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TreaTing acuTe coronary Syndrome: ThiS Time iT’S perSonal
TreaTing
acuTe coronary Syndrome:
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ThiS Time iT’S perSonal
Thanks to the promise of precision medicine, a heart drug ditched three years ago by European multinational Roche Holding AG (Roche) is getting a second shot at a Phase 3 trial.
As a potential treatment for patients with acute coronary syndrome (ACS), the drug, Dalcetrapib, had in its first go around made it all the way through to Phase 3 before Roche halted its development due to a lack of meaningful efficacy results. Now, a Sanderling Ventures spin-out company in Montréal, DalCor Pharmaceuticals, has licensed the drug from Roche and launched a new Phase 3 trial to prove its viability as a personalized cardiovascular therapy. This will be a first in cardiovascular disease. As part of this new trial, DalCor says it will work with the Montréal Heart Institute and Roche Diagnostics to screen more than 33,000 patients across 30 countries in the hopes of identifying 5,000 patients who stand to benefit from its ability to boost “good” cholesterol because they have the right genetic profile. As Robert McNeil, managing director of Sanderling and CEO of DalCor explains, the big difference is that this time personalization is the name of the game.
“It all comes down the underlying principle behind precision medicine, a patients’ different genetic profile impacts how useful or harmful a drug is to the system,” he says, elaborating that not all drugs are one size fits all. In the case of Dalcetrapib, two Montréal Heart Institute (MHI) researchers Drs. JeanClaude Tardif and Marie-Pierre Dubé, have shown that patients with a certain genotype on a specific gene called ADCY9 (adenylate cyclase 9 on chromosome 16) exhibited reduced cardiovascular risk when treated with dalcetrapib as compared to placebo.
It was the pharmacogenomics data presented in this study that convinced McNeil that Dr. Tardif’s findings were groundbreaking. He remembers vividly his excitement when he heard about these findings from Dr. Tardif first-hand.
“A mutual friend called me up one day and said, “I’d like you to come and listen to a story of a colleague of mine that you might find interesting, about a possible drug.” So about a week later I was in his office with Dr. Tardif and basically, he showed me the results of Dalcetrapib in the original Roche Phase 3 trial, which I was aware of and he said, “But if you take what we discovered and look at a particular genotype, there is quite a different outcome.””
“Basically, there is a distinct difference in how Dalcetrapib performs in a group of people with a certain genetic composition,” says McNeil, citing that in Tardif and Dubé’s study, this patient group had a 39 per cent decrease in combined clinical outcomes of heart attacks, strokes, unstable angina, coronary revascularizations and cardiovascular deaths when taking the drug.
“First a 39 per cent decrease in hard outcomes on top of statins is a very big improvement, and second, it was the first time in cardiovascular disease that we had evidence that a drug could impact those who have a certain
genetic composition,” continues McNeil.
McNeil had always thought that eventually someone would try to take a precision medicine approach to treat cardiovascular disease, especially with advancements in the field deepening our understanding of the molecular and genetic basis of more and more diseases. Now, Dr. Tardif’s study had shown definite proof that this was the case.
“I’ll say a lot of people did not pick up on it with the vast majority of people probably saying, “Oh, this is a drug which failed a clinical trial” and one of the most dangerous things in the world is to try to parse through a failed clinical trial, finding the patients where it did work, and then do a trial on those patients. Those fail very frequently. However, Dr. Tardif’s data was unique: first, there were two Phase 3 trials, second there were prospective studies undertaken and it’s very rare to have such excellent data from a pharmacogenomics analysis. So I said, “Fine, I’ll do it. What do you need?” And he says, “$50 million.” And I said, “Okay, you got it.” That was the beginning.”
McNeil wasn’t the only DalCor representative blown away by Dr. Tardif’s research. Louise Proulx, DalCor’s chief development officer was very impressed by the pharmacogenomics data as well.
“We met with experts, clinicians and geneticists and they were all curious, wondering how true those data were. And we all agreed we had to go for it; we had to do a Phase 3 trial in this target population.”
She adds there were other factors that made the decision to license the drug and sponsor the trial an easy one.
“For starters, the drug was already de-
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risked in a sense, having showed an excellent safety profile in studies with more than 17,000 patients. One other thing that reassured us in terms of the drug itself, is the formulation of the tablets and all that has already been agreed upon with the FDA. It’s very reassuring to know there should be no issues with that,” says Proulx.
Best of all, DalCor isn’t in this alone. Like many precision medicines, there is a need for a companion diagnostic to help find the target population the drug is meant to treat. In this case, DalCor has turned to Roche Diagnostics to develop a diagnostic test that will be a key part of a pharmacogenomicsguided dalcetrapib treatment and be used in the planned Phase 3 clinical trial.
