DalCor Keeps Faith In CETP Biomarker, Despite No Dice For Merck's REVEAL Genetic Analysis
Executive Summary
Hopes for a precision approach for the vast cardiovascular disease population live on – past failed studies of HDL-raising drugs and lack of evidence for genetic typing in Merck's latest analysis of anacetrapib in REVEAL.
DalCor Pharmaceuticals says it's still confident about its dal-GenE outcomes study of genetically selected patients treated with the cholesterol-modulating CETP inhibitor dalcetrapib, but the odds on its big gamble are arguably worsening after a new analysis of Merck & Co. Inc.'s REVEAL outcomes study of anacetrapib did not support the hypothesis.
A retrospective analysis of data from Merck's massive REVEAL outcomes study of its CETP inhibitor anacetrapib, presented at the American College of Cardiology (ACC) annual meeting on March 18, did not show a trend for a benefit among the carriers of the ADCY9 (adenylate cyclase) rs1967309 AA genetic subtype.
The genetic sub-study of the trial, which was run in about 20,000 patients with stable coronary disease, was funded by Merck and lead investigator and presenter Jemma Hopewell, a University of Oxford epidemiologist, received funding from the British Heart Association.
Anacetrapib had demonstrated a modest but significant 7% reduction in risk for major adverse cardiovascular events (MACE) in REVEAL, which was released in 2017. (Also see "Big REVEAL: Merck's Anacetrapib Surprises With Success, But What Next?" - Pink Sheet, 27 Jun, 2017.) But the company dropped the candidate anyway amid a challenging commercial environment and with questions about whether the accumulation of the drug in adipose tissue would present regulatory challenges. (Also see "Merck Calls It Quits On Anacetrapib" - Pink Sheet, 11 Oct, 2017.)
Saving CETP With Genetic Testing
Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol ester from high-density lipoproteins to low-density lipoproteins, which can raise high-density lipoprotein (HDL), while some members of the class also provide substantial reductions in LDL.
Orally available CETP inhibitors were once the stuff of blockbuster dreams and the hopes of making up for genericization of statins, despite an early failure by Pfizer's CETP inhibitor torcetrapib due to safety issues. (Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 Apr, 2012.) The report of a 138% increase in HDL and a 39.8% decrease in LDL for Merck's anacetrapib in the Phase III DEFINE study had knocked the socks off cardiologists attending the American Heart Association annual meeting in November 2010, but the REVEAL study was to be the real test. (Also see "Merck’s Anacetrapib Debut Many Years Away, Despite Robust Phase III Data" - Pink Sheet, 22 Nov, 2010.)
The bubble burst with the failure of two outcomes studies – Roche's dalcetrapib in 2012 (dal-OUTCOMES) and Eli Lilly & Co.'s evacetrapib in 2015 (ACCELERATE). (Also see "Who Suffers From Lilly's Evacetrapib Failure?" - Pink Sheet, 12 Oct, 2015.)
But these studies had shorter follow-up – two years – in contrast with four years for REVEAL, which some experts believe partly explains the difference in results.
Some development is still ongoing, however. Privately held DalCor has been pursuing a precision medicine approach for dalcetrapib, which it licensed from Roche in 2016. (Also see "DalCor To Develop Failed Roche CETP Inhibitor In Genetic Subgroup" - Scrip, 22 Apr, 2016.)
Experimental research suggests that inactivity of ADCY9 is good for heart health. And Roche's research had shown that the effect of dalcetrapib varied depending on the ADCY9 rs1967309 subtype.
DalCor has explained that those with the "AA" polymorphism at the rs1967309 location in the ADCY gene who were treated with dalcetrapib – about 20% of the patients genotyped in dal-OUTCOMES – had 39% fewer further cardiovascular events compared with the placebo arm in the study. (Also see "DalCor To Develop Failed Roche CETP Inhibitor In Genetic Subgroup" - Scrip, 22 Apr, 2016.)
In Roche's dal-OUTCOMES study, those with the "GG" genotype had a numerically higher risk for events (27%), those with "AG" had slightly numerically lower risk (6%) and in contrast the AA cohort had a significant reduction of risk of 39%.
A similar trend was noted in a retrospective analysis of Lilly's ACCELERATE study of evacetrapib, although the reduction in risk for the AA type was more modest at 12% and was not significant.
DalCor's Phase III dal-GenE outcomes study of over 6,000 patients with a recent acute coronary syndrome (ACS) event and the AA genetic type is evaluating dalcetrapib against placebo. The study completed enrollment in December and results are due in late 2020 or early 2021. DalCor had teamed up with Roche Molecular Systems for an ADCY9 companion diagnostic to screen enrollees.
REVEAL Genetic Analysis Disappoints
Results from the REVEAL retrospective genetic analysis presented at the ACC meeting differ from the findings of Roche and Lilly, however.
