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FDA advisory committee OKs mipomersen for familial hypercholesterolemia
In a narrow 9-6 vote, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee today recommended approval for mipomersen for the treatment of homozygous familial hypercholesterolemia. However, the approval comes with concern for a lack of safety data.
Mipomersen (Genzyme Corporation) is the second orphan medication recommended for approval by the FDA committee in 2 days for the homozygous familial hypercholesterolemia — a rare disease that affects just one in 1 million, or 300 patients in the United States. Yesterday, the panel approved lomitapide (Aegerion Pharmaceuticals), an oral agent with the same indication.
The drug is an apolipoprotein B (apo-B) synthesis inhibitor, a second-generation antisense drug that is expected to decrease the production of apo-B. Mipomersen comes in the form of a 200-mg once-weekly subcutaneous injection.
Significant safety issues
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.
In the pivotal trial with homozygous familial hypercholesterolemia patients, the drug lowered LDL by 24.7%. However, serious adverse events, including cardiac disorders, were experienced by 10 of 261 patients (3.8%) compared with 4 of 129 patients in the placebo group. The most common adverse events included injection site reactions, flu-like symptoms and elevations in liver transaminases.
According to data, injection site reactions were experienced by 84% of patients treated with the drug, compared with 33% of those treated with placebo. Of these patients, 28% of mipomersen-treated patients discontinued treatment due to the injection site reaction.
Flu-like symptoms were reported among 30% of mipomersen-treated patients and 16% of placebo-treated patients. Of those, 15% of mipomersen-treated patients discontinued treatment due to the flu-like symptoms (ie, fatigue, pyrexia, chills and peripheral edema).
Regarding liver transaminases, 22 patients (8%) of the mipomersen group in 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% in patients treated with mipomersen, which troubled panel members. They 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.
In addition to these adverse events, the panel addressed the benign and malignant tumors found in 23 of 749 patients (3.1%) who were administered mipomersen during clinical testing neoplasms.
“I think we’re all deeply concerned about the severity of [homozygous familial hypercholesterolemia],” panelist Jeffrey B. Schwimmer, MD, from the department of pediatrics at the University of California, San Diego, said after the vote. “I voted ‘no’ because of the risk–benefit ratio. The degree of LDL- lowering overall was not as robust as one would like in order to be certain of a benefit.”
Schwimmer also highlighted concern for which patient population could in fact benefit from the drug, and said he found the dropout percentage to be “striking,” considering the lack of treatment options available for this patient population. Other panelists echoed his sentiments.
Looking ahead
Given the uncertainties about the potential risk for liver toxicity and safety database limitations, the agency proposed a Risk Evaluation and Mitigation Strategy (REMS) 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 hepatic effects. This would also include monitoring patients and certifications for physicians and pharmacies.
Mary McGowan, MD, senior medical director of clinical research at Genzyme, told the committee that the REMS will include ongoing and post-approval studies that will continue to collect data. This includes registry/observational safety study (MIPO39) and an ongoing 60-week double blind, placebo-controlled study in 480 severe homozygous familial hypercholesterolemia patients (MIPO38).
MIPO38 was started in December 2011. McGowan said they have enrolled 77 patients and have developed two cohorts, which they will each include 240 patients. McGowan said the study will help explore improvements in terms of tolerability by having patients titrate into the study.
“The first 8 weeks, patients will have a dose every other week. The second thing we’re doing is having two different dosing schedules. One is a dosing schedule continuing to do just as we did in the past with 200 mg weekly. The other is dosing at 70 mg three times per week. We do have some early evidence that perhaps 70 mg three times per week will increase symptoms and decrease injection site reactions,” McGowan said.
The committee agreed that further studies are needed to assess the safety and glucose testing should be included in their ongoing investigations.
Although the FDA is not required to follow the recommendations of the committee, it usually does.
For more information:
EMDAC Clinical Briefing Document. NDA 203568
Perspective
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I think it is very exciting that we may have two new effective therapies available for patients with homozygous familial hypercholesterolemia, which is a life-threatening condition that is very difficult to treat. 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.