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Role of PCSK9 inhibition continues to evolve
The role of PCSK9 inhibitors in the field of CV medicine continues to evolve, as data accumulate showing dramatic reductions in LDL and atherosclerotic CVD events, especially in high-risk patient groups such as patients with recent ACS, multivessel CAD and peripheral artery disease.
Results from CVD outcomes trials, including FOURIER and recently ODYSSEY OUTCOMES, which was presented at the American College of Cardiology Scientific Session in March, demonstrated that reducing LDL to very low levels with available PCSK9 inhibitors was superior to standard of care for reducing adverse CV events.
The target population for PCSK9 inhibition has also broadened since the initial approvals. In mid-September, Regeneron and Sanofi announced that the FDA agreed to review a supplemental biologics license application to add an indication stating that alirocumab (Praluent) improves CVD outcomes, based on the ODYSSEY OUTCOMES trial. This comes on the heels of a December 2017 announcement by Amgen that the FDA approved evolocumab (Repatha) for the prevention of MI, stroke and coronary revascularization in adults with established CVD.
About 15% of U.S. adults have diabetes or atherosclerotic CVD, and about half of these individuals receive lipid-lowering treatment, according to a town hall event held at the ACC Scientific Session in March. Among patients who are treated with high-intensity statins, 80% do not achieve LDL levels below 70 mg/dL.
However, barriers to widespread access to PCSK9 inhibitors remain. As a result, cardiologists have been working to determine which patients will most benefit from these therapies and how to improve access. In November, an economic study of ODYSSEY OUTCOMES was presented at the American Heart Association Scientific Sessions and shed some light on appropriate price points and patient populations for alirocumab.
“Although you would anticipate that having two outcomes trials with such great results would dramatically change the payer’s perspective and ease up on their blocking prescriptions, it hasn’t worked out that way,” Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC, chief medical officer of Excel Medical Clinical Trials, clinical affiliate professor of biomedical science at Florida Atlantic University in Boca Raton and immediate past president of the American Society of Preventive Cardiology, said in an interview. “We still have tremendous barriers to access for appropriate patients.”
Cardiology Today interviewed physicians in the field about the promises and challenges of PCSK9 inhibitors, including strategies to improve access and determine which patients are most appropriate to receive these therapies.
Barriers persist
One of the biggest barriers to accessing PCSK9 inhibitors is simply getting drug approval by payers. Eighty percent of claims for PCSK9 inhibitors are rejected on the first attempt, Baum told Cardiology Today. According to the FH Foundation, of 110,577 patients diagnosed with familial hypercholesterolemia, only 1,188 had a prescription for a PCSK9 inhibitor, let alone an approval. Of note, more patients with Medicare are approved for PCSK9 inhibitors compared with patients with commercial insurance, according to the town hall discussion.
Cost is another issue that hinders access to patients who might benefit from a PCSK9 inhibitor.
“Physicians and clinicians in a cost-effective era are much more reluctant to use extensive drugs for what they think may not be value for the patient or for the amount of money involved,” Michael H. Davidson, MD, FACC, FACP, FNLA, clinical professor of medicine and director of preventive cardiology at University of Chicago Medicine and Cardiology Today Editorial Board Member, said in an interview.
The two PCSK9 inhibitors on the market, alirocumab and evolocumab, were initially introduced to the market with a suggested price tag of approximately $14,000 per year.
In October, Amgen reduced the list price of evolocumab by 60%, bringing it down to $5,850 per year, which will dramatically reduce patient copays for the PCSK9 inhibitor, according to a company press release.
“We hope that then leads to much broader access to the drug so that every patient who needs it gets it,” David M. Reese, MD, Amgen’s executive vice president of research and development, told Cardiology Today. “We know that there are 3.4 million patients in the country who are at high risk where the drug can be effective. Certainly, as someone who has been involved with this in the long term, my goal is to see that we get access to as many of those patients as possible.”
Other efforts to address these barriers are underway. Earlier in 2018 and prior to announcing the price decrease, Amgen announced an agreement with CVS Health to provide streamlined access to evolocumab through its CVS/Caremark commercial formularies and also featured the RepathaReady program, which offers patient and provider assistance to improve access via co-pay cards, insurance assistance and more.
