PCSK9 Sales Still Slow, But May Get Boost From Label, Guideline Changes
Executive Summary
Amgen's report of higher sales and news of priority review for an outcomes benefit claim for Repatha bode well, but a negative JAMA editorial is another knock on the PCSK9 inhibitor class.
Amgen Inc.'s Repatha and Sanofi/Regeneron Pharmaceuticals Inc.'s Praluent are still struggling to get off the ground – but there is hope ahead for the PCSK9 inhibitors in terms of better labeling and better positioning in treatment guidelines for cholesterol reduction due in early September.
In its July 31 second-quarter earnings release, Sanofi reported €42m ($50m) in sales for Praluent (alirocumab), following Amgen's report of $83m for Repatha (evolocumab) sales on July 25. (Also see "Amgen Beats Consensus, Raises Earnings Guidance, But Is It Sustainable?" - Scrip, 25 Jul, 2017.)
During its earnings call, Sanofi CEO Olivier Brandicourt said that his company and partner Regeneron were very committed to the success of the PCSK9 product. (Also see "Sanofi 2Q: Dupixent's First Set Of Sales Are On Track" - Scrip, 31 Jul, 2017.)
"We're spending and reinvesting a lot of time and money behind the launch of the brand, and we're making sure that physicians understand the appropriate patient profile," the exec said.
Data from Sanofi/Regeneron's ODYSSEY Outcomes trial, which are due in the first quarter of 2018, will provide a more complete understanding of the effect of PCSK9 inhibition on cardiovascular events in general, he said.
During Regeneron's Aug. 3 earnings call, President George Yancopoulos reiterated that ODYSSEY Outcomes results, especially if incorporated into treatment guidelines, would boost uptake. "While we continue to be disappointed by the uptake of the PCSK9 inhibitor class, we are encouraged by ongoing discussions with payers with respect to improvement in utilization management criteria," Exec VP-Commercial Robert Terifay told the call, noting that CVS Caremark has just announced Praluent would get co-preferred status on its commercial formularies.
Terifay also pointed out that the potential resolution of the patent dispute with Amgen "could have an impact on demand." The case was heard by a US federal appeals court in June. (Also see "Praluent Injunction Goes Unmentioned At PCSK9 Patent Case Appeal" - Pink Sheet, 6 Jun, 2017.)
The sales trajectories for both products have been slow in comparison to expectations for the class, following launch in 2015 (see table).
Amgen has been hoping for a boost following the release of its outcomes trial, FOURIER, in March. But during the firm's July 25 earnings call, Amgen said that Repatha is being used in the populations outlined in labeling, that is patients with a prior cardiovascular event and at risk of having another one, and those with familial hypercholesterolemia.
Amgen execs also noted that the abandonment rate of scripts – patients put off by their co-pay or deductible – has dropped to 24% and that it is clear that the company is assisting patients with financial need.3Q
"We're getting a higher access to patients there. So, we see a continued usage and expansion by existing physicians. We are capturing about between 300 and 400 new prescribers per month … the prescriber base is growing as we go forward," Anthony Hooper, executive vice president of global commercial operations, said during the earnings call.
PCSK9 Inhibitors Sales History
Will Outcomes Data Do The Trick?
The companies have cited a number of factors behind their slow launches, notably the lack of support by insurance companies, even for patients who meet the labeling recommendations of high risk cardiovascular disease and familial hypercholesterolemia. With annual wholesale acquisitions costs of about $14,500 each, the high price tags in the highly genericized cholesterol market and lack of outcomes data have been drawbacks.
The companies have been awaiting the outcomes trials to invigorate the market, but there have been some concerns about the level of benefit seen in Amgen's FOURIER study and some payers and practitioners want the added assurance of ODYSSEY Outcomes. (Also see "Is Amgen's FOURIER Enough For Physicians, Payers To Expand Repatha Use?" - Scrip, 17 Mar, 2017.)
In FOURIER, Repatha demonstrated an added 15% reduction in risk for major cardiovascular events, including cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization. But it did not show a significant reduction in cardiovascular mortality.
Amgen announced July 27 that the US FDA granted Repatha priority review for a supplemental BLA filing for reducing cardiovascular events, based on the FOURIER results, noting that this reflects the importance of treating high-risk patients. The user fee date for the claim is Dec. 2. In its statement, the company also noted that a second application seeking to expand the lipid-lowering indication to include additional patient populations studied was also accepted by FDA.
A change in labeling plus a stronger recommendation for PCSK9 inhibitors in professional guidelines could go far in helping Repatha and possibly also Praluent by default become more accepted in the cardiology community.
Focus On Guidelines
Updated treatment guidelines would also go a long way. The major guidelines for cholesterol drugs are issued by the American College of Cardiology (ACC) and the American Heart Association (AHA) and not updated that frequently. The last release was in 2013 and moved away from LDL targets and toward risk reduction based on age and other factors. (Also see "Time, And Price, Are Right To Prescribe Statins To the Masses" - Pink Sheet, 2 Dec, 2013.) The next update is due by the end of 2018, according to the ACC.
