Article: Hyperlipidemia: Are the PCSK9 inhibitors bouncing back?

Published in Pharma Times

The promise of a new era of cholesterol management, heralded by the launch of highly effective PCSK9 inhibitors, has been complicated by significant barriers to uptake of the next-generation products in multiple markets.

These obstacles partly reflect initial premium pricing of the two available PCSK9 inhibitors, Praluent (alirocumab) and Repatha (evolocumab). Price differentials have been all the more marked given the established reliability of low-cost, genericised statins as a tool for lowering cholesterol.

In that light, many physicians, thought leaders and payers opted to wait for persuasive outcomes data that would substantiate the ability of the PCSK9 inhibitors to offset higher costs with long-term gains in preventing mortality, hospitalisation or other serious cardiovascular events.

Now at least some of those outcomes data are on the table. Moreover, the manufacturers of Praluent and Repatha have made substantial pricing or contracting concessions to healthcare payers, in their efforts to boost adoption of PCSK9 inhibitors as a new gold standard for cholesterol management and cardiovascular health.

Does this mean PCSK9 inhibitors are now poised to achieve something like their original potential – as a more effective, and also in the long run cost-effective, alternative to standard cholesterol reduction with statins?

Recent data from Therapy Watch, a patient audit conducted by research consultancy Research Partnership, on patient profiles for the PCSK9 inhibitors in major European markets suggest that the emerging landscape for these products is more nuanced. Barriers such as market access, pricing and reimbursement are affecting the overall growth of the PCSK9 inhibitor class and limiting product use to specific groups of patients.

It will take careful targeting to high-risk patient groups if the PCSK9 inhibitors are to break through both as therapeutic game-changers and compelling commercial prospects.

The PCSK9 inhibitor rationale

The two currently marketed PCSK9 inhibitors, Praluent and Repatha, were launched by Sanofi/Regeneron and Amgen respectively in the latter half of 2015. Praluent secured US approval in July 2015, ahead of Repatha in August of the same year. In Europe the positions were reversed. The European Commission granted Repatha its marketing authorisation in July 2015, with Praluent following in September 2015.

One important feature of the European approvals was broader indications – and hence potential access to a larger patient population – compared with the narrower and more cautious approvals for PCSK9 inhibitors in the US. The US Food and Drug Administration (FDA) notably excluded patients intolerant to statin therapy, where there was some uncertainty about the products’ long-term benefit-risk equation.

Advisers to the agency were also conflicted over what statin intolerance actually meant objectively and how that was conveyed in clinical trials of the PCSK9 inhibitors. In the end, the FDA effectively hedged its bets by approving labelling for patients on ‘maximally tolerated’ statin therapy.

Nonetheless, Sanofi/Regeneron and Amgen were able to position Praluent and Repatha as the next-generation of cholesterol management for patients at high risk of cardiovascular events, and as a clear therapeutic advance on statins. The manufacturers have been making continuous efforts and have achieved expanded preventive labelling for their products to include risk reduction for major cardiovascular events, based on positive results from ODYSSEY OUTCOMES and FOURIER studies, respectively.

It helped that both products delivered an impressive efficacy and safety profile in clinical trials. In particular, they were found to reduce low-density lipoprotein cholesterol (LDL-C) levels by as much as 60%, usually in combination with a statin or another lipid-lowering therapy, ezetimibe.

This is also supported by Therapy Watch data, which shows that both PCSK9 inhibitors are almost equally effective in lowering LDL-C levels. Patients on Repatha and Praluent have been reported to show a mean reduction of around 50% since their last CV event.

Drawbacks of statins

Successive generations of statin drugs have been widely used to manage cholesterol and, by implication, to help ward off cardiovascular conditions such as coronary heart disease. Their rise to the gold standard for cholesterol-lowering has not come without dissent, though. Some scientists argue that the benefits of statins and their association with heart disease have been overstated.

Nonetheless, the UK’s National Institute for Health and Care Excellence (NICE) considered statins safe and effective enough, and at an attractively low cost, to be recommended as a primary-prevention tool for healthy people with a 10% or greater risk of developing cardiovascular disease (CVD) within the next 10 years.

US authorities such as the American College of Cardiology/American Heart Association and the Preventive Services Task Force have also recommended statins for primary prevention of CVD, in selected populations and with varying entry thresholds. Joint guidelines from the European Society of Cardiology/European Atherosclerosis Society set a higher threshold for preventive therapy than the US or NICE recommendations.

That is not to say statins are optimally effective, or indeed problem-free. Some patients fail to achieve recommended LDL-C targets despite being on maximum tolerated or high-intensity doses of statins, thus remaining at very high risk of serious cardiovascular events such as heart attacks and strokes. This problem is especially pronounced in patients with familial hypercholesterolaemia (FH).

Moreover, some patients cannot tolerate statins at all, or at the higher doses. As a consequence, these patients fall short of their LDL-C reduction goals and remain at very high CVD risk. Apart from intolerance, some side-effects are associated with these drugs, such as muscle pains, cramps and weakness, increased risk of diabetes, dizziness, headache, diarrhoea or drug-drug interactions.

Current landscape for PCSK9 inhibitors

The acknowledged drawbacks of statin therapy, combined with restricted indications for PCSK9 inhibitors and concerns about prohibitive costs in the general population, have carved out a niche space for uptake of the new-generation therapies.

