Clinical Overview: Guiding Patients Through Treatment with PCSK9 Inhibitors

It has been just over a year since the first proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor was approved by the FDA in the United States, offering a new and different treatment option for patients with certain types of high cholesterol.

Praluent (alirocumab, Sanofi-Aventis) was approved by the FDA on July 24, 2015,¹ and Repatha (evolocumab, Amgen) received US approval on August 27, 2015.² The PCSK9 inhibitors are among the most significant additions to the therapeutic arsenal for treating high cholesterol since the first statins were approved in 1987.³

PCSK9 inhibitors are monoclonal antibodies to PCSK9, which is expressed in the liver. Under normal conditions, PCSK9 binds to low-density lipoprotein receptors (LDL-R), and leads to LDL-R degradation. LDL-R are important because they serve to bind to LDL particles and remove them from circulation in the blood. If LDL-R are not available to remove LDL from the blood because they are bound to PCSK9 and degraded, the amount of circulating LDL in the blood increases.

Therefore, inhibiting PCSK9 from binding to LDL-R increases the availability of LDL-R to remove LDL particles from the blood.³ The available LDL-R is then able to be recycled and used for continuous removal of LDL particles from the blood, instead of becoming bound to PCSK9 and, ultimately, heading down the pathway to LDL-R degradation.

Praluent (alirocumab)⁴

Praluent (alirocumab, Sanofi-Aventis) was approved by the FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL cholesterol (LDL-C). The effect of alirocumab on cardiovascular morbidity and mortality has not been determined.

The recommended starting dose is 75 mg, administered subcutaneously once every 2 weeks. The majority of patients achieve sufficient LDL lowering with this dose. However, if the LDL response is inadequate at 75 mg every 2 weeks, the dose may be increased to the maximum dose of 150 mg administered every 2 weeks. LDL levels should be measured within 4 to 8 weeks of initiating alirocumab, or after a dose adjustment, in order to assess response.

Alirocumab injections are available in 75-mg/ml or 150-mg/ml strengths, in either a single-dose pre-filled pen or a single-dose pre-filled syringe for subcutaneous use, which patients can self-administer. If a dose is missed, the patient should be instructed to administer the injection within 7 days of the missed dose and then resume their original dosing schedule. If the missed dose is not administered within 7 days, the patient should be instructed to wait until the next originally scheduled dose.

It is important that patients receive proper training on the administration of alirocumab. The patient should allow the dose to warm to room temperature for 30 to 40 minutes prior to use, and the injection should be given as soon as possible after it has warmed up. The dose should be discarded if it has been at room temperature for 24 hours or longer. As with any parenteral drug product, the device should be inspected visually for any particulates or discoloration.

Aseptic technique should be used, with the injection site being rotated each time. Alirocumab should be injected into the thigh, abdomen, or upper arm, but not into areas of active skin disease or injury (such as sunburns, rashes, swelling, or skin infections). It can sometimes take up to 20 seconds to inject alirocumab. The use of alirocumab is contraindicated in patients with a history of serious hypersensitivity reactions to the drug. If signs or symptoms of an allergic reaction occur, treatment should be discontinued.

The most commonly observed adverse reactions in clinical studies were nasopharyngitis, injection-site reactions, and influenza. No dose adjustments are required for mild or moderate hepatic or renal impairment, and no overall differences were seen in patients ≥75 years treated with alirocumab compared with a younger population.

As with any therapeutic protein, there is a risk for development of immunogenicity with alirocumab use. In pooled results, 4.8% of patients treated with alirocumab had anti-drug antibodies compared to 0.6% with control patients. Patients who developed anti-drug antibodies had a higher incidence of injection-site reactions compared with patients who did not develop anti-drug antibodies (10.2% vs 5.9%). Meanwhile, 1.2% of patients treated with alirocumab developed neutralizing antibodies, but the long-term consequences of continuous treatment in those cases are unknown.

