Pharma and Profits. John L. LaMattina

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