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Lomitapide: A Risky Drug for Lowering Cholesterol

Worst Pills, Best Pills Newsletter article November, 2013

Lomitapide (JUXTAPID) is a newly approved drug used to lower cholesterol in people with homozygous familial hypercholesterolemia, or HoFH, which is a rare genetic disease affecting approximately 300 people in the U.S.[1] Patients with HoFH have difficulty moving cholesterol from their blood into their tissues, resulting in very high blood cholesterol levels. HoFH patients are at high risk for developing severe atherosclerotic cardiovascular disease[2] — the hardening and narrowing of the...

Lomitapide (JUXTAPID) is a newly approved drug used to lower cholesterol in people with homozygous familial hypercholesterolemia, or HoFH, which is a rare genetic disease affecting approximately 300 people in the U.S.[1] Patients with HoFH have difficulty moving cholesterol from their blood into their tissues, resulting in very high blood cholesterol levels. HoFH patients are at high risk for developing severe atherosclerotic cardiovascular disease[2] — the hardening and narrowing of the arteries — early in life.

Lomitapide was approved as an orphan drug,[3] meaning that it is meant to treat a rare disease affecting less than 200,000 people.[4] Its critical clinical testing involved only 29 people.[5] Although it is currently approved for the small group of patients with HoFH and is sold only through a restricted program, it is possible that it eventually will be used by many more people for treating high cholesterol. The drug’s label includes a black box warning (the strongest safety advisory mandated for a drug’s labeling by the Food and Drug Administration [FDA]) regarding liver toxicity,[6] and testing in animals and humans has confirmed an abundance of safety concerns.[7]

About Orphan Drugs

Because there are only an estimated 300 people[8] in the U.S. with HoFH, lomitapide qualifies for orphan drug status.

The orphan drug designation has tremendous advantages for drug companies and has been sought by many companies in recent years. Once the FDA accepts an application for orphan drug status, the drug company that submitted the application is eligible for tax credits for the costs of clinical research, a waiver of filing fees (in 2009, this amounted to more than $1 million per application), seven-year exclusivity for marketing, and help with research study designs.

Companies seeking an orphan drug designation also can get help from a number of organizations, such as National Organization for Rare Diseases and Rare Disease Day, that publicize rare diseases.[9],[10] There also is an Office of Rare Diseases at the National Institutes of Health[11] and an Office of Orphan Products Development at the FDA.[12],[13]

It is not uncommon for a manufacturer to try to get approval for the population at greatest risk and then subsequently expand the drug’s use by testing in other populations less seriously at risk. This process of following up initial approval with indications for a broader population is a technique that drug companies have found lucrative. The FDA has tried to limit this practice in this case by requiring the company to develop a restricted program under which only certified health care providers and pharmacies may prescribe and distribute the drug.[14] It remains to be seen whether this program will be effective at preventing off-label use.

About lomitapide

Lomitapide was originally conceived as a drug to lower cholesterol in people with mixed dyslipidemia (abnormal levels of cholesterol or other fats in the blood), but in 2000, the company stopped its program to develop the drug for this purpose, as a result of concerns over side effects.[15]

Later, a researcher[16] at the University of Pennsylvania saw patients with HoFH as a potential population for whom the benefits might be seen as outweighing the risks.[17] In 2007 he was able to find a manufacturer willing to develop it.[18] By limiting the target population to patients with HoFH, who were at especially high risk for atherosclerosis, the company obtained approval from the FDA in December 2012 and from the European Medicines Agency in August 2013.[19],[20]

Lomitapide, which comes in capsule form, is effective in significantly lowering blood cholesterol levels.[21] However, for the HoFH population, it must be used in combination with a low-fat diet and other cholesterol-lowering treatments, including drugs or, where available, periodic treatments using a technology called apheresis (which involves removing blood from the patient through one tube connected to a vein, passing the blood through a machine that removes cholesterol and then returning the blood to the patient through another tube).

Risks of lomitapide

The list of adverse events associated with lomitapide, both in animals and humans, is extensive.

Gastrointestinal events associated with lomitapide included diarrhea, nausea, vomiting, dyspepsia and abdominal pain. Gastrointestinal events affected 27 of the 29 subjects (93%) in the premarket clinical study.[22] Events such as vomiting and diarrhea are particularly problematic because they can affect the levels of other drugs that a patient is taking and the dosages of these other drugs may require adjustment.

It appears that the most dangerous adverse effects of lomitapide relate to liver toxicity. The drug’s label begins with a black box warning stating that the drug causes an increase of liver enzymes and increases hepatic fat, which “may be a risk factor for progressive liver disease, including steatohepatitis [fatty liver disease often seen in alcoholics[23]] and cirrhosis [irreversible scarring of the liver which can progress to liver failure[24]].”

Many patients are unable to tolerate the drug’s side effects: Six of the original 29 patients in the premarket clinical trial dropped out prior to the end of the initial 26-week study,[25] and two of the 18 patients who continued into a long-term extension study dropped out as well.[26] Thus, it is possible that some patients may not be able to stay on the drug long enough to experience any benefit.

Lomitapide also interferes with the absorption of fat-soluble nutrients, and for this reason, patients must take daily doses of both fat-soluble vitamins and four specific fatty acids to avoid deficiencies.[27] In animal studies of lomitapide, there were deficiencies in four fat-soluble vitamins (A, D, E and K). Rats suffered systemic hemorrhage at 17 times and death at 70 times the exposure in humans (the bleeding was prevented by adding vitamin K).[28]

Furthermore, fetal malformations occurred in both pregnant rats and ferrets when the levels of drug in the animals’ blood were less than or equal to those of humans at the 60 mg daily dose.[29] As a result, women who may be or might become pregnant are warned to take a pregnancy test before starting lomitapide and to use contraception while on treatment.[30] However, oral contraceptives are among the drugs that interfere with lomitapide metabolism causing lomitapide blood levels to increase.[31] In addition, hormone absorption from oral contraceptives may be incomplete if vomiting or diarrhea occurs while taking lomitapide.[32] Therefore, use of additional contraceptive methods is necessary to reliably prevent pregnancy.

