In our November 20, 2012 article on this blog, entitled “Novel hypercholesterolemia drugs move toward FDA decisions”, we discussed two drugs–Aegerion Pharmaceuticals’ lomitapide, and Isis/Sanofi/Genzyme’s mipomersen. In October 2012, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that both drugs be approved for treatment of homozygous familial hypercholesterolemia (HoFH).
In that article, we discussed issues involved in the development and commercialization of lomitapide–a small-molecule drug, and mipomersen–an antisense oligonucleotide, for treatment of HoFH, a rare genetic disease which is mechanistically related to more common types of hypercholesterolemia. We also stated that were were awaiting FDA action–expected in the next several weeks after publication of our article–on the approval of the two drugs.
On Christmas Eve–December 24, 2012–a day on which few people in the United States and in many other countries were thinking about work–Aegerion (Cambridge, MA) announced that the FDA had approved lomitapide for treatment of HoFH. Lomitapide has been given the brand name Juxtapid.
The FDA based its approval of lomitapide on the results of a pivotal Phase 3 study, which evaluated the safety and effectiveness of the drug in 29 adult patients with HoFH. As we discussed in our November 20, 2012 article, the results of this study were published in the online version of The Lancet on November 2, 2012.
As we also discussed in our earlier article, lomitapide has serious adverse effects, including hepatic fat accumulation and elevated liver aminotransferase levels. According to the December 24, 2012 Aegerion press release, the most common adverse reactions seen in the Phase 3 study were gastrointestinal, including diarrhea, nausea, vomiting, dyspepsia and abdominal pain. Ten of the 29 patients in the study had at least one elevation in liver enzymes greater than or equal to three times the upper limit of normal. Liver enzyme elevations were managed through dose reduction or temporary discontinuation of dose. Hepatic fat accumulation was also observed in the Phase 3 trial.
As we also discussed in our earlier article, a finding of elevated liver aminotransferase levels is enough to stop development of most drugs. As of October 2012, the FDA and its Advisory Panel believed that a risk evaluation and mitigation strategy (REMS) would support appropriate use of these drugs in patients with homozygous FH, because of their life threatening disease, and because they have limited therapeutic options.
According to the December 24, 2012 Aegerion press release, the label for lomitapide contains a Boxed Warning citing the risk of hepatic toxicity. A Boxed Warning is the strongest warning that the FDA requires.
Lomitapide is avaiable only through the Juxtapid Risk Evaluation and Mitigation Strategy (REMS) Program. Aegerion will certify all health care providers who prescribe Juxtapid and the pharmacies that will dispense the medicine.
The goals of the REMS are:
- To educate prescribers about the risk of hepatotoxicity associated with the use of lomitapide, and the need to monitor patients during treatment with the drug.
- To restrict access to therapy with lomitapide to patients with a clinical or laboratory diagnosis consistent with HoFH.
The safety and efficacy of lomitapide have not been established in patients with hypercholesterolemia who do not have HoFH. The effects of the drug on cardiovascular morbidity and mortality has not been determined. The safety and effectiveness of lomitapide have not been established in pediatric patients.
In addition to establishing the REMS, Aegerion has made a commitment to the FDA to conduct a post-approval, observational cohort study. The company has also developed a comprehensive support services program for patients and their healthcare providers.
As we discussed in our November 20, 2012 article, Aegerion will be marketing lomitapide on its own, without a larger partner, and has been ramping up its marketing and sales organization in anticipation of approval. The company has set up a website for the product, www.juxtapid.com.
We await the FDA’s decision on the approval of mipomersen, to see how this chapter in the hypercholesterolemia drug development story will unfold.
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