PCSK9 Inhibitors' First Birthday Brings Sluggish Sales And More Bad Press
Executive Summary
Analysis published in the Journal of the American Medical Association is the latest to argue that PCSK9 inhibitors are not cost-effective.
About one year after approval, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are still struggling to get established and are still suffering bad publicity over high prices. Outcomes data still to come could help with flagging sales, but it increasingly seems that to get past the gates put up by payers, the companies will need to lower their prices.
With proven ability to dramatically lower LDL cholesterol on top of standard of care statin therapy, PCSK9 inhibitors developed by Amgen Inc. and Sanofi/Regeneron Pharmaceuticals Inc. had been highly anticipated for many years.
Treating all eligible patients with PCSK9 inhibitors would save $29bn over five years, but cost an additional $592bn, according to an analysis in JAMA.
Amgen's Repatha (evolocumab) was the first out of the gate, securing clearance in the European Union on July 21, 2015. Sanofi/Regeneron's Praluent (alirocumab) was then approved by FDA on July 24, the sponsors having used a costly priority review voucher to beat Amgen to market. Repatha cleared FDA in August.
The drugs' initial approvals are for higher risk populations, such as patients with cardiovascular disease and with genetic conditions predisposing them to very high cholesterol, like heterozygous familial hypercholesterolemia. But the sponsors hope to expand labeling when outcomes data become available. Data from Sanofi and Regeneron's ODYSSEY outcomes study could be out as early as later this year and Amgen's FOURIER outcomes study is due to report in the first quarter of 2017.
That could help open the market, but evidence continues to mount that the drugs need to be priced lower.
Prior to approval, analysts had projected annual pricing of $4,000 to $8,000 annually for PCSK9 inhibitors although some insurance companies predicted, rightly as it turned out, that the price would be over $10,000 a year. (Also see "Formulary Focus: PCSK9 Drug Prices May Lead Payers To Impose Coverage Restrictions" - Pink Sheet, 26 Jan, 2015.)
Both PCSK9 inhibitors were priced at about $14,000 per year, a decision that has faced a lot of criticism by payers and clinicians, especially because cardiovascular outcomes data are not available yet for either product.
Sales Disappointments
Consequently, both products have struggled to get off the ground in the US or Europe.
At the American College of Cardiology annual meeting in April, clinicians reported difficulties getting insurance coverage even for very high-risk patients with very high cholesterol, and Amgen said at the time that most claims were denied. (Also see "PCSK9 Sponsors, Payers In The Ring At ACC" - Pink Sheet, 11 Apr, 2016.)
This has translated into disappointing sales. Sanofi and Regeneron reported sales of $24m for the second quarter. (Also see "Regeneron Emphasizes Pipeline Promise As Eylea Pricing Pressure Builds" - Scrip, 4 Aug, 2016.). Amgen did not release sales figures until its third quarter on the market, when it acknowledged continuing issues with reimbursement and reported sales of $27m. (Also see "Amgen Plugs Away On Repatha, With Hope For New Monthly Product" - Scrip, 27 Jul, 2016.)
Reimbursement intelligence company Real Endpoints had actually predicted in early July 2015 that the drugs would not get substantial market uptake. The company had analyzed safety and efficacy and convenience, among other factors, and determined that the PCSK9 inhibitors had low value because of the lack of meaningful outcomes data at the time of launch and expected high pricing. It predicted "payers will have an extraordinary opportunity to control costs in this class.”
An analysis by Symphony Health Solutions found that in the first nine months of launch, the rate of rejection for PCSK9 inhibitors was 88.4% for commercial plans and 77.2% for Medicare. The final rejection rate was 73.3% for commercial plans and 53.3% for Medicare.
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PCSK Inhibitors: Global Sales, First Year On Market |
||||
|
Product |
3Q2015 |
4Q2015 |
1Q2016 |
2Q2016 |
|
Sanofi/Regeneron's Praluent |
$4m |
$7m |
$13m |
$24m |
|
Amgen's Repatha |
Not reported |
Not reported |
$16m |
$27m |
Insurers Flex Muscles
In response to the high prices, the insurance companies have adopted a range of strategies, including securing deep discounts. In one of the first major coverage decisions, pharmacy benefit manager Express Scripts Holding Co. announced in October 2015 that it had sealed deals for both Praluent and Repatha to be included on its formulary.
In November, Harvard Pilgrim Health Care announced a “first in the nation” type of pay-for-performance exclusive contract with Amgen for Repatha. In this deal, Amgen agreed to provide pricing discounts to the insurer if patients taking the cholesterol-lowering drug fail to reach certain outcomes measures or if utilization exceeded predetermined levels (see timeline).
