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PCSK9 Inhibitors: The Facts At-a-Glance

PCSK9 Inhibitors: The Facts At-a-Glance

  • PCSK9 Inhibitors: A New Class of Antihyperlipidemic PCSK9 = Proprotein convertase subtilisin/kexin type 9. Two PSCK9 inhibitors approved by FDA, summer 2015. Evolocumab (Repatha,™ Amgen) Praluent® (alirocumab, Sanofi /Regeneron). FDA approval based on evidence showing marked reduction (up to 70%) in LDL vs placebo.

  • PCSK9 enzyme helps bring LDL receptor to the surface of hepatocytes, where they can remove cholesterol from the blood. PCSK9 inhibitors: Fully humanized monoclonal antibodies designed to imitate rare genetic disorder in which loss of function genes result in decreased PCSK9 activity leading to low LDL that lead to low rates of CVD; inactivate the PCSK9 enzyme, preventing the degradation of LDL receptors and increasing hepatic clearance of LDL, resulting in lower serum LDL levels.

  • FDA Indications for Use [2, 3] Adjunct to diet and maximally tolerated statin therapy in adult patients requiring additional medication and who have: Heterozygous familial hypercholesterolemia; clinical atherosclerotic disease CVD; homozygous familial hypercholesterolemia (additional indication for evolocumab).

  • Evolocumab and alirocumab have similar effects on LDL (no head-to-head trials for direct comparison) [4] Alirocumab: 39% to 62% ↓ LDL; Evolocumab: 47% to 56% ↓ LDL; New meta-analysis [5] evaluated 24 phase 2 or 3 RCTs comparing PCSK9 inhibitor therapy vs placebo: LDL significantly decreased by ~50% with PCSK9 inhibitors (P

  • PCSK9 inhibitors added to statin monotherapy: Studies found a PCSK9 inhibitor added to statin monotherapy may ↓ LDL by additional 50%-70% [6] Meta-analysis: [7] 20 RCTs evaluating PCSK9 inhibitors added to various agents vs placebo found combined therapy with PCSK9 inhibitors[7]: Significantly lowers LDL, total cholesterol, triglycerides, apolipoprotein-B, lipoprotein(a); Increases HDL, apolipoprotein-A1.

  • Dosage and administration: Alirocumab: SQ injection every 2 weeks at 75 mg [2] May increase to max dose of 150 mg every two weeks. Evolocumab: SQ injection every 2 weeks at 140 mg[3]. May increase to 420 mg once every four weeks. Contraindications: Hx hypersensitivity reactions to evolocumab, alirocumab. No dose adjustments needed in mild to moderate hepatic and renal impairment.

  • Favorable safety profile. Common side effects [2,3] Nasopharyngitis, injection site reactions, influenza. Less common but potentially concerning side effects [2,3]. Hypersensitivity reactions, neurocognitive issues, myalgias, GI disturbance. Meta-analysis5 found no increase in serious adverse events for PCSK9 inhibitor therapy vs placebo. Most studies have only about 6 months of follow-up data.

  • Potential long-term outcomes. Long term effects of very low LDL are unknown. Studies to date have not been powered to look at mortality or CVD adverse events. Meta-analysis by Navarese et al suggested [5]: 50% statistically significant reduction in all-cause mortality. 50%, nonsignificant reduction in cardiovascular mortality. But: Low total number of events, wide confidence intervals

  • Annual cost of PCSK9 inhibitors may create barriers to access. Evolocumab: $14,100 Alirocumab: $14,600. Companies may provide co-pay incentives and/or offer to cover part of the costs.

  • TAKE HOME POINTS: PCSK9 inhibitors inactivate the PCSK9 enzyme, preventing the degradation of LDL receptors on the surface of hepatocytes and increasing hepatic clearance of LDL, resulting in lower serum LDL levels. PCSK9 inhibitors are indicated as adjunctive treatment to diet and maximally tolerated statin therapy in adults requiring additional medication for heterozygous familial hypercholesterolemia, clinical atherosclerotic disease CVD, or homozygous familial hypercholesterolemia (additional indication for evolocumab).

  • TAKE HOME POINTS: PCSK9 inhibitors may decrease LDL by up to 50% compared to placebo, and by an addition 50-70% when combined with statins. Long-term follow-up on CV outcomes is needed, but preliminary evidence suggests a decrease in all-cause and CV mortality with PCSK9 inhibitors. Other potential issues include high cost, hypersensitivity reactions, and neurocognitive issues.

FDA approval of the first-in-class PCSK9 inhibitors evolocumab and alirocumab in summer 2015 was met with a full spectrum of response, from elation among advocates for patients with variants of familial hypercholesterolemia to grave reservations among scientists who feel that LDL cholesterol level is not a reliable surrogate for cardiovascular benefit. Results are remarkable -- a dose-dependent reduction in LDL-C (up to 70%) occurred at between 4 and 14 days with a 2 to 8+ week delay in return to baseline with each agent.

Whether you agree or disagree with the FDA decision, understanding the PCSK9 antibodies and how they work is worth the time it will take to view the short primer we offer in the slides above.

 

 

 

 

 

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References: 

1. Rubenfire M. PCSK9 Inhibitors in the Cardiovascular Field: Ten Points to Remember.  American College of Cardiology website. Accessed October 22 2015 at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2015/06/15/15/32/are-pcsk9-inhibitors-the-next-breakthrough-in-the-cardiovascular#sthash.JU5K6LTU.pdf

2. Praluent [package insert]. Accessed October 22 2015 at: http://products.sanofi.us/praluent/praluent.pdf

3. Repatha [package insert]. Accessed October 22 2015 at: http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf 

4. Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 Inhibitors — The Clinical Benefit of Lipid Drugs. N Engl J Med. 2015;373:1588-1591. DOI: 10.1056/NEJMp1508120

5. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and meta-analysis. Ann Intern Med. 2015;163:40-51. doi: 10.7326/M14-2957. http://www.ncbi.nlm.nih.gov/pubmed/?term=10.7326%2FM14-2957.

6. McKenney JM. Understanding PCSK9 and anti-PCSK9 therapies. J Clin Lipidol. 2015;9:170–186. http://www.lipidjournal.com/article/S1933-2874(15)00002-1/fulltext?mobileUi=0

7. Li C, Lin L, Zhang W, et al. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials. J Am Heart Assoc. 2015;4:e001937. doi: 10.1161/JAHA.115.001937.

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