“The purpose of the companion diagnostic or CDx test as we call it, is to select or find the patients within the larger group that have the specific genotype linked to a positive response to Dalcetrapib,” says Michele D’Elia, manager, Medical Affairs at Roche Diagnostics. He adds that the test will work like most genetic based PCR assays.
“In every healthy cell we have all the same genomes; you take blood, then you isolate the white blood cells and you’re able then to look at specific genes that are located on a specific chromosome. In this case, it’s a specific gene called ADCY9, which shows at a certain sequence that there is a signature that would identify patients that are likely to respond more to Dalcetrapib,” he explains. He adds that the diagnostic test will not change anything related to the objective of the drug treatment except to ensure the patients who receive it will be the ones that actually benefit from the compound.
There is a process in place to generate a commercial version of this test approved by the FDA.
“Eventually, if the outcomes of the Phase 3 trial reflect what the retrospective analysis of the Dr. Tardif’s study did, then the companion diagnostic will be sold commercially alongside the drug,” he says.
Roche’s familiarity with the drug should aid its efforts in this regard. Moreover, this collaboration is important for Roche Diagnostics in breaking new ground in the precision medicine space. According to Francois Drolet, director of Business Development Roche Diagnostics, the company has made a personalized healthcare strategy an integral part of its business plan.
“It’s funny how it works, something takes you somewhere you hadn’t anticipated,” he remarks. “After the company pulled the plug on the Dalcetrapib program three years ago, I’m not sure we expected to be involved again with the success of this drug. But this concept of precision medicine and having companion diagnostics is moving to dominate medical practice. For example, if you look at the oncology space today, one third of the drugs that are prescribed have a biomarker associated with them. With Her2 and Herceptin® (trastuzumab) as probably the best example. Herceptin is not overly compelling as a treatment for breast cancer in a general population, but if you administer the drug to those with the correct genetic marker it shows significant medical benefit. That is what we’re trying to achieve, and I think we’re getting pretty good success lately if you look at our pipeline. We are bringing the concept of companion diagnostics into other disciplines, such as neuroscience and respiratory disease. For us, with this particular test, it would be breaking through with the first companion diagnostic test in the cardiovascular disease space, so we’re very proud to be associated with this project,” says Drolet.
The economics are confidential, but there will also be a financial reward for Roche if it’s successful.
Roche isn’t the only partner in this initiative. The Montréal Heart Institute will be retained by DalCor as the lead Academic Research Organization provider for the Phase 3 trial, to be conducted in partnership with MedPace, an international Contract Research Organization. This also insures that Dr. Tardif and his team remain heavily involved in the project and can further investigate the drug’s biological mode of action.
As for the cost of taking Dalcetrapib back into Phase 3 trials, DalCor estimates it will take $250 million to complete the project.
“The way we established that number, is there’s a screening portion to the trial where we have to distinguish who our trial population will be, then establishing the trial in 30 countries and so on. That’s a major part of that $250 million,” says Proulx.
Aligning the development of a drug and diagnostic design program also requires a lot of careful planning she adds.
“Once we develop the companion diagnostic, then we need drug supply for the trial, so manufacturing and distribution around the world over a period of five years. We have a very detailed budget,” she says.
The payoff if successful could be in the billions. Specifically, before Roche’s setback with the molecule, some industry analysts had estimated that dalcetrapib could have achieved up to $10 billion in annual sales.
“That number changes of course with this new personalized medicine or precision medicine approach, but it’s still a significant figure, in the billions,” Proulx states.
Going forward, McNeil says DalCor is the fifth company that Sanderling has launched in Quebec since 2013, and it won’t be the last. As part of its program dedicated to help bolster the biomedical industry in Quebec, Sanderling has plans to form as many as eight companies in Quebec, representing a potential investment of more than $500 million.
“We do like investing in new technologies and innovative big products, that’s where the excitement is,” says McNeil. “With DalCor we hope to build a very large, substantial organization which can fund other projects which we will have over time and reduce our need for venture capital.”
For now though, the focus will be on DalCor, and proving that Dalcetrapib actually works. He is excited by the promise this trial holds for the future in personalized treatment for cardiovascular patients based on genomics.
“There’s a lot of evidence that says it does, but on the other hand we still have to prove it and if we do, there will be a substantial benefit to a meaningful part of our world population,” says McNeil.
To see this story online visit www.biotechnologyfocus.ca/ treating-acute-coronarysyndrome-this-time-its-personal/
