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38924911000001101

New Medicines

Nilemdo (EU); Nexletol (US)Hypercholesterolaemia, as adjunct to maximally-tolerated statin in patients with high cardiovascular risk or familial hypercholesterolaemia

Information

Nilemdo (EU); Nexletol (US)
New molecular entity
Daiichi Sankyo
Esperion

Development and Regulatory status

Launched
Launched
Approved (Licensed)
December 2020
Dec 20Available in UK. 180mg oval f-c tab marked ESP and 180, 28=£55.44 [26].
Apr 20Approved in EU [25].
Feb 20U.S. Food and Drug Administration (FDA) has approved bempedoic acid (Nexletol) tablet, an oral once-daily non-statin LDL-Cholesterol (LDL-C) lowering medicine, as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. Commercial launch is anticipated Mar 20 [21-23]
Jan 20Recommended for EU approval by CHMP - the full indication is "in adults with primary hypercholesterolaemia (heterozygous familial and non‑familial) or mixed dyslipidaemia, as an adjunct to diet: in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL‑C goals with the maximum tolerated dose of a statin (see sections 4.2, 4.3, and 4.4) or, alone or in combination with other lipid-lowering therapies in patients who are statin‑intolerant, or for whom a statin is contraindicated” [20].
Mar 19EU Marketing Authorisation Application validated by EMA [17].
Jan 19Daiichi Sankyo Europe will market oral bempedoic acid and bempedoic acid / ezetimibe combination tablet in the European Economic Area, the U.K. and Switzerland [18].
Nov 17Esperion expects regulatory approval in the US in Q1 2020 [10].
Mar 17Esperion announce that the FDA has confirmed that their PIII clinical trial programme is adequate to support a licence application for the LDL-cholesterol lowering indication; they expect to submit licensing applications for this indication to the FDA and EMA by the first half of 2018. Assuming successful completion of the CLEAR-Outcomes study, they expect to seek licence extensions for CVD risk reduction by 2022 [9].
Feb 17Large (est. n=12,600) multi-national cardiovascular outcomes trial started (NCT02993406) with an estimated primary completion date of Dec 2021 [8].
Dec 16Three further PIII trials initiated in the US evaluating short-term (12 week) LDL-cholesterol lowering in a range of patient populations (NCT03001076, NCT02988115, and NCT02991118); estimated primary outcome date for all three is June 2018 [8].
Jan 16PIII trial programme started with a multi-national safety and tolerability study (NCT02666664) [7].
Sep 15Esperion announces that it will accelerate its plans to start the safety study because any concern regarding the benefit/risk assessment of ETC-1002 could necessitate a completed CV outcomes trial before approval [6].
Aug 15FDA advises Esperion that approval of ETC-1002 in the HeFH (heterozygous familial hypercholesterolemia) and ASCVD (clinical atherosclerotic cardiovascular disease) patient populations will not require the completion of a CV outcomes trial. Esperion is still planning a CVOT prior to NDA filing to pursue broader label indications related to CVD risk reduction. A PIII study with 4,000 patients ETC-1002 will start later this year [5].
Jul 15FDA removes its restrictions on testing a 240-mg dose of ETC-1002. Esperion is planning to start a PIII trial with a 180mg dose later this year, but the FDA´s decision gives them the option of moving forward with a stronger dosage in the future [4].
Jan 15US FDA lifts a partial clinical hold because of concerns over toxicity that limited Esperion from running studies longer than 6 months [1].
Nov 14Esperion is planning a PIII programme of bempedoic acid in pts with hypercholesterolaemia and other cardiometabolic risk markers [2].

