For Now, PBMs Just Say No to High-Cost PCSK9 Inhibitors

When the FDA approved the first 2 PCSK9 inhibitors this summer, there was plenty of attention from health plans and cardiologists alike to scope of the labels, especially relative to what European regulators allowed for these breakthrough cholesterol drugs. But when the approvals came down for alirocumab (Praluent) on July 24, 2015, and for evolocumab (Repatha) on August 27, 2015, the next question was: what will they cost?^1-3

First, Sanofi-Regeneron set the price of alirocumab at $14,600 a year for both the 75-mg and 150-mg injections—a eye-popping $40 a day.⁴ Then, despite speculation that Amgen might price evolocumab well below its competitor, the second drug came in at $14,100 a year for its 140-mg injection^.5 Both drugs are given twice a month, although evolocumab plans to have a 420-mg monthly dose available next year.

The first entrants in this long-awaited class of monoclonal antibodies, which reduced low-density lipoprotein (LDL) cholesterol up to 60% in clinical trials, arrived well above the $7000 to $12,000 annual cost that analysts predicted.6 ExpressScripts, the nation’s largest pharmacy benefits manager (PBM), and CVS Health, the second-largest, had spent months before the FDA actions making it clear they intended to leverage the presence of 2 drugs to demand savings for their clients, and ultimately, consumers.^6-8

As the prices were set reaction from the 2 PBMs came quickly: get ready to negotiate.

CVS Health announced August 10, 2015, after alirocumab was approved and a decision on evolocumab was pending, that the PBM would not bother to talk to Sanofi-Regeneron about setting discounts until alirocumab had a competitor^.9 This move came after alirocumab’s sponsors paid $67.5 million to transfer an orphan drug voucher to jump ahead of Amgen in the approval process.¹⁰ CVS Health Chief Medical Officer Troyen Brennan, MD, MPH, told Reuters that CVS would have a management program that would take into account a patient’s history of heart dis-ease, diabetes, cardiovascular risk fac-tors, and experience with statins before authorizing use of a PCSK9 inhibitor.⁹

What the FDA Approved. The PBMs are aided by the fact that labels for alirocumab and evolocumab are nearly identical. Both PCSK9 inhibitors are authorized to treat heterozygous familial hypercho-lesterolemia and atherosclerotic cardio-vascular disease, such as heart attacks and strokes, where maximally tolerated statins are not doing enough to lower LDL cholesterol. Evolocumab received an additional indication for homozygous familial hypercholesterolemia.^2,3 While the US approvals do not cover patients who simply can’t tolerate statins, which Europeans regulators allowed, they do cover enough high-risk heart disease patients that market estimates have varied from 6 to 10 million patients a year.¹¹

It doesn’t appear those with hypercholesterolemia will have too many problems gaining access to the drug, and CVS has indicated as much, both in an email to Evidence-Based Diabetes Management and in public comments referencing those with “rare genetic conditions.”¹² Those with high-risk heart disease will be expected to exhaust all treatment options before gaining access, however.

ExpressScripts’ Chief Medical Officer Steve Miller, MD, in a statement issued the evening of the evolocumab approval, said that the drug class could become “the most costly therapy our country has seen.” Until the pharmacy and ther- apeutics (P&T) committee completes its review in September, the drug would only be available through an exception process that will restrict PCSK9 inhibi-tors to those who meet the strictest terms of the FDA recommendations.¹³

Manufacturers could avoid exclusions by working with PBMs on favorable pricing. Miller said: “We would only exclude one of these products if our P&T commit-tee determines that the product we cover is at least clinically equivalent to the one we exclude. And only then would we exclude one of these products if that exclu-sion would deliver significant savings for our clients and patients.”¹³

CVS was less specific after the evolocumab approval, but the company inferred that most patients would have to wait until after the P&T committee had reviewed both therapies and price nego-tiations had occurred. “As per our standard approach, new-to-market products are not included on the formulary until they are reviewed by the CVS/Caremark Pharmacy and Therapeutics Committee and recommended for inclusion,” the company said in a statement.¹⁴

