May 29, 2020
In this episode of PopHealth Perspectives, Kiersten Combs, vice president, US Cardiovascular and Metabolic Disease (US CVMD) and Naeem Khan, MD, vice president, medical, US CVMD, AstraZeneca, discuss the recent approval of Farxiga (dapagliflozin), and explain how this treatment lowers the disease burden and hospitalizations for patients with heart failure.
Julie Gould: Welcome back to "Pop Health Perspectives," a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.
Today, we are joined by Kiersten Combs, Vice President of the Cardiovascular and Metabolic Disease commercial business at AstraZeneca, as well as Naeem Khan, Vice President of Cardiovascular and Metabolic Disease, leading the medical division also at AstraZeneca.
They discuss their recent approval of Farxiga and explain how this treatment lowers disease burden, as well as hospitalizations, for patients with heart failure.
Kiersten Combs: Hi, I'm Kiersten Combs. I'm the Vice President of our cardiovascular metabolic commercial business within the US at AstraZeneca. I've been in health care for probably over 20 years at this point. 16 of my years have been with AstraZeneca and have worked really across our different cardiovascular metabolic brands in many different ways over the years.
Naeem, over to you.
Naeem Khan: Thanks, Kiersten. My name is Naeem Khan. I'm the VP for Cardiovascular and Metabolics. I lead the medical division for AstraZeneca here in the US. I've been in health care for greater part of 25‑plus years, with 18 of those spent here with AstraZeneca since I left the hospital.
Julie: Excellent. Can you briefly discuss the recent approval of Farxiga for reducing the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction with and without type 2 diabetes?
Kiersten: On Wednesday of this week, the FDA granted us approval of what we refer to as our DAPA‑HF indication, which was the study in which this indication has come from. As you said, Farxiga is now indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with reduced ejection fraction heart failure, both those with and without type 2 diabetes.
This is really a monumental indication for us. It builds upon our DECLARE indication as well as our indication to lower A1C with Farxiga. This indication is specifically monumental because this is the first medicine in the class that is approved for the treatment of hospitalization of heart failure with patients with reduced ejection fraction.
Not only is it the first approved in the class, it's also the first medicine within the class that has been approved for treatment of any type of patient outside of diabetes.
Those two pieces really advance the science for Farxiga and really will have a meaningful impact on clinical practice, specifically for these patients with heart failure, which is a growing patient population within the United States. It's a very insidious disease for these patients that really impacts not only their overall health but really their quality of life also.
Julie: What existing data led the research investigators to examine this drug? Can you summarize those major study findings?
Naeem: Sure. It goes back to 2008 when all diabetes drugs, including SGLT2s, were required to do cardiovascular outcome trials. We did the largest outcome trial done in SGLT2 inhibitors. That was called DECLARE. DECLARE was a study in 17,000 patients with type 2 diabetes across the broad spectrum of cardiovascular risk.
It enrolled patients both with established cardiovascular disease ‑‑ that's about 6,900 of those patients ‑‑ and about 10,000‑odd patients who had multiple risk factors, who had not yet had an event.
What we saw was when dapagliflozin 10 mg was given versus placebo, we saw a significant benefit in the relative risk reduction for the primary endpoint of hospitalization for heart failure and CV death, which is a 17% relative risk reduction.
That got our eye. We said, "OK, this is working in hospitalization for heart failure and producing CV death and also from another trial from the class."
Based on that, we went forward to create the DAPA‑HF study, on which our data and our current label is based, which was a landmark study which actually had 4,700 patients who had NYHA class II to IV, who had left ventricular ejection fraction of 40 or less within the last 12 months, who were randomized to dapagliflozin versus placebo. Placebo was standard of care.
Basically, what we did was on a background of therapy that was equal across the board, we saw that treating with dapagliflozin versus placebo when they had the best standard of care I've seen in studies over the last 20 years, with diuretics at 94%, with ACE inhibitors/ARB/ARNI at about 94%, beta blockers at 96%, MRAs at 71%, and even ARNIs at 11%.
We saw the benefit of a 26% relative risk reduction with a p‑value of 0.00001. That gave us the data and the points and the information that brought us to where we are with regards to this label and indication.
Kiersten: What is so remarkable about the two studies that Naeem just talked about is if you think about it, our DECLARE indication was really done in the most broad patient population with type 2 diabetes and that these were patients with either CV risk factors or established cardiovascular disease.
Then you take that through to then our DAPA‑HF data, which is now for the treatment of heart failure in patients with or without type 2 diabetes on top of the standard of care. This really sets up. You can see that the medical community has taken a notice. They took notice when it was presented at ESC.
The FDA granted us Fast Track designation for the development of our heart failure program. We were issