Stacey Ness, PharmD, CSP, MSCS, AAHIVP

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,

 and Repatha (evolocumab, Amgen) received US approval on August 27, 2015.

 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.

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.

 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, 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, 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;

		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

		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

		Myerson, M.  PCSK9 Inhibitors: A Brief Primer.  Medscape, March 28, 2016.  Available at 

http://www.medscape.com/viewarticle/861024

		Praluent Prescribing Information, Sanofi-Aventis, October 2015 Available at 

http://products.sanofi.us/praluent/praluent.pdf

		Repatha Prescribing Information, Amgen Inc., July 2016.  Available at: 

http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf

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.

Stacey 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.  

Articles

PCSK9 inhibitors are among the most significant tools targeting high cholesterol to arrive since the first statins were approved by the FDA.

Clinical Overview: Guiding Patients Through Treatment with PCSK9 Inhibitors

SPECIALTY DRUG TREND IS NOT ONLY INCREASING IN THE COMMUNITY SETTING

, but also among pharmacies that service patients (i.e. residents) who live in senior care settings such as long term care (LTC) facilities.

The 2016 Managed Health Care Associates (MHA) Independent Long Term Care Member Study

 included a section on specialty medications, which consisted of an analysis of LTC pharmacy dispensing data. Although this is MHA’s sixth year looking at specialty within LTC, due to methodology changes (including short cycle dispensing requirements), the results cannot be compared between previous years prior to study period 2015.

This year’s study periods included an analysis of data from January 1 to September 30, 2014 (study period 2015) versus January 1 to September 30, 2015 (study period 2016). The analysis included claims data from 1231 pharmacies encompassing over 184 million claims.

Almost 3.5 million patients from all 50 states were represented in the study. This article will examine some overall trends, as well as take a deeper dive into specific therapeutic categories.

The results from this study illustrated that LTC pharmacies included in the analysis have seen:

		Significant growth among select specialty categories within LTC pharmacies

		25% increase in the utilization of medications used to treat hepatitis C, a marked decrease from the 289% growth seen in this category in the 2015 study

		13% growth in the use of medications to treat multiple sclerosis

		37% increase in medications used to treat inflammatory conditions (including rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis)

		9% decrease in the use of injectable osteoporosis medications

		13% increase in the use of medications to treat HIV

		71% increase in immune globulin therapy

		Relatively stable utilization among oncology products with a 2% decrease in oral oncology products. (See Chart 1: Specialty Therapy Percent Growth Rx Count in LTC from 2015 to 2016 Study Period: All Participants) 

Although results from prior years are not comparable, the same methodology was used for the 2015 study (analyzing data from January 1 to September 30, 2013 (study period 2014) vs study period 2015) as the 2016 study. Growth trend for the 2015 study and 2016 study is shown in Chart 2.

Multiple sclerosis (MS) therapies within LTC demonstrated an overall growth of 13% for the 2016 study period. Copaxone (glatiramer acetate subcutaneous injection), the various dosage forms of Rebif (interferon beta-1-a subcutaneous injection), and Gilenya (fingolimod) posted the largest percentage increases.

For the second consecutive year, Rebif remains the most utilized MS drug in the LTC setting by prescription count, overtaking Copaxone in last year’s 2015 MHA Study. Top MS therapies with sustained or increased growth in Rx count in LTC from study period 2015 to 2016 include:

The newer oral disease modifying agents for the treatment of MS, Aubagio (teriflunomide), approved in September 2012, and Tecfidera (dimethyl fumarate), approved in March 2013, continue to have minimal utilization in the LTC setting.

This may be a result of these agents being available via limited distribution through preferred specialty pharmacies, which may be a barrier in accessing these agents through an LTC facility setting.

Recently approved agents Plegridy (peginterferon beta-1a), which was approved by the FDA in August 2014, and Lemtrada (alemtuzumab), which was approved in the United States in November 2014, had minimal utilization in the LTC patient population.

Glatopa (glatiramer acetate), the first generic disease modifying agent for MS, was approved in April 2015 and will be included in the 2017 study. This year marks the first year neurologists have been the primary prescribers of MS treatments for patients residing in LTC facilities. The last 3 years have seen a significant growth in neurologists prescribing MS medications in the LTC space.

Neurologist prescribing constituted 8.7% of MS medications prescribed in the LTC in study period 2014, compared with 25% of prescribing MS medications in LTC in study period 2015, and 32% in study period 2016. Internal medicine and general practice prescribers also have a significant prescribing presence in this space (see Chart 3).

Biologics for inflammatory conditions also saw significant growth of 37% in the 2016 study. These products are used to treat diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis.

Year over year growth in prescription count was noted for each of the following:

Xeljanz and Otezla, oral options for RA, psoriatic arthritis, and plaque psoriasis, grew the most in study period 2016. Humira continues to be the most widely utilized biologic for inflammatory conditions in the LTC patient population. Cosentyx (secukinumab) was approved in January 2015 and will be included in the 2017 study. Internal medicine, general practice, and rheumatology prescribers continue to be the lead specialties writing for biologics in LTC facilities (see Chart 4).

Utilization of medications to treat hepatitis C virus (HCV) rose 25% in the LTC population from the 2015 to 2016 study period, but that impressive growth trend paled in comparison with the 289% growth seen in this therapeutic class from study period 2014 to study period 2015.

As anticipated, we do see that the trend and utilization in this therapeutic category continue to increase for the newer agents and decrease for older therapies, as treatment guidelines and clinical practice continue to evolve.

Harvoni (ledipasvir and sofosbuvir) was approved in October 2014 for HCV genotypes 1, 4, 5, and 6; Viekira Pak (ombitasvir, paritaprevir, and ritonavir with dasabuvir) was approved in December 2014 for HCV genotype 1; Technivie (ombitasvir, paritaprevir, and ritonavir) was approved in July 2015 for HCV genotype 4; and Daklinza (daclatasvir) was approved in July 2015 in combination with sofosbuvir to treat HCV genotype 3 HCV.

Additional approvals in this therapeutic category are anticipated in 2016 (see Chart 5). Gastroenterologists lead the prescribing of HCV medications, accounting for 43% of the prescribed prescriptions for LTC residents, up slightly from 40% in last year’s study period.

The trend in oncology in the 2016 study marked the second straight year of a 2% decrease in oral oncology products in the LTC space. Although overall growth dipped slightly in oral oncology, there was significant growth in many branded oral oncology agents from study period 2015 to 2016.

Among the branded agents experiencing growth in the LTC space:

Ongoing flat-to-decreased prescribing in the oral oncology therapeutic category within LTC may be due to many of the newer oral oncology agents being launched as limited distribution products through preferred specialty pharmacies, which may be blocking access to these agents in the LTC facility setting. Prescribing for oral oncology products was driven by internal medicine, representing 40% of prescribers.

General practice accounted for 32% of oral oncology prescribing, as oncologists accounted for 5% of the prescriptions in the oral oncology therapeutic category to LTC residents.  

Prescriptions for HIV therapies in the LTC setting grew by 13% from the 2015 to 2016 study period. This may continue to reflect the fact that a growing number of people aged 55 and older are living with HIV. The CDC estimates that persons aged 55 and older accounted for almost one quarter (24%) of the people living with HIV infection in the United States in 2012.

This represents a jump from 19% in 2010 and is expected to further increase. In addition, older Americans are more likely than younger people to be diagnosed with HIV later in the course of their disease, meaning a delayed start to treatment and potentially more damage to their immune system. This represents a potential opportunity for LTC facilities specializing in HIV/AIDS treatment.

Long-term care pharmacies have seen significant growth among select specialty categories.