Читать книгу Pharma and Profits - John L. LaMattina - Страница 10

The introduction of the statin class of drugs revolutionized the treatment of heart disease. These drugs, notably Lipitor^TM and Crestor^TM, lower the levels of low‐density lipoprotein cholesterol (LDL‐c), the “bad cholesterol.” Numerous studies over the years have shown that these pills reduce heart attacks and strokes in vulnerable populations, that is, those with significant risk factors like atherosclerosis, diabetes, smoking, and a family history of heart disease. In fact, the availability of statins changed medical practice so that physicians now recommend LDL‐c levels less than 100 mg/dl [1].

While statins are impressive drugs, a new class of drugs known as PCSK9 inhibitors emerged, which proved to be even more exciting. These are not pills 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 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 Repatha^TM 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 Repatha^TM, 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 Repatha^TM for at least six months before being eligible for full reimbursement. Each contract sets a time limit on how long Repatha^TM 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. Repatha^TM 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 Repatha^TM. 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 Repatha^TM 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 Repatha^TM 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 Praluent^TM also dropped to $5850. Regeneron CEO, Dr. Len Schleifer, explained the rationale for such a price cut. “In 2018, we lowered the Praluent^TM net price for health plans that were willing to improve patient access and affordability. While lowering the net cost to payers did improve access, seniors who were prescribed Praluent^TM were often still unable to afford it due to high copay costs or co‐insurance at many Medicare Part D plans”[10].

There was, however, more competition on the horizon. The Medicines Company was developing a drug called inclisiran that represented a whole new approach to blocking PCSK9. Licensed from Alnylam, inclisiran (Leqvio^TM) is an antisense oligonucleotide that targets specific messenger ribonucleic acid (mRNA) sequences thereby disrupting the production of PCSK9 directly in the liver. The first meaningful clinical results for inclisiran were generated in a phase 2 study called ORION‐1 and they were impressive [11].

 Total 501 patients at high risk of cardiovascular disease and who had elevated LDL‐c were randomized to receive a single dose of placebo or inclisiran (200 mg, 300 mg, or 500 mg) or two doses (at days 1 and 90) of placebo or 100 mg, 200 mg, or 300 mg of inclisiran.

 The primary endpoint of the study was the change from baseline in LDL‐c level at 180 days.

 At day 180, mean reductions in LDL‐c were 27.9–41.9% after a single dose of inclisiran and 35.5–52.6% for two doses.

 The two‐dose 300 mg regimen of inclisiran produced the best results with 48% of patients having LDL‐c levels below 50 mg/dl.

 There were no serious adverse events for inclisiran.

Why impressive? After all, the magnitude of LDL‐c drops with inclisiran was on the same order of Praluent^TM and Repatha^TM. Inclisiran was, however, going to be a drug that only needed to be dosed twice a year, whereas the PCSK9 antibodies need to be dosed twice a month. Given that administration of biological drugs like these can cost over a $1000/visit, the switch to inclisiran could save the healthcare system a lot of money. But the real benefit could be pricing.

An interview with Dr. Clive Meanwell, then CEO of The Medicines Company, on the results of the ODYSSEY OUTCOMES study was quite illuminating [12].

First of all, he believed that Sanofi and Regeneron did a “marvelous trial” that demonstrated the value of PCSK9 inhibitors in treating cardiovascular disease. The data for Praluent^TM were presented at the American College of Cardiology (ACC) in 2018. But he was surprised that, on that same day, the Institute for Clinical and Economic Review (ICER), an independent, nonpartisan research organization, published its pricing analysis of these results. (It should be noted that ICER had been highly critical of the initial list prices for Praluent^TM and Repatha^TM.) Here is the ICER summary.

“Based on the results of the ODYSSEY Outcomes trial, ICER has calculated two updated value‐based price benchmarks, net of rebates and discounts, for alirocumab (Praluent^TM) in patients with a recent acute coronary event: $2,300‐$3,400 per year if used to treat all patients who meet trial eligibility criteria, and $4,500‐$8,000 per year if used to treat higher‐risk patients with LDL cholesterol > 100 mg/dL despite intensive statin therapy.”

Meanwell was personally pleased that ICER immediately commented on the ODYSSEY results as well as the Praluent^TM price reduction. He believed that the launches of Praluent^TM and Repatha^TM have been “abject failures” and had argued that these drugs need to be priced in such a way as to facilitate availability to patients. It is pretty clear that Sanofi and Regeneron made the ODYSSEY OUTCOMES results available to ICER well ahead of the ACC meeting, in order to help put these data into perspective with respect to value. This proactivity is highly unusual – if not unprecedented. Meanwell said that “ICER has held out an olive branch to change the way drugs are priced” and believed that this type of interaction will be a key component for how drugs will be priced in the future.