“Since January, we have reached agreements with several payers, which allowed us to significantly improve the percentage of patients that could receive Repatha with just physician attestation,” Murdo Gordon, Amgen’s executive vice president for global commercial operations, told Cardiology Today. “A physician could say, ‘This patient needs Repatha because they fit the criteria,’ and the approval on that became much easier by us signing more than 20 contracts.”
The spotlight was recently on PCSK9 inhibitor costs in May, when Sanofi and Regeneron announced an agreement with pharmacy provider Express Scripts to offer alirocumab at a reduced cost in exchange for “straightforward, more affordable access.” The agreement, which went into effect on July 1, marks alirocumab as the exclusive PCSK9 inhibitor on the Express Scripts formulary and simplifies documentation required to guarantee insurance coverage of alirocumab, according to a press release.
“The intent of our agreement with Express Scripts was to simplify the documentation necessary to secure insurance coverage and help reduce out-of-pocket cost for patients,” according to a prepared statement from the company to Cardiology Today. “We have heard anecdotally from patients who have experienced significant improvements in the authorization process and in all of our 2019 contract proposals, we are including simplified utilization management in return for greater rebates.”
An additional barrier is the need for prior authorization for a PCSK9 inhibitor.
“Any time you have prior authorizations required, it is a hassle for the doctor and their staff,” Davidson said.
New analysis, guidelines
In November, the new Guideline on the Management of Blood Cholesterol, issued by the AHA, ACC and 10 other professional societies, was presented at the AHA Scientific Sessions, recommending a stepped approach for statins, ezetimibe, and PCSK9 inhibitors for patients with established CVD and who are at very high risk for another event.
At the same meeting, findings from the ODYSSEY OUTCOMES economics trial were presented, which found that alirocumab was cost-effective up to $6,319 per year at a willingness to pay threshold of $100,000. Within hours of the cost-effectiveness analysis presentation, the cholesterol guidelines were out of date based on the cost-benefit information alone, Baum said.
“Based on both absolute clinical benefit and cost-effectiveness, alirocumab may offer good value in patients with a history of ACS, particularly if the LDL cholesterol is greater than or equal to 100 mg/dL despite maximally tolerated statin therapy,” Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School, executive director of interventional cardiovascular programs in the Heart and Vascular Center at Brigham and Women’s Hospital and Cardiology Today’s Intervention Chief Medical Editor, said during presentation of the data.
Commenting on the findings, Mark Hlatky, MD, director of the health services research master’s degree program and professor of health research and policy and cardiovascular medicine at Stanford University, told Cardiology Today, “There are a lot of steps in between patient access to the drugs and this economics study. Recent price reductions, specifically list price reductions, should reduce out-of-pocket payments by patients.”
Some cardiologists remain cautious about the cost-effectiveness of this therapy, particularly in patients with an LDL level of 100 mg/dL or greater.
“One thing I’m afraid of is that people are going to get the wrong idea about the LDL of 100 mg/dL as some sort of magic number,” Baum said in an interview. “I don’t know any cardiologist or lipidologist who thinks that 100 [mg/dL] is the magic number. The 100 issue with ODYSSEY OUTCOMES was a trial design result and that’s it. I would urge both payers and practitioners not to look at the 100 mg/dL and not to say that it’s a magic number, because it isn’t.
“From a cost-effectiveness standpoint, the problem is that the valuation of a life is a very difficult thing. You get into very muddy waters when you start putting a dollar sign on somebody’s heart attack or stroke. That’s a problem area which I’m not sure how to resolve,” Baum said.
Improvements over time
Experts who spoke with Cardiology Today said they have observed improvements in barriers to access over time. Overall understanding, awareness and acceptance of this therapy has also improved among patients and clinicians.
