January 09, 2020
High cholesterol (or hypercholesterolemia) has climbed to nearly epidemic levels in the U.S. Approximately 30 million U.S. adults suffer from atherosclerotic cardiovascular disease (ASCVD), resulting in an estimated 1.2 million heart attacks and 795,000 strokes annually.1 If trends continue, total direct ASCVD medical costs are expected to triple from 2012 to 2030, soaring to $918 billion annually.2
In the summer of 2015, the Food and Drug Administration (FDA) granted market approval for new cholesterol-lowering drugs that belong to a class called PCSK-9 inhibitors and carry the potential to modify these statistics dramatically.3, 4
2-3% of your population may be eligible for lifelong PCSK-9 inhibitor drug therapy.
Who Should Take PCSK-9 Inhibitors?
Although approximately 73.5 million people in the U.S. have high cholesterol, not all are candidates for treatment with PCSK-9 inhibitors.7 Since their release in 1987, statins, like Lipitor and other cholesterol-lowering medications (available as inexpensive generics), have been, and continue to be, the standard treatment option.8 PCSK-9 inhibitors, in particular, are targeted for a subset of individuals who have:
- Inherited conditions caused by a genetic mutation that lads to high levels of LDL-C at an early age;
- High-risk status andwho, despite taking the appropriate measures of care (on maximally tolerated station therapy), are unable to reach their LDL-C goals, or who have
- Station intolerance.*
These patients tend to struggle more with managing cholesterol on a statin alone (see below).
*NOTE: Praluent and Repatha have yet to be officially approved for use in the case of statin intolerance.
PCSK-9 Inhibitors: Game Changers for Some Patients
Patients who struggle with high cholesterol are characterized by high levels of the PCSK-9 protein. As such, they possess abnormally low levels of hepatic LDL-C receptors, which are so crucial to the routine collection and degradation of circulating LDL-C. Put simply, individuals who have high levels of PCSK-9 have high levels of LDL-C and, therefore, are at higher risk for cardiovascular disease. The new PCSK-9 inhibition drugs essentially act by preventing the “turning on” of the PCSK-9 protein so that the body’s LDL-C receptors remain unimpeded by the protein, and can assume their proper function of removing LDL-C from the body.
Specifically, the PCSK-9 inhibition drugs are targeted for the following groups who struggle to control their cholesterol on a statin:
Patients with genetic predisposition: heterozygous or homozygous familial hypercholesterolemia (HeFH & HoFH)
- HeFH: Estimated U.S. population size: 620,000 (1 in 500 people) people;27
- HoFH: Estimated U.S. population size: (1 in 1 million) people;28
- Genetically prone to elevated levels of LDL-C. Pretreatment level > 190 mg;
- Not well controlled on the current station drugs and majority of patients do not reach their LDL-C goals; and
- High risk for ASCVD event.29
- Estimated U.S. population size: 1 million people (conservative estimate).
- Multiple risk factors in addition to hypercholesterolemia, including diabetes and/or a previous ASCVD event.
- Not well controlled on the current statin drugs and the majority of patents do not reach their LDL-C goals. Up to 20% of people on statins are not hitting their target LDL-C levels.
- High risk of future ASCVD event.26
- Estimated U.S. population size: up to 3.5 million people.
- Most common symptom presentation is muscle pain, which can occur in up to 15% of patient treated with statins.
This latter population, however, is not so easily identifiable. There is reasonable concern that, without a clear definition, the classification of “statin intolerance” can and will vary from one patient to the next.32 The National Lipid Association (NLA) guidelines suggest that failure to tolerate at least two statins constitutes station intolerance.
