushtronex system 420 mg/ 3.5mL; 3.5 ml Evolocumab (Repatha) prefilled syringe 140 mg/ml; 1 ml Alirocumab (Praluent) Pen-injector 75 mg/ml; 1 ml Alirocumab (Praluent) Pen-injector 150 mg/ml; 1 ml Cost/Dose $ $1, $ $ $ Source: Lexicomp Pricing.

63 Summary 1. Guidelines recommend statins for the prevention of cardiovascular events for those with clinical ASCVD, diabetes, hyperlipidemia and at increased ASCVD risk. 2. PCSK9 inhibitors can be used in patients who fail to achieve treatments goals on statins, cannot tolerate statins or have familial hyperlipidemia. 3. PCSK9 inhibitors increase LDL receptors on hepatocytes resulting in more LDL degradation. 4. The two PCSK9 inhibitors available on the market are Alirocumab (Praluent) and Evolocumab (Repatha). 5. The dosage forms of these medications are easy to use. 6. Patients should be educated on storage administration, symptoms of allergic reaction and adverse effects of these agents.

64 References Abifadel et al. Nat Genet Jun;34(2): Boekholdt et al. J Am Coll Cardiol Aug 5;64(5): Guyton et al. An assessment by the Statin Intolerance Panel: 2014 update. J Clin Lipidol May-Jun;8(3 Suppl):S Ito MK, Santos RD. J Clin Pharmacol Jan;57(1):7-32. Jacobson et al. Journal of Clinical Lipidology. 2015;9: Jellinger et al. Endocrine Practice. 2017;23(2):1-87. Marais AD, Kim JB, Wasserman SM, Lambert G. Pharmacol Ther Jan;145: Orringer et all. Journal of Clinical Lipidology (11): Praluent- alirocumab injection, solution. Sanofi-Aventis. DailyMed [online]. Updated July Repatha- evolocumab injection, solution. Amgen. DailyMed [online]. Updated July Robinson et al. New England Journal of Medicine. 2015;372(16): Sabatine et al. New England Journal of Medicine. 2015;372(16): Stone et al. J Am Coll Cardiol Jul 1;63(25 Pt B):