Due to differences in assays and methodology, comparison of the incidence of antibodies for a product with the incidence of antibodies for other products may be misleading. The efficacy of alirocumab was analyzed in 5 double-blind placebo-controlled trials that enrolled 3499 patients. Thirty-six percent were patients with HeFH, and 54% were non-FH patients who had clinical atherosclerotic cardiovascular disease. All patients were receiving a maximally-tolerated dose of a statin, with or without other lipid-modifying therapies.

Three studies used an initial dose of 75 mg every 2 weeks followed by criteria-based titration to 150 mg every 2 weeks, and 2 studies used only a 150-mg dose once every 2 weeks. The first study assigned patients to alirocumab 150 mg every 2 weeks or placebo. At week 24, the treatment difference between alirocumab and placebo, in mean LDL percent change, was —58% (95% CI, –61% to –56%; P <.0001).

The second study assigned patients to 75 mg every 2 weeks or placebo and showed the treatment difference between the 2 groups in mean LDL percent change at 12 weeks was —45% (95% CI, –53% to –39%). Studies 3 and 4 enrolled patients with HeFH: at week 12, the treatment difference between alirocumab 75 mg every 2 weeks and placebo, in mean LDL percent change, was -48% (95% CI, –52% to –44%).

Study 5 focused on patients with HeFH who were randomized to receive alirocumab 150 mg every 2 weeks or placebo. At week 24, the mean percent change from baseline in LDL was —43% in the alirocumab group and –7% in the placebo group; the treatment difference, in mean LDL percent change, was –36% (95% CI, –49% to –24%).

Repatha (evolocumab)5

Repatha (evolocumab, Amgen Inc) received approval as an adjunct to diet and maximally-tolerated statin therapy for treatment of adults with HeFH or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Evolocumab is also indicated as an adjunct to diet and other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

The effect of evolocumab on cardiovascular morbidity and mortality has not been determined. The recommended dose of evolocumab for adults with HeFH or clinical atherosclerotic cardiovascular disease is 140 mg every 2 weeks or 420-mg once a month. For adults with HoFH, the recommended dose is 420 mg once a month. Evolocumab is available as a single-use 140-mg prefilled SureClick autoinjector or prefilled syringe for subcutaneous self-administration.

It is also available as a single-use 420-mg/3.5 mL solution in a Pushtronex system, which is an on-body infusor with a prefilled cartridge. If a patient misses a biweekly or once monthly dose, he or she should be instructed to administer the injection as soon as possible if there are more than 7 days until the next scheduled dose or to omit the missed dose and administer the next dose according to the original schedule in the case of an injection that is remembered within 7 days or less of the next scheduled dose.

As with alirocumab, it is vital to provide patients with proper training on the administration of evolocumab. It should be kept in the refrigerator, and the patient should allow the syringe or autoinjector to warm to room temperature for at least 30 minutes prior to use. The single-use on-body infusor also should be warmed to room temperature for at least 45 minutes.

The dose should be allowed to come naturally to room temperature and should not be warmed any other way. Evolocumab can be kept at room temperature in the original carton for up to 30 days. As with any parenteral drug product, the device should be inspected visually for any particulates or discoloration. Aseptic technique should be used, and evolocumab should be injected into the thigh, abdomen, or upper arm; however, the drug should not be injected into areas that are tender, bruised, red, or hardened.

The injection site should be rotated each time. The 420-mg dose of evolocumab can be administered either using the single-use on-body infusor with prefilled cartridge, and infusing over 9 minutes, or by giving 3 of the 140-mg injections consecutively within 30 minutes using the single-use prefilled autoinjector or single-use prefilled syringe. Latex-sensitive patients should be advised that the needle cover of the glass single-use prefilled syringe and the single-use prefilled autoinjector contains dry natural rubber.

