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    PCSK9 Inhibitors and Cardiovascular Outcomes: Clinical Success May Not Guarantee Commercial Success

    The result for FOURIER, the cardiovascular (CV) outcomes trial for Amgen’s PCSK9 inhibitor Repatha (evolocumab) will be presented in a matter of days at ACC.17. Should the data demonstrate clinically meaningful reductions in CV events, such as acute coronary syndromes and stroke, the results will herald another huge step forward in the battle against CV disease. Stakeholders are all hoping for at least the same magnitude of risk reduction we have seen with the high potency statins, which if achieved will be a game changer, according to thought leaders. Moreover, it could finally confirm the ‘lower-the-better’ LDL-cholesterol hypothesis.

    Amgen has already spoiled the party somewhat: we know the results are positive. And of course that means they have a blockbuster drug on their hands, right? The statins hold several spots on the all-time top-selling drugs list. Millions of people have atherosclerotic CV disease and millions more take a statin to prevent CV disease. And now PCSK9 inhibitors can be delivered in convenient monthly injections. So let’s put everyone who needs it on a PCSK9 inhibitor and let the billions roll in for developers year after year, right?

    Think again. The statins emerged as first-line treatment in a therapeutic space that was calling out for novel drugs. And they are still very good drugs. Moreover, they are oral therapies that do not cost the earth. In contrast, Repatha and its chief competitor Sanofi/Regenon Pharmaceuticals’ Praluent (alirocumab) are very expensive injectable biologics that must contend with generic statins and ezetimibe. In addition, Esperion Therapeutics’ bempedoic acid (ETC-1002) and possibly even Merck’s anacetrapib are oral, once-daily treatments that could emerge as competitors. These drugs may not be as efficacious as PCSK9 inhibitors but we expect them to be priced much lower. Furthermore, in the not too distant future, Repatha and Praluent may not even be the best drug targeting PCSK9. The Medicine Company/Alnylam Pharmaceuticals’ inclisiran is showing similar efficacy and could only require injection twice a year (Phase II data for inclisiran is also being presented at ACC.17).

    To date, uptake of PCSK9 inhibitors has been slow. This is in part due to the limited pool of eligible patients, but the real stumbling block is the cost. At an annual U.S. price of more than $14,000, payers have placed several cost controls to restrict access to these novel agents, including prior authorization and step therapy with a high potency statin and ezetimibe. If the FOURIER results lead to an expanded label for Repatha to treat almost all ASCVD patients, the impact on healthcare budgets would be colossal. Even with positive CV benefits, proving the cost-effectiveness of PCSK9 inhibitors to payers will still be challenging. Payers are going to need to be convinced that, not only do these drugs save lives and prevent CV disease, but that they will reduce the drain on healthcare resources overall in the long term. In fact, payers could well keep, and even increase, the restrictions on access to the PCSK9 inhibitors, forcing the use of statins, ezetimibe, and eventually bempedoic acid and anacetrapib before a PCSK9 inhibitor is permitted. In fact, payers could well argue that if we know that lower is better for LDL-cholesterol, does it matter how we get there? The payers might even suggest that it should be ‘the cheaper the better’.

    Money talks, and it talks particularly loudly, when it comes to healthcare budgets and the impact of costly drugs. Positive results from FOURIER are undoubtedly important and will be a boost for patients, physicians, and shareholders in Amgen alike. However, such data might mean that Repatha is a ground breaking clinical success but not necessarily a record commercial success.