PCSK-9 Inhibitors are Safe, Effective, Injectable Specialty Medications
PCSK-9 inhibitors are not a cure for hypercholesterolemia and are prescribed as an ongoing maintenance therapy for the duration of the patient’s life. As indicated previously, they are not a first-line treatment or replacement for statins, but are intended for use in combination with statins, unless a patient is deemed “statin-intolerant.” The treatment calls for a life-long injection routine, involving the use of either a prefilled syringe or pen. Regeneron/Sanofi has made Praluent (alirocumab) available in biweekly (every 2 weeks) injections of 75 mg or 150 mg or monthly injections of 300 mg, while Amgen has made Repatha (evolocumab) available in 140 mg biweekly, or 420 mg monthly injections.9
PCSK-9 inhibitors have shown great promise since early trial phases. For example:
- Studies revealed an additional 60%-75% LDL-C reduction among some patients taking statins.11 Overall, the majority of patients see a 50% reduction in LDL-C from baseline;
- Maximum LDL-C reduction was seen in just four weeks and was maintained over the study period;
- Repatha clinical trials demonstrated that LDL-C reduction was maintained for up to 52 weeks;12
- Approximately 80% of patients on Praluent hit their treatment goals on 75 mg, while 85%-95% reached their goals on the 150 mg dose;13 and
- In addition to a reduction in LDL-C, other positive outcomes emerged from these trials, such as an increase in “good cholesterol” (high-density lipoprotein (HDL)) and a decrease in triglyceride levels.14
At drug launch, a reduction in LDL-C was deemed an acceptable surrogate endpoint for improved cardiovascular health.15 Studies have shown that a ~40 mg (1 mmol/L) reduction of LDL-C is associated with a 22% relative reduction in major cardiovascular events.16 Now, results from the manufacturers’ extensive, multi-year outcomes studies draw a more definitive line between PCSK-9 use and a lower risk of an ASCVD event, such as a heart attack or stroke. Nearly two years after releasing their drug on the market, Amgen shared results from their FOURIER trial which demonstrated that Repatha reduced the risk of it’s primary endpoint (cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or coronary revascularization) by 15% and of its key secondary endpoint (cardiovascular death, non-fatal MI or non-fatal stroke) by 25%.17 In the Regeneron/Sanofi ODYSSEY trial, Praluent similarly was shown to reduce both the risk of cardiovascular events and all-cause mortality, each by 15%.18
In clinical trials, the most common side effects were injection site reactions, generalized itching and cold or flu-like symptoms. In general, the drugs have shown to be very well tolerated and boast a low rate of discontinuation due to side effects (similar to that seen in placebo). What’s more, general adherence was surprisingly unimpeded despite the mode of administration (injection).10 However, safety is continually being assessed in the real world and through more widespread use beyond the “controlled” conditions of a clinical trial.
Assessing the Impact
While Praluent and Repatha are intended for use in specific populations (as outlined above), these drugs would theoretically work in any high cholesterol case and are equally as powerful as statins, if not more so. As such, when PCSK-9s launched at exceptionally high price points, PBMs, health plans and employers alike held their breath, waiting to see if demand would lead to expanded use of the new drugs in the broader, high cholesterol population and among those with a history of coronary artery disease.14
Expecting wide-spread use by large patient populations, pharmacy benefit manager (PBM) Prime Therapeutics had initially estimated, based on the originally projected cost of $10,000 per patient per year, that these new drugs could cost the nation’s health care system as much as $23 billion a year.15 The actual launch prices of these drugs proved even more shocking: Praluent entered the market at $560 per bi-weekly injection (for either dose) or roughly $14,600 per patient per year, dwarfing the cost of statins which are just $4 per month.3,15 Repatha boasted a slightly reduced list price of $542.31 for each bi-weekly injection, or $14,100 per patient per year.19 Surprisingly, even among appropriate patient populations, uptake hasn’t at all lived up to expectations. Until recently, the process for obtaining these drugs had been a rather onerous one, requiring heavy lifting on the part of the patient and provider to justify minimum eligibility requirements. In some cases patients waited up to nine months to receive the product. Many have speculated that the Hepatitis C storm, which caught the industry by surprise, set the tone for a rather cautious approach to the PCSK-9s.
