In 2015, Repatha (evolocumab) and Praluent (alirocumab) received significant publicity during their launch. These new PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors publicity focused on two elements; 1) the potentially huge 54–77% reduction in LDL cholesterol and 2) the ~$14,000 annual US treatment cost (see our article: Are the PCSK9 Inhibitors, Repatha and Praluent, the new Sovaldi?). So how successful has the PCSK9 inhibitors launch been and what are the implications for them in the future?
In commercial terms, both Repatha and Praluent have got off to slower than expected starts, with Repatha achieving global Q3 2016 revenues of only $40 million. The main reasons appear to be the unwillingness of insurers to fund the new treatments, low physician support and the lack of hard outcome data.
One of the major challenges has been the price associated with PCSK9 inhibitors, which launched with a list price of ~$14,000. In the US, it has been reported that discounts of ~50% have been offered to health insurers, which potentially brings down the cost of the PCSK9 inhibitors to a comparable level with European countries. However, even at $7,000/year the cost is still significantly more than the cost of high dose statins and given that patients are likely to be on these treatments for the rest of their lives, the resulting budget impact can be significant. Furthermore, justification of the launch price hasn’t been helped by the US’s Institute for Clinical and Economic Review, which suggested an 85% price decrease (to $2,177 annual treatment cost) was the appropriate price level for these treatments to be considered cost effective.
For those patients in the US that are potentially eligible for Praluent or Repatha, payers have placed barriers to prescription, resulting in restricted patient access. One is the prior authorisation that covers the PCSK9 inhibitors, where doctors have to prove that the patient has hypercholesterolaemia and has already tried two statins. This prior authorisation can consist of over 40 questions and even with the appropriate documentation, physicians have been finding that the insurer’s rejection rate for first time prescriptions was over 77%. After five appeals, over 60% patients wanting to use PCSK9 inhibitors are still not funded by the insurers, highlighting that payers do not currently believe the value of PCSK9 inhibitors, instead preferring the alternative treatments.
Another factor behind the slow uptake has been a reluctance with physicians. Whilst the majority of physicians do believe that the LDL reductions are significant, but not all physicians believe that reduction will translate into tangible outcomes. This, combined with the barriers that are being imposed by payers, is hindering the uptake of the PCSK9 inhibitors.
For physicians and payers to encourage wider use of the PCSK9 inhibitors, evidence needs to be produced regarding the potential significant reduction in cardiovascular (CV) events from these treatments. Both Amgen and Regeneron have initiated long term cardiovascular trials to address this need, which are expected to read out in 2017 (Repatha) and 2018 (Praluent). What level constitutes a significant reduction is another matter, with most physicians stating around a 20% reduction in CV events, whilst some payers have speculated that the reduction in events would need to be closer to 50%. A recent interim analysis for Praluent has provided little insight, as the bar for halting the trial was set at 20% reduction in CV events was not met. Had the outcomes trial been halted early, it would have been a huge boost to both Praluent and Repatha.
So what does this mean for the PCSK9 inhibitors class? Fundamentally, little will change in the management or uptake of these products until the results of the cardiovascular outcomes trials are known and then it will be down to magnitude of the CV reduction that will be important to the commercial success of these molecules. It is clear that a 20% or greater reduction in CV events is required in order to drive wider use of Praluent and Repatha, but the reality may be more nuanced.
There are also a number of interesting implications for other biologics considering to enter similar disease populations like cholesterol reduction. First, even with a significant reduction in surrogate markers, payers still want to be convinced of the clinical outcomes data, particularly if there are other therapies that are currently effectively managing the disease. Second, payers can put in place multiple prescribing obstacles to limit physician uptake if they don’t believe in the treatment or the current evidence base. Thirdly, widespread physician support is not guaranteed if physicians do not believe the price level fully reflects the value of the product.
Finally, it all comes down to price and perceived value. At the moment, both payers and physicians do not believe that at the current price level, Praluent and Repatha offer significant value for widespread use. Both PCSK9 inhibitors have had some success in the UK and Germany where reimbursement is restricted beyond the regulatory label for very small patient populations, which had a high unmet need. This demonstrates that access can be achieved at the current price level, but only for a small subset of patients, which significantly limits the revenue potential for these products. This implies that whilst not failures, it is highly unlikely that Praluent and Repatha will achieve their revenue forecasts, at least in the short term, until the benefit in the broader patient population is demonstrated.