“Based on the evaluation of the P&T committee, we will evaluate the inclusion and position of both Repatha and Praluent on our formulary. In addition, consistent with past practices, CVS/ Caremark will actively negotiate with the drug manufacturers in an effort to control costs for patients and payers.¹⁴

Both Sanofi-Regeneron and Amgen promised that health plans and PBMs will receive discounts from the whole-sale price and that programs will be created for needy patients who otherwise would lack access to the drugs. But the standoff that appeared to be shaping up in late August distressed some who observed that never before had it been so clear that payers and pharmacy managers, not doctors or even the FDA, were deciding when a drug would be appropriate. And this was happening because of price, despite the therapeutic potential.

John LaMattina, a senior partner at PureTech Ventures and a Forbes contributor, wrote, “The payers are making no mention of extending the lives of patients with CV [cardiovascular] disease nor the impact of reducing heart attacks and strokes to healthcare costs. This doesn’t seem to be a major concern to them. Limiting their own costs, however, is paramount. Welcome to the new world of medicine.”¹⁵

Different Points of View. Drug makers and PBM leaders clearly see the pric-ing equation differently. In announcing Praluent’s price, Sanofi-Regeneron said it was inexpensive relative to other monoclonal antibodies and that pricing took into account the cost of heart disease to the US healthcare system.⁴ PBMs, by contrast, fear a day when this high-priced therapy could be seen as a routine alternative to a low-cost stand-by, statins.^7,8,15

The current FDA approval is not the problem, and everyone knows it. Unlike European regulators, FDA limited the scope of its approval for now while it awaits the results of long-term cardio-vascular outcomes trials, which it has required since the mid-2000s to avoid letting dangerous products flood the market. While it may take until 2017 for the full results of these trials to be presented, Amgen was already touting plans to present some data at a conference days after the FDA approval of evolocumab. Of the 2 sponsors, Amgen made the stronger push at the FDA ad-visory committee level and at recent scientific meetings to eventually extend availability to patients who can’t toler-ate statins.^10,16

Both drugs work by blocking proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that when missing causes LDL cholesterol levels to drop by 55% to 60%, depending on the condition and whether it is used in combination with other therapy such as metformin.

The high cost of the PCSK9 inhibitor class drew the attention of the Campaign for Sustainable Rx Pricing, a Washington, DC—based group that seeks to educate lawmakers and the public about solutions to rein in the cost of new drugs. “The approval of Repatha is another example of a breakthrough medication with a too high price tag,” said John Rother, president of the National Coalition on Health Care and the campaign’s leader. “With several game-changing medications in the pipeline, we need to address the underlying issue of how these prices are set from the start before they hit the market.”¹⁷

A Return to Tight Guidelines? CVS is not just counting on current negotia-tions to limit its exposure. On the same day that Brennan announced that the PBM would await a competitor in the PCSK9 inhibitor class before trying to set alirocumab’s price, Chief Scientific Officer William Shrank, MD, MSHS, pub-lished a commentary in the Journal of the American Medical Association that calls for a return to highly specific guidelines from the American College of Cardiology (ACC) and the American Heart Association, as existed before the 2013 update that increased the pool of patients eligible to receive statins.¹⁸

“There is a need for consensus around management strategies for patients with high cholesterol, given that the cost differential between proven older therapies and this new class of drugs is substantial,” Shrank said.¹⁸

ExpressScripts’ Miller also called for greater specificity in the wake of the evolocumab pricing. Today’s guidelines, he said, do not “provide clarity as to how these expensive new medications could fit in the treatment paradigm, potentially resulting in some scenarios where a prescriber could consider a PCSK9 inhibitor for a low-risk patient.”¹³

So far there has been no word from the professional associations on such an update, but ACC President Kim Allan Wil-liams Sr, MD, FACC, said the organization awaits the results of the long-term safety trials now under way. Full results could take as long as 2017 to complete, but it appears that Amgen at least is anxious to present positive safety data on CV outcomes as soon as data become available.¹⁹

