PHILADELPHIA — The investigational drug apabetalone (Resverlogix) did not reduce the risk for major adverse cardiovascular events (MACE) in BETonMACE, a phase 3 trial of patients who had recent acute coronary syndrome (ACS), type 2 diabetes, and low HDL cholesterol.
But this might be because the trial of this novel agent — which acts at the epigenetic level, turning genes on and off — was underpowered, both the lead author and an outside expert suggest.
Apabetalone inhibits bromodomain and extra-terminal (BET) proteins, which are epigenetic transcription modulators of inflammation, thrombogenesis, and lipoprotein lipid metabolism.
Results from three pooled phase 2 trials suggested that apabetalone might lower the risk for MACE — defined as cardiovascular (CV) death, non-fatal myocardial infarction (MI), or stroke — in similar high-risk patients.
Building on this, BETonMACE enrolled 2400 patients, anticipating 250 instances of MACE at 18 months, with 30% more events in the placebo group than in the apabetalone group.
However, the actual rates of MACE were similar in the two groups.
Nevertheless, "this first proof-of-concept trial really shows promise for epigenetic modification with apabetalone," said Kausik K. Ray, MD, professor of Public Health and director of Cardiovascular Disease Prevention, Imperial College London, reporting the results in a late-breaking trial session at the American Heart Association Scientific Sessions 2019.
There were favorable trends toward less CV death, non-fatal MI, and congestive heart failure (HF) with the study drug, and it was generally well tolerated, he told theheart.org | Medscape Cardiology.
"We have learned a lot about safety and likely treatment effect," which can be used to inform the next study, said Ray, who receives honoraria from Resverlogix along with other pharmaceutical companies.
"There is cautious optimism for this drug," the assigned discussant Svati H. Shah, MD, professor of Medicine, Duke University, Durham, North Carolina, summarized to the audience.
"While it's not ready for use in patients, I would say that these results suggest that an adequately powered clinical trial is needed," she said.
Ray agreed: "A slightly larger study (4000 to 4500 patients) in the same population with more events (450 to 500) should be performed, which would have a good chance of showing benefits for the first epigenetic BET protein modulator."
Like Ray, Shah speculated that the trial had a negative primary efficacy outcome likely because it was underpowered; other possible explanations are that there may have been an unintended pleiotropic effect, or the drug does not actually work on MACE.
The treatment was safe in a longer trial than the previous trials, and the only safety signal was a transient elevation in liver function tests, she pointed out.
These findings can be used to design a larger trial with the same type of patients or researchers can "pick subgroups where the effects were strongest, like patients with kidney disease," Shah told theheart.org | Medscape Cardiology.
"However, I think you have to be very cautious about these subgroup analyses that were not adjusted for multiple comparisons. To me, the better option is to use the same patient population as BETonMACE but with a larger sample size."
Trial Rationale and Method
The design of BETonMACE, the first cardiovascular outcomes trial for apabetalone, built on findings from a pooled analysis of three phase 2 trials: ASSERT, SUSTAIN, and ASSURE.
For example, the pooled analysis showed that outcomes were best in patients with high C-reactive protein (CRP), type 2 diabetes, and low HDL-cholesterol levels.
From 2015 to 2018, BETonMACE enrolled patients at 195 sites in 13 countries: eight in eastern Europe, plus Argentina, Germany, Israel, Mexico, and Taiwan.
The patients all had unstable angina (limited to 25% of patients) or MI in the 7 to 90 days prior to the screening visit; type 2 diabetes; and low HDL cholesterol, defined as below 40 mg/dL in men, and below 45 mg/dL in women.
The researchers powered the trial assuming that MACE would occur in 10.5% of patients in the placebo group and 7.47% of patients in the apabetalone group over the 18-month period.
They screened 3937 patients and enrolled 2425. Participants had a median age of 62 years, 75% were male, and they had had diabetes for a mean of 8.5 years.
Close to three-quarters (73%) had MI (half had STEMI, half non-STEMI), and the rest had unstable angina.
Most patients (80%) had percutaneous coronary intervention (PCI) for the index ACS and, on average, they were randomized within 38 days.
The patients received a statin (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg) during a 1- to 2-week run-in.
Then they were blinded and randomized 1:1 to apabetalone (100 mg orally, twice daily) or matching placebo until the trial end (250 instances of MACE).
At baseline, 51% were on atorvastatin and 49% were on rosuvastatin, and most (90%) were on high-dose statins.
There was "good use" of ACE inhibitors/angiotensin II blockers, beta blockers, and antiplatelet agents, Ray noted. Most patients were on metformin, and few were on SGLT2 inhibitors or GLP1 receptor agonists.
They had a mean A1C of 7.4%; well controlled LDL cholesterol (mean, 70 mg/dL) and, as required, low HDL cholesterol (mean, 33 mg/dL).
The primary efficacy end point, MACE, occurred in 274 patients during a median follow-up of 26 months: 12.4% of patients in the placebo group vs 10.3% of patients in the apabetalone group (hazard ratio [HR], 0.82; 95% CI, 0.65 - 1.04; P = .11).
"Given that the primary end point is not significant, everything else that I show you should be considered nominal, hypothesis-generating, or exploratory, " Ray cautioned, before presenting secondary end point results followed by primary end point results in prespecified subgroups.
There was a trend toward a lower risk for cardiovascular death or nonfatal MI, a slightly lower risk for hospitalization for heart failure, but also a slightly higher risk for stroke. However, these secondary end point findings need to be interpreted with caution.
Similarly, "if we look at subgroups, again this has to be taken with caution, given the [negative] primary end point," Ray continued.
There were no differences in the primary outcome based on sex, statin type, or having A1C above or below the median. However, there was a greater benefit in patients who had baseline LDL cholesterol below the median or estimated glomerular filtration rate (eGFR) below the median.
Overall, both patient groups had similar rates of adverse events (68%) and serious adverse events (29%).
However, more patients in the apabetalone group than in the placebo group discontinued the study because of an adverse event (9.4% vs 5.7%), and discontinuation because of elevated liver function tests was higher in the apabetalone group (2.9% vs 0.9%).
The study was funded by Mezzion. Ray discloses receiving honoraria from Amgen, Sanofi, Regeneron, Esperion, Medicines Company, Boehringer Ingelheim, Novo Nordisk, Kowa, Resverlogix, Dr Reddys, Cipla, Algorithm, Zuelling Pharma, Silence Therapeutics, Cerenis, Lilly, Astra Zeneca, Bayer, Akcea, MSD, and Novartis; and research grants from Amgen, Sanofi, Regeneron, MSD, and Pfizer. The disclosures of the other authors are listed in the abstract. Shah discloses that she has an unlicensed patent for a related research finding and received research funding from the National Heart, Lung and Blood Institute, the American Heart Association, Pfizer (through Duke University), and Project Baseline.
American Heart Association (AHA) Scientific Sessions 2019: Abstract LBS.01. Presented November 16, 2019.
Medscape Medical News © 2019
Cite this: BETonMACE: Negative Trial, but 'Cautious Optimism' on Apabetalone - Medscape - Nov 26, 2019.