The FDA said today that it had granted approval to the novel cholesterol-lowering drug mipomersen sodium for use as an adjunct to diet and drug therapy in patients with homozygous hypercholesterolemia. The drug, which was developed by Isis Pharmaceuticals, will be marketed under the brand name of Kynamro by Genzyme.
Kynamro was approved as an orphan drug, which the FDA describes as meaning it was developed to treat a condition affecting less than 200,000 people. The standard of approval for orphan drugs is less rigorous than other drugs. There has been some confusion about the number of people who have homozygous familial hypercholesterolemia. The FDA and ISIS/Genzyme said the condition affects about one in every million people.
In December the FDA approved lomitapide (Juxtapid, Aegerion) for the same condition. These are the first drugs specifically developed and approved for familial hypercholesterolemia.
Kynamro will carry a boxed warning about the serious risk of liver toxicity. Clinical studies with the drug found that it raised liver enzymes and led to accumulation of fat in the liver. The FDA said this "could lead to progressive liver disease with chronic use."
Kynamro was approved with a Risk Evaluation and Mitigation Strategy (REMS) which will require certification of prescribers and pharmacies, as well as documentation that the drug is being properly used with each new prescription.
The FDA said the most common adverse reactions with Kynamro were injection site reactions, flu-like symptoms, nausea, headache and elevations in liver enzymes.
The FDA is requiring the sponsor to perform four postmarketing studies, including a long-term registry of patients to assess the long-term safety of the drug, and an enhanced pharmacovigilance program to monitor potential problems.
“Kynamro is the first systemic antisense drug to reach the market and is the culmination of two decades of work to create a new, more efficient drug technology platform. As evidenced by our robust pipeline, our antisense drug discovery technology is applicable to many different diseases, including the treatment of a chronic and rare disease, like HoFH,” said Stanley Crooke, the chair and CEO of Isis, in a press release.
In October, an FDA advisory panel voted to recommend approval of mipomersen, though the panel expressed considerable caution about the potential for liver damage. In December the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended that the drug not be approved for use in Europe.
The FDA is requiring four postmarketing studies for Kynamro: the development of a sensitive assay that binds double-stranded (ds) DNA; a study to assess for the presence of antibodies to ds-DNA in patients treated with Kynamro; a long-term registry of patients with HoFH to determine the long-term safety of Kynamro; and an enhanced pharmacovigilance program to monitor reports of malignancy, immune-mediated reactions, and hepatic abnormalities in patients treated with Kynamro.
Here is the Isis and Genzyme release:
Genzyme and Isis Announce FDA Approval of KYNAMRO™ (mipomersen sodium) Injection for the Treatment of Homozygous Familial Hypercholesterolemia
CAMBRIDGE, Mass. & CARLSBAD, Calif.--(BUSINESS WIRE)--Genzyme, a Sanofi company (EURONEXT: SAN and NYSE: SNY), and Isis Pharmaceuticals Inc. (NASDAQ: ISIS), today announced that the U.S. Food and Drug Administration (FDA) has approved its New Drug Application (NDA) for KYNAMROTM (mipomersen sodium) injection. KYNAMRO, given as a 200 mg weekly subcutaneous injection, has been approved as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).
“Today’s FDA approval of KYNAMRO is great news for patients with HoFH who are in need of additional treatment options for this rare, and often under-diagnosed disease,” said Genzyme President and CEO, David Meeker, M.D. “As the leader in treatments for rare diseases, we are pleased to bring our expertise to HoFH patients living with this serious condition to better help them manage their disease.”
HoFH is a rare inherited condition that makes the body unable to remove LDL cholesterol, often called the “bad” cholesterol, from the blood, causing abnormally high levels of circulating LDL cholesterol. In the United States, HoFH, an orphan indication, occurs in approximately one in one million individuals. For those with HoFH, heart attacks and death often occur before age 30.
“People living with Homozygous FH may not appear to be sick, but they live with the burden of this rare disease every day,” said Katherine Wilemon, President and Founder the FH Foundation "The approval of KYNAMRO gives the HoFH community hope that HoFH can be effectively managed.”
The FDA approval triggers a $25 million milestone payment to Isis from Genzyme.
“KYNAMRO is the first systemic antisense drug to reach the market and is the culmination of two decades of work to create a new, more efficient drug technology platform. As evidenced by our robust pipeline, our antisense drug discovery technology is applicable to many different diseases, including the treatment of a chronic and rare disease, like HoFH,”said Stanley T. Crooke, M.D., Ph.D., Chairman of the Board and CEO of Isis. “We look forward to continuing to work with Genzyme toward a successful commercial launch of KYNAMRO and global expansion into other markets.”
Safety data for KYNAMRO are based on pooled results from four Phase 3, randomized, double-blind, placebo-controlled trials with a total of 390 patients of which 261 patients received weekly subcutaneous injections of 200 mg of KYNAMRO and 129 patients received placebo for a median treatment duration of 25 weeks. Eighteen percent of patients on KYNAMRO and 2% of patients on placebo discontinued treatment due to adverse reactions. The most common adverse reactions in patients treated with KYNAMRO that led to treatment discontinuation and occurred at a rate greater than placebo were: injection site reactions (5.0%), alanine aminotransferase (ALT) increased (3.4%), flu-like symptoms (2.7%), aspartate aminotransferase (AST) increased (2.3%), and liver function test abnormal (1.5%).
KYNAMRO is an antisense drug and is metabolized without affecting the CYP450 pathways used in commonly prescribed drugs, and thus has potential for no drug-drug interactions. No clinically relevant pharmacokinetic interactions were reported between KYNAMRO and warfarin, or between KYNAMRO and simvastatin or ezetimibe.
KYNAMRO contains a Boxed Warning citing the risk of hepatic toxicity. Patients taking KYNAMRO should have liver enzyme testing before starting the drug and periodically thereafter.See below for Important Safety Information about KYNAMRO.
The safety and effectiveness of KYNAMRO have not been established in patients with hypercholesterolemia who do not have HoFH. The effect of KYNAMRO on cardiovascular morbidity and mortality has not been determined.
Because of the risk of hepatotoxicity, KYNAMRO is available only through a Risk Evaluation and Mitigation Strategy (REMS) called the KYNAMRO REMS. The goals of the KYNAMRO REMS are:
- To educate prescribers about the risk of hepatotoxicity associated with the use of KYNAMRO, and the need to monitor patients during treatment with KYNAMRO as per product labeling.
- To restrict access to therapy with KYNAMRO to patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia (HoFH).
KYNAMRO may cause serious side effects, including liver problems. A doctor should be informed of any liver problems, including liver problems while taking other medicines, or if a patient has any of these symptoms of liver problems while taking KYNAMRO: nausea, vomiting, fever, loss of appetite, being (or feeling) more tired than usual, yellowing of eyes or skin, dark urine, itching, or stomach pain.
Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking KYNAMRO should consume no more than one alcoholic drink per day.
Caution should be exercised when KYNAMRO is used with other medications known to have potential for hepatotoxicity.
KYNAMRO should be used during pregnancy only if clearly needed. Females who become pregnant during KYNAMRO therapy should notify their healthcare provider.
Safety and effectiveness have not been established in pediatric patients.
KYNAMRO is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.
The safety and effectiveness of KYNAMRO as an adjunct to LDL apheresis have not been established; therefore, the use of KYNAMRO as an adjunct to LDL apheresis is not recommended.
KYNAMRO is contraindicated in the following conditions:
- Moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases.
- Patients with a known hypersensitivity to any component of this product.
COMMON SIDE EFFECTS
In clinical trials the most commonly-reported adverse reactions were injection site reactions occurring in 84% of patients receiving KYNAMRO versus 33% of placebo treated patients. The most common injection site reactions were erythema (59%), pain (56%), hematoma (32%), pruritus (29%), swelling (18%) and discoloration (17%). Injection site reactions did not occur with every injection but resulted in discontinuation of therapy in 5% of patients in pooled phase 3 trials.
Flu-like symptoms, defined as any one of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue and occurring within 2 days of injection, have been reported more frequently in patients receiving KYNAMRO (30%) versus placebo (16%) in the pooled Phase 3 trials. Flu-like symptoms did not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled phase 3 trials.
Genzyme has pioneered the development and delivery of transformative therapies for patients affected by rare and debilitating diseases for over 30 years. We accomplish our goals through world-class research and with the compassion and commitment of our employees. With a focus on rare diseases and multiple sclerosis, we are dedicated to making a positive impact on the lives of the patients and families we serve. That goal guides and inspires us every day. Genzyme’s portfolio of transformative therapies, which are marketed in countries around the world, represents groundbreaking and life-saving advances in medicine. As a Sanofi company, Genzyme benefits from the reach and resources of one of the world’s largest pharmaceutical companies, with a shared commitment to improving the lives of patients. Learn more at www.genzyme.com.
Sanofi, a global and diversified healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients’ needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).
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