Challenges with PCSK9 Inhibitors Use in Asia Given Real-World Data Implications

See article vol. 30: 1123-1131

Even though PCSK9 inhibitors, human monoclonal antibodies of PCSK9, were approved by the FDA in 2015 approximately 12.5 years after the first report of PCSK9 as a cause of autosomal dominant hypercholesterolemia in 2003 ¹⁾ , there have been issues with real-world impacts aligning with clinical trials. These clinical trials showed 40%–50% LDL-C lowering effects with small adverse reactions for both alirocumab and evolocumab ²⁾ . Following the impacts of powerful LDL-C lowering effects, the FOURIER and ODYSSEY OUTCOMES studies demonstrated clinical event reductions with PCSK9 inhibitors ^{3 , 4)} . Asian countries participated in these studies, and the event reduction effects were shown to be similar between Asian and other patients. With these data, lipid management guidelines changed in many countries to implement PCSK9 inhibitors that reduce cardiovascular events. This led to the use of PCSK9 inhibitors for LDL-C control in high-risk patients who had insufficient LDL-C reduction under combinations of maximally tolerated statins and ezetimibe. While “the lower, the better” approach to LDL-C seems straightforward, as shown by a number of clinical trials, the relatively high cost of the PCSK9 inhibitors complicated the real-world prescription and distribution of these interventions.

Using real-world data, Lin et al. showed a slightly lower LDL-C reduction effect from PCSK9 inhibitors compared with the clinical trial data ⁵⁾ . One potential reason for the reduced LDL-C lowering effects, the authors highlight, is a pattern of spacing out injection times for each PCSK9 inhibitor due to its high cost. In their study, the Taiwan National Health Insurance (NHI) reimbursed 53.1% of patients who met the Taiwan NHI reimbursement criteria. Several other studies have shown poor adherence to PCSK9 inhibitors due to cost ^{6 , 7)} . In Singapore, Chng et al. analyzed 80 patients who were prescribed PCSK9 inhibitors ⁷⁾ . The majority of these patients were self-paying. While PCSK9 inhibitors were efficacious, safe, and well-tolerated in real-world practice as shown in the clinical studies, the discontinuation rate was as high as 34.5% for alirocumab and 27.5% for evolocumab. The most common reason for discontinuation was the high treatment cost for both interventions. These data show that the cost and reimbursement situations are affecting treatments for patients who are at high risk for cardiovascular events. Moreover, these data show patients who are on PCSK9 inhibitors, but a considerable number of other patients likely exist who are not treated with PCSK9 inhibitors due to cost factors.

Careful cost-effective analysis helps more effectively balance intervention costs with savings through proactive interventions and increased quality of life benefits. In the case of PCSK9 inhibitors, some researchers suggested that overestimates of budget impact by healthcare system decision makers contributed to current reimbursement structures ^{8 , 9)} . And prelaunch predictions of the budget impact of newly developed drugs were reported to be considerably overestimated versus the actual sales; furthermore, PCSK9 inhibitors had a higher than average prediction “error” ⁸⁾ . During prelaunch, the desire of pharmaceutical companies to highlight the potential for new interventions may contribute to overestimated demand, particularly with considerable new interventions, like PCSK9 inhibitors, where there were more unknowns. When looking at the prelaunch phase of PCSK9 inhibitors, the companies possibly looked at the number of high-risk patients with a high LDL-cholesterol level and aggressive journal articles to estimate their forecasts but also potentially underweighted realistic prescribers’ opinions. Unfortunately, high cost and overestimating budget impact caused alarm among decision makers and led to early access restrictions, which is what we still see in the current PCSK9 inhibitor market. Another analysis on PCSK9 inhibitor utilization shown with IQVIA’s Multinational Integrated Data Analysis System indicates that greater PCSK9 inhibitor utilization tended to be in countries with a larger ability and likely higher willingness to pay, as measured by current health expenditure as a percentage of gross domestic product (CHE%GDP) ¹⁰⁾ . CHE%GDP ranged from 3.8 to 16.9 across countries and 3.8 to 11.0 across Asia. Given the current state, driven to some degree by “ability and willingness to pay” for PCSK9 inhibitors, what can we do to more effectively deliver this useful but relatively expensive drug to the right patients? Lin et al. concluded in their paper that we need to find ways to tackle the reimbursement restriction together with physicians, governments, insurance systems, and pharmaceutical companies ⁵⁾ .

More than 5 years after the launch of PCSK9 inhibitors, we have realistic information on prescribers and patients who could benefit the most, and yet we are still struggling with cost and reimbursement issues to prescribe PCSK9 inhibitors appropriately. Subanalyses of the FOURIER and ODYSSEY OUTCOMES studies have started depicting “very high-risk patients” who would benefit more from PCSK9 inhibitors through the prevention of cardiovascular events. While proposing a risk-stratified clinical practice guideline for PCSK9 inhibitors and ezetimibe use, an international panel including patients suggested having a shared decision-making process ¹¹⁾ . The panel pointed out uncertainty in the evidence concerning patient value and preferences and the influence of availability and cost. With this perspective in mind, I suggest prioritizing cost-effectiveness analysis to help indicate realistic target patient groups so groups of stakeholders across different healthcare systems can decide how best to improve appropriate access to PCSK9 inhibitors for their highest-impact patients.

Conflicts of Interest

None.