Genzyme, a Sanofi company, and Isis Pharmaceuticals Inc. (NASDAQ: ISIS), today announced that new two-year data from a phase 3 long-term extension study of KYNAMRO® (mipomersen sodium) injection was presented at a scientific session at the annual American Heart Association meeting in Chicago, IL. In the study, a retrospective analysis showed that patients treated with KYNAMRO for a mean of two years had a significant reduction in Major Adverse Cardiovascular Events (MACE) compared to two years prior to therapy.
CAMBRIDGE, Mass. & CARLSBAD, Calif.--(BUSINESS WIRE)--“This analysis is very encouraging as the rate of MACE declined sevenfold after two years of treatment with KYNAMRO in patients with homozygous and heterozygous familial hypercholesterolemia (FH),” said Dr. John Kastelein, M.D., Ph.D., professor of medicine, chairman of the department of vascular medicine, Academic Medical Center, University of Amsterdam. “This analysis represents an important finding and supports the potential for further study of the therapeutic benefit of KYNAMRO in patients.”
This retrospective analysis included 104 patients who enrolled in the long-term extension study of KYNAMRO after having completed one of the KYNAMRO phase 3 blinded, randomized, placebo-controlled 6-month trials in patients with homozygous and heterozygous FH. All patients who completed at least two years of treatment with KYNAMRO were included in the analysis. The rate of MACE in patients treated with KYNAMRO for two years were adjudicated by an independent committee and compared to the rate of MACE in the same patients based on their medical history prior to treatment with KYNAMRO.
In this analysis, MACE were identified in 62% of patients during two years prior to KYNAMRO treatment, and 9% of patients during a mean of 24.4 months after initiation of treatment with KYNAMRO. MACE were defined as myocardial infarction (MI), stroke, unstable angina (UA) and revascularization procedures (PCI/CABG).
Number of MACE in
Number of MACE in
|MACE rate |
(per 1000 patient-months)
The marked reduction in MACE coincided with the absolute mean reductions in LDL cholesterol levels (-49 to -113 mg/dL) reported for the phase 3 FH clinical trials.
"Patients with homozygous FH have extreme cholesterol levels and are at significant risk for cardiovascular events. KYNAMRO is approved for use in these patients in the U.S. to reduce LDL-cholesterol, apoB, total cholesterol and non-HDL cholesterol as an adjunct to lipid lowering medication and diet. The data presented today are encouraging and add to the broad lipid lowering profile observed in these patients,” said Dr. Sotirios Tsimikas, M.D., professor of medicine and director of vascular medicine at the University of California, San Diego and vice president of clinical development and leader of the cardiovascular franchise at Isis.
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).
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF HEPATOTOXICITY
KYNAMRO can cause elevations in transaminases. In the KYNAMRO clinical trial in patients with HoFH, 4 (12%) of the 34 patients treated with KYNAMRO compared with 0% of the 17 patients treated with placebo had at least one elevation in alanine aminotransferase (ALT) ≥3x upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR) or partial thromboplastin time (PTT).
KYNAMRO also increases hepatic fat, with or without concomitant increases in transaminases. In the trials in patients with heterozygous familial hypercholesterolemia (HeFH) and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, from 0% at baseline, measured by magnetic resonance imaging (MRI). Hepatic steatosis is a risk factor for advanced liver disease; including steatohepatitis and cirrhosis.
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT, AST regularly as recommended. During treatment, withhold the dose of KYNAMRO if the ALT or AST are ≥3x ULN. Discontinue KYNAMRO for clinically significant liver toxicity.
Because of the risk of hepatotoxicity, KYNAMRO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYNAMRO REMS.
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.
WARNINGS AND PRECAUTIONS
KYNAMRO can cause elevations in transaminases and hepatic steatosis.
Prior to initiation of treatment with KYNAMRO, measure a full liver panel to include ALT, AST, total bilirubin, and alkaline phosphatase. If the baseline liver-related tests are abnormal, consider initiating KYNAMRO after an appropriate work-up and the baseline abnormalities are explained or resolved.
During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum).
After the first year, conduct these tests at least every 3 months. Discontinue KYNAMRO for persistent or clinically significant elevations.
If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with KYNAMRO and identify the probable cause.
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, for example isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of KYNAMRO with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
KYNAMRO has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
Injection site reactions have been reported in 84% of patients receiving KYNAMRO therapy. These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling. To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed. Injection site reactions do not occur with all injections but resulted in discontinuation of therapy in 5% of patients in pooled Phase 3 trials.
Flu-like symptoms have been reported in 30% of patients receiving KYNAMRO therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue. Flu-like symptoms, which typically occur within 2 days after an injection, do not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled Phase 3 trials.
USE IN SPECIFIC POPULATIONS
Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. KYNAMRO should be used during pregnancy only if clearly needed.
Nursing Mothers: It is not known whether KYNAMRO is excreted in human milk. Because many drugs are excreted in human milk a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Females of Reproductive Potential: KYNAMRO may cause fetal harm. Females who become pregnant during KYNAMRO therapy should notify their healthcare provider. Females of reproductive potential should use effective contraception during KYNAMRO therapy.
Renal Impairment: The safety and efficacy of KYNAMRO treatment in patients with known renal impairment or in patients undergoing renal dialysis have not been established. Due to the lack of clinical data and KYNAMRO’s renal safety profile, KYNAMRO is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.
In clinical trials the most commonly-reported adverse reactions were injection site reactions (84%), flu-like symptoms (30%), nausea (14%), headache (12%), and elevations in serum transaminases, specifically ALT (10%).
About KYNAMRO® (mipomersen sodium) injection
KYNAMRO is indicated as a first-in-class, oligonucleotide inhibitor, of apolipoprotein B-100 synthesis. KYNAMRO is 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). KYNAMRO reduces LDL-C by preventing the formation of atherogenic lipoproteins, the particles that carry cholesterol through the bloodstream. KYNAMRO acts by blocking the production of apo B, the protein that provides the structural core for these atherogenic particles, including LDL. For more information, please visit www.kynamro.com.
About Homozygous Familial Hypercholesterolemia (HoFH)
HoFH is a rare genetic disease characterized by extreme cholesterol levels. People with HoFH have inherited mutations that limit the body’s ability to clear cholesterol. HoFH is extremely rare. As with other rare diseases, the true prevalence of HoFH may be underestimated because of inadequate data and under-diagnosis. Today, it is estimated that HoFH affects about 44,000 people globally. Medical literature includes different criteria for marking an HoFH diagnosis. HoFH may be diagnosed by clinical or genetic parameters, and may be considered in cases of unusually high LDL-C. Because HoFH is genetic, it is important that all family members of people with HoFH know their cholesterol levels, regardless of their age.
About Genzyme, a Sanofi Company
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).
About Isis Pharmaceuticals, Inc.
Isis is exploiting its leadership position in antisense technology to discover and develop novel drugs for its product pipeline and for its partners. Isis’ broad pipeline consists of 34 drugs to treat a wide variety of diseases with an emphasis on cardiovascular, metabolic, severe and rare diseases, including neurological disorders, and cancer. Isis’ partner, Genzyme, is commercializing Isis’ lead product, KYNAMRO®, in the United States and other countries for the treatment of patients with homozygous FH. Isis has numerous drugs in Phase 3 development in severe and rare and cardiovascular disease. These include a novel triglyceride lowering drug, ISIS-APOCIIIRx, for patients with familial chylomicronemia syndrome; ISIS-TTRRx, which Isis is developing with GSK to treat patients with the polyneuropathy form of TTR amyloidosis; and, ISIS-SMNRx, which Isis is developing with Biogen Idec to treat infants and children with spinal muscular atrophy, a severe and rare neuromuscular disease. Isis’ patents provide strong and extensive protection for its drugs and technology. Additional information about Isis is available at www.isispharm.com.
Isis Pharmaceuticals® is a registered trademark of Isis Pharmaceuticals, Inc.
Genzyme® and KYNAMRO® are registered trademarks of Genzyme Corporation. All rights reserved.
Sanofi Forward Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future financial results, events, operations, services, product development and potential, and statements regarding future performance. Forward-looking statements are generally identified by the words “expects”, “anticipates”, “believes”, “intends”, “estimates”, “plans” and similar expressions. Although Sanofi’s management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forwardlooking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such product candidates, the absence of guarantee that the product candidates if approved will be commercially successful, the future approval and commercial success of therapeutic alternatives, the Group’s ability to benefit from external growth opportunities, trends in exchange rates and prevailing interest rates, the impact of cost containment policies and subsequent changes thereto, the average number of shares outstanding as well as those discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2013. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements.
Isis Forward Looking Statement
This press release includes forward-looking statements regarding the development, activity, therapeutic benefit, safety and commercial potential of KYNAMRO in treating patients with homozygous FH. Any statement describing Isis’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Isis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis’ programs are described in additional detail in Isis’ annual report on Form 10-K for the year ended December 31, 2013, and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.
In this press release, unless the context requires otherwise, “Isis,” “Company,” “we,” “our,” and “us” refers to Isis Pharmaceuticals and its subsidiaries.
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