Q&A: Novel drug may replace ‘watchful waiting’ approach to aortic stenosis care
Key takeaways:
- A first-of-its-kind therapy successfully slowed plaque progression in patients with aortic stenosis.
- Ataciguat may reduce the need for surgical or transcatheter aortic valve replacement.
A novel therapeutic showed significant promise in slowing aortic valve calcification, potentially extending time until or eliminating need for transcatheter or surgical intervention for stenosis, researchers reported.
Jordan D. Miller, PhD, associate professor, cardiovascular disease researcher and co-vice chair of basic science research in the department of cardiovascular surgery at Mayo Clinic, and colleagues conducted a phase randomized controlled trial designed to test whether changes in nitric oxide signaling could slow aortic calcification in patients with meaningful aortic valve stenosis.
The trial drug, ataciguat (HMR 1766, R Bio), is the first drug able to bind to oxidized soluble guanylate cyclase (sGC), the main receptor for nitric oxide, and reactivate the molecule.
The trial enrolled 46 patients with aortic stenosis, with an average age of approximately 73 years and the majority being men. The patients were randomly assigned to 6months of ataciguat or placebo.
Using echocardiography, cardiac CT and X-ray, the researchers observed an approximately 70% slowing in plaque progression compared with placebo and improvements in aortic valve area and left ventricular function.
Healio spoke with Miller about ataciguat, how the novel drug works and its impact o aortic stenosis progression.
Healio: What is the basis for the study of nitric oxide signaling as a mechanism of slowing aortic calcification?
Miller: For decades, we’ve known that nitric oxide can do “good things” in the CV system: t promotes vascular relaxation, prevents blood clotting, reduces inflammation and much more, which made it a very attractive therapeutic target. There are a number of CVD in which oxidative stress is increased, which promotes the degradation of nitric oxide and its downstream protective signaling cascades, and several investigators published reports that increases in oxidative stress accelerate calcification of blood vessels. So, all the biological pieces were falling into place for losses in nitric oxide signaling being a contributor to accelerated progression of aortic valve calcification, we just needed the right tools to restore nitric oxide signaling in diseased tissues.
Unfortunately, this has been one of the biggest limitations in the field: itric oxide does so much systemically, that drugs targeting it often elicit significant side effects (e, reduced blood pressure). We had already amassed a large amount of data using geneticallyaltered models of valve disease that reducing nitric oxide signaling could accelerate valve calcification, but it wasn’t until NIH established the New Therapeutic Uses program that we gained access to a unique drug that we thought would work perfectly in this indication.
Clinically, both patients and providers are in desperate need of a drug that slows progression of valve disease, as the current treatment paradigm is “watchful waiting” followed by surgery when valve function is severely impaired. Collectively, we had the biology, the drug and the unmet clinical need fall into place at just the right time
Healio: What is ataciguat and how does it work?
Miller: Ataciguat is a drug that binds to nitric oxide’s receptor, a molecule called sGC. While there are other drugs that can bind to sGC, the unique attribute of ataciguat is that it only binds to sGC when it is in an oxidized or diseased state. This was perfect for us. We knew oxidative stress was high in the valve, which should generate a lot of oxidized sGC for ataciguat to bind to, and we needed to minimize the activation of sGC systemically to avoid side effects.
With our mechanistic work in cells and animals, we found that ataciguat effectively reduced key pathways that drive valve calcification (e, bone morphogenetic protein signaling), and ultimately prevented progression of valve calcification and progression of valve stenosis in our mouse model of valve disease. In addition, ataciguat did not have a negative effect on bone ossification — and may even have a positive effect on bone — suggesting nitric oxide has site-specific, context-dependent effects on tissue calcification, which was pivotal for moving this forward to human studies
Healio: What changes in stenosis did you observe in the trial and how long will the slowing of plaque progression last?
Miller: Our key findings fall into three categories: effects of ataciguat on valve calcification, valve function and ventricular function. We knew our primary outcome variable — valve calcification — would be the fastestchanging variable in these studies, and we found that ataciguat slowed progression of valve calcification by 69.8% on average.
Our secondary outcome variable, aortic valve area, changes much more slowly over timeWhile our study wasn’t statistically powered to detect a change in valve area, we did observe a tendency for valve function to be preserved, and on average, declines in valve area were slowed by 45.8%.
Finally, we observed the left ventricle appeared to have preserved function in patients treated with ataciguat. More specifically, we observed significant attenuation of declines in EF, and tendencies toward slower progression of LV hypertrophy and diastolic dysfunction.
Collectively, the internal consistency of our data, combined with the fact we used multiple imaging approaches to make these measurements, strongly suggests ataciguat interferes with the progression aortic valve stenosis and adverse ventricular remodeling associated with it. It appears these changes are robust after 6 months of treatment, and future hase 3 trials, done for full approval by the FDA, will have longer follow-up2 years or longer.
Healio: Who is the ideal patient for this kind of novel therapeutic?
Miller: Currently, the ideal patient is someone who has moderate aortic valve calcification and stenosis, as they are highly likely to worsen over time. This makes evaluation of riskobenefit ratios during shared decisionmaking much more straightforward. As we accrue more data and longer-term follow-up, we’ll likely gain evidence that “the earlier you start slowing valve calcium, the better,” and I could see a time in the future where patients with mild aortic valve stenosis would start this drug at the time of diagnosis, thereby receiving greater cumulative benefit during their lifetime, and perhaps preventing the need for surgery.
Patients with bicuspid aortic valves — who often develop valve calcification and stenosis earlier in life — would receive great benefit from earlier intervention and longer treatment with this drug. But there’s a lot of work to be done to get there
Healio: What are the next steps for ataciguat research?
Miller: We have been able to identify an industry partner who has the resources and experience to bring ataciguat through a hase 3 trial, and if successful, to market. Through these studies, we’ve also been able to gain a deeper understanding of the biology of ataciguat, and other activators of sGC, and are actively exploring other uses for this class of drug. Collectively, it’s an exciting time for patients, providers and scientists
Healio: Anything else you would like to add?
Miller: This is an incredibly exciting time for patients with aortic valve stenosis and the providers who care for them. We anticipate ataciguat will be a first-in-class treatment for aortic valve stenosis, and transform how patients with this disease are managed. We’re also grateful for the New Therapeutic Uses program at NIH and Biotechnology and Genomics for funding, Sanofi for providing ataciguat and other extensive support, for our colleagues at Mayo Clinic and the University of Minnesota who have worked on this for the past decade, and the patients who participated in this trial
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