Genotyped data were available for most of the study participants. But there was no meaningful difference in the genotypes on effects for non-HDL cholesterol or HDL cholesterol. And there was no interaction for separate events, including myocardial infarction, coronary death and presumed stroke, Hopewell reported (see table).
|
Genetic Sub-Study Results: REVEAL Event Rates |
|||
|
ADCY9rs1967309 type |
Anacetrapib-allocated |
Placebo-allocated |
Hazard ratio (95% CI) |
|
GG |
451/3553 (12.7%) |
468/3421 (13.7%) |
0.92 (0.81-1.05) |
|
AG |
572/4560 (12.5%) |
615/4636 (13.3%) |
0.94 (0.84-1.06) |
|
AA |
193/1520 (12.7%) |
205/1520 (13.5%) |
0.93 (0.76-1.13) |
|
All participants |
1216/9633 (12.6%) |
1288/9577 (13.4%) |
0.93 (0.86-1.01) |
|
Source: J. Hopewell, ACC 2019; study funded by Merck |
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Why DalCor Holds A Torch For CETP
Nevertheless, DalCor believes it has reason to keep the faith that its dal-GenE trial will succeed. There were important differences in trial design. The company pointed out that Roche's dal-OUTCOMES study was done in patients with a recent ACS whereas Lilly's ACCELERATE study was done in patients with ACS or stable coronary disease, and Merck's REVEAL study was done in patients with stable disease. Hence the patient population in dal-OUTCOMES was the sickest, ACCELERATE was in the middle and REVEAL patients were most stable.
"It is important to note that the REVEAL and dal-OUTCOMES studies, both measuring reduction of major cardiovascular events, were conducted in significantly different patient populations. Uniquely, in dal-OUTCOMES, and in the dal-GenE study, all patients were required to have a documented acute coronary syndrome within three months prior to entering the study. This contrasts with the REVEAL study where all with an ACS in less than three months were excluded from the trial," the company said in a statement provided to Scrip.
DalCor stressed that its dal-GenE study has the exact same patient population as dal-OUTCOMES and noted that it can test a smaller population, roughly 6,000, because of the unique precision medicine approach.
"DalCor will continue to advance this study, the first interventional precision medicine outcomes trial for cardiovascular disease to bring unequivocal answer regarding the potential benefit of dalcetrapib," the company said
DalCor also believes the difference in genetic study results may come down to differences in the drugs themselves.
"Anacetrapib is a potent, reversible CETP, which leads to dose-dependent reductions in LDL-C and more than a 100% increase in HDL-C. Dalcetrapib is a non-competitive inhibitor that irreversibly binds to CETP, which leads to lower magnitude increases in HDL-C and does not reduce LDL-C," the company explained.
DalCor CEO Fouzia Laghrissi-Thode said in an interview with Scrip that the study is powered to pick up benefit as low as 15%, but that she would not be surprised if they see a a benefit more in the range of 20%-25%.
REVEAL genetic study lead investigator Hopewell stressed to Scrip that it is important that the dal-GenE study continue to provide a robust and definitive assessment of the effects of dalcetrapib on event rates in people with the AA subtype.
"There are differences between the drugs in terms of their pharmacology, their biochemical efficacy, and the underlying populations in which the studies were undertaken. Thus, although the results from REVEAL suggest that any differential response to CETP inhibition by ADCY9 genotype is unlikely to be a class effect, only results from the ongoing dal-GenE trial will directly assess the impact of dalcetrapib on major vascular events in those with the rs1967309 AA genotype, and we await the results of this trial, which are anticipated in 2021," Hopewell said in an emailed response to questions from Scrip after the ACC meeting.
CETP's Play In "Promiscuous" Pathway
The drugs in the CETP class are clearly different, commented Anand Rohatgi, a preventive cardiologist at UT Southwestern who has conducted research in HDL function, including work for Merck about the effects of anacetrapib.
One important difference is the effect on standard lipids. Hopewell noted in her ACC presentation that in dal-OUTCOMES, dalcetrapib raised HDL by 30% and had zero effect on LDL and apoliprotein B (apoB). By contrast, in ACCELERATE, evacetrapib raised HDL by 130% and reduced LDL by 40% and apoB by 20%. So, anacetrapib offers a purer test of CETP inhibition.
The differences in effects on lipids had been apparent and had led Rohatgi to think that the outcome of dal-OUTCOMES might not be positive.
And due to the differences in the members of the CETP class, Rohatgi doesn't believe that the latest results from Merck's REVEAL genetic study have implications for DalCor's trial. Nevertheless, if the REVEAL sub-analysis had been positive, it would have provided a little more support for the biological argument that there is a role for CETP inhibitors in the AA genetic subset, he said.
There is still much to be understood about HDL and the CETP mechanism – CETP inhibitors are accessing part of the lipid pathway that is promiscuous and multitargeted, not one linear pathway, Rohatgi said.
"It's possible there is an effect, but it is really specific to certain types of drugs that inhibit CETP like dalcetrapib," Rohatgi said.
"From a biology standpoint it is interesting What the heck is this mutation doing and how relevant is it to atherosclerosis and lipid biology?" Rohatgi said.
DalCor's outcomes trial will be the real test and it will be interesting whatever they find. However, even if it is positive, hunting for patients with the mutation will be a challenge and the market is crowded with PCSK9 inhibitors and other classes, he said.
While the genetics outlook is still to be decided, what has been well established following the CETP outcomes studies other failed trials of drugs like niacin is that following changes in the HDL marker alone doesn’t show whether a particular interaction leads to improved outcomes, the clinician said. (Also see "HPS2-THRIVE Post-Mortem: Lessons Learned For CV Drug Developers" - Pink Sheet, 18 Mar, 2013.)
HDL is a non-specific marker of metabolic status that is influenced by a lot of factors like weight, insulin sensitivity and alcohol that make the marker fluctuate. The role of HDL number, particle size and functionality is also still unclear, he said.
Trial failures may have reinforced to the practicing cardiologist that it isn’t important to pay attention to HDL for now, but research interest in HDL goes on, Rohatgi said.