Educational Efforts Are First Front Of Marketing Battle For PCSK9s

With reams of PCSK9 data showing robust lowering of LDL – a trusted surrogate – under their belt, sponsors aim to win over prescribers, payers and patients ahead of outcomes trial releases.

Sanofi thinks it has already made a lot of headway in raising awareness of injectable PCSK9 inhibitors for cholesterol lowering ahead of the imminent filing of its alirocumab, but the company knows it still has a lot of work to do if it is to penetrate a market stacked with trusted oral generics.

The American Heart Association annual meeting from Nov. 15-19 featured encouraging additional data from Sanofi/Regeneron Pharmaceuticals Inc.and competitor Amgen Inc. on pivotal trials of PCSK9 inhibitors in LDL lowering for patients unable to reach targets. Both are positioning their drugs in a variety of dyslipidemia market segments, including the rare genetic condition familial hypercholesterolemia (FH), secondary prevention in high-risk patients and statin intolerant patients.

Amgen filed its evolocumab in late August and Sanofi/Regeneron plan to file alirocumab, with the proposed trade name Praluent, by the end of 2014. Sanofi’s purchase of a priority review voucher will even up the timelines even with the later submission date, if it makes that filing deadline; evolocumab is under standard review with an Aug. 27, 2015 user fee date (Also see "Sanofi/Regeneron’s PCSK9 Inhibitor Gets Reassuring CV Data – And A Priority Review Voucher" - Pink Sheet, 30 Jul, 2014.). That also assumes Amgen is unsuccessful in its attempt to block alirocumab with a patent infringement suit (Also see "PCSK9 Battleground Hits The Court, Not The Market, After Amgen Sues" - Pink Sheet, 17 Oct, 2014.).

Phase III data for both drugs look very good so far, though outcomes studies will be the real test of efficacy and safety, and are not expected until late 2017 or early 2018. Further behind, Pfizer Inc. is developing the PCSK9 inhibitor bococizumab. Pfizer has been looking to differentiate bococizumab through what it sees as a broader program that includes primary prevention as well as secondary prevention (see related story, (Also see "A Closer Look At Pfizer’s Pivotal Program For PCSK9 Bococizumab" - Pink Sheet, 8 Dec, 2014.)).

At the 2014 AHA meeting, Sanofi presented data from six trials that are part of its ODYSSEY development program for alirocumab: ODYSSEY-COMBO I, -ALTERNATIVE, -OPTIONS I, -OPTIONS II, -HIGH FH and the -LONG TERM safety study, after reporting top-line results for all of these in the summer (Also see "Sanofi/Regeneron’s PCSK9 Inhibitor Gets Reassuring CV Data – And A Priority Review Voucher" - Pink Sheet, 30 Jul, 2014.). Data from the LONG TERM study, which showed a reduction in the rate of cardiovascular events for alirocumab vs. placebo in high-risk patients taking the maximum tolerated dose of statins, had been presented at the European Society of Cardiology meeting on Aug. 31 and were also updated at AHA (Also see "Sanofi/Regeneron’s Alirocumab Cuts CV Events And Cholesterol" - Pink Sheet, 1 Sep, 2014.).

Sanofi highlighted results from 10 Phase III studies reported to date during its “New Medicines Day” investor presentation on Nov. 20 (Also see "Sanofi Reassures Investors About Diabetes Franchise, Says Late-Stage Pipeline Will Reduce Lantus Dependence" - Pink Sheet, 24 Nov, 2014.). Harold Bays, medical director and president of Louisville Metabolic and Atherosclerosis Research Center, noted a consistent reduction of LDL from baseline across the 10 trials, ranging from 36%-51% in the OPTIONS II study to 61% in the LONG TERM safety study. Safety is a top priority – and in the LONG TERM study, rates of treatment-emergent events were similar between alirocumab and placebo, Bays added

A Matter Of Education?

Even with efficacy and safety data looking so positive so far, Sanofi says that it knows it has its work cut out in educating prescribers and patients about PCSK9 inhibitors, in light of the dominance of generic statins, said Victoria Carey, who heads U.S. commercial for alirocumab at Sanofi. In addition to statins, Merck & Co. Inc.’s oral cholesterol absorption inhibitor Zetia (ezetimibe) is available as an add-on or alternative drug and loses patent status in 2017. Zetia’s profile got a big boost with the positive results from the IMPROVE-IT outcomes study at the AHA meeting (Also see "PCSK9s Get Boost From IMPROVE-IT; Outcomes Data Restores Faith In LDL Surrogate" - Pink Sheet, 17 Nov, 2014.).

Amgen has also initiated a range of advertising and educational efforts to raise awareness about the unmet need for and value of PCSK9 inhibitors, as the firm discussed during an investor call in March coinciding with the American College of Cardiology annual meeting (Also see "Preparing For Battle: PCSK9 Sponsors Stake Their Ground" - Pink Sheet, 7 Apr, 2014.). A newcomer to cardiology, Amgen said at an investor day in October that it would be commercially ready to launch evolocumab upon FDA approval, having reallocated sales reps from other therapeutic areas and recruited a specialist cardiovascular sales force with established relationships with cardiologists (Also see "Amgen On PCSK9 Inhibitor Evolocumab: “We Are Ready To Go”" - Pink Sheet, 28 Oct, 2014.).