Amgen said it is not promoting the FOURIER data prior to getting a label including the results, but it is working with payers to re-evaluate and challenge utilization management criteria. The company has seen a "high level of willingness from payers and PBMs [pharmacy benefit managers] to relook at their utilization management criteria to ensure that the processes are reasonable," Hooper said.
"We do believe that once the FDA ratifies the data and puts it in the label, we'll be in a much better position to see an opening of access through the payers," Hooper said.
Although it takes a long time for ACC/AHA guidelines to be updated, the organizations do sometimes issue advice in the form of expert decision pathway reports based on a less rigorous review of evidence.
A draft version of an update to the ACC Expert Consensus Decision Pathway on the role of non-statin therapies for managing cardiovascular risk was issued in May and the final document will serve as a bridge to the formal evidence review used to make evidence-based recommendations, the ACC explained.
The draft gives more prominence to PCSK9 therapies, putting them on par as an add-on treatment option with Merck & Co. Inc.'s Zetia (ezetimibe) for high-risk secondary prevention patients unable to get enough LDL-lowering with statins. In the previous version, issued in 2016, Zetia was preferred over PCSK9 inhibitors.
The change came in response to FOURIER data and also outcomes data for Pfizer Inc.'s investigational PCSK9 inhibitor bococizumab in the SPIRE studies, explained lead author Donald Lloyd-Jones, a Northwestern Memorial cardiologist, and colleagues on the ACC task force on expert consensus decision pathways.
Amgen's Sean Harper, executive vice president of research and development, said during the company's earnings call that the guidance helps clinicians see where "clinical evidence is new and evolving."
"While the document is still in draft form, we find the concepts reflect the excellent safety profile and efficacy of Repatha and to suggest evidence-based utilization in appropriate patient populations. We expect the final publication of this document in Q3 of this year," Harper said.
The ACC received 300 comments on the 2016 and 2017 task force pathway reports and plans to issue a final version of the update in early September. The final version has changed significantly from the draft version, the ACC told Scrip.
Multiple professional societies have updated their expert consensus documents and guidelines on the use of PCSK9 inhibitors, including the National Lipid Association and American Association of Clinical Endocrinologists, Amgen's Harper noted.
Pathway documents and recommendations of societies show the "weight of evidence" continuing to build around Repatha and may have an influence on reimbursement, according to Amgen.
Mixed Reviews
However, the FOURIER results have had mixed reviews. Cardiovascular event rates dropped in the trial, but a mortality benefit was not proven. There was discussion at the time of the release that mortality benefit may have been shown with longer follow-up. But some key opinion leaders said price was still the major issue and could still limit use, despite performance on the trial's primary endpoint, and that even a 50% discount off the $14,500 annual list price would still not be enough. (Also see "Can Cholesterol Drug Sponsors Make The Case For Statin Intolerance?" - Scrip, 20 Apr, 2017.)
The Institute for Clinical and Economic Review, which is influential with payers, analyzed the FOURIER data and in May issued a report that actually lowered the value-based pricing benchmark for Repatha. (Also see "Amgen Faces New ICER Roadblock To Repatha Reimbursement" - Scrip, 15 Jun, 2017.)
ICER determined that for the population targeted in FOURIER, Repatha with statins was "comparable or better" than statins alone, whereas previously ICER determined that the drug looked "promising but inconclusive" compared to statins.
In an editorial in the Journal of the American Medical Association on July 24, biostatistics expert John Ioannidis of the Stanford Prevention Research Center noted the divergence of guidelines. Guidelines from the US Preventive Services Task Force (USPSTF) could lead to 10 million fewer patients being treated with cholesterol drugs for primary prevention compared to the current ACC/AHA guidelines, but would still include a bigger patient population for statins than under European or Canadian guidelines, he said.
"This diversity in recommendations probably reflects remaining gaps in the available evidence," Ioannidis said.
Ioannidis also noted the high cost of PCSK9 drugs, at $14,000 per year.
"Treatment of fewer than 20 million US adults with evolocumab at the cost of this single drug would match the entire cost for all other prescription pharmaceuticals for all diseases in the United States combined (20 million × $14,000 per year = $280 billion per year). Given the extremely high rates of cardiovascular disease (approximately 40% for ages 40-59 years and 70% for ages 60-79 years, including hypertension) and potentially aggressive marketing campaigns of the pharmaceutical industry, the population for these drugs in the United States alone could exceed 20 million people," Ioannidis said.
"Multiplying the cost of pharmaceutical care without any evidence for saving lives cannot be justified at this point," Ioannidis concluded.
The clinician advised more emphasis on lifestyle interventions until more evidence is available.