inhibitors in preventing adverse cardiac events, the makers of PraluentTM and RepathaTM had to carry out cardiovascular outcome trials (CVOTs) in patients with known atherosclerotic cardiovascular disease (ASCVD). CVOTs are a huge deal. They generally involve studying anywhere from 10 000 to 25 000 patients over the course of as many as five years. The cost can be $500 million to $1 billion. But such an investment was important to prove the value of PCSK9 inhibitors. A successful outcome in a CVOT would dramatically expand the patient population eligible to receive PCSK9 inhibitors. After all, heart disease is still the leading killer worldwide and these drugs were believed to be major breakthroughs. Thus, cardiologists, heart patients, and payers awaited the results of these CVOTs, albeit for different reasons.
In situations like this, a point often missed is the value that industry‐sponsored clinical trials bring to medical science. At this time, no one knew if heart patients would benefit by lowering LDL‐c to 30 mg/dl. Only drug companies have the resources to run a CVOT designed to answer such a fundamental biology question. Institutions like the National Institutes of Health do not have the capacity to invest $1 billion for one such trial. Yes, these companies benefit financially with a positive trial, but regardless of the outcome, science benefits, as valuable insights are gained.
The first CVOT to read out was Amgen’s study with RepathaTM called FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in subjects with Elevated Risk). As often happens in science, the results were not as clear‐cut as one would have hoped. Here are some key findings:
The study enrolled 27 564 men and women, 80% of whom already had a heart attack. The other 20% had experienced a stroke or pain in their limbs due to narrowed arteries.
Those taking only statins had LDL‐c levels on average of 92 mg/dl, which was well within the recommended range. But those on RepathaTM and a statin had an average LDL‐c of 30 mg/dl. More impressive was that 25% of those in the RepathaTM arm of the study reached LDL‐c levels of 19 mg/dl – an unprecedented number [4].
RepathaTM reduced heart attacks by 27% (from 4.6/100 patients to 3.4/100), strokes by 21% (from 1.9/100 patients to 1.4/100), and procedures like stents and bypass surgeries by 22% (from 7/100 patients to 5.5).
Those last data concerning cardiovascular events disappointed many experts. They expected a 31% reduction in heart attacks and strokes [5]. Why was there such a difference? Some speculated that Amgen stopped the study at 2.2 years and perhaps, had it gone longer – say five years – a better result would have been observed.
The CVOT carried out by Regeneron and Sanofi for PraluentTM, known as ODYSSEY OUTCOMES, had a better result. While there were differences in the study designs (e.g. this trial lasted 2.8 years), the results in some respects were similar to FOURIER.
There were 18 924 patients enrolled who had experienced an acute coronary syndrome 1–12 months before entering the study and they were equally divided between receiving PraluentTM and placebo along with their maximal statin dose.
The primary endpoint of this trial was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.
There were 903 such experiences for those patients on PraluentTM (9.5%) vs. 1052 (11.1%) on placebo. However, PraluentTM showed one big difference. Unlike RepathaTM, PraluentTM lowered the overall death rate. While the reason for this difference is not clear, it could be attributed to the longer length of the PraluentTM study [6].
It must be noted that there was another entrant in the PCSK9 antibody race – Pfizer’s bococizumab. Pfizer got into the game later than Amgen and Regeneron/Sanofi and, as a result, decided to run its CVOT with bococizumab early in the clinical trial process so its own outcome results would appear at a similar time as the competition.
This was not a trivial decision to make as it called for an upfront investment of hundreds of millions of dollars. However, the early clinical studies looked promising, and this was, after all, an area that was well precedented. What could go wrong?
Stunningly, Pfizer had to stop the trial after 52 weeks [7]. The clinical profile that emerged for bococizumab included an unexpected attenuation of LDL‐c lowering over time, as well as a higher level of immunogenicity and a higher rate of injection‐site reactions compared with the other PCSK9 inhibitors. None of this was anticipated based on the preclinical and early clinical data already accumulated. As a result, Pfizer dropped bococizumab from development. Overnight, Pfizer lost a promising compound in its pipeline. Hundreds of millions of dollars were sacrificed with no commercial return. Nothing in biomedical R&D is a given.
Still, there were two PCSK9 antibodies that had completed their CVOTs with moderate success. The next obvious question was how best they should be used, especially given their steep price. Typical was the view of Yale cardiologist, Dr. Harlan Krumholz:
“This study raises the issue of pricing and value. The drug has been priced at about $14,000/year – in part on the promise of a dramatic reduction in risk that was anticipated because of its marked effect on lowering cholesterol. Now that we can see what the drug can achieve, a natural question is: What is this amount of risk reduction, on top of statins, worth?”
At this point, Amgen took an interesting stance on the pricing of RepathaTM in light of the FOURIER results. It offered a “money‐back guarantee” for this product [8]. Basically, if a patient has a heart attack while on RepathaTM, the payer is eligible for a full rebate from Amgen for the drug’s cost.
How does such a program work? Amgen spokesperson Kristen Neese was kind enough to provide me an explanation. In effect, there is not a one‐size‐fits‐all plan. Rather, contracts are negotiated payer by payer. The one requirement is that a patient must be treated with RepathaTM for at least six months before being eligible for full reimbursement. Each contract sets a time limit on how long RepathaTM is expected to protect the heart patient. After all, these are people with heart disease who will likely suffer a fatal cardiovascular event at some point. RepathaTM should not be expected to provide patients immortality. When asked how long the time limit for the money‐back guarantee would be, Ms. Neese said that is negotiated with each payer.
She pointed to the Amgen’s deal that is in place with Harvard Pilgrim Health Care. In this case, the price that the plan pays is based on how much LDL‐c is being achieved with RepathaTM. If a patient’s LDL‐c gets to 30 mg/dl, there is one set price. If the patient’s LDL‐c fails to get below 60 mg/dl, a lower price is paid. Ms. Neese stressed that the RepathaTM pricing plan is not a gimmick but part of Amgen’s commitment to value‐based contracting. She believed that, at the time of writing this book, the Amgen plan was unique in the industry.
As governments, payers, patients, physicians, and the biopharmaceutical industry all struggle with pricing of new breakthrough medicines, one would have to think that Amgen’s approach will be emulated. If a company wants a high price for a new drug, then it will have to provide some assurances of benefit for patients and value for payers.
Beyond money‐back guarantees, competitive factors were driving down the price of PCSK9 inhibitors. The first was a good old‐fashioned price war. Amgen began by cutting its price of RepathaTM by 60%, saying that this reduction was geared toward “helping patients afford the medicine at the pharmacy counter.” Ms. Neese added that the new $5850 price was in line with the net price that Amgen was receiving after discounts and rebates to pharmacy benefits managers and health insurers [9]. Of course, Regeneron and Sanofi had to respond and, a few months later, the list price of PraluentTM also dropped to $5850. Regeneron CEO, Dr. Len Schleifer, explained
