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Repatha & Praluent: A Tale Of Two Rivals...

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Rivalry is the life of trade, and it makes for some of the most compelling stories. The pharma industry, one of the fastest-growing economic sectors, too is dotted with many rivalry stories.

Let us take you through the battle between Praluent and Repatha, two cholesterol-lowering drugs that belong to the same class known as PCSK9 inhibitors.

Praluent, developed by Sanofi (SNY) and Regeneron Pharmaceuticals Inc. (REGN), was approved by the FDA on July 24, 2015, while Repatha, developed by Amgen Inc. (AMGN), received FDA approval on August 27, 2015.

However, in Europe, Repatha was the first to receive the regulatory nod - i.e. on July 21st, 2015 while Praluent was approved on September 28, 2015.

The recommended starting dose of Praluent is 75 mg administered subcutaneously every 2 weeks or alternatively 300 mg every 4 weeks (monthly) for patients who prefer less frequent dosing. The recommended subcutaneous dosage of Repatha is either 140 mg every 2 weeks or 420 mg once monthly.

Repatha and Praluent work by blocking PCSK9 (proprotein convertase subtilisin/kexin type-9), a liver-derived protease enzyme. This enzyme controls the number of low-density lipoprotein receptors, which help to regulate blood cholesterol levels.

Any mutation in PCSK9 reduces LDL receptor levels in the liver, leading to high levels of LDL cholesterol. Therefore, by blocking PCSK9's ability to work, Repatha and Praluent make more receptors available to get rid of LDL cholesterol from the blood and, as a result, lower LDL cholesterol levels. Since lowering LDL cholesterol reduces the incidence of cardiovascular disease, Repatha and Praluent garnered a lot of attention while in clinical development itself.

However, at the time of approval, the cardiovascular outcomes trials on the two PCSK9 drugs were underway, and a clear picture about the drugs' ability to prevent heart attack and stroke was not known then.

Even before the two drugs were approved, Amgen had filed a patent infringement suit against Sanofi and Regeneron in October 2014.

In March 2016, a jury ruled that two of Amgen's patents on Repatha were valid. Following the patent win, Amgen urged the U.S District Court in Delaware to block the marketing and sale of Sanofi/ Regeneron's Praluent. Over the course of the litigation, there were counter appeals by Sanofi/ Regeneron to reverse the March jury verdict.

In January of this year, Delaware federal judge Sue Robinson ruled in favor of Amgen, banning the marketing, selling or manufacturing of Praluent in the U.S. for 12 years. But the ban didn't come into effect immediately as the judge gave Sanofi and Regeneron 30 days time to appeal the verdict, which meant that the ban was to come into effect from February 21st, 2017.

But, following the defendants' petition to stay the order pronounced by Judge Sue Robinson, a federal appeals court suspended the permanent injunction on February 8, 2017, allowing Sanofi /Regeneron to continue with the sale of Praluent, pending their appeal.

More good news for Sanofi /Regeneron followed - with an Appellate Court, on October 5, 2017, ordering a new trial and vacating the permanent injunction in the ongoing patent case regarding Praluent.

Now, let's talk about outcomes...

As the bitter patent dispute has been boiling over, the sparring rivals have been providing an update on their respective cholesterol drug trials.

Last November, Sanofi/Regeneron announced that their cardiovascular outcome study with Praluent, known as ODYSSEY OUTCOMES, will continue as planned, based on the recommendation of an independent Data Monitoring Committee (DMC) after it completed a second pre-specified interim analysis.

Amgen released the final results from Repatha cardiovascular outcomes study, known as FOURIER, in March of this year.

The FOURIER study was designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduced cardiovascular events. The trial involved 27,564 patients with cardiovascular disease and LDL cholesterol levels 70 mg/dL or higher on statin therapy. The median duration of follow-up in this trial was 2.2 years.

According to the study results, the Repatha arm was associated with a 15 percent reduction in the risk of extended major adverse cardiac events (MACE) composite, i.e., the primary endpoint. The MACE included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death.

Repatha also reduced the risks of heart attack, stroke and coronary revascularization by 27%, 21%, and 22%, respectively compared to placebo. However, when individual outcomes were examined, Repatha had no effect on cardiovascular death by itself.

