Guest Editorial: PCSK9-Inhibitors: Riding the Wave of Swift Development and Approval – A Journey of Hope, Roadblocks and Outcomes

The study of lipoproteins and their impact on cardiovascular disease states can be traced back to observations made in the 17th and 18th centuries.(1) Nearly two centuries later, in 1985, Brown and Goldstein demonstrated that the low-density lipoprotein receptor (LDLR) served as the principal regulator of serum low-density lipoprotein cholesterol (LDL-C) levels, a discovery that earned them the Nobel Prize in Medicine.(2) Their description of a key cell surface protein receptor set the stage for the development of several lipid-lowering therapies and established the low-density lipoprotein (LDL) hypothesis. In 2003, the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene was associated with previously uncharacterized autosomal dominant hypercholesterolemia and hypobetalipoproteinemia.(3) The discovery of this protein as an important regulator of the LDL-R led to the development of several anti-PCSK9 monoclonal antibodies (mAbs).

The development and commercialization of PCSK9 MAbs is remarkable for its potential impact and for its abridged timeline. The pathway from discovery to clinical trials to U.S. Food & Drug Administration (FDA) approval was accomplished in 12 years. In 2015, the FDA approved the PCSK9 MAbs evolocumab and alirocumab for use in clinical cardiovascular disease and familial hypercholesterolemia (FH). The initial enthusiasm for use of this novel therapy was dampened by concerns regarding its steep cost for these prevalent conditions. Financial analysts predicted a high level of caution by payers. Both alirocumab and evolocumab were introduced to the market with annual list prices that exceeded $14,000. A forecast by the Institute for Clinical and Economic Review estimated that the drugs would cost the United States $1.2 billion in the first year after approval.(4)

Indeed, the introduction of PCSK9 MAbs into clinical practice has been constrained by significant cost, with insurers responding by creating barriers to limit their access. Insurers imposed a requirement for prior authorization (PA) on all PCSK9 MAb prescriptions. Unfortunately, some insurers adopted a categorical “fail first” approach, issuing denials on all prescriptions. (5) In fact, when alirocumab was released, as many as 90% of prescriptions were immediately rejected despite appropriate documentation of need.(5) An FH Foundation survey of 163 patients revealed a 79% denial of PCSK9 inhibitor prescriptions, regardless of the fact that 35% were written for FH patients in need of secondary prevention.(6) In particular, single providers and smaller practices with minimal administrative assistance struggled to prescribe the therapy.(7)

Table 1. Modified from Live Presentation – April 27, 2018; Las Vegas, NV. Underberg J, MD; Davidson M, MD; and Morris P, MD. Test Your Confidence in the Use of PCSK9 Inhibitors.

The superb efficacy and favorable safety profile encouraged stakeholders and other national organizations to advocate for greater access. The National Lipid Association (NLA) worked with the FH Foundation, American Society of Preventive Cardiology (ASPC), American College of Cardiology (ACC), and American Association of Clinical Endocrinology (AACE) to review and address the principal challenges that restricted appropriate access to these medications.(7) These efforts were successful in holding the payers accountable by requiring their documentation of inappropriate denials and high co-payments.

In addition, town hall-style meetings were held across the country to address PCSK9 MAb access concerns. Providers and patients were invited to forums to share their experiences. Over time, prior authorizations were easier to obtain. But instead of rejecting applications outright, insurers continued to pass on costs to the patients by charging high co-payments. Pharmaceutical companies responded by providing grants and access cards. Unfortunately, the logistical challenges continue to leave many patients without access to the medicine and providers without a predictable pathway to enable patient access. In addition, Medicare recipients are contractually prohibited from accessing the prescription-cost grants and access cards sponsored by the pharmaceutical companies.(7)

The NLA, FH Foundation, Preventive Cardiovascular Nurses Association (PCNA), ASPC and others collaborated to create an easy-to-use PCSK9 inhibitor checklist and made forms available online.(7) In addition, structured appeal-letter templates were created and made accessible for responsible public use after a first denial. Health care providers and patients now have a tool to promote dramatic LDL-C lowering and improve cardiovascular morbidity and mortality. It is a testament to the joint efforts of the entire community of stakeholders that access to these drugs is increasingly available and affordable.

The publication of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial(8) recently led to a change in FDA-approved indications for evolocumab (see Table 2). Likewise, following the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY) trial(9), the FDA granted approval for the same indications for the use of alirocumab. These outcomes led to the inclusion of these medications as part of the 2018 Guidelines on the Treatment of Blood Cholesterol.(10) Notably, these guidelines also emphasized responsible use of these drugs with respect to need, given the high cost and based on mid-2018 pricing.

It has required a great deal of effort from multiple organizations – including pharmaceutical companies, insurance providers, patients, advocacy groups, and healthcare providers – to provide patients with greater access to PCSK9 MAbs. Table 1 is a compilation of a group of experts’ “clinical pearls” for improving access to PCSK9 MAbs.(5) The promise of this powerful therapy can only be realized if our patients are able to take the medicine. Thanks to these collaborative efforts, we are providing improved access to care every day.

Disclosure statement: Ms. Ross received honoraria from Amarin, Amgen, Sanofi, Regeneron, and Experion.

Table 2. Navigating the Approval Process – Clinical Pearls.