Author + information
- †Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School–University of Queensland School of Medicine, New Orleans, Louisiana
- ‡Department of Preventive Medicine, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
- ↵∗Reprint requests and correspondence:
Dr. Richard V. Milani, Ochsner Heart and Vascular Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121.
- antisense oligonucleotides
- apolipoprotein B
- cholesterol inhibitors
- hypolipidemic agents
- lipid-regulating agents
Coronary heart disease (CHD) remains the leading cause of death in the United States, and its foundational therapy, risk factor control, remains problematic (1). Data from the National Health and Nutrition Examination Survey suggest that from 2005 to 2010, only 45% of United States patients with hypercholesterolemia achieved low-density lipoprotein (LDL) cholesterol control, and fewer than 1 in 3 patients with hypertension and hypercholesterolemia attained control of both disorders (2). These failures of treatment do not appear to be due to lack of provider awareness, as most physicians are cognizant of guideline-based goals; rather, they can be largely ascribed to what has been called therapeutic inertia, which occurs when a provider fails to increase therapy when treatment goals are unmet (3,4) (Table 1). In uncontrolled hypertension, the prevalence of therapeutic inertia is remarkably high, reported in 86.9% of visits when the blood pressure was ≥140/90 mm Hg (5).
In addition to these prevalent but correctable impediments to achieving evidence-based goals, patients may less commonly present with genetic disorders for which existing therapies are genuinely insufficient. In the case of lipid management, patients with homozygous familial hypercholesterolemia (HoFH) (frequency of 1 in 1 million) and severe forms of heterozygous familial hypercholesterolemia (frequency of 1 in 500) experience high rates of cardiovascular morbidity and mortality, and conventional therapy with statins, ezetimibe, newer bile acid sequestrants, and extended-release niacin formations generally fail to achieve LDL cholesterol levels anywhere near goal (6). Clearly, newer pharmacotherapies are needed to address populations with these unique genetic conditions.
To stimulate interest in meeting the needs of small populations with rare diseases who have been “orphaned” from pharmaceutical development because of poor economic potential, Congress passed the Orphan Drug Act in 1983. The legislation created financial incentives in the form of substantial tax incentives (totaling half the development costs), clinical research and development subsides, fast-track development and approval, and enhanced patent protection and marketing rights for pharmaceutical manufacturers who create drugs for Americans with a “rare disease or condition” (7). These incentives were fashioned to kindle interest in developing pharmaceutical agents when otherwise, there would be “no reasonable expectation that the costs of drug development and marketing would be recovered in future sales of the drug in the United States,” and by most measures, the Orphan Drug Act has been a successful program to many of the 20 million to 25 million Americans currently afflicted with rare diseases (7,8). To date, 425 indication designations covering 347 drugs have been approved, and this success has led to the adoption of similar orphan programs in Japan (1993) and the European Union (2000) (9,10).
Thirty years after its passage, however, the political, social, and economic context has evolved, and the orphan drug market has transformed itself into a big business, currently exceeding $61 billion in annual revenue, with projected growth to $105 billion by 2017 (8,11). By 2018, orphan drugs are expected to constitute 15.9% of worldwide prescription sales, excluding generics, and today, the 5 most expensive drugs in the world are orphan drugs, with price tags ranging from $300,000 to $409,500 per year (Table 2) (10,12). Because of such high prices, almost a third of all orphan drugs marketed today will exceed $1 billion in annual sales (13).
A new orphan drug entering the cardiovascular arena is mipomersen, a second-generation antisense oligonucleotide developed for patients with HoFH. Given as a weekly subcutaneous injection, mipomersen inhibits apolipoprotein B-100 protein synthesis in the liver, leading to reductions in apolipoprotein B–containing lipoproteins (including LDL cholesterol) in the circulation. Phase 3 clinical trials conducted in patients with HoFH and heterozygous familial hypercholesterolemia on background statin therapy have demonstrated reductions in LDL cholesterol of 25% to 28% (14,15). Side effects reported include frequent injection site reactions, flu-like symptoms, increases in hepatic fat, and liver function test abnormalities. On the basis of these findings, the United States Food and Drug Administration approved mipomersen in January 2013 (as a risk evaluation and mitigation strategy) as an adjunct to diet and drug therapy in patients with HoFH, whereas its European counterpart, the Committee for Medicinal Products for Human Use, recommended against approval because of safety concerns (16,17).