This pricing and utilization landscape, however, is now changing rapidly. Regeneron/Sanofi led the charge in a deal with Express Scripts (ESI) (effective July 1, 2018), where they agreed, through a higher rebate strategy, to lower the net cost of Praluent to within the range suggested by a cost-effectiveness review put forth by the Institute for Clinical and Economic Review (ICER) ($4,460-$7,975) for patients acquiring the drug through ESI. Wherever point of sale rebates (POS) are not implemented, however, the employee or dependent’s copay would continue to be based off of the full price of the drug ($14,600). The arrangement eased prior authorization requirements for coverage of PCSK-9s and thus has invited speculation about a dramatic increase in utilization, not only among the intended treatment populations but also potentially outside of these target groups.20
This deal would essentially 1) ease the approval process for physicians, given that doctors will now only need to sign an attestation that the patient meets FDA criteria and has a history of uncontrolled LDL cholesterol levels despite taking maximally tolerated statins, 2) encourage a shift in the use of manufacturer rebates - a portion of which will now go directly to the consumer and 3) encourage a shift to “awarding market access in exchange for fair prices” as acknowledged by Steve Miller, Chief Medical Officer of ESI.21 Amgen recently took one step further and introduced a brand new National Drug Code (NDC) for Repatha, effectively lowering the list price by 60% to $5,850 per year. Repatha is now available at two different price points— with the new lower-priced drug representing a striking deviation from standard rebating structure. While still excluded from ESI’s National Preferred Formulary (Praluent is preferred), Repatha has secured an exclusive spot on ESI’s new National Preferred Flex Formulary (which excludes Praluent). This new drug reimbursement list is an effort to encourage manufacturers to slowly move away from paying rebates after a prescription is filled.22 The industry may see yet another major market shake-up, if potential competitor, Esperion, successfully brings its PCSK-9 drug to market charging $9 or $10 per day as promised.20
What Employers Can Do
- Educate employees about the risks of high cholesterol, the availability of traditional treatments, and the options to improve cardiovascular health via diet and exercise.Patients should be working with a physician on a treatment plan and behavior modification program, and should be on a traditional lipid-lowering regimen before even being considered for PCSK-9 inhibitor treatment. Employers may choose to implement well-being initiatives aimed at raising awareness about the dangers of high cholesterol, and particularly target communications for employees who may be at risk. To date, 78% of employers have implemented biometric screening programs and, for many years, have encouraged members to “know their numbers” for HDL, LDL and total cholesterol.23
- Talk to your PBM and health plan to understand how they standardly adjudicate the PCSK-9 inhibitor drug class and stay informed. These medications are classified as specialty drugs and, are subject to customary specialty dispensing protocols (e.g., restricted specialty networks, available only at certain retail venues, quantity limits). Expanded long-term safety and efficacy data and value-based pricing arrangements are crucial to plan-sponsor coverage decisions. Pay careful attention to formulary placement, as this data, as well as any unique pricing arrangements, will undoubtedly elicit a change in formulary. You’ll want to keep your employees informed.
- Examine PCSK-9 utilization among your population to date and assess the impact of any changes made by your PBM to the formulary and prior authorization protocol. Data analysis projects that approximately 2%-3% of a company’s covered members may be at high risk and thus initially eligible for PCSK-9 inhibitor use.24 While the price tags on these drugs, even after recent arrangements, are significantly higher than those on statin drugs, they may be offset by a reduction in ASCVD-associated events and thus overall cost on the medical side: The lifetime cost of treating a single heart attack can range from $760,000 to $1 million, depending on how severe the acute event. These numbers take indirect costs into consideration as well, including lost productivity, absenteeism and disability.25 It will be important to continue to monitor any future spikes in utilization mirroring changes in PA criteria. Be sure to also inquire about new formulary arrangements that offer lower-priced PCSK-9 drugs and an alternative to standard rebate structure.
- Implement continuous coverage review through utilization management and prior authorization criteria for PCSK-9 inhibitor therapies.Implementing checks and balances tied to guidelines is crucial to ensuring appropriate use of PCSK-9 inhibitors. If a patient is properly managed on a low cost statin, there is no reason why they should be switched to a completely different drug mechanism and regimen (oral to injection). PCSK-9 use should be reserved for those populations previously discussed. Patients should not be “trying out” the PCSK-9 inhibitor class unless they have been unsuccessful at achieving their LDL-C goals on statins despite taking all appropriate measures. Employers should consider adopting their PBM’s recommended utilization management program and cost-saving strategies. More exhaustive step therapy protocols might even be possible given the distinct dosage variations associated with these drugs. Praluent users, for instance, may theoretically be required to “fail first” on the 75 mg dose before advancing to the higher dose option. Additionally, PBMs should require clinical proof/evidence to corroborate a case of statin intolerance.3,9
- Ensure that your PBM is negotiating a competitive pricing strategy for the new PCSK-9 inhibitor drug class. Partner with your PBM to get the most value from agreements with pharmaceutical manufacturers, including those that involve a shift in the use of rebates, to the direct benefit of your employee consumer. PBMs have been able to negotiate sizeable discounts for a “preferred” treatment in the class.
- Consider designing and enforcing an adherence/compliance management program for PCSK9-eligible employees. The fact that this drug therapy is administered as a biweekly or monthly injection raises concerns about long-term adherence. These shots are less desirable than taking a pill and are, even with recent discounts, considerably more expensive.15 Therefore, it is crucial for employers to encourage proper education, onboarding and ongoing management of these patients. Employers may want to consider offering employee incentives for participating in behavior modification coaching and for remaining adherent to evidence-based treatment protocols.