However, Sanofi and Regeneron’s pricing decision directly impacted The Medicines Company. Meanwell was already planning to broaden access to inclisiran once approved via a significantly lower price than the initial list prices for Praluent^TM and Repatha^TM. He envisioned inclisiran to be the PCSK9 inhibitor for the masses – a drug priced so that anyone with documented ASCVD and anyone who has already had a heart attack would have access to it. Could this propel inclisiran to the front of the line?

Meanwell continued: “Just lowering our price to that of Praluent^TM and Repatha^TM is not enough. Product differentiation will be important assuming that everyone is operating in the same value window. We will resort to old fashioned product performance. Drugs with the best performance always rise to the top.”

His comments were based on the phase 2 results. As we have seen, phase 3 studies can provide surprises – in a negative way. However, that has not been the case for inclisiran’s program. Two phase 3 studies particularly stand out – ORION‐10 (US based) and ORION‐11 (Europe and South Africa based) with the former enrolling 1561 patients with ASCVD and the latter 1627 ASCVD or ASCVD risk‐equivalent.

 Patients were randomized to get either inclisiran or placebo on day 1, day 90, day 270, and day 450. The results were as hoped for: ORION‐10 showed a 52.3% drop in LDL‐c vs. placebo and ORION‐11 a 49.9% reduction. Apart from injection‐site adverse effects, inclisiran was well tolerated [13].

How important were these results? Well, shortly after these data were made public, Novartis bought The Medicines Company for $9.7 billion [14]. Here is what Novartis CEO Vas Narasimhan had to say.

“We are excited about entering an agreement to acquire The Medicines Company as inclisiran is a potentially transformational medicine that reimagines the treatment of atherosclerotic heart disease and familial hypercholesterolemia. With tens of millions of patients at higher risk of cardiovascular events from high LDL‐c, we believe that inclisiran could contribute significantly to improved patient outcomes and help healthcare systems address the leading global cause of death. The prospect of bringing inclisiran to patients also fits with our overall strategy to transform Novartis into a focused medicines company and adds an investigational therapy with the potential to be a significant driver of Novartis’s growth in the medium to long term.”

It is important to note that a CVOT for inclisiran will not be completed until 2024 (ORION‐4). The FDA did approve inclisiran (brand name: Leqvio^TM) at the end of 2021. But, Novartis discarded Meanwell’s vision for this drug. CEO Narasimhan believed that Leqvio^TM represented a revolutionary approach to treating heart disease and priced it accordingly – $3 250 per dose ($6 500 a year)[15].

Regardless of the Leqvio^TM surprise, PCSK9 modulation is a far more economically viable option than the original $14 600 per year price tag. As a result, patients with heart disease are going to benefit. Dr. Steve Miller said that these drugs would become “the most costly therapy our country has ever seen.” That has proven to be an exaggeration.

* * * * * * * * * * * * * *

There are some similarities between the hepatitis C and the PCSK9 drug stories. Both involved great science leading to true medical breakthroughs that benefit millions of patients around the globe. Yet, the excitement for both breakthroughs was unfortunately muted by price concerns – however justified. In fact, the cost of these drugs was said to threaten the entire healthcare system. But, competition pushed down their prices so it is difficult for insurers to deny access.

But for me, the PCSK9 saga added two new wrinkles. The first was the payers’ blatant refusal to allow access to millions of heart patients who could have benefitted from these drugs. Yes, payers had already begun to flex their muscles, for example, in limiting access to specialty rare disease drugs. But this time, cardiologists were greatly dissuaded in prescribing these drugs to those at high risk of a heart attack by being required to submit multiple rounds of paperwork to justify the needs of their patients.

The second stunner was that Amgen began offering money‐back guarantees for Repatha^TM. When you consider that this medicine is prescribed to heart patients who are most likely to eventually die from a cardiovascular event, a money‐back guarantee is pretty mind‐boggling no matter how the agreement is constructed.

There was a time when a company solely focused on getting an FDA approval for its new drug. Once that approval was in hand, commercial success was a reasonable probability. That is no longer sufficient for a new medical breakthrough. Payers now have a big seat at the table. They can make or break a new product. It is a new world.