Lomitapide also caused tumors in the liver and small intestines of mice and liver damage in rats when taken at exposures slightly higher than those used in humans.[33]

Public Citizen opposition

On Oct. 17, 2012, Public Citizen testified before an FDA advisory committee convened to consider whether lomitapide should be approved.[34] We strongly opposed approval because of the evidence of toxicity of the drug and the lack of sufficient research demonstrating that it offered benefits over current available treatments that outweighed these risks.[35] We argued that more precise clinical trials testing lower doses of lomitapide combined with apheresis treatments — the best, first-line therapy for HoFH — needed to be done. Such trials could determine whether lower doses of the drug with apheresis might be more effective and safer treatments for these patients than the doses that were ultimately approved.[36]

Monitoring required

Patients taking lomitapide must undergo periodic blood tests to monitor for signs of liver damage.[37]

Patients and their physicians also must carefully monitor all other drugs being used at the same time as lomitapide. There are many drugs that increase exposure to lomitapide, which can cause lomitapide levels in the blood to rise to dangerous levels.[38] Lomitapide may also increase exposure to other drugs.[39] Because of these drug interactions, there are many drugs that should not be taken or taken at a lower dose when using lomitapide or the lomitapide dose itself should be reduced.[40],[41] Finally, grapefruit juice should be avoided when taking lomitapide because it blocks the breakdown of lomitapide.[42]

What You Should Do

If you have elevated LDL-cholesterol levels, there are many safer drugs to take. Do not use lomitapide. Although it may be tempting for physicians to recommend a drug that promises large reductions in cholesterol, lomitapide comes with too many potential adverse events to make it worth the risk.

The article “Elevated Cholesterol Levels” at WorstPills.org provides an overview of nondrug approaches to lowering cholesterol and offers advice on when drug treatment is and is not necessary.[43]

References

[1] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[2] Ibid.

[3] Ibid.

[4] Food and Drug Administration. How to apply for orphan drug designation. http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm365086.htm. Accessed October 22, 2013.

[5] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[6] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf. Accessed October 22, 2013.

[7] Supported by “risks” section, infra.

[8] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[9] National Organization of Rare Disorders. http://www.rarediseases.org/. Accessed October 22, 2013.

[10] Rare Disease Day. http://www.rarediseaseday.org/. Accessed October 22, 2013.

[11] National Institutes of Health. http://rarediseases.info.nih.gov/. Accessed October 22, 2013.

[12] Food and Drug Administration. Developing orphan products. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm107293.htm. Accessed October 22, 2013.

[13] Food and Drug Administration. Developing products for rare diseases and conditions. http://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/default.htm. Accessed October 22, 2013.

[14] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf. Accessed October 22, 2013.

[15] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[16] University of Pennsylvania. http://www.med.upenn.edu/apps/faculty/index.php/g275/p17778. Accessed October 22, 2013.

[17] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[18] Ibid.

[19] Aegerion Pharmaceuticals. Aegerion Pharmaceuticals receives European approval for LOJUXTA(TM) (lomitapide) to treat homozygous familial hypercholesterolemia (HoFH). http://ir.aegerion.com/releasedetail.cfm?ReleaseID=782124. Accessed October 22, 2013.

[20] European Medicines Agency. LOJUXTA. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002578/human_med_001668.jsp&mid=WC0b01ac058001d124. Accessed October 22, 2013.

[21] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[22] Center for Drug Evaluation and Research. Labeling. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000LBL.pdf. Accessed October 22, 2013.

[23] Wikipedia. Steatohepatitis. http://en.wikipedia.org/wiki/Steatohepatitis. Accessed October 22, 2013.

[24] Wikipedia. Cirrhosis. http://en.wikipedia.org/wiki/Cirrhosis. Accessed October 22, 2013.

[25] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[26] Summary Review; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000SumR.pdf. Accessed October 22, 2013.

[27] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203858s002lbl.pdf. Accessed October 22, 2013.

[28] Center for Drug Evaluation and Research. Medical review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000MedR.pdf. Accessed October 22, 2013.

[29] Ibid.

[30] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203858Orig1s000LBL.pdf . Accessed October 22, 2013.

[31] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf. Accessed October 22, 2013.

[32] Ibid.

[33] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf. Accessed October 22, 2013.

[34] Public Citizen. Testimony of Sidney Wolfe, M.D., and Michael Carome, M.D. http://www.citizen.org/documents/2078.pdf. Accessed October 22, 2013.

[35] Ibid.

[36] Ibid.

[37] Aegerion Pharmaceuticals. JUXTAPID. http://www.aegerion.com/Collateral/Documents/English-US/Prescribing_Information%20june%202013.pdf. Accessed October 22, 2013.

[38] JUXTAPID drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203858s000lbl.pdf. Accessed October 22, 2013.

[39] Ibid.

[40] Ibid.

[41] JUXTAPID drug label. Section 7: Drug interactions. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203858s002lbl.pdf. Accessed October 22, 2013.

[42] JUXTAPID drug label. Section 7.2. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203858s002lbl.pdf. Accessed October 22, 2013.

[43] Worst Pills, Best Pills. /chapters/view/42. Accessed October 22, 2013.

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