“Importantly for me as a provider, the barriers are less insurmountable than they were before,” Robert Rosenson, MD, FACC, FACP, FAHA, FESC, professor of medicine (cardiology) at Mount Sinai School of Medicine and director of cardiometabolic disorders at Mount Sinai Medical Center, told Cardiology Today. “In 2017, it was difficult for patients with class I indications such as heterozygous familial hypercholesterolemia (FH) or homozygous familial hypercholesterolemia or prior atherosclerotic CVD events with a high LDL cholesterol on a maximum dose of statins to receive insurance approval for a PCSK9 inhibitor. Now with the consistent clinical trial outcome data, the obstacles are less. I have not encountered the same challenges that I have had in the past. That is encouraging.”
“Access remains an issue, but it has gotten better for me. Access is knowledge about using the drug; coverage, which has improved dramatically; and access is affordability on the patient side,” James Underberg, MD, MS, FACPM, FACP, FASH, FNLA, FASPC, clinical assistant professor of the department of medicine at NYU Langone Health, director of Bellevue Hospital Lipid Clinic in New York and past president of the National Lipid Association, told Cardiology Today.
The overall goal is to ensure that the right patients are receiving this therapy, Baum said.
“The problem is that [the insurance companies] are not the ones who should determine who the right patients are. It should be the clinicians, the doctors, the nurse practitioners, the physician assistants who prescribe these medications. We are the ones who know who the right patients are to get the medicine, not the payers,” he said.
The definition of the “right patient” for a PCSK9 inhibitor varies from payer to payer, experts said. For example, some payers require genetic testing for FH, while other payers require certain CV events or the presence of tendon xanthomas for patients with FH.
Tools for the health care professional
The ASPC this year launched a mobile app to improve the payer’s process for PCSK9 inhibitors, which can be done via a 10-step process. The app, which can be downloaded from the App Store for Apple products or Google Play for Android products, features other tools, information on denials, the best and worst insurance plans, specialty pharmacies, a list of insurance commissioners, and a link to helpful resources and partner associations.
Thorough documentation is also another helpful strategy for those prescribing PCSK9 inhibitors. An oft-cited barrier is related to issues in documentation, which can be resolved through staff support, checklists and experience. Additional information in a patient’s chart can aid in the process and includes factors such as LDL levels, diagnosis, events that occurred, statin history, reason for discontinuing statin therapy and recommendations to support the use of PCSK9 inhibitors.
“I always make a point of trying to get all that documentation in the summary the day I try to prescribe the medicine,” Underberg told Cardiology Today. “More than anything, the key is documentation.”
Further research, future directions
While the FOURIER and ODYSSEY OUTCOMES trials generated greater interest on the CV impact of PCSK9 inhibitors, research continues.
Additional studies have evaluated, or are currently evaluating, PCSK9 inhibitors in other populations, such as those with metabolic syndrome, PAD and younger patients. Baum noted that pediatric studies with PCSK9 inhibitors are starting, which he sees as beneficial “to make these drugs available to children with familial hypercholesterolemia.” Rosenson said he is also interested in the efficacy of PCSK9 inhibitors in patients with chronic kidney disease. “We haven’t had very many good successes with cholesterol-lowering therapy in that population,” he said.
Cardiology Today asked Rita F. Redberg, MD, MSc, FACC, cardiologist and professor of medicine at University of California, San Francisco and a Cardiology Today Editorial Board Member, about the future of PCSK9 inhibitor research. “I’d like to see studies that have actual clinical outcomes including cardiovascular and all-cause mortality, as well as data on myocardial infarction, where the myocardial infarction is clearly defined as a clinical event and not a troponin bump,” Redberg said.
In addition, she said, “having two drugs on the market has not done much for lowering the price. ... In a true marketplace, competition would drive down prices, but drug pricing does not follow market principles.”
Another area of focus is primary and primordial prevention.
“The question is what we consider primordial prevention, and that is starting someone a lot younger in life can get even greater benefit overall,” Davidson told Cardiology Today. “That’s what the genetics studies are showing us, that earlier intervention, even less intense intervention, but long-term intervention can result in an even greater benefit to patients. That’s the next frontier for lipid management.”
