The statin class provided a major breakthrough for managing high cholesterol, a key modifiable risk factor for cardiovascular (CV) disease, and are now the dominant first-line therapy. These orally administered, once-daily drugs are now inexpensive, and more importantly, they reduce the risk of CV events and save lives. This efficacy coupled with a generally benign safety profile has led to widespread prescribing of statins. Among this class are three multi-blockbuster drugs: Merck’s Zocor (simvastatin), AstraZeneca and Shionogi’s Crestor (rosuvastatin), and Pfizer’s Lipitor (atorvastatin) are amongst the best-selling drug of all time.
However, no drug is perfect. Statins can cause muscle problems in a small proportion of patients and there is a link to a greater risk of new-onset diabetes mellitus, plus very weak evidence for impaired cognition. Overall, the vast majority of physicians argue that the benefits of statins far outweigh the risks, but outside of the medical community, statins have a somewhat damaged reputation. The widespread use and success of statins has led to increased scrutiny of the class by the lay press, resulting in news stories that have caused alarm among some people. Now, a considerable proportion of people who could benefit from a statin perceive themselves to be intolerant or refuse to even trial the drugs. These people and those who are really are intolerant remain at increased risk of CV disease, compared with statin users.
The alternatives to statins are limited. Merck’s Zetia/Ezetrol (ezetimibe) offers low-density lipoprotein (LDL)-cholesterol reduction only in the range of the less-potent stains, and although its IMPROVE-IT CV outcomes trial demonstrated a significant benefit over placebo, there has been debate amongst experts as to how clinically meaningful these results were; the FDA was not impressed enough to update any labels based on the IMPROVE-IT findings. Then, aside from the poorly tolerated and modestly efficacious bile acid sequestrants, the only other options are the new proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors. These injectable antibodies effectively lower LDL-cholesterol both in statin-treated and in statin-intolerant patients, and also provide CV benefits on tops of statins. The stumbling block? They cost $14,000 year in the United States, making them prohibitively expensive for many patients and a target for strict cost controls from payers. All in all, millions of people who cannot or will not take a statin are missing out when it comes to effectively reducing their CV risk.
“If there is another drug that comes along that is taken orally, reduces LDL-cholesterol dramatically, that can be taken as a pill, and would be less expensive, then I think that will be a strong competitor for the PCSK9 inhibitors.” U.S. Cardiologist
But there is hope for these patients and one which is expected to be relatively affordable. Indeed, Esperion Therapeutics’ bempedoic acid (ETC-1002) could be the next big thing for blood cholesterol management. Bempedoic acid targets adenosine triphosphate (ATP) citrate lyase, an enzyme that acts earlier in the cholesterol biosynthesis pathway than the enzyme targeted by the statins. Like Zetia/Ezetrol, bempedoic acid can only lower LDL-cholesterol to around the same degree as the less-potent statins. What is exciting is the potential for its use in combination with generic ezetimibe. Products like Vytorin, Merck’s fixed-dose combination of ezetimibe and simvastatin, can offer LDL-cholesterol reductions approaching that of the high potency statins, and it is this level of efficacy that can make the difference for statin intolerant patients who are at higher risk for atherosclerotic CV disease. Esperion certainly thinks so, making statin intolerant patients the primary focus of the development program for their drug candidate. Moreover, there does not appear to be the safety issues raised with other emerging oral therapies, and the small molecule formulation is unlikely to be as costly as the PCSK9 monoclonal antibodies.
“Bempedoic acid does not have any baggage we know of, like anacetrapib with its lingering drug levels four years later.” U.S. Cardiologist
After conducting interviews with experts in the field, survey of practicing physicians, and our own literature reviews, we here at DRG think bempedoic acid has the profile to meet an important unmet need for patients who cannot or do not want to take a statin. If priced similarly to branded statins or Zetia/Ezetrol, DRG’s Dyslipidemia market forecast for 2016-2026 projects that bempedoic acid could be prescribed to millions of people, and make billions of dollars. Although it may not achieve the revenues of the statins, it may become the mainstay of treatment for those who cannot or do not want to take one.
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