Kowa Pharmaceuticals America, Inc. Announces INTREPID Trial Results in The Lancet HIV Showing Superior LDL Cholesterol Reduction with LIVALO^® (pitavastatin) Compared with Pravastatin in Adults with HIV and Dyslipidemia

MONTGOMERY, AL, April 19, 2017 – Kowa Pharmaceuticals America, Inc. today announced publication of results of the INTREPID Trial (HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia) in The Lancet HIV. Results of the Phase 4 trial showed that LIVALO^® (pitavastatin) 4 mg was superior to pravastatin 40 mg in reducing LDL cholesterol (LDL-C) in adults with HIV and dyslipidemia and had a comparable safety profile.

"Dyslipidemia affects more than three-fourths of people with HIV, putting them at significantly increased risk for cardiovascular disease. However, treatment of elevated LDL cholesterol in this patient population is challenging because of drug interactions between statins and commonly used antiretroviral agents," said Douglas Ward, M.D., co-author of the INTREPID study publication, Clinical Associate Professor of Medicine at George Washington University Medical School and physician at the Dupont Circle Physicians Group. "The finding that LIVALO was more effective than pravastatin in lowering LDL cholesterol and was well tolerated in HIV patients with dyslipidemia suggests it could be a viable treatment option for managing dyslipidemia and contributing factors in adults with HIV."

"The INTREPID trial is the first to evaluate the efficacy and safety of LIVALO in this difficult-to-treat patient population. The results not only demonstrate that LIVALO is superior to pravastatin in lowering LDL cholesterol, but also in maintaining moderate-intensity LDL cholesterol reduction similar to the non-HIV infected adult population," said Craig Sponseller, M.D., Chief Medical Officer, Medical Affairs, of Kowa Pharmaceuticals America, Inc. "Furthermore, LIVALO can be used in patients receiving complex antiretroviral therapy at the highest dose of LIVALO because it is not mainly metabolized via the cytochrome P450 enzyme system. This study, along with the landmark REPRIEVE trial to evaluate the effect of LIVALO on primary prevention of cardiovascular disease in adults with HIV, underscores our commitment to providing a safe and effective treatment option for clinically complex patient populations, such as the elderly, patients with diabetes or patients who take multiple medications for co-morbid conditions."

INTREPID Study Design and Results

The prospective, randomized, double-blind, active-controlled, Phase 4 superiority trial enrolled adults with HIV (CD4 cell counts >200 cells/mm³ and HIV-1 RNA <200 copies/mL) and dyslipidemia (LDL-C between 130-220 mg/dL, triglycerides ≤400 mg/dL) at 45 sites in the United States and Puerto Rico. A total of 252 study participants were randomized to LIVALO 4 mg (126 patients) or pravastatin 40 mg (126 patients) with matching placebos once daily for 12 weeks, followed by a 40-week safety extension. The primary endpoint was percent change in fasting serum LDL-C from baseline to week 12 in the modified intention-to-treat population. The safety analysis included all participants who took at least one dose of study medication.

Results showed that LIVALO demonstrated a statistically significant and superior reduction in LDL-C compared with pravastatin at 12 weeks (31.1 percent vs. 20.9 percent; p<0.0001); significant differences between the two treatment groups were sustained through week 52. Reductions in non-HDL-cholesterol and apo B from baseline were significantly greater with LIVALO than with pravastatin after 12 weeks of therapy (-26.9 percent and -18.7 percent in non-HDL-cholesterol, p<0.0001; and -23.3 percent and -16.5 percent in apo B, p<0.0001) and after 52 weeks of therapy (-26.1 percent and -19.0 percent in non-HDL-cholesterol, p=0.012; and -25.4 percent and -19.6 percent in apo B, p=0.018).

There were no significant changes in parameters of glucose metabolism and insulin resistance for either treatment at week 12 or week 52. Compared to baseline, no significant effects on fasting glucose or HbA1c were observed for either LIVALO or pravastatin at 52 weeks of treatment, and no participant had a post-baseline abnormal fasting glucose or HbA1c level that was reported as a treatment-emergent adverse event (TEAE). The change in fasting plasma insulin also was not significantly different from baseline for either treatment.

In a pre-specified safety assessment, there were no significant between-treatment differences from baseline to week 52 in HIV-1 RNA (0.03 log copies for LIVALO and 0.07 log copies for pravastatin; p=0.82) or CD4 cell counts (-8.3 cells/mm³ for LIVALO and 36.5 cells/mm³ for pravastatin; p=0.19). The percentage of patients with virologic failure was similar in the two groups (3 percent in the LIVALO group and 5 percent in the pravastatin group).

TEAEs were reported in 85 (67.5 percent) LIVALO-treated participants and 88 (69.8 percent) pravastatin-treated participants. The majority of these events were of mild (59.9 percent overall) or moderate (28.6 percent overall) severity. The most common TEAEs were diarrhea in the LIVALO group (9.5 percent) and upper respiratory tract infection in the pravastatin group (11.1 percent). Myalgia occurred in two (1.6 percent) LIVALO participants and three (2.4 percent) pravastatin participants, and caused study discontinuation in one (0.8 percent) participant in each treatment group. Treatment-related TEAEs were reported for 16 (12.7 percent) LIVALO-treated participants and 12 (9.5 percent) pravastatin-treated participants. Treatment-emergent serious adverse events (SAEs) occurred in seven participants (5.6 percent) in the LIVALO group and three participants (2.4 percent) in the pravastatin group. No SAE was assessed to be treatment-related. One SAE (cerebrovascular accident in the pravastatin group) resulted in study discontinuation.

The Lancet HIV publication of the INTREPID trial results is available here.

About LIVALO

LIVALO is an HMG-CoA reductase inhibitor (statin).

INDICATIONS AND USAGE

Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.

PRIMARY HYPERLIPIDEMIA AND MIXED DYSLIPIDEMIA

LIVALO (pitavastatin) is 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

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

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.
• Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing LIVALO with colchicine.
• 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.

© Kowa Pharmaceuticals America, Inc. (2016) - LIV-RA-0101 PI V-11-2016

About Kowa Company, Ltd. and Kowa Pharmaceuticals America, Inc.

Kowa Pharmaceuticals America, Inc., headquartered in Montgomery, AL, is focused primarily in the area of cardiometabolic diseases. Established in September 2008, Kowa Pharmaceuticals America focuses its efforts on the successful commercialization of its current and near-term portfolio of pharmaceutical products, and business development activities. For more information about Kowa Pharmaceuticals America, visit www.kowapharma.com.

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