The question also remains of how low to go, in terms of LDL. In a post hoc analysis of ODYSSEY OUTCOMES, the treatment effect of alirocumab to prevent all-cause death was stronger in patients whose baseline LDL was at least 100 mg/dL compared with those with lower baseline LDL. Patients with a baseline LDL greater than 100 mg/dL also had a 24% reduced risk for major adverse CV events, 28% reduced risk for CHD death and 31% reduced risk for CV death. In FOURIER, there was a significant 59% mean reduction in LDL in the evolocumab group (median LDL, 30 mg/dL), including 42% who achieved LDL 25 mg/dL vs. 0.1% in the placebo group.
“The medicines are so good, they are so effective, they are so well-tolerated that [payers] are worried about floodgates opening, too many people getting access and it being a financial burden,” Baum told Cardiology Today. “There’s no question that these drugs are phenomenal. There’s just no question about that.” – by Darlene Dobkowski
- References:
- Baum SJ, et al. Gaining Access to PCSK9 Inhibitors: Unveiling of a New Mobile App. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
- Bhatt DL, et al. LBS.01 – Late Breaking Clinical Trial: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
- Bonaca MP, et al. Circulation. 2017;doi:10.1161/CIRCULATIONAHA.117.032235.
- Cannon CP, et al. J Am Coll Cardiol. 2018;doi:10.1016/S0735-1097(18)32308-8.
- Cohen JD, et al. J Clin Lipidol. 2017;doi:10.1016/j.jacl.2017.04.120.
- Grundy SM, et al. Circulation. 2018;doi:10.1161/CIR.0000000000000625.
- Grundy SM, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.002.
- Hess GP, et al. Circulation. 2017;doi:10.1161/CIRCULATIONAHA.117.028430.
- Rosenson RS, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.04.054.
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- For more information:
- Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC, can be reached at 7900 Glades Road, #400, Boca Raton, FL 33434; email: sjbaum@fpim.org; Twitter: @sethjbaummd.
- Deepak L. Bhatt, MD, MPH, can be reached at Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115; email: dlbhattmd@post.harvard.edu; Twitter: @dlbhattmd.
- Michael H. Davidson, MD, FACC, FACP, FNLA, can be reached at 150 E. Huron St., Suite 900, Chicago, IL 60611; email: mdavidso@bsd.uchicago.edu; Twitter: @mdavidsonmd.
- Mark Hlatky, MD, can be reached at Stanford University School of Medicine, HRP Redwood Building, Room 150, 259 Campus Drive, Stanford, CA 94305; email: hlatky@stanford.edu.
- Rita F. Redberg, MD, MSc, FACC, can be reached at Cardiovascular Care and Prevention Center at Mission Bay, 535 Mission Bay Blvd. South, San Francisco, CA 94158; email: rita.redberg@ucsf.edu; Twitter: @rfredberg.
- Robert Rosenson, MD, FACC, FACP, FAHA, FESC, can be reached at Mount Sinai Comprehensive Health Program Downtown, 275 Seventh Ave., 12th Floor, New York, NY 10001; email: robert.rosenson@mssm.edu.
- James Underberg, MD, MS, FACPM, FACP, FASH, FNLA, FASPC, can be reached at Murray Hill Medical Group, 317 E. 34th St., 7th Floor, New York, NY 10016; email: james.underberg@nyumc.org; Twitter: @lipiddoc.
Disclosures: Baum reports he has consulted and served on scientific advisory boards for Amgen, Regeneron and Sanofi and has performed clinical research for alirocumab and evolocumab. Bhatt reports he has financial ties with numerous drug and device companies, including receiving research funding from Regeneron and Sanofi. Davidson reports he is on the speakers bureau for Amgen, Regeneron and Sanofi. Hlatky and Redberg report no relevant financial disclosures. Rosenson reports he is performing clinical trials for Amgen, has performed research for Regeneron and The Medicines Company and served on the data and safety monitoring board for Sanofi. Underberg reports he is on the scientific advisory board for the FH Foundation, a consultant for Amgen and a member of the speakers bureau for Amgen, Regeneron and Sanofi. Reese and Gordon are employees of Amgen. The ODYSSEY OUTCOMES study was funded by Sanofi and Regeneron. The FOURIER study was funded by Amgen.