In addition to the pushback from insurance companies on pricing, PCSK9 inhibitors have been targeted and depicted unfavorably in cost-effectiveness analyses.
In September 2015, the Institute of Clinical and Economic Review published a draft cost-effectiveness analysis noting that pricing for PCSK9 inhibitors should be up to $4,811 per year, which was about 67% less than the list prices. (Also see "PCSK9 List Price Discounts Of 67% To 85% Suggested By ICER Analysis" - Pink Sheet, 14 Sep, 2015.)
A couple months later, ICER's final report concluded that value-based price benchmarks of $5,404-$7,735 were linked to long-term value to patients, and as low as $2,177 when potential short-term budget impact is considered.
JAMA Strikes Again
The Journal of the American Medical Association (JAMA) published a new cost-effectiveness analysis on PCSK9 inhibitors by UCSF professor Dhruv Kazi and colleagues on Aug. 16. It's not the first time the medical publication has taken on the PCSK9 prices; in April, an editorial on the GAUSS-3 results for Repatha used the ICER analysis to argue that the drugs were not cost-effective for statin-intolerant patients. (Also see "Amgen’s Statin Intolerance Study May Not Cure What Ails PCSK9 Inhibitors" - Pink Sheet, 3 Apr, 2016.)
In the latest piece, the researchers used the Cardiovascular Disease Policy Model to calculate costs for using a PCSK9 inhibitor in approved indications on top of standard of care statin therapy, assuming an annual cost of $14,350, in comparison to Merck & Co. Inc.'s Zetia (ezetimibe) plus a statin, an annual cost of $2,878. They also considered costs for patients with statin intolerance, assuming 10% were not able to take standard therapy.
Researchers focused their analysis on atherosclerotic cardiovascular disease (ASCVD) and HeFH, the approved indications. For the analysis, they assumed that PCSK9 inhibitors would prevent events, although outcomes data are not available yet. Statistics on the incidence of ASCVD and associated adverse events in the US were used to assess total costs for chronic therapy.
Of 1.7 million adults with HeFH, they estimated that 61% could be eligible for treatment with a PCSK9 inhibitor. Using a PCSK9 inhibitor instead of Zetia would cost $323bn more than if Zetia were used. Of this, $17bn would be offset by savings related to prevention of events.
Considering costs and savings, researchers said that the cost in this indication is $503,000 per quality per adjusted life year gained. Typically, a cost per QALY more in the $100,000 range or lower is desirable.
For the ASCVD analysis, researchers estimated that 8.5m out of 13m with the condition could be eligible for treatment. Mean LDL was 109mg/dL in this population. Treating these patients with PCSK9 inhibitors for life instead of Zetia would cost $3.3tn more than what it would cost to treatment with Zetia. Of this figure, $155bn would be saved through prevention of events. The cost per QALY for this indication is $414,000.
Price Reduction By Two-Thirds Urged
PCSK9 inhibitors are meant to be given for a lifetime, and at the list prices or prices with modest discounts, the increase in health care expenditures "could be staggering, despite cost savings from averted ASCVD events," Kazi and colleagues wrote.
At the price of about $14,000, treating all eligible patients with PCSK9 inhibitors would save $29bn over five years, but cost an additional $592bn, an increase of 38% on prescription drug expenditures, the authors noted.
"Reducing annual drug costs to $4,536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY," the researchers concluded.
Even if the PCSK9 inhibitors prove to be highly effective for preventing ASCVD, they are "not cost-effective at 2015 prices, and achieving commonly accepted cost-effectiveness thresholds would require price reductions by more than two-thirds," the article stated.
The authors also suggested that it may be possible to improve the cost-effectiveness outlook by targeting use at segments of the population that are at higher. It may be possible to restrict treatment in HeFH to patients with a higher LDL threshold and for those with cardiovascular disease, limit use to those with a recent heart attack.
However, the authors also noted that "results of multiple scenario analyses suggest that reducing the price of PCSK9 inhibitors remains the primary approach to improving the value of these therapies."
In response to the JAMA paper, Amgen said that the analysis represents just one point of view. Another analysis published by S.R. Gandra and colleagues in Clinical Cardiology in June suggested a value-based price for Repatha of up to $15,000, "which is significantly higher than both the current list price and net price being paid by payers in the U.S," the company said in a statement.
Amgen stresses that value assessments should be done in a transparent, rigorous manner, with broad stakeholder engagement.
"We remain concerned that these types of assessments are focused on ringing alarm bells from a payer perspective, rather than focusing on a rigorous analysis that fully reflects the patient perspective of value," Amgen said.
The company said that it strongly believes in the clinical and economic value of Repatha.