Emerging Treatment Option for Hypercholesterolemia

Azelia Brown, Mercer University College of Pharmacy

Elevated blood levels of low density lipoproteins (LDL) are stated to increase risk for atherosclerotic cardiovascular events.  Statins are the reported agent of choice with proven efficacy, though variation in therapeutic response may require the use of additional therapy. [1]

Serine protease proprotein convertase subtilisin–kexin type 9 (PCSK9) is an enzyme that promotes the degradation of LDL receptors which reduces LDL re-uptake and leads to increased LDL levels. [2]  Some PCSK9 agents are monoclonal antibodies that work by sequestering PCSK9 and preventing it from binding to LDL receptors. Inclisiran interferes with ribonucleic acid, reducing the hepatic production PCSK9. [3]

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol [3]
Design Randomized, double-blind, placebo-controlled, phase 2, multicenter; N= 497
Objective To evaluate the effects of different doses and dosing intervals for the use of inclisiran
Study Groups Single dose groups: placebo (n= 65); inclisiran 200 mg (n= 60), 300 mg (n= 62) or 500 mg (n= 66) on day 1

Two dose groups: placebo (n= 62); inclisiran 100 mg (n= 62), 200 mg (n= 63), or 300 mg (n= 61) on day 1 and 90

Methods Follow-up visits were conducted every two weeks for the first month and then every month thereafter.  Fasting blood samples were conducted at each visit and end-of trial evaluations were conducted at day 210.  If patient’s LDL levels were not within 20% of the starting level, follow-up was conducted every 30 days until day 360 or until LDL levels were within 20% of baseline.  Adverse effects, vital signs, laboratory values, and electrocardiograms were obtained at follow-up visits.
Duration 1 year
Primary Outcome Measure Percentage change from baseline in LDL cholesterol level at day 180
Baseline Characteristics
Single dose regimens Two dose regimens
Placebo 200 mg 300 mg 500 mg Placebo 100 mg 200 mg 300 mg
Mean age, years ± SD 62 ± 11.4 63.9 ± 10.8 63.9 ± 12.8 62.1 ± 12.5 62.8 ± 10.3 65.2 ± 9.4 62.3 ± 10.9 64.1 ± 9.4
Male, % 65 65 67 71 53 62 63 74
White, % 92 90 90 95 94 92 97 95
Previous ASCVD, % 69 72 77 55 74 69 65 70
Statin use, % 70 53 75 65 77 71 67 73
Cholesterol, mg/dL
Total cholesterol, average 207.7 200 201.4 218.3 208.4 207.7 219.1 221.7
LDL, average 128.5 122.8 117.8 136.9 125.2 128.5 138.8 131.3
Triglycerides, Median 125 115 134 130 137 126 127 132
Mean PCSK9, ng/dL 404.7 460.3 408.9 416.7 431.3 394.2 437.4 416.3
Results
Single dose regimens Two dose regimens
Placebo 200 mg 300 mg 500 mg Placebo 100 mg 200 mg 300 mg
Change in LDL, % 2.1 -27.9 -38.4 -41.9 1.8 -35.5 -44.9 -52.6
Change in total cholesterol, % 1.8 -17.6 -23.7 -26.6 0.7 -22.4 -26.8 -33.2
Change in triglycerides, % 6.4 1.1 -12.8 -12.2 -3 -6.3 0.7 -14.2
Change in PCSK9, % 2.2 -47.9 -56 -59.3 -1.2 -53.2 -66.2 -69.1
Adverse Events Common Adverse Events: injection reactions (4% in one dose groups, 7% in two dose groups)

Greater than 2% across all groups: myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea, injection-site reactions and  dizziness

Serious Adverse Events: inclisiran (11%);  placebo (8%) — specific events not disclosed
Percentage that Discontinued due to Adverse Events: 0.4% (herpes zoster infection [placebo group, n= 1]; nasopharyngitis/influenza [two-dose 100 mg group, n= 1])
Study Author Conclusions The two dose 300 mg group showed the greatest LDL reduction.

 

Targeting PCSK9 RNA, like targeting circulating PCSK9, can lead to effective LDL lowering while having a lower injection burden than other PCSK9 inhibitors.  There may also be increased compliance with inclisiran over daily statin use leading to more effective cholesterol reduction.  There is insufficient data to determine if the lipid reduction seen with inclisiran will result in a reduction in cardiovascular events, though some previous PCSK9 inhibitors (with different mechanisms of action) have shown to reduce major cardiovascular events.  The size and duration of this trial cannot rule out less frequent side effects or determine if inclisiran improves mortality outcomes.

 

References

[1] Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161:161-172.

[2] Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-1272.

[3] Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017.

 

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