The question is whether pressure will build to make the PCSK9 class more broadly available to those who experi-ence statin intolerance or who have high LDL cholesterol and risk factors for de-veloping type 2 diabetes mellitus (T2DM), and whose physicians might prefer to try something other than a statin, in light of a trial that showed at least 1 statin may have hastened the progression to T2DM for those already at risk of developing the disease.²⁰ Since the European approval for evolocumab is already much broader and the label for alirocumab overseas will be as well,^1,21 both clinical trial and real-world data will be available over the next 2 years.

A clue to the drug makers’ future arguments may have been unveiled in March, when Marc Sabatine, MD, MPH, of Brigham and Women’s Hospital, discussed evolocumab’s potential at the 2015 meeting of ACC in San Diego. While he insisted that statins are the “foundation” for all treatment (and deflected all questions on price), Sabatine would later make Amgen’s case for extend-ing the drug’s label to statin-intolerant patients during the FDA advisory committee hearing in June. Regulators declined to do that for now, but they could change their minds should trials show long-term benefits of reducing heart at-tacks and strokes.^10,16

Medicine, Sabatine said at the March meeting, has not fully considered the potential benefits of dramatically lowering LDL cholesterol in patients for whom modest reductions are currently possi-ble. “When we think about how much we should lower LDL cholesterol, we haven’t found a floor beyond which we haven’t found a benefit,” he said.¹⁰ References

1. European Commission approves Amgen’s new cholesterol-lowering medication Repatha (evolocumab), the first PCSK9 Inhibitor to be approved in the world, for treatment of high cholesterol [press release]. Thousand Oaks, CA: PRNewswire; July 21, 2015. http://wwwext.amgen.com/media/me-dia_pr_detail.jsp?year=2015&releaseID=2069405. Accessed August 30, 2015.

2. FDA approves Repatha to treat certain patients with high cholesterol [press release]. Silver Spring, MD: FDA Newsroom; August 27, 2015. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm460082.htm. Accessed August 30, 2015.

3. FDA approves Praluent to treat certain patients with high cholesterol [press release]. Silver Spring, MD: FDA Newsroom; July 24, 2015. www.fda.gov/NewsEvents/Newsroom/Pres-sAnnouncements/ucm455883.htm. Accessed August 30, 2015.

4. Sanofi and Regeneron announce FDA approval of Praluent (alirocumab) injection, the first PCSK9 inhibitor in the US, for the treatment of high LDL cholesterol in adult patients [press release]. Paris France, and Tarrytown, NY: Sanofi website; July 24, 2015. www.news.sanofi.us/2015-07-24-Sanofi-and-Regeneron-Announce-FDA-Approval-of-Praluent-alirocumab-In-jection-the-First-PCSK9-Inhibitor-in-the-U-S-for-the-Treatment-of-High-LDL-Cholesterol-in-Adult-Patients. August 30, 2015.

5. FDA approves Amgen’s new cholesterol-lowering medication Repatha (evolocumab) [press release]. Thousand Oaks, CA: Amgen website; August 27, 2015. www.amgen.com/media/ media_pr_detail.jsp?releaseID=2082837. Accessed August 30, 2015.

6. Pierson R. Update 1-CVS urges cost controls for new cholesterol, specialty drugs. Yahoo Finance website. http:// finance.yahoo.com/news/cvs-urges-cost-controls-cholester-ol-170425184.html. Published February 17, 2015. Accessed August 27, 2015.

7. Smith A. On lessons learned: ExpressScripts’ Steve Miller, MD, discusses HCV experience, PCSK9 inhibitors and more. Am J Manag Care. 21(SP11):SP367-SP368.