The emerging clinical data should help build support, but the companies have a long road ahead of them given the expected cost of the products.

“We all know in the U.S. market, any new innovation is under a lot of price pressure. This is no different, especially when the standard of care is close to being generic across the board,” Carey told Sanofi’s Nov. 20 investor presentation.

Getting established in the market will require education of payers, prescribers and customers, she said. Neither Sanofi nor Amgen would comment on price at their latest investor meetings, but as biologics targeted at what the companies see as areas of unmet need, the PCSK9 inhibitors are expected to be expensive.

With payers, Sanofi/Regeneron will be looking to underscore potential benefits for reducing costs associated with CV morbidity and mortality, which surpass $300 billion in the U.S. alone (see box). Trials of statins have repeatedly supported the link between lower LDL and fewer events, and the IMPROVE-IT results underscored that.

The Case For Unmet Need In Dyslipidemia

• In U.S., CVD costs $193 billion in direct health expenditures and $122 billion in indirect expenses related to mortality
• LDL-C contributes to 60% of coronary heart disease and 40% of all ischemic strokes
• Despite available treatment options, 24 million high-risk patients fail to reach LDL-C goals

Source: Sanofi

Sanofi believes that payers recognize that PCSK9 inhibitors could be an effective tool for further reducing risk, as long as the new therapies are targeted at those who really need them, Carey maintained.

“Payers really want to partner with us to make sure the appropriate patients have access to our drugs – that the right patients are getting the right dose at the right time,” the exec said.

Nobody thinks that PCSK9 inhibitors will take over from statins, but given the “tremendous, impressive” efficacy and a very favorable side effect profile, the class should play a strong role in helping patients reach lower LDL levels, commented Ed Schoonveld, managing principal in market access and pricing at the U.S.-based sales and marketing consultancy ZS, in an interview.

If the medical community and regulators accept the data supporting the filings of the PCSK9 inhibitors, Schoonveld expects that following approval, payers will not withhold access or make it difficult to get the drugs for eligible patients until outcomes data are available, because that would not be a wise medical decision, though they will want confirmation of a benefit later on. Furthermore, reducing risk could save money, though this may not be perceived as a benefit for health systems that are not integrated and are more short-term/price-oriented in their thinking, he told “The Pink Sheet”.

Sanofi believes PCSK9 inhibitors are currently in good standing in the medical community. During the investor call, Carey said that awareness among potential specialist prescribers of PCSK9 inhibitors has been growing and is already very high. In a survey done in the second quarter, about 73% of specialists in the U.S. expressed awareness of the class, up from 62% in the fourth quarter of 2013. Specialist awareness in Europe was lower, however; in Germany it was 52% in the second quarter of 2014 vs. 36% in the fourth quarter of 2013, and for the U.K, it was 54% for 2014 and 49% for 2013.

Furthermore, the number of specialist physicians who said they were likely or very likely to prescribe has been climbing “across the globe over time,” reaching 70% in the U.S., 64% in the U.K. and 71% in Germany, Carey said. “Clearly, among specialists, the intent to prescribe is there,” she commented.

Sanofi cited its education efforts associated with medical congresses and said that it expects that following the AHA and ESC meetings, willingness to prescribe is even higher now.

While Sanofi has a “long tradition” with specialist physicians, given its experience with the antithrombotics Lovenox (heparin) and Plavix (prasugrel), as well as the insulin Lantus, Carey noted that about half of patients in the PCSK9 target populations are managed by primary care doctors, especially in the U.S., and said that Sanofi and partner Regeneron “have a lot of work to do to educate those customers on the medical need as well as role of PCSK9.”

Amgen has similarly concluded that initial uptake and prescribing will be by specialists, but that primary care doctors would continue the scripts.

Getting Patients On Board

Sanofi and Regeneron are also bearing in mind that once doctors prescribe the drug, the patient still has to accept and fill the script. This willingness differs depending on the target patient group. Looking at survey data for the U.S. market collected in 2012/2013, 70% of patients with heterozygous FH said that they would fill and use a PCSK9 inhibitor, compared to about half of patients in three other groups tested – statin intolerants, primary and secondary risk prevention. In Europe, about 65% of patients with statin intolerance or eligible for primary or secondary prevention said that they would be willing to fill and use a PCSK9 script (heFH was not tested in Europe).

Sanofi is aiming to drive patient acceptance and adherence over time and expects that convenience will matter a lot. In addition to clinical datasets, the drugs will be differentiated based on practical matters like dosing and ease of use of the subcutaneous delivery device.

Alirocumab will be administered through a pre-filled syringe or auto-injector that delivers dose in a 1 mL single injection. Sanofi cites its experience teaching patients how to inject themselves through its marketing of basal insulin.

“We are going to leverage years of experience in diabetes as we train our patients to accept the injection and then surround the patient with the support they need to adhere to alirocumab over time. This is a core capability Sanofi has developed through its diabetes franchise and one we will leverage in the marketplace,” Carey said.