Category

First-in-class, small-molecule compound with a dual mechanism of action, inhibiting ATP citrate (pro-S)-lyase and stimulating AMP-activated protein kinase (AMPK). This inhibits fatty acid and cholesterol synthesis, and enhanced fatty acid oxidation.
The UK population has one of the highest average serum cholesterol levels in the world, with two thirds having a serum cholesterol level greater than 5.2mmol/L.
Hypercholesterolaemia, as adjunct to maximally-tolerated statin in patients with high cardiovascular risk or familial hypercholesterolaemia
Oral

Further information

Yes

Trial or other data

Jul 20Analysis of 4 RCTs (NCT02666664, NCT02991118, NCT03001076, and NCT02988115; n=3623) found bempedoic acid decreased LDL-C by 18% vs placebo when added to maximally tolerated statins in patients with atherosclerotic CVD or heterozygous familial hypercholesterolemia or both, but was linked to more frequent increased uric acid and gout [24].
Nov 19PIII CLEAR Wisdom RCT (NCT02991118; n=779) found that, in patients at high risk for cardiovascular disease receiving maximally tolerated statins, bempedoic acid lowered LDL-C more than placebo at week 12 (–15.1%vs 2.4%, difference, –17.4% p<0.001) [19].
Mar 19Initial results from PIII CLEAR Wisdom trial (NCT02991118) announced at conference. Preliminary data (n=779) shows bempedoic acid led to a relative reduction in LDL-cholesterol by 17% with statins, vs placebo and maintained reductions in LDL-cholesterol for a year [16].
Mar 19Safety concerns flagged with published results of the CLEAR-Harmony study. More patients died in the bempedoic acid group (n=15) vs placebo (n=2). However in their write-up of the study the authors stated that "observed imbalances in deaths from cancer are likely to be a chance finding" and an accompanying editorial notes that while the imbalance is "potentially alarming", the 95% confidence intervals renders “the relative risk values virtually meaningless.” [15].
Mar 19Results of PIII CLEAR-Harmony (NCT02666664, n=2230) published in the NEJM. In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to higher incidence of overall adverse events (primary endpoint) and led to lower LDL cholesterol levels (secondary endpoint) than placebo. The incidence of adverse events leading to discontinuation of the regimen was higher with bempedoic acid vs placebo (n=162 [10.9%] vs. 53 [7.1%]), as was the incidence of gout (n=18 [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 0.5 mmol/L, representing a change of −16.5% from baseline (difference vs. placebo in change from baseline, –18.1%; p<0.001) [14].
Oct 18Results of 52 week PIII trial to evaluate the LDL-C lowering efficacy and the safety and tolerability of bempedoic acid 180 mg compared to placebo in 779 patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) announced. An additional LDL-C reduction of 17 percent (vs. placebo, p<0.001) was found, also reductions in C-reactive protein and HbA1C in diabetic patients [13].
May 18Study 3 (1002-046) meets primary endpoint. This was a 24-week pivotal PIII randomised, double-blind, placebo-controlled, multicentre study in the US and Canada which evaluated the LDL-C lowering efficacy and safety of bempedoic acid 180 mg/day vs. placebo (added to background lipid-modifying therapy) in 345 pts with hypercholesterolemia who are considered statin intolerant. Pts were randomided 2:1 to receive bempedoic acid or placebo. The study achieved LDL-C lowering totaling 26% in pts on bempedoic acid who remained on treatment at both week 12 and week 24 (an absolute reduction of 43 mg/dL) vs. placebo (p<0.001). The study met its primary endpoint with LDL-C lowering of 23% at 12 weeks (an absolute reduction of 39 mg/dL) vs. placebo which had a decrease of 1% (p<0.001). Bempedoic acid also achieved a reduction of 25% in hsCRP vs. placebo which had an increase of 3% (p<0.001). In statin-intolerant pts, bempedoic acid was safe and well-tolerated and muscle-related adverse events were lower in the bempedoic acid group vs. placebo. There were no clinically relevant differences in the occurrence of adverse events (AEs) and no differences between the treatment group and the placebo group in discontinuations due to muscle-related AEs. Serious AEs in the bempedoic acid arm were 6% vs.3.6% for placebo [12].