8. ICER launches new drug assessment program with $5.2 million award from the Laura and John Arnold Foundation [press release]. Houston TX, and Boston, MA: Laura and John Arnold Foundation website; July 21, 2015. www.arnoldfounda-tion.org/icer-launches-new-drug-assessment-program-with-5-2-million-award-from-the-laura-and-john-arnold-foundation/. August 30, 2015.

9. Caffrey MK. CVS to wait for 2nd approval before seeking prices on PCSK9 inhibitors. American Journal of Managed Care website. www.ajmc.com/newsroom/cvs-to-wait-for-2nd-approval-before-seeking-prices-on-pcsk9-inhibitors. Published August 10, 2015. Accessed August 27, 2015.

10. Caffrey MK. Cholesterol-fighting drug evolocumab also reduces cardiovascular events, study finds. American Journal of Managed Care website. www.ajmc.com/conferences/ acc15/Cholesterol-Fighting-Drug-Evolocumab-Also-Reduces-Cardiovascular-Events-Study-Finds. Published March 16, 2015. Accessed August 27, 2015.

11. Staton T. Sanofi draws line in the sand for Praluent payer fight. FiercePharmaMarketing website. www.fiercepharma-marketing.com/story/sanofi-draws-14600-line-sand-praluent-payer-fight/2015-07-27. Published July 27, 2015. Accessed August 28, 2015.

12. Associated Press. Amgen wins approval for second biotech cholesterol drug. New York Times website. www.nytimes.com/ aponline/2015/08/27/business/ap-us-cholesterol-drug-amgen.html?_r=0. Published August 27, 2015. Accessed August 27, 2015.

13. Caffrey MK. Repatha, Amgen’s PCSK9 competitor, gains FDA approval. American Journal of Managed Care website. www.ajmc.com/newsroom/evolocumab-amgens-pcsk9-competitor-gains-fda-approval. Published August 27, 2015. Accessed August 27, 2015.

14. Caffrey MK. For now, pharmacy managers just say no to high-cost PCSK9 cholesterol drugs. American Journal of Man-aged Care website. www.ajmc.com/focus-of-the-week/0815/ for-now-pharmacy-managers-just-say-no-to-high-cost-pcsk9-cholesterol-drugs. Published August 28, 2015. Accessed August 28, 2015.

15. LaMattina J. The new cholesterol lowering drugs epitomize the drug pricing battles. Forbes website. www.forbes.com/ sites/johnlamattina/2015/08/27/the-new-cholesterol-lowering-drugs-epitomize-the-drug-pricing-battles/. Published August 27, 2015. Accessed August 27, 2015.

16. Oakes K. Evolocumab is second PCSK9 inhibitor approved to lower LDL in high-risk patients. Cardiology News website. www.ecardiologynews.com/specialty-focus/lipid-metabolic-disorders/single-article-page/evolocumab-is-second-pcsk9-inhibitor-approved-to-lower-ldl-in-high-risk-patients/5df4611 dee3d60eec3596451d356fc89.html. Published August 27, 2015. Accessed August 29, 2015.

17 FDA approves Repatha, new cholesterol-lowering treatment [press release]. Washington, DC: Campaign for Sustainable Rx Pricing, sent via email. August 28, 2015.

18. Shrank WH, Barlow JF, Brennan TA. New therapies in the treatment of high cholesterol: an argument to return to goal-based lipid guidelines [published online August 10, 2015]. JAMA. 2015. doi:10.1001/jama.2015.10017.

19. Amgen to present new long-term Repatha (evolocumab) data at ESC Congress 2015 [press release]. Thousand Oaks, CA: Amgen website; August 25, 2015. www.amgen.com/ media/media_pr_detail.jsp?releaseID=2081820. Accessed August 30, 2015.

20. Ridker PM, Danielson E, Fonseca FAH, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. doi: 10.1056/NEJMoa0807646.

21. Sanofi’s cholesterol drug Praluent backed for European approval. PMLive website. www.pmlive.com/pharma_news/ sanofis_cholesterol_drug_praluent_backed_for_european_ap-proval_787622. Published July 27, 2015. Accessed August 29, 2015.

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