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This past summer, the FDA approved two PCSK9 inhibitors to treat certain patients with hypercholesterolemia that does not respond to conventional drugs. Our July 24 story about the approval of the first of these agents is republished here; following is an update on what has happened with PCSK9 inhibitors in the succeeding months.

One of the most important developments in cardiology in 2015 was the approval of the first PCSK9 inhibitors, led by alirocumab (Praluent) in July and followed by evolocumab (Repatha) in August.

With the enthusiasm over the cholesterol lowering both achieved in the pivotal clinical trials, few doubted that approval would come. Now that the two are on the market, clinicians told 乌鸦传媒 that the key hurdle has been getting them paid for, as both have a wholesale acquisition cost of more than $14,000 a year.

On the Market

Effective but overpriced was the conclusion of the New England Comparative Effectiveness Public Advisory Council in September. The group's (published in December) concluded:

"Extrapolating from the LDL cholesterol level reductions, our cost-effectiveness analysis estimates an NNT₅ [number needed to treat for 5 years] of 28. These results assume clinical benefits that are being tested in ongoing trials. Despite our favorable assumptions, cost-effectiveness ratios for PCSK9 inhibitors far exceed commonly accepted thresholds. Achieving cost-effectiveness at a threshold of $100,000/QALY [quality-adjusted life-year] would require price reductions of 60% to 63% compared with current prices."

The U.K.'s National Institute for Health and Care Excellence (NICE) said that it would not recommend evolocumab for use in the country's national health service because it is too expensive and has not been shown to improve long-term clinical outcomes.

While those concerns haven't made U.S. insurers and pharmacy benefit managers say no, deals and discounts have been the order of the day, as many analysts predicted even before the FDA approvals were set.

In October, the nation's largest pharmacy benefit company, Express Scripts, put both drugs on its national preferred formulary. Then in November, evolocumab (Repatha) scored the first "win" in the battle for prescriptions with an exclusive on the CVS/Caremark formulary.

UnitedHealth announced that alirocumab would be its for its Oxford unit and its OptumRx pharmacy benefits manager.

Amgen said it would offer "value-based contracts" to ease payers' concerns by linking the net price of evolocumab to expected LDL cholesterol reductions and anticipated use, such as with the struck with Harvard Pilgrim.

"Given the lack of clinical differentiation between the PCSK9 inhibitors, the race to market and gaining physician familiarity are particularly important for these drugs' developers," analytics company Decision Resources Group .

One early adopter, , who runs a lipid clinic at Scripps Clinic and Research Foundation in La Jolla, Calif., told 乌鸦传媒, though, that evolocumab may have a leg up on alirocumab in the clinic. He noted that the latter "is indicated for use in addition to diet and maximally-tolerated statins in patients with heterozygous familial hyperlipidemia and clinical atherosclerotic cardiovascular disease patients who require additional LDL lowering. Repatha by Amgen has this indication but also is indicated in homozygous familial hyperlipidemia. Repatha has a slightly broader indication."

In the Clinic

The indication proposed for evolocumab was adults with standard lipid disorder -- including patients who are statin-intolerant -- as well as people 12 and older with homozygous familial hypercholesterolemia.

For alirocumab, the proposed indication was adults with primary hypercholesterolemia (nonfamilial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes. It also included statin-intolerant patients or those "for whom a statin is not considered clinically appropriate."

Cardiologists speaking with 乌鸦传媒 have indicated that they're jumping right into use of the class, particularly for their familial hypercholesterolemia patients. In the first months after approval, almost all of the cardiologists contacted by 乌鸦传媒 estimated that 10% to 15% of their patients would be on PCSK9 inhibitors within a year.

Primary care clinicians, on the other hand, said they were largely holding off on prescribing the PCSC9 inhibitors. Cost and lack of cardiovascular outcomes trial data were commonly cited by primary care physicians contacted by 乌鸦传媒:

• "They're very expensive; my patients are going to be reluctant to use them because of that. ... I'm probably going to be a late adopter ... just because I want to see evidence this drug is going to help patients before I prescribe it." -- , of Lutherville Personal Physicians, part of Mercy Medical Center, in Lutherville, Md.
• "We don't use them a lot in primary care. ... The problem is they are very costly. They have to be given by injection, and we don't have any long-term safety data." -- , of the Cleveland Clinic
• "The average practitioner probably should not be administering PCSK9 inhibitors. They are extraordinarily expensive and they have to be administered by injection." -- , of Houston Methodist

That trend fit the recommendations of the New England Comparative Effectiveness Public Advisory Council, which called for prescribing of PCSK9 inhibitors to be restricted to specialists in lipid managment, "given the complexities of caring for patients with familial hypercholesterolemia or statin intolerance."

The group also called on specialty societies to update clinical guidance, "including treatment goals based on target LDL-cholesterol level," and for establishment of clear clinical protocols to identify patients with true statin intolerance.

How long it might take for those guidelines to emerge remains murky, but the first cardiovascular outcomes trial data with a PCSK9 inhibitor could be out before the new year is up.

From the American Heart Association:

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