Bempedoic Acid CLEAR Serenity Study Results Published in the JAHA Demonstrated Significant LDL-Cholesterol Lowering and

Publicado 02/04/2019 11:11:49CET

-- Bempedoic acid is an oral, once-daily ATP citrate lyase (ACL) inhibitor that reduces cholesterol and fatty acid synthesis in the liver -- Bempedoic acid significantly reduced LDL-Cholesterol (LDL-C) vs placebo at week 12 (primary endpoint, absolute reduction -36mg/dL, -21,4%) -- Over 24-weeks, bempedoic acid was observed to be well-tolerated, and the muscle-related adverse event rate did not differ from placebo -- Treated patients showed lower rates of new-onset or worsening of diabetes compared with those on placebo

MUNICH and ANN ARBOR, Michigan, April 2, 2019 PRNewswire/ -- Daiichi Sankyo Europe GMbH (hereafter, 'Daiichi Sankyo') and Esperion Therapeutics announced today that results from the 345 patient, 24-week, Phase 3 double-blind, placebo-controlled study of bempedoic acid (CLEAR Serenity, also known as Study 3) were published in the Journal of the American Heart Association (JAHA). Bempedoic acid is being developed as a complementary, convenient, once-daily, oral therapy for the treatment of patients with elevated low-density lipoprotein cholesterol (LDL-C). Bempedoic acid and the bempedoic acid / ezetimibe combination tablet new drug applications are under regulatory review for marketing authorisation by the European Medicines Agency (EMA) and have been submitted to the United States Food and Drug Administration (FDA).

The JAHA publication highlights that bempedoic acid met the primary efficacy endpoint and significantly lowered LDL-C by 21% (absolute reduction -36mg/dL) at 12-weeks.(1)

The publication also shows key secondary efficacy endpoints at 12 and 24 weeks and safety and tolerability outcomes, demonstrating that bempedoic acid:(1)

-- significantly reduced hsCRP, an important marker of the underlying inflammation associated with cardiovascular disease, by 24%; -- showed numerically fewer muscle-related adverse events compared with placebo (BA 12.8% vs placebo 16.2%); -- was observed to be well-tolerated; -- showed numerically fewer new-onset or worsening of diabetes compared with the placebo group (BA 2.1% vs 4.5% placebo).

"In the challenging group of patients with statin intolerance, CLEAR Serenity demonstrates that bempedoic acid reduced LDL-C significantly more than placebo. Patients taking bempedoic acid reported less frequent occurrences of myalgia and muscular weakness compared with placebo. These results demonstrate bempedoic acid could offer a well-tolerated and effective oral therapeutic option especially for the millions of patients needing LDL-C lowering but have difficulty tolerating statin treatment due to muscle-related side effects," said Ulrich Laufs, MD, PhD.

"For patients who have experienced the side effects commonly attributed to statin treatment and can't or won't take statins, there is an urgent need to significantly lower their LDL-C and hsCRP levels. The publication of the CLEAR Serenity Study in the Journal of American Heart Association further demonstrates that bempedoic acid could be a well-tolerated and efficacious treatment option for hypercholesterolemia patients, including those patients considered statin intolerant," said Wolfgang Zierhut, MD, Head of Antithrombotic and Cardiovascular Medical Affairs Department at Daiichi Sankyo Europe.

Design of Global Phase 3 Study 3 (1002-046, also known CLEAR Serenity)

The 24--week, global pivotal Phase 3 randomised, double-blind, placebo-controlled, multicenter study evaluated the LDL-C lowering efficacy and safety of bempedoic acid 180 mg/day versus placebo added to background lipid-modifying therapy in patients with hypercholesterolemia who are considered statin intolerant. The study was conducted at 67 sites in the U.S. and Canada. A total of 345 patients were randomised 2:1 to receive bempedoic acid or placebo. The primary efficacy objective was to assess the 12-week LDL-C lowering efficacy of bempedoic acid versus placebo. Secondary objectives included evaluating the 24-week LDL-C lowering efficacy of bempedoic acid versus placebo and its effects on other risk markers after 12 weeks of treatment, including hsCRP. Safety and tolerability were evaluated through continuous monitoring of patients.

Bempedoic Acid / Ezetimibe Fixed Dose Combination Tablet

Through the complementary mechanisms of action of inhibition of cholesterol synthesis (bempedoic acid) and inhibition of cholesterol absorption (ezetimibe), the bempedoic acid / ezetimibe fixed dose combination tablet is a non-statin, orally available, once-daily, LDL-C lowering therapy. Inhibition of ATP Citrate Lyase (ACL) by bempedoic acid reduces cholesterol biosynthesis and lowers LDL-C by up-regulating the LDL receptor. Inhibition of Niemann-Pick C1-Like 1 (NPC1L1) by ezetimibe results in reduced absorption of cholesterol from the gastrointestinal tract, thereby reducing delivery of cholesterol to the liver, which in turn upregulates the LDL receptors. Phase 3 data demonstrated that this well tolerated combination results in a 35% lowering of LDL-C when used with maximally tolerated statins, a 43% lowering of LDL-C when used as a monotherapy, and a 34% reduction in high sensitivity C-reactive protein (hsCRP). Rates of treatment-emergent adverse events, muscle-related adverse events and discontinuations were similar in the bempedoic acid and placebo treatment groups.(2)

Bempedoic Acid

With a targeted mechanism of action, bempedoic acid is a first-in-class, complementary, oral, once-daily ATP Citrate Lyase (ACL) inhibitor that reduces cholesterol and fatty acid biosynthesis and lowers LDL-C by up-regulating the LDL receptor. Similar to statins, bempedoic acid also reduces high sensitivity C-reactive protein (hs-CRP), a key marker of inflammation associated with cardiovascular disease.(3) Bempedoic acid is a prodrug that requires activation by the very long-chain acyl-CoA synthetase-1 (ACSVL1). Furthermore, it was demonstrated that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for bempedoic acid to potentially avoid the myotoxicity associated with statin therapy.(4) Completed Phase 2 and Phase 3 studies conducted in almost 4,800 patients, and approximately 3,100 patients treated with bempedoic acid, have produced an additional 20% LDL-C lowering when used with maximally tolerated statins, up to 30% LDL-C lowering as monotherapy, 35% LDL-C lowering in combination with ezetimibe when used with maximally tolerated statins and up to 48% LDL-C lowering in combination with ezetimibe as monotherapy.(5) Rates of treatment-emergent adverse events, muscle-related adverse events and discontinuations were similar in the bempedoic acid and placebo treatment groups.(3)

The effect of bempedoic acid on cardiovascular morbidity and mortality has not yet been determined. The company initiated a global cardiovascular outcomes trial (CVOT) to assess the effects of bempedoic acid on the occurrence of major cardiovascular events in patients with, or at high risk for, cardiovascular disease (CVD) who are only able to tolerate less than the lowest approved daily starting dose of a statin and considered "statin intolerant." The CVOT -- known as CLEAR Outcomes -- is an event-driven, randomised, double-blind, placebo-controlled study expected to enroll approximately 12,600 patients with hypercholesterolemia and high CVD risk at over 1,000 sites in approximately 30 countries.(6)

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