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New treatment options for familial hypercholesterolemia on the horizon
FDA advisory committee recently voted in favor of two agents for this rare condition.
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Two orphan medications were recommended for approval by the FDA Endocrinologic and Metabolic Drugs Advisory Committee in October for the treatment of homozygous familial hypercholesterolemia — a rare disease that affects just one in 1 million, or 300 patients, in the United States.
Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant genetic disease, known for marked elevations in LDL plasma levels and premature atherosclerotic CVD. Patients with the rare disease tend to develop early, severe atherosclerotic CVD and sometimes early cardiac-related death.
Although the current treatment option for patients with HoFH and other severe forms of hypercholesterolemia remains LDL apheresis, many patients have difficulty following the process.
Christie M.
Ballantyne
“It is exciting that we may have two new effective therapies available for patients with homozygous familial hypercholesterolemia. If approved, both drugs should be used by specialists in the indicated patients with careful follow-up, as we don’t yet have enough data about long-term safety and side effects,” Christie M. Ballantyne, MD, professor of medicine at Baylor College of Medicine and director of the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart Center in Houston, said in an interview.
Lomitapide: An oral option
By a 13-2 vote on Oct. 17, the FDA advisory panel recommended approval of lomitapide (Aegerion Pharmaceuticals), a small-molecule inhibitor of microsomal triglyceride transfer protein (MTP). This action of MTP inhibition is thought to prevent the synthesis of chylomicrons and VLDL.
In clinical studies, lomitapide combined with a low-fat diet and other lipid-lowering medications reduced mean LDL to 190 mg/dL, down 40.1% from baseline (336 mg/dL at baseline; P<.0001). Additional data presented during the meeting revealed significant effects on HDL and apolipoprotein B.
Committee members harbored concerns about severe adverse events, including hepatic steatosis, and use in lower-risk populations, such as those with heterozygous familial hypercholesterolemia. Additionally, committee members questioned whether the drug would be suitable for the pediatric population, as the clinical trials did not include children.
William R. Hiatt
“In a broad population, there’s not a doubt in my mind there will be severe liver toxicity occurring in a few patients,” committee member William R. Hiatt, MD, FACP, of the University of Colorado School of Medicine, said during the meeting. Hiatt voted in favor of the new drug application.
In a phase 3 trial, 11 of 29 patients (38%) experienced alanine aminotransferase (ALT) more than three times the upper limit of the normal range. Seven patients experienced a peak of more than five times the upper limit of the normal range. The mean absolute change in hepatic fat from baseline to week 26 showed an increase of 8.1% and an increase of 7.4% at week 78.
“The approval recommendation for lomitapide was much more enthusiastic than that of a similar intervention, mipomersen [the following day],” Sergio Fazio, MD, PhD, professor of medicine and pathology and director of the Vanderbilt Lipid Laboratory and co-director of the atherosclerosis research unit, said in an interview.
Sergio Fazio
“In both cases, the panel recommended strict adherence to the patient-type officially targeted, namely the HoFH subject. However, the definition of homozygosity for FH is only accurate when done at the genetic level, whereas the phenotypic characterization is open to interpretation,” Fazio added.
He said it will be interesting to see whether genetic testing of patients with extreme hypercholesterolemia will be considered for recommendation by the FDA and covered by insurers.
Mipomersen: An injectable option
On Oct. 18, committee members voted 9-6 in favor of the approval for mipomersen (Genzyme Corp.). Mipomersen is an ApoB synthesis inhibitor. Mipomersen comes in the form of a 200-mg once-weekly subcutaneous injection.
Committee member Robert J. Smith, MD, of Alpert Medical School of Brown University in Rhode Island, who voted against approval, expressed his understanding of the need for better treatments for the rare disease.
“However, I felt it was critical not to let that become an enthusiasm that might cloud my willingness to consider the adverse affects that might be associated with this medication and on the consequences for individuals who are receiving benefit or for individuals who aren’t receiving those great benefits. My primary concern in my ‘no’ vote is safety. Based on the data presented, I believe there’s a need for expanded safety data pre-approval, especially in regard to liver toxicity,” Smith said after the vote.
Although the drug was found to lower LDL by 24.7%, the potential for serious adverse events troubled panel members.
Regarding liver transaminases, 22 patients (8%) in the mipomersen group from the pooled phase 3 trials, had ALT levels greater than three times the upper limit of normal on at least two consecutive occasions at least 7 days apart, compared with none in the placebo group.
Hepatic steatosis occurred in 7.3% of patients treated with mipomersen. Panel members also expressed concern about the uncertainty of the long-term consequences of drug-induced hepatic steatosis with mipomersen, and whether the steatosis could progress to nonalcoholic steatohepatitis (NASH) is unknown.
Safety strategies for moving forward
Given uncertainties about the potential risk for liver toxicity in both medications, along with the safety database limitations for mipomersen, the agency proposed a Risk Evaluation and Mitigation Strategy that would restrict access to the drug to medically appropriate patients only and provide education to prescribers on the uses of mipomersen and the risks associated with the medications. This would also include monitoring patients and certifications for physicians and pharmacies.
The FDA has assigned a Prescription Drug User Fee Act action date of Dec. 29 for completion of its review of the New Drug Application for lomitapide and Jan. 29 for mipomersen. An application for marketing approval of mipomersen is currently pending in the European Union.
Disclosure: The panel members report no relevant financial disclosures related to the medication sponsors. Ballantyne has received consultancy fees for Aegerion and Genzyme. Fazio has been a consultant to Aegerion, Kowa, Lupin, Merck, Roche and Sanofi. Fazio has also received research support from ISIS, Merck and Pfizer.