Everyone who knows anything about lipids and cardiovascular (CV) disease loves the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: dyslipidemia experts, giant pharma companies, and even humble analysts all recognize the excellent low-density lipoprotein cholesterol (LDL-C)-lowering efficacy, the high likelihood of real CV benefits, and the clean safety profile of the PCSK9 inhibitors, they are one of the (it) drug classes for 2015. Even the European Medical Agency (EMA)s Committee for Medicinal Products for Human Use (CHMP) has shown the class some love, recommending Amgen's evolocumab (Repatha) for approval. No surprises there. The surprise was the amount of love shown by the CHMP. Most stakeholders and analysts had speculated that the quick development progress of the PCSK9 inhibitor class, plus the lack of long-term safety and CV outcomes trial (CVOT) data would make regulatory authorities err on the side of caution and limit use to niche populations initially, followed by a label expansion on the back of positive CVOT data. But approval from the EMA for a wide dyslipidemia population will likely occur in a matter of months: click here to see the EMA's press release for the full details of the proposed indications for Repatha. Consequently, the odds of the FDA loving the PCSK9 inhibitors in the United States have just been slashed.

Amgen must love the EMA's CHMP. As, too, will Sanofi and Regeneron, co-developers of alirocumab (Praluent), which is the other PCSK9 inhibitor under regulatory review in Europe and the United States; the data for both is so similar that a positive recommendation for alirocumab must surely follow. On the other hand, Pfizer, which has its PCSK9 inhibitor bococizumab in Phase III, is likely to be less enthusiastic about the CHMP's decision. Bococizumab is approximately two years behind evolocumab and alirocumab in terms of pivotal LDL-C-lowering trials. However, the CVOTs for the three drugs are expected to complete within months of each other. If evolocumab and alirocumab were restricted to niche populations and a limited number of physicians, bococizumab would have a much easier task of capturing market share if all three drugs were granted broad labels at a similar time. But now a wide range of physicians will likely be gaining familiarity with alirocumab and evolocumab across the entire spectrum of potential patients making the task of establishing bococizumab in the market a much more difficult prospect. However, Pfizer has in the past faced late market entry and done reasonably well. Anyone hear of a little drug called Lipitor?

But what does this mean for the dyslipidemia market going forward. Firstly, the EMA and FDA have not approved these agents with broad labels yet, but it does look likely. The high unmet need for additional LDL-C-lowering therapies and the great enthusiasm that physicians have for these drugs are strong market drivers, but practice guidelines, competitors, drug pricing, and other market access issues could limit the impact of the PCSK9 inhibitors.

Some recent lipid guideline updates have been strongly in favor of only considering the strongest evidence, which may see the responsible professional organizations delay restructuring their recommendations until the PCSK9 inhibitors, CVOT data is published, which could slow uptake. Moreover, further research into the effect of LDL-C levels from CV risk reduction and safety perspectives is needed. It seems to be the lower the LDL-C the better, but could we go too low?

Generic statins will continue to lead the way as first-line treatments in most patients with high LDL-C and elevated CV risk. However, it will now get very interesting in the second-line space. Merck's Zetia and Vytorin (ezetimibe and ezetimibe/simvastatin, respectively) appear to have modest but statistically significant improvements in CV morbidity, but few other non-statin therapies have recent, good-quality evidence of such benefits. However, the emerging CETP inhibitors, Merck's anacetrapib and Eli Lilly's evacetrapib, are likely to offer greater benefits than Zetia or Vytorin, and if competitively priced they could push the PCSK9 inhibitors down the treatment paradigm; notably, the CTP inhibitors are likely to need positive CVOT trial data for approval, owing to historical class issues.

Many analysts forecasted that the PCSK9 inhibitors would be priced at approximately $10,000 per year prior to the CHMP's recommendations, based on the excellent efficacy, purported CV benefits, the cost of manufacturing these injectable antibody formulations, and the small target populations they were predicted to have initially. Now, that the PCSK9 inhibitors are likely be available to a much broader population at launch, do I expect the price to come down dramatically? No. First, the need is still there, despite the array of lipid modifying agents on the market, LDL-C is still a major risk factor for CV disease. Second, there is little in the way of competition for the PCSK9 inhibitors, with respect to risk-benefit, although an oral PCSK9 inhibitor might change things (click here to see my colleague Stefanie Hoffarts thoughts on oral formulations shaking up drug classes dominated by injectables). So, I think the prices for PCSK9 inhibitors will be high. High prices are likely to see cost controls imposed on the PCSK9 inhibitors by payers, although draconian restrictions are unlikely owing to the long-term financial benefits from reductions in CV events. Overall, considering the high prevalence of lipid disorders, I believe these drugs are likely to be blockbusters several times over.

So, is there anyone who doesn't love PCSK9 inhibitors? Apart from the companies who don't have one in development, that is

Tim Blackstock, M.B. Ch.B., M.Phil., is a Senior  Analyst in the Cardiovascular, Metabolic, and Renal Disorders team at Decision Resources Group.

In-depth analysis of dyslipidemia, with accompanying epidemiology driven sales forecast models, are presented in Decision Resources Group's Dyslipidemia Pharmacor, available here.

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