In this issue of the Journal, Thomas et al. (18) evaluate the use of mipomersen in 157 patients without a genetic disorder of lipid metabolism but in whom CHD was established or there was high risk for its development, who had not met LDL cholesterol goals while on statin therapy (mean LDL cholesterol 123 mg/dl). Interestingly, only 40% of patients were taking the maximal Food and Drug Administration–approved statin dose, and only 57% were taking second a lipid-lowering agent, thus mirroring a level of therapeutic inertia commonly described in the general population. After weekly injections over 26 weeks, mipomersen-treated subjects demonstrated a reduction in LDL cholesterol of 36.9% (with 76% falling below an LDL cholesterol level of 100 mg/dl), compared with placebo LDL cholesterol reductions of 4.5% (with 38% falling below an LDL cholesterol level of 100 mg/dl). Mipomersen treatment, however, was accompanied by a high frequency of significant side effects, including injection site reactions, flu-like symptoms, liver function test abnormalities, and hepatic steatosis, such that 43% of mipomersen-treated subjects dropped out of the study. In contrast to patients with HoFH, among whom the dropout rate was 18%, this therapy was judged unacceptable and intolerable in a population of patients with a lower underlying disease risk and in whom multiple less cumbersome treatment alternatives are currently available (14). The investigators conclude that clinicians should “focus on managing patient expectations.” Rather, we should refocus our delivery system to better manage and control health measures in chronic disease. In hypertension, for which only half of patients achieve goal blood pressures, reorganizing the delivery model to include telemonitoring and pharmacist intervention resulted in 71% of patients’ achieving blood pressure control, compared with 53% using the existing delivery model (19,20). For most patients with CHD or at risk for CHD who do not have uncommon genetic disorders, newer, more expensive and cumbersome pharmacotherapies should not be our first priority, but rather a reorganization of clinical practice to include nonphysician practitioners.
For patients with HoFH, orphan drugs are clearly needed, and in addition to mipomersen, a second orphan has been recently approved by the Food and Drug Administration, also as a risk evaluation and management strategy. Lomitapide is given once daily as oral therapy and has demonstrated impressive reductions in LDL cholesterol (40% to 50%) in patients with HoFH by inhibiting microsomal triglyceride transfer protein; however, this was accompanied by side effects including steatosis, gastrointestinal symptoms, and liver function test abnormalities (21). The good news for patients with HoFH is that both mipomersen and lomitapide can offer the opportunity to lower LDL cholesterol closer to goal, potentially reducing the substantial burden of disease they have faced until now. Their collective financial burden, however, will be substantial: lomitapide runs $235,000 to $295,000 a year, depending on the patient, and mipomersen will cost $176,000 per year (13).
These and other orphan drugs can offer hope to those with an estimated 7,000 rare diseases that exist today (22). The only question now will be if we can afford the bill.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Lavie is a speaker and consultant for AbbVie, GlaxoSmithKline, and Amarin Pharma. Dr. Milani has reported that he has no relationships relevant to the contents of this paper to disclose.
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- ↵EvaluatePharma. Orphan drug report 2013. Available at: http://www.evaluategroup.com/Default.aspx. Accessed July 27, 2013.
- Kalorama Information, a Division of MarketResearch.com. Growth expected in orphan drug markets: finds new Kalorama report. Available at: http://www.prweb.com/releases/2013/6/prweb10863817.htm. Accessed July 26, 2013.
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- European Medicines Agency. Refusal of the marketing authorisation for Kynamro (mipomersen). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002429/WC500136279.pdf. Accessed July 25, 2013.
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