The use of evolocumab is contraindicated in patients with a history of serious hypersensitivity reactions to the drug. If signs or symptoms of an allergic reaction occur, treatment should be discontinued. The most commonly observed adverse reactions in clinical studies were nasopharyngitis, upper respiratory infection, influenza, back pain, and injection-site reactions.

No dose adjustments are required for mild or moderate hepatic or renal impairment, and no overall differences were seen in patients ≥75 years treated with evolocumab compared with a younger population. As with any therapeutic protein, there is a risk for development of immunogenicity: in pooled results, 0.1% of patients treated with at least 1 dose of evolocumab tested positive for binding antibodies.

These patients were further evaluated for neutralizing antibodies, and none of the patients tested positive for neutralizing antibodies. There was no evidence that the presence of anti—drug-binding antibodies impacted treatment, but the long-term consequences are unknown. Due to the differences in assays and methodology, comparison of the incidence of antibodies to a product with the incidence of antibodies to other products may be misleading.

The efficacy of evolocumab for patients with clinical atherosclerotic cardiovascular disease was assessed in 2 multicenter, double-blind, randomized, placebo-controlled trials. The first study evaluated evolocumab 140 mg every 2 weeks, evolocumab 420 mg once monthly, or placebo as add-on therapy to maximally-tolerated statin therapy. The differences between evolocumab and placebo, in mean percent change in LDL-C from baseline to week 12, were —71% (95% CI, –81% to –61%; P <.0001) and –63% (95% CI, –76% to –50%; P Ë‚.0001) for the 140-mg every 2 weeks and 420-mg once monthly dosages, respectively.

Study 2 looked at patients with clinical atherosclerotic cardiovascular disease who received protocol-determined, background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or evolocumab 420 mg administered subcutaneously once monthly. The difference between evolocumab patients and placebo patients, in mean percent change in LDL-C from baseline to week 52, was —54 % (95% CI, –65% to –42%; P Ë‚.0001).

In the third study that looked at patients with HeFH on statins, with or without other lipid-lowering therapies, the differences between evolocumab and placebo, in mean percent change in LDL-C from baseline to week 12, were —61% (95% CI, –67% to –55%; P <.0001) and –60% (95% CI, –68% to –52%; P <.0001) for the 140-mg every 2 weeks and 420-mg once monthly dosages, respectively. In study 4, the efficacy of evolocumab was evaluated in patients with HoFH.

Thirty-three patients received subcutaneous injections of evolocumab 420 mg once monthly, and 16 patients received placebo as an adjunct to other lipid-lowering therapies. The difference between evolocumab and placebo in mean percent change in LDL-C from baseline to Week 12 was —31% (95% CI, –44% to –18%; P <.0001) in patients with HoFH.&ensp;

References

• FDA approves Praluent to treat certain patients with high cholesterol, US FDA, July 24, 2015. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm Accessed: August 29, 2016
• FDA approves Repatha to treat certain patients with high cholesterol, US FDA, August 27th, 2015 Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm Accessed: August 29, 2016
• Myerson, M. PCSK9 Inhibitors: A Brief Primer. Medscape, March 28, 2016. Available at http://www.medscape.com/viewarticle/861024 Accessed August 31, 2016.
• Praluent Prescribing Information, Sanofi-Aventis, October 2015 Available at http://products.sanofi.us/praluent/praluent.pdf Accessed: August 31, 2016
• Repatha Prescribing Information, Amgen Inc., July 2016. Available at: http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf Accessed: August 31, 2016

The above information is a selective summary of publicly available information and is accurate as of the date of writing. Please consult the sources for complete reference information. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc.

About the AuthorStacey Ness, Pharm.D., RPh, CSP, MSCS, AAHIVP has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, National Association of Specialty Pharmacy, Specialty Pharmacy Certification Board, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist, a credentialed HIV Pharmacist, a Certified Specialty Pharmacist, and currently serves as the Senior Director of Specialty Clinical Services at Managed Health Care Associates, Inc., a health care services organization based in Florham Park, NJ.