NEW YORK (GenomeWeb) –Pharma firm Dalcor remains optimistic regarding its work to salvage the cardiology drug dalcetrapib and see it approved by the US Food and Drug Administration for a biomarker-specific patient population, despite negative results presented by a competitor earlier this week.
The company's approach to the drug, a cholesterylester transfer protein (CETP) inhibitor, follows a precision medicine model that has become common in oncology but would be a milestone for the cardiology drug space.
Dalcor picked up dalcetrapib from Roche several years ago after that company's Dal-Outcomes trial failed to demonstrate benefit in the overall population but did seem to work in a subset of subjects with an AA genotype at rs1967309 in the ADCY9 gene. Dalcetrapib-treated AA patients saw a 39 percent decline in cardiovascular events compared to those treated with a placebo. In contrast, patients with a GG genotype did worse on the drug than on a placebo.
This initial finding came from a retrospective genome-wide association study led by researchers at the Montreal Heart Institute. But it was enough for Dalcor to raise funds to secure rights to the drug and begin the process of starting from scratch to prospectively prove its efficacy in a biomarker-defined population.
Dalcor CEO Fouzia Laghrissi-Thode said that Roche's decision to jettison dalcetrapib, despite the ADCY9 hypothesis generated by the GWAS, came as the company was moving away from cardiovascular drugs and focusing more on oncology and other areas. Since taking over the drug, Dalcor has set itself the goal to replicate the Dal-Outcomes study and announced late last year that it had completed enrollment of about 6,000 patients, expecting the trial to read out in late 2020 or early 2021.
Despite abandoning the drug, Roche has partnered with the firm for genotyping in the new Dal-Gene trial. If the study is successful, the company would then provide clinical companion diagnostic testing to identify patients eligible for treatment.
As the company has pushed forward, it saw some potentially disappointing news for its efforts this week with a presentation by Merck at the American College of Cardiology annual meeting from a re-analysis of the pivotal trial of its own, also failed, CTEP inhibitor anacetrapib. Company investigators reported that ADCY9 AA patients in the Reveal trial of anacetrapib had largely similar rates of cardiovascular events as those with a GG genotype.
Reveal enrolled 30,000 patients, of which Merck identified about 1,500 who were rs1967309 AA and were randomized to take anacetrapib on top of statins, while another 1,500 were treated with statins alone. In the treatment arm, 12.7 percent of the AA group had a major vascular event, compared with 13.5 percent of those taking just statins. This translated to a non-significant hazard ratio of 0.93.
Responses to the new Merck results have suggested that the findings highlight a risk Dalcor is facing in the Dal-Gene trial, and that they enhance doubts over its potential for success. But the company has argued that it doesn't think that the Merck analysis has direct bearing on its own program.
For one, dalcetrapib was initially trialed in sicker patients than the Merck drug, which was being advanced for a lower-risk broader population. "The population which was treated in Dal-Outcomes [was] excluded in the Merck study because patients could only be randomized after 12 weeks of acute coronary syndrome, while in Dal-Outcomes, we [were treating patients during that 12 weeks]," Laghrissi-Thode explained.
The two drugs also differ in how they alter cholesterol levels. Anacetrapib affects both HDL and LDL — raising the former and lowering the latter — while dalcetrapib is a comparatively "weak" inhibitor, only affecting HDL.
The influence of genotype on the larger CETP drug class has been somewhat muddy. The Merck findings echo in some ways what researchers saw for Eli Lilly's drug evacetrapib when they reported last year that ADCY9 genotype also failed to significantly affect the efficacy of that compound.
But Dalcor's Laghrissi-Thode argued that although the Eli Lilly analysis data didn't reach statistical significance, it did in fact reflect the same pattern seen with dalcetrapib. "They picked up exactly the … same pattern," she said, "with the AA improving, the GG worsening, and AG being neutral," even though they missed the P-value.
Although the new Merck analysis is another blow to the possibility of ADCY9 mediating response across all CETP inhibitors, Laghrissi-Thode argued that it can't be translated to dalcetrapib's particular case.
As part of its investigation of ADCY9 after the Dal-Outcomes GWAS, the company has collected various other data that presents rationale for a mechanism connecting the gene with cardiovascular disease pathways.
"We have done analyses of other studies that Roche had," Laghrissi-Thode said. "One is a plaque study called Dal-Plaque2, and you see exactly the same thing … with imaging you see that AA [patients] have an improvement of their plaque, a reduction. And you see a worsening in the GG [patients].
"We [also] looked at the other biomarkers, like CRP [and] inflammation, in Dal-Outcomes and saw [the same pattern,]" she added.
The group also went back to the bench with investigators at the Montreal Heart institute, seeing a clear influence between ADCY9 genotype and the build-up of atherosclerosis in mouse models.
Although biomarker subgrouping has become a significant aspect of drug development in oncology, the cardiovascular space has seen much less of this type of model. But Laghrissi-Thode said that that may change if Dal-Gene is successful. "There is very little innovation coming in cardiovascular [drugs] and most of the big players are not continuing to invest in [this space] because of the cost of the trials. To get approval, you need outcomes and most of the studies are 15,000-patient trials that you have to run for at least three or four years," she said.
With Dal-Gene, "by having the right genotype identified in advance, we bring the size of this trial to 6,000 patients," she added.
Aside from the way that this changes the practicality of advancing drugs, Laghrissi-Thode argued, payors in the cardiovascular field are also becoming keener to see precision treatments tailored to the patient. "Even if the current treatments like statins and PSKC9 drugs have had terrific, terrific benefit for patients … you need to treat a lot of patients to reduce the risk," she said. "I think the payor would appreciate if we tell them we need to screen five patients and then we'll pick up the one who has the right gene who will have the highest likelihood to get benefit from the treatment."
For Dal-Gene, "we will know by the end of this year, which is when we are expecting to have futility analysis," Laghrissi-Thode said. "Based on the current events rate [we should have] collected 70 percent of the events … towards the end of this year."
If that analysis is positive and the study goes to completion, the team will need 582 events to be able to detect 15 percent relative risk reduction above and beyond the standard of care, she added, and expects to reach that some time around the end of 2020.
"We have full support from our investors to carry the program all the way to the finish line. We are fully funded for that," Laghrissi-Thode added. "So I'm quite confident that we'll bring an unequivocal answer. And if we're fortunate that this answer is positive, it will be a paradigm shift in the way post-[acute coronary syndrome] patients are treated."