The FOURIER trial also demonstrated that Repatha, when added to statin therapy, reduced LDL-C from a median of 92 to 30 mg/dL, a reduction of 59% at week 48, which was sustained throughout the study.

The results of new analysis from the FOURIER study presented in September 2017 revealed that the diabetes subgroup experienced a 57 percent mean reduction in LDL-C levels when treated with Repatha while patients in the non-diabetes subgroup treated with Repatha experienced a 60 percent mean reduction at 48 weeks.

With the FOURIER trial yielding encouraging results, the FDA deemed it fit to expand the use of Repatha to reduce the risk of heart attack, stroke and coronary revascularization as recently as December 1, 2017.

Pricey price?

The U.S. Wholesale Acquisition Cost (WAC) price of Praluent, excluding discounts, is $14,600 per year, while that of Repatha is $14,100 per year. In a recent oral presentation, Amgen revealed that after rebates and discounts, Repatha's net price ranges between $7,700 and $11,200 a year. In contrast, it reportedly costs only $250 a year when generic statins are used for the treatment of cholesterol.

Agreed, Repatha and Praluent lower cholesterol levels even more so than statins without the side effects of statins. The two injectable drugs were even touted to be major moneymakers, with Wall Street analysts expecting them to quickly achieve blockbuster sales.

But for all the hype, though, Repatha and Praluent have not lived up to their expectations, and their sales figures bear testimony.

The global net sales of Praluent were $116 million in the full year 2016 and $131 million in the first nine months of 2017. And Repatha has fared no better - with sales of $141 million in 2016 and $221 million in the first nine months of 2017.

What ails this pair?

Due to the high price, patients are unable to get insurance coverage for Repatha and Praluent. Even if they have coverage for these drugs, not many patients fill those prescriptions due to high copays.

According to a new study published in the American Heart Association's journal Circulation, "less than half of patients received their insurer's approval for prescriptions Repatha and Praluent. About 1 out of 3 patients, who had their prescription approved, did not purchase or receive the medication".

Will a middle ground be reached?

A recent report compiled by the Institute for Clinical and Economic Review states that the value-based price for Repatha should be $1,725 to $2,242 for annual treatment cost. Value-based pricing is the cost of the drug that would align with its benefits to patients.

Amgen, on its part, defends its pricing of Repatha citing results from a new Repatha economic analysis published in the Journal of the American Medical Association (JAMA) Cardiology.

The economic analysis, conducted by the world's leading cardiologists from UCLA and the Thrombolysis in Myocardial Infarction (TIMI) Study Group, an academic research organization of Brigham & Women's Hospital and an Affiliate of Harvard Medical School, suggests that Repatha used in patients at high-risk for cardiovascular events is cost-effective at net prices at or below $9,669. This estimate is in line with the discount range typical for biologic medicines in the U.S. market when applied to the U.S. list price of Repatha, says Amgen. As mentioned earlier, after rebates and discounts, Repatha's net price is said to range between $7,700 and $11,200 a year.

However, even at the discounted price, the drugs are still too pricey, argue some researchers.

Will Sanofi/Regeneron's ODYSSEY be a thriller?

Sanofi/Regeneron's ongoing ODYSSEY OUTCOMES study is designed to determine whether the addition of Praluent to intensive statin therapy reduces major adverse cardiac events among patients who had previously experienced an acute coronary syndrome, such as a heart attack or unstable angina.

The study has enrolled 18,000 patients, and data is expected in early 2018.

Closing Thoughts...

Unless the doctors and insurers are convinced that Repatha and Praluent are worth the money, they may be reluctant to prescribe or provide coverage for the drugs. Because of the sky-high prices, access to these medicines remains a significant challenge for the patients.

Will the companies provide further grounded evidence for the cost-effectiveness of Repatha and Praluent to convince physicians and payers? Will the companies reassess the pricing of the drugs? Maybe a clearer picture will emerge when the ODYSSEY OUTCOMES study results are out.

by RTT Staff Writer

For comments and feedback: editorial@rttnews.com

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