Pivotal trial for bempedoic acid sets up a mild-mannered contender
Novel oral drug bempedoic acid safely but modestly reduced LDL when added to maximally-tolerated statin therapy, the CLEAR Harmony pivotal trial showed.
The small molecule agent reduced mean LDL cholesterol level by 16.5% from baseline (-19.2 mg/dL), which was 18.1 percentage points more than seen with placebo (P<0.001), Kausik Ray, MD, MPhil, of Imperial College London, and colleagues reported in the New England Journal of Medicine (NEJM).
Adverse events were similarly common between groups both overall and for serious cases only, though bempedoic acid was associated with more adverse events leading to discontinuation (10.9% vs 7.1%, P=0.005) and a higher incidence of gout (18 patients [1.2%] vs two [0.3%], P=0.03).
These findings are on par with the LDL lowering seen in other trials with bempedoic acid, including topline results announced for the other pivotal trial (CLEAR Wisdom) slated for presentation on Monday at the American College of Cardiology.
A Seat at the Table
Bempedoic acid would be a useful addition to the armamentarium (if the FDA approves the indication that was submitted in February) but not a blockbuster, several cardiologists suggested to MedPage Today.
"The LDL reduction is modest, but we do need other non-statin drugs, especially for statin intolerant patients," commented Christopher Cannon, MD, of Brigham and Women's Hospital and Harvard in Boston. "It is slightly less potent than ezetimibe (which is 24% relative LDL reduction). But we are all most excited about their combination drug of bempedoic acid and ezetimibe."
In a prior phase III trial, a bempedoic acid/ezetimibe combination pill
yielded a 32% LDL reduction.
"I think this compound will be a good second- or third-line therapy with biggest uptake in statin intolerant patients," Michael Miller, MD, of the University of Maryland in Baltimore, told MedPage Today. "As monotherapy, I would not anticipate significant uptake at this time based on all of the other proven LDL lowering therapies available, and it would not impact PCSK9 [inhibitor] use, except in intolerant patients."
"Since ezetimibe is generic, has similar efficacy and has no safety signals, there is no reason to use bempedoic acid instead of ezetimibe added to statin," added Jennifer Robinson, MD, MPH, of the University of Iowa in Iowa City.
The effect would likely be additive to statin plus ezetimibe, she noted. But the lower the starting LDL, the smaller the absolute LDL reduction. "Based on CTT meta-analysis, 16 mg/dL reduction in LDL-C would be expected to reduce the relative risk of major CVD events by about 9%. Recall that IMPROVE-IT with similar reduction in relative risk of CVD risk over 7 years did not receive FDA approval for CVD event reduction."
With the greater need for discontinuation due to side effects, "my bottom line is that I'm kind of underwhelmed," said William O'Neill, MD, of the Henry Ford Hospital in Detroit. "I honestly think we're going to be better served by looking at more aggressive strategies like a statin and PCSK9 inhibitor."
Howard Weintraub, MD, of the NYU Center for the Prevention of Cardiovascular Disease in New York City, too, called the LDL lowering magnitude "encouraging, but not strongly motivating."
"We do not have the benefit of cardiovascular outcome data with this medication. Its attractiveness to payors will obviously be determined by its price, but should also be determined by the absence of [proof of] efficacy in event reduction," he suggested.
While adjudicated major adverse cardiac events tended to go in the right direction for bempedoic acid (4.6% vs 5.7%) in CLEAR Harmony, the trial was too short and underpowered to look at outcomes.
The CLEAR Outcomes cardiovascular outcomes trial for bempedoic acid added to maximally-tolerated statin/ezetimibe in statin-intolerant individuals is underway, with results expected in 2022.
This population should have a higher baseline LDL, so an 18% reduction would go further, Robinson noted. For example, if the baseline LDL was 130 mg/dL, there would be a 23 mg/dL drop. "Based on CTT, this would be expected to reduce major CVD events [by] 13%. This is about what was observed for PCSK9 inhibitors over [a] 2-2.6 year mean follow-up (15% reduction in major CVD events)."
Bempedoic acid works upstream from the target for statins by inhibiting ATP citrate lyase, "a key enzyme in the cholesterol biosynthesis pathway." Because it requires activation by an enzyme not found in most peripheral tissues, "an important feature differentiating bempedoic acid from statins is its liver-specific action," the researchers noted.
CLEAR Harmony included 2,230 adults with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both who had an LDL of at least 70 mg/dL despite a stable regimen of maximally-tolerated statin therapy either alone or in combination with other lipid-lowering therapies. Use of PCSK9 inhibitors was excluded for the first 24 weeks; gemfibrozil (Lopid) or simvastatin (Zocor) at doses greater than 40 mg per day was also not allowed.
Participants were randomly assigned 2:1 to 180-mg bempedoic acid once daily or matching placebo for 52 weeks.
LDL lowering with bempedoic acid persisted through week 52 "with minimal attenuation of effect," the researchers noted. The effects didn't differ by statin or other therapy use but did appear greater for women than men.
Bempedoic acid was tied to a nominal excess of muscular disorder events (13.1% vs 10.1%, P=0.05), driven more by extremity pain than myalgia or muscle spasms or weakness. New-onset or worsening diabetes was significantly less common with bempedoic acid than placebo (3.3% vs 5.4%, P=0.02).
The increase in gout appeared not to be a chance finding, as there was a significantly greater change in uric acid and creatinine levels with bempedoic acid. The researchers noted that "the putative mechanism is competition between the bempedoic acid glucuronide metabolite and uric acid for the same renal transporters that are involved in the excretion of these compounds."
Miller said he wasn't too worried about the gout risk.
Cannon agreed. "The safety looks reasonable in this study. Gout seems to be a minor issue, but might be something that docs would need to track and then stop the medication if it developed."
However, it "could certainly temper enthusiasm in patients with moderately elevated uric acid levels and a history of gout," said Weintraub.
Adding to the reassurance was a separate Mendelian randomization study in which genetic variants that mimic the effect of bempedoic acid appeared to lower plasma LDL cholesterol levels by the same mechanism of action as statins and were tied to a similar reduction in cardiovascular risk per unit decrease in LDL.
Also, people with genetically-based lifelong inhibition of ATP citrate lyase showed no association with an increased risk of cancer, Brian Ference, MD, of the University of Cambridge, England, and colleagues reported in the same NEJM issue.
"The genetic confirmation seems good to have. But we ultimately need the outcomes trial," said Cannon.
Both studies were supported by Esperion Therapeutics (along with other grants for the mendelian randomization study).
Ray reported financial relationships with Esperion, Abbvie, Amgen, AstraZeneca, Sanofi, Regeneron, MSD, Pfizer, Medco, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr. Reddy's, Lilly, and Zuellig Pharma.
Ference reported relationships with Esperion Therapeutics, Amgen, Merck, CiVi Pharma, DalCor, KrKa Pharmaceuticals, Ionis Pharmaceuticals, The Medicines Co, Pfizer, Regeneron, Sanofi, American College of Cardiology, European Society of Cardiology, European Atherosclerosis Society, and Novartis.
Read the original article on Medpage Today: Novel Oral LDL Drug Helps, If Modestly