New Superiority Trial Showed LIVALO® (pitavastatin) 4 mg Provided Significantly Greater LDL-C Reduction in HIV-Infected Adults with Dyslipidemia versus Pravastatin 40 mg

ATLANTA, March 7, 2013 /PRNewswire/ -- Kowa Pharmaceuticals America, Inc. and Eli Lilly and Company (NYSE:LLY) announced results of a study evaluating the efficacy of LIVALO^® (pitavastatin) 4 mg compared with pravastatin 40 mg in reducing low-density lipoprotein cholesterol (LDL-C) in HIV-infected adults with high cholesterol, or dyslipidemia. The study was designed as a superiority trial for the primary endpoint, percent reduction in LDL-C, and evaluated HIV-infected adults with dyslipidemia; with and without viral Hepatitis B or C. The study met its primary endpoint.¹

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Results showed that, after 12 weeks of therapy, pitavastatin had a significantly greater decrease in LDL-C compared with pravastatin (pitavastatin -49.4 mg/dL and pravastatin -33.6 mg/dL, 31% vs 21% reduction in LDL-C, respectively, p<0.001). The results were presented yesterday at a late-breaking poster presentation at the 20th Conference on Retroviruses & Opportunistic Infections (CROI) in Atlanta, GA. ¹    

Dyslipidemia is common in people with HIV infection.² HIV-infected adults are at an increased risk for cardiovascular disease due to many factors, including lipid abnormalities.³ 

"We are pleased that the study objective was met, showing superiority of pitavastatin 4 mg to pravastatin 40 mg on LDL-C reduction in HIV-infected adults with dyslipidemia, and we look forward to further analysis of these data," said Dr. Craig Sponseller, Vice President of Medical Affairs, Kowa Pharmaceuticals America, Inc.

Study investigator, Dr. Judith Aberg, Director of Virology, Bellevue Hospital Center and Director, Division of Infectious Diseases and Immunology, NYU School of Medicine, said, "In HIV-infected patients with high cholesterol, data such as these represent an important step in understanding lipid management in this immunocompromised patient population."

The overall incidence of treatment emergent adverse events (TEAEs) was 61.1% for pitavastatin and 62.7% for pravastatin. The most frequently reported TEAEs overall (in >2% of subjects in either treatment group) included diarrhea (13 subjects, 5.2%), upper respiratory tract infection (13 subjects, 5.2%), sinusitis (12 subjects, 4.8%), headache (10 subjects, 4.0%), nausea (10 subjects, 4.0%), nasopharyngitis (9 subjects, 3.6%), and blood creatine phosphokinase increased (8 subjects, 3.2%).  Eleven subjects were discontinued from the study due to a TEAE (4.4%).¹

About the Study
In the 12-week, Phase 4, randomized (1:1), double-blind, double-dummy, active-controlled, parallel-group study, 252 patients were randomized to receive once-daily doses of pitavastatin 4 mg or pravastatin 40 mg.  The primary efficacy analysis (ANCOVA) used percent change in LDL-C as the dependent variable, and treatment, site, and viral hepatitis B or C infection as independent variables. The major secondary lipid endpoints assessed were total cholesterol, HDL-C, non-HDL-C and triglycerides. Safety assessments included adverse events, clinical/laboratory tests, HIV-1 RNA, CD4 count, and virologic failure.¹ 

About LIVALO
LIVALO is a HMG-CoA reductase inhibitor indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia.

Limitations of Use:

• Doses of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4 mg once daily dosing of LIVALO.
• The effect of LIVALO on cardiovascular morbidity and mortality has not been determined.
• LIVALO has not been studied in Fredrickson Type I, III, and V dyslipidemias.

In addition to being launched in the U.S. in June 2010, LIVALO has been approved in Japan and 32 other countries as of January 2013.

Primary Hyperlipidemia and Mixed Dyslipidemia
Primary hyperlipidemia is defined as an elevation of cholesterol, particularly "bad" cholesterol (LDL-C), triglycerides (TG), or both. Mixed dyslipidemia is usually characterized by an elevation of LDL-C, TG, and a decrease in the "good" cholesterol (HDL-C) in the blood.

IMPORTANT SAFETY INFORMATION FOR LIVALO^® (pitavastatin) tablets

CONTRAINDICATIONS
LIVALO is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.