At present, the PCSK9 inhibitors are seen mostly as add-on therapy where patients cannot achieve their LDL-C reduction goals. The high-risk target population typically includes people with familial hypercholesterolaemia (FH), where PCSK9 inhibitors are used for primary prevention; and patients with significant atherosclerotic CVD as well as elevated LDL cholesterol, despite being on maximally tolerated statin therapy (Secondary prevention).

Research Partnership’s Therapy Watch data suggest that a carefully targeted strategy may help the PCSK9 inhibitors to pick up speed. Eighty percent of patients currently on PCSK9 inhibitors in key EU markets (Germany, Italy, Spain and the UK) are taking the products for secondary prevention – ie, they have already experienced at least one cardiovascular event in their lifetime.

In demographic terms, the Therapy Watch data indicates that the high-risk target population for PCSK9 inhibitors is primarily older males (the majority between 50 and 70 years) with unhealthy lifestyles. That means they are overweight or obese, physically inactive and smokers.

Sluggish uptake

Despite additional evidence from manufacturers’ clinical trials that the PCSK9 inhibitors can lower the risk of serious cardiovascular events such as heart attacks, strokes, and revascularizations (Repatha), as well as reducing all-cause mortality (Praluent), in high-risk patients, uptake of the new products has so far remained quite sluggish.

In 2017, for example, Repatha and Praluent registered global sales of $319 million and $195 million respectively, up from $141 million (+126%) and $116 million (+68%) respectively in 2016, the brands’ first full year on the market after launch.

Some acceleration of sales was noted as Repatha and Praluent moved into 2018, although the PCSK9 inhibitors were originally tagged as billion dollar-plus blockbusters. In the third quarter of 2018, Repatha sales growth was tracking at 35% year on year and Praluent at 62% (both in US dollars).

Prescribing trends to date suggest that physicians treat Repatha and Praluent essentially as mirror products, with comparable efficacy in lowering cholesterol levels.

Prohibitive costs

Probably the most significant obstacle to uptake of the PCSK9 inhibitors, has been cost. The products launched in the US at a list price of around $14,000 per patient per year, a considerable premium on the costs of primarily genericised statins.

This disparity was highlighted in cost-benefit analyses by health-technology assessment bodies such as the Institute for Clinical and Economic Review (ICER) in the US, which concluded that the PCSK9 inhibitors were significantly overpriced even in the light of the FOURIER and ODYSSEY outcomes data.

Nonetheless, re-evaluations of this kind based on ongoing outcomes studies, and subsequent manufacturer efforts to address issues of cost and value, may eventually help to ease some of the tough barriers to PCSK9 inhibitor uptake imposed by reimbursement authorities, medical guidelines or insurance companies and their go-betweens, such as US pharmacy benefit managers (PBMs).

These disincentives to prescribing or coverage of the new drugs have included prior-authorisation conditions, unfavourable formulary placement, high patient co-payments, prescribing protocols or other utilisation-management strategies.

At the same time, physicians need to be convinced more fully that the risk-benefit profile and outcomes potential of the PCSK9 inhibitors justify the extra costs in the high-risk or statin-exhausted/intolerant patients for whom the drugs are labelled and recommended.

Pricing, contracting concessions

One factor that could help to galvanise sales of PCSK9 inhibitors is the manufacturers’ recent acknowledgment that affordability is a sticking point. In October 2018, Amgen announced that it was cutting the US list price of Repatha by 60% to $5,850 per year, which it said would lower co-payments for Medicare patients in particular.

For their part, Sanofi and Regeneron struck an agreement with Express Scripts in May 2018 to lower the net price of Praluent for the US PBM’s plan members to within the range – $4,460 to $7,975 per year – suggested by the ICER as cost-effective for higher-risk patients with cholesterol levels of LDL ≥100 mg/dL, despite intensive statin therapy.

In return, Express Scripts gave Praluent exclusive formulary status for US plans enrolled in its Cholesterol Care Value programme, while simplifying markedly the documentation required from physicians to secure insurance coverage for the drug.

In February 2019, Sanofi and Regeneron went further and cut the US list price of Praluent by 60% to $5,850 per year, mirroring Amgen’s dramatic price reduction the previous autumn.

Price discounting has also proved an effective market-access tool for the PCSK9 inhibitors outside the US. In the UK, for example, NICE recommended both Repatha and Praluent for funding through the National Health Service in England.

However, NICE’s final draft guidance was conditional on agreed Patient Access Schemes (ie, undisclosed discounts) and restricted usage in patients with primary hypercholesterolaemia or mixed dyslipidaemia whose cholesterol remained too high despite lifestyle changes and treatment with other cholesterol-lowering drugs.

Picking up speed

As a clearer picture emerges from clinical trials or real-world studies of the PCSK9 inhibitors’ impact on cardiovascular outcomes including mortality, we may see value-based pricing agreements for the drugs that tie reimbursement more explicitly to agreed endpoints.

Nonetheless, these schemes can be complex and burdensome to administer compared with the upfront price concessions, discounts or rebates already negotiated and in the public domain for Repatha and Praluent.

The newer drugs also appear to be substituting for more aggressive statin intervention at lower cost. In the Therapy Watch data, a decline of around 20% in usage of high-intensity statins such as atorvastatin and rosuvastatin was seen among patients who had initiated PCSK9 inhibitor therapy.

This suggests that the message about cost-effectiveness and improved cardiovascular outcomes with the PCSK9 inhibitors, at least in high-risk patients, is getting through to some physicians and payers in key European markets. It may hint at a brighter future for a therapy class whose uptake to date has not been an easy ride.