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 PraluentTM 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 (LeqvioTM) 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 PraluentTM and RepathaTM. 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 PraluentTM 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 PraluentTM and RepathaTM.) 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 (PraluentTM) 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 PraluentTM price reduction. He believed that the launches of PraluentTM and RepathaTM 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 PraluentTM and RepathaTM. 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 PraluentTM and RepathaTM 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: LeqvioTM) at the end of 2021. But, Novartis discarded Meanwell’s vision for this drug. CEO Narasimhan believed that LeqvioTM represented a revolutionary approach to treating heart disease and priced it accordingly – $3 250 per dose ($6 500 a year)[15].
Regardless of the LeqvioTM 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