The PCSK-9 inhibitor drug class has the potential to save lives through the lowering of harmful LDL-C levels that so often contribute to ASCVD. Both initial and long-term outcomes trials have proven these drugs to be highly effective. Despite the fact that the market is seeing a favorable shift in PCSK-9 cost structure, the newer price tag on these drugs is not to be taken lightly. While considerably lower than the initial launch price tag, the cost of these drugs is far greater than that associated with statin use. Furthermore, any concessions associated with price reduction may lead to far greater unnecessary utilization, and thus costs. To avoid this scenario, employers need to promote appropriate use within the specific populations for which these drugs are intended. Furthermore, employers should leverage partnerships to gain best pricing, eligibility and administrative protocols, especially now that long-term outcomes have been assessed.
- 1 | National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: National Institutes of Health, US Dept of Health and Human Services; 2012. http://www.nhlbi.nih.gov/research/reports/2012-mortality-chart-book.
- 2 | Mozaffarian D et al. (2015). Heart disease and stroke statistics – 2015 update. A report from the American Heart Association. Circulation, 13: e29-e322. http://circ.ahajournals.org/content/131/4/e29.full.pdf+html
- 3 | Pollack A (July 24, 2015). New drug sharply lowers cholesterol, but it’s costly. The New York Times. http://www.nytimes.com/2015/07/25/business/us-approves-drug-that-can-sharply-lower-cholesterol-levels.html?elq_cid=1305408&x_id=&_r=0
- 4 | Gray N. (March 2015). 9 important things to know about PCSK-9 cholesterol drugs. BioPharma Dive. March 2015. http://www.biopharmadive.com/news/9-important-things-to-know-about-pcsk9-cholesteroldrugs/377519/.
- 5 | Pfizer, Inc. (2015). Pfizer launches first annual PCSK9 competitive grants program to advance cardiovascular disease research. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_launches_first_annual_pcsk9_competitive_grants_program_to_advance_cardiovascular_disease_research.
- 6 | Stone NJ, Robinson J, Lichtenstein AH, et al.(2014). 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 63(25):2889-2934. https://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.full.pdf.
- 7 | CDC (2015). High cholesterol facts. http://www.cdc.gov/cholesterol/facts.htm.
- 8 | White S (2007). Statins: A Success Story Involving FDA, Academia and Industry. Update Magazine: Bimonthly publication of the Food and Drug Law Institute. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm082054.htm.
- 9 | Beasley D (May 26, 2015). Fight over hot new cholesterol drugs may be won in milligrams. Reuters: Health.
- 10 | Sanofi (June 11, 2015). Presentation to NBGH’s National Committee on Pharmacy Benefits and Specialty Medicine (PBSM).
- 11 | Dorey E (April 15, 2015). Cholesterol-busting PCSK9 drugs. The Pharmaceutical Journal. http://www.pharmaceutical-journal.com/news-and-analysis/features/pcsk9-inhibitors-the-next-cholesterol-loweringblockbusters/20068181.article.
- 12 | Blom DJ et al. (2014). A 52-week placebo-controlled trial of Evolocumab in hyperlipidemia. The New England Journal of Medicine, 370(19):1809-1819. http://www.nejm.org/doi/full/10.1056/NEJMoa1316222.
- 13 | Robinson JG et al. (2015). Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events.The New England Journal of Medicine, 372(16):1489-1499. http://www.nejm.org/doi/full/10.1056/NEJMoa1501031.
- 14 | Shrank W, Lotvin A, Singh S, Brennan T (February 17, 2015). In the debate about cost and efficacy, PCSK9 inhibitors may be the biggest challenge yet. Health Affairs Blog. http://healthaffairs.org/blog/2015/02/17/in-the-debate-about-cost-and-efficacy-pcsk9-inhibitors-may-be-the-biggest-challenge-yet/.
- 15 | Silverman E (June 9, 2015). How much?! Those new cholesterol drugs could be $23 billion a year. The Wall Street Journal: Pharmalot. http://blogs.wsj.com/pharmalot/2015/06/09/how-much-those-new-cholesteroldrugs-could-cost-23-billion-a-year/.
- 16 | Cholesterol Treatment Trialists’ (CTT) et al. (2015). Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. The Lancet, 385(9976):1397-1405. http://www.ncbi.nlm.nih.gov/pubmed/25579834.
- 17 | American College of Cardiology (March 17, 2017). Evolocumab Significantly Reduces Risk of Cardiovascular Events. Accessed June 4, 2018. http://www.acc.org/about-acc/press-releases/2017/03/16/22/25/fri-9amevolocumab-significantly-reduces-risk-of-cardiovascular-events
- 18 | Jancin, B (March 10, 2018). ODYSSEY outcomes trial redefines secondary cardiovascular prevention. Cardiology News. Accessed June 6, 2018. https://www.mdedge.com/ecardiologynews/article/160512/acc-conference-coverage/odyssey-outcomes-trial-redefines-secondary.
- 19 | Winslow R (July 24, 2015). FDA approves cholesterol drug from Regeneron, Sanofi. The Wall Street Journal. http://www.wsj.com/articles/fda-approves-cholesterol-drug-from-regeneron-sanofi-1437762374?elq_cid=1305408&x_id
- 20 | Sagonowsky, E (March 10, 2018). Regeneron’s Praluent pulls off PCSK9 coup with 29% cut to death risks in most vulnerable patients. Accessed June 5, 2018. https://www.fiercepharma.com/pharma/sanofi-regeneronpraluent-odyssey-outcomes.
- 21 | Caffrey, M (May 4, 2018). 5 things to know about the Praluent–Express Scripts deal. Accessed June 5, 2018. http://www.ajmc.com/newsroom/5-things-to-know-about-the-praluentndashexpress-scripts-deal.
- 22 | Beasley, D (Nov. 13, 2018). Express Scripts offers new formulary for lower list-price drugs. https://www.reuters.com/article/us-express-scripts-rebates/express-scripts-offers-new-formulary-for-lower-list-price-drugsidUSKCN1NI1FQ. Accessed December 19, 2018.
- 23 | Fidelity Benefits Consulting Presentation (March 25, 2015). Taking action to improve employee health: Sixth annual employer-sponsored health and well-being survey.
- 24 | Gorcyca K et al. (2015). Prevalence of atherosclerotic cardiovascular disease (ASCVD) and diabetes populations in the United States. Journal of Clinical Lipidology, 9(3): abstract. http://www.lipidjournal.com/article/S1933-2874(15)00118-X/abstract.
- 25 | Pierce E (2015). The costs of surviving cardiovascular disease: It’s enough to give you a heart attack! InsureMe. http://www.insureme.com/health-insurance/heart-attack-and-stroke.
- 26 | PCSK-9: A recent discovery in understanding cholesterol regulation (online video). Amgen, Inc., 2015. http://www.cholesterolneversleeps.com/what-is-pcsk9.html
- 27 | Yuan G, Wang J, Hegele RA (2006). Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. Canadian Medical Association Journal, 174(8):1124-1129. http://www.ncbi.nlm.nih.gov/pubmed/16606962
28 | Cuchel M, et al. (2014). Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. European Heart Journal Advance Access published online
July 22, 2014. http://eurheartj.oxfordjournals.org/content/early/2014/07/22/eurheartj.ehu274
- 29 | Sanofi (June 11, 2015). Presentation to the Business Group’s National Committee on Pharmacy Benefits and Specialty Medicine (PBSM).
- 30 | Gray N (March 2015). 9 important things to know about PCSK9 cholesterol drugs. BioPharma Dive. http://www.biopharmadive.com/news/9-important-things-to-know-about-pcsk9-cholesteroldrugs/377519/
- 31 | Shrank W, Lotvin A, Singh S & Brennan T (February 17, 2015). In the debate about cost and efficacy, PCSK9 inhibitors may be the biggest challenge yet. Health Affairs Blog. http://healthaffairs.org/blog/2015/02/17/in-the-debate-about-cost-and-efficacy-pcsk9-inhibitors-may-be-the-biggest-challenge-yet/
- 32 | Fitchett DH, Hegele RA, & Verma S. (2015). Statin intolerance. Circulation, 131: e389-e391. http://circ.ahajournals.org/content/131/13/e389.full
- 33 | Food and Drug Administration Center for Drug Evaluation and Research. The Endocrinologic and Metabolic Drugs Advisory Committee meeting (June 9, 2015). Briefing Document: Praluent (alirocumab) injection. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449865.pdf
- 34 | Statin intolerance. 2014 National Lipid Association (NLA) Fall Clinical Lipid Update. https://www.lipid.org/sites/default/files/PresentationsFrom2014NLAFallCLU.pdf