Pharma and Profits. John L. LaMattina

but biological drugs (antibodies) that must be given by injection. They are designed to block an enzyme that mechanistically limits the effectiveness of statins. When PCSK9 antibodies are combined with statins, the LDL‐c lowering effects are stunning, with levels as low as 30 mg/dl observed. No other therapy can approach such results. Given the consensus that the lower your LDL‐c, the less likely you are to suffer a heart attack or stroke, these results offered great hope to heart patients.

      Two PCSK9 antibodies garnered US Food and Drug Administration (FDA) approvals almost simultaneously: Praluent^TM (from Regeneron/Sanofi) on 24 July 2015 and Repatha^TM (from Amgen) on 27 August 2015. The launches of these drugs should have been celebrated by the cardiovascular medical community. Instead, any enthusiasm was tempered when the prices of these drugs were announced: $14 600 per patient per year for Praluent^TM and $14 000 per patient per year for Repatha^TM. It should be noted that these are list prices. Furthermore, these are not pills but injectable biologics that are expensive to manufacture, store, and distribute. Thus, these prices were expected to be higher than oral statins – but not that much higher.

The ensuing outcry was to be expected. Dr. Steve Miller of Express Scripts, echoing his previous views on hepatitis C drugs, said that “Even if physicians adopt this new therapy slower than anticipated, it is clear that PCSK9 inhibitors are on a path to become the costliest therapy class that this country has even seen”[2]. In reality, this did not happen. In fact, 2020 sales of these drugs were quite modest with sales of $887 million for Repatha^TM and $358.8 for Praluent^TM. How could such expensive breakthrough drugs generate such disappointing sales?

      Just because a drug has been approved by the FDA does not mean that insurance companies will pay for it. First, there were two PCSK9 inhibitors available, so payers encouraged Amgen and Regeneron/Sanofi to bid against each other for positions on their formularies. Remember, the roughly $14 000 price tag was the list price. Details for the deals that companies strike with payers are confidential. Given the choice between Regeneron’s Praluent^TM and Amgen’s Repatha^TM, Express Scripts opted for the former. While he did not say what Express Scripts was actually paying for Praluent^TM, Dr. Len Schleifer, chief executive officer (CEO) of Regeneron, glumly told a Forbes Healthcare Summit audience, “Dr. Miller drives a hard bargain.” Clearly, Express Scripts as well as other payers were shelling out far less than $14 000 for these medicines.

      But beyond negotiating lower prices, payers also limited the ability of patients and physicians to access these drugs. Despite high‐risk patients having inadequate LDL‐c lowering on statins, studies found 80% of doctors’ prescriptions for PCSK9 therapy were denied by payers. After repeated justifications and appeals by the prescribing physician, only 25% of PCSK9 prescriptions were approved by commercial payers and about 50% for Medicare [3]. How could those denials be justified?

      There was no doubt that the drugs lowered LDL‐c. There were, however, no data that proved that heart attack and strokes were less likely at 30 mg/dL than at 75 mg/dl (which is what is generally achieved with a high dose of a statin like Lipitor^TM). As a result, payers only allowed these drugs to patients with extraordinarily high LDL‐c levels. The concept of “lower is better” for LDL‐c to reduce cardiovascular events seemed correct intuitively. However, it was still only a theory.

To prove the true value of the PCSK9 inhibitors in preventing adverse cardiac events, the makers of Praluent^TM and Repatha^TM 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 Repatha^TM 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 Praluent^TM, 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