Proof is in the endpoints
By: Anke van Engen, MSc | October 25, 2016
Slow uptake of PCSK9 inhibitors offers valuable lessons to sponsors about the importance of hard clinical data to win approval from payers.
In the summer of 2015, the US Food and Drug Administration (FDA) approved Praluent (alirocumab) and Repatha (evolocumab), two new injection-based lipid-lowering treatments that are the first products approved in a new class of drugs known as proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. Previously, the only drugs available to lower cholesterol were statins, which don’t always work for patients. PCSK9 inhibitors can be used in combination with statins or as an alternative for the three-to-four percent of patients who experience serious side effects from that class of drugs.
When these drugs were first approved, the industry anticipated they would be the next blockbusters, however adoption rates have been unexpectedly slow, in large part because Health Technology Assessment (HTA) bodies aren’t convinced the value is worth the price. To better understand the decision rationale Quintiles analysed HTA recommendations and key decision drivers for evolocumab and alirocumab in primary hypercholesterolaemia and mixed dyslipidaemia, using Quintiles’ proprietary HTA Accelerator platform.>
We will be presenting the results of this research in a poster at ISPOR's 19th Annual European Congress October 29-November 2 in Vienna, entitled: Drivers in HTA Decision-Making for Cholesterol Lowering PCSK9 Inhibitors. Here are the highlights.
These two drugs come with high prices tags of more than $14,000 per year before negotiated rebates in the US while in Europe, evolocumab costs £4,423 per patient per year in the UK and range from €8,931 to €12,366 in France. This is dramatically higher than the cost of statins, which are largely now off patent and can cost as little as a few hundred dollars per patient per year.
But price isn’t the only issue. While PCSK9 inhibitors have been proven to dramatically lower LDL cholesterol, developers haven’t yet proven that this lower cholesterol will significantly reduce the occurrence of heart attacks, strokes and other cardiovascular-related events in these patients, which is the real value proposition for these drugs. In our research, these two issues emerged as key concerns for HTA bodies.
In the study, we reviewed 28 HTAs on evolocumab (17), alirocumab (9), and a combination of the two (2), using Quintiles’ HTA Accelerator database. We focused our reviews on decision-drivers for recommendations in terms of clinical benefit, economic outcomes and patient populations.
Alirocumab and evolocumab are both indicated in primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in combination with statins (except in cases of intolerance or contraindication to statins). Alirocumab is also indicated in homozygous familial hypercholesterolaemia. HTA bodies assessed the value of both drugs in the various patient populations breaking the hypercholesterolaemia further down by patient at low or high risk of cardiovascular events. Seven assessments resulted in negative recommendations and all agencies gave a negative recommendation for patients without high risk of cardiovascular events restricting access to alirocumab and evolucumab those only specific subpopulations in the label. .
In reviewing the reasoning behind these decisions we determined that uncertain clinical evidence due to lack of hard endpoints and safety data from long term follow-up studies have been clear barriers to gaining market access for both alirocumab and evolocumab. With the majority of HTA bodies looking for value for money, the observed outcomes are not unexpected.
The developers recognize that they need this data if they want to secure payer approval, and they are currently conducting large cardiovascular outcomes trials in order to make the connection, with initial results expected later this year. If they can prove that the cholesterol-lowering effects of these drugs directly impact cardiovascular events, the HTA bodies may adopt a more favourable view on this drug class, enabling evolocumab and alirocumab to ultimately gain significant market shares.
But there is a broader lesson to be learned from how HTA bodies reacted to these drugs. It is not enough for developers to demonstrate surrogate endpoints – i.e. lower cholesterol. They need to bring definitive clinical evidence to the table if they want regulators and payers to support the high cost of innovative new treatments.
To do that, developers have to start thinking about what data will win HTA approval at the outset of their research, and choose protocols and endpoints that deliver a convincing portfolio of evidence – especially in markets with national payers who are deeply concerned about the budget impact of such treatment options. It may take a little longer to assemble this data, but if it results in positive recommendations from HTAs it will have been worth the effort.