Mar 18PIII study (Study 4 or 1002-048) evaluating the LDL-C lowering efficacy, safety and tolerability of bempedoic acid versus placebo in patients with (or at high risk of) atherosclerotic cardiovascular disease with hypercholesterolemia inadequately treated with background ezetimibe 10 mg and up to the lowest daily starting dose of a statin has completed. The 12-week study met its primary endpoint with LDL-C lowering totaling 28 percent [11].
Feb 17CLEAR Outcomes trial (NCT02993406) initiated. This multinational study, estimated recruitment 12,600, is intended to study cardiovascular outcomes in adult patients who are statin intolerant (unable to tolerate lowest licensed dose of statin). Participants will receive bempedoic acid or placebo and the primary outcome will be a cardiovascular composite (CV death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina, or coronary revascularisation) at 3.5 years; estimated primary outcome date is Dec 2021 [8].
Dec 16Three further PIII studies in the CLEAR series initiated. All three placebo-controlled trials are intended to confirm safety and tolerability, and efficacy in lowering LDL-cholesterol: NCT03001076 (est. n=225) as add-on to ezetimibe, NCT02988115 (est. n=300) in statin-intolerant patients, and NCT02991118 (est. n=750) in patients not adequately controlled on current therapy. Primary outcome for all three studies is percent change in LDL-cholesterol at 12 weeks, and estimated primary completion date June 2018 [8].
Jan 16Multi-national NCT02666664 (CLEAR-Harmony) PIII study is intended to confirm safety and tolerability - 2233 patients with hyperlipidaemia and high cardiovascular risk have been randomised to bempedoic acid or placebo. Primary outcome is treatment-related adverse effects up to 52 weeks and estimated primary completion date is May 2018 [8].
Mar 15ETC-1002 met its primary goal in a PIIb study in 134 patients with high LDL cholesterol. A combination of ETC-1002 and statins lowered LDL by 17% on the lowest ETC-1002 dose and 24% at the highest, while those taking statins alone posted a 4% reduction. There was no increase in muscle-related side effects, and dropout rates were lower in the treatment arm than in the placebo group. The results echoed earlier positive mid-stage results for ETC-1002. Esperion is planning to enrol about 4,000 patients in a PIII study later in 2015 to confirm the treatment´s effect on LDL cholesterol [3].
Feb 15Due to its dual mechanism of action, bempedoic acid may be useful in patients who are intolerant of statins. The drug may also be useful in the treatment of diabetes and obesity, and for the lowering of elevated blood pressure [2].
Nov 14Esperion Therapeutics complete a PIIb trial which assessed the safety and efficacy of bempedoic acid (120 mg/day or 180 mg/day) alone, or in combination with ezetimibe, in patients with hypercholesterolaemia (1002-008; NCT01941836). The randomised, double-blind trial enrolled 349 patients, with or without a history of statin intolerance, at 62 sites in the US. Positive top-line results were reported in Oct 14 [2].
Jun 14Esperion initiates a PII trial to evaluate the efficacy and safety of bempedoic acid in patients with hypercholesterolaemia and hypertension, compared with placebo (1002-014; NCT02178098). The primary endpoint is change in calculated LDL-cholesterol, assessed at week six. The secondary endpoint is change in systolic and diastolic blood pressure at day- and night-time, assessed at week six. The randomised, double-blind trial intends to enrol 144 patients in the US. In July 2014, first patient was dosed in the trial. Top-line results are expected in 2Q 2015 [2].
Feb 14A PIIb trial in patients with hypercholesterolaemia and a history of statin intolerance began (1002-009; NCT02072161). The placebo-controlled trial is comparing multiple doses of bempedoic acid in patients receiving ongoing statin therapy with the active comparator ezetimibe over 12 weeks, and is intended to demonstrate superior efficacy and similar tolerability between the two treatments. Enrolment of 134 patients was completed in the US in October 2014. Top-line results are expected in the 1Q 15 [2].

Evidence based evaluations