WARNINGS AND PRECAUTIONS

Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.

• LIVALO should be prescribed with caution in patients with predisposing factors for myopathy
• The risk of skeletal muscle effects (e.g., myopathy, and rhabdomyolysis) increases in a dose-dependent manner with advanced age (>65 years), renal impairment, inadequately treated hypothyroidism, and in combination use with fibrates or lipid-modifying doses of niacin (>1 g/day)
• LIVALO should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin
• Concomitant administration of LIVALO with gemfibrozil should be avoided
• LIVALO therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. LIVALO therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled seizures)
• Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, and to discontinue LIVALO if these signs or symptoms appear
• There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. IMNM has not been reported with LIVALO therapy
• Advise patients to promptly report if muscle signs and symptoms persist after discontinuing LIVALO as this may be a sign of IMNM requiring immediate medical attention

Liver Enzyme Abnormalities
Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including LIVALO.

• It is recommended that liver enzyme tests be performed before the initiation of LIVALO and if signs or symptoms of liver injury occur
• There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIVALO, promptly interrupt therapy. If an alternate etiology is not found do not restart LIVALO
• Advise patients to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice
• LIVALO should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease

Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIVALO.

ADVERSE REACTIONS
In short-term controlled studies, the most frequent adverse reactions reported by >2% of patients treated with LIVALO 1 mg, 2 mg, and 4 mg, respectively, and at a rate > placebo were back pain (3.9%, 1.8%, 1.4% vs 2.9%), constipation (3.6%, 1.5%, 2.2% vs 1.9%), diarrhea (2.6%, 1.5%, 1.9% vs 1.9%), myalgia (1.9%, 2.8%, 3.1% vs 1.4%), and pain in extremity (2.3%, 0.6%, 0.9% vs 1.9%). This is not a complete listing of all reported adverse events.

For additional information please see the full Prescribing Information provided, or visit www.LivaloRx.com.

LIV-RA-0058 PS82458 1/2013

About Kowa Company, Ltd. and Kowa Pharmaceuticals America, Inc.
Kowa Company, Ltd. (KCL) is a privately held multinational company headquartered in Nagoya, Japan. Established in 1894, KCL is actively engaged in various manufacturing and commercial activities in the fields of pharmaceutical, life science, information technology, textiles, machinery and various consumer products. KCL's pharmaceutical division is focused on cardiovascular therapeutics, with sales of the company's flagship product LIVALO, totaling $567 million in Japan in 2012, and was launched in the United States in June 2010.

Kowa Pharmaceuticals America, Inc. (KPA) is a pharmaceutical company specializing primarily in the area of cardiometabolic diseases. The company, started in 2001 as ProEthic Pharmaceuticals, Inc., was acquired by KCL in September of 2008. A privately held company, KPA directs its efforts towards the acquisition, licensing and marketing of pharmaceutical products.

exchange rate used $1=90JPY

About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers – through medicines and information – for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.  P-LLY

This press release contains certain forward-looking statements about LIVALO^®, a HMG-CoA reductase inhibitor indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia.  This release reflects Lilly and Kowa's current beliefs; however, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization.  There is no guarantee that future study results and patient experience will be consistent with study findings to-date or that LIVALO will be commercially successful.  For further discussion of these and other risks, see Lilly's filings with the United States Securities and Exchange Commission.  Lilly undertakes no duty to update forward-looking statements.

LIVALO is a registered trademark of the Kowa group of companies.

LIV-MT-0557
PS82743

¹ Data on File: Sponseller C, Morgan R, Campbell S, et al.  Pitavastatin 4 mg Provides Greater LDL-C Reduction Compared to Pravastatin 40 mg over 12 weeks of Treatment in HIV-infected Adults with Dyslipidemia.  Poster presented at the 20th Conference on Retroviruses & Opportunistic Infections,  March 3-6, 2013; Atlanta, GA.

² Boccara F. Lang S, Meuleman C, et al. HIV and Coronary Heart Disease. Journal of the American College of Cardiology. 2013; 61(5):511-523.
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³ Malvestutto CD, Aberg JA. Management of dyslipidemia in HIV-infected patients. Journal of Clinical Lipidology. 2011; 6(4):447-462.

SOURCE Kowa Pharmaceuticals America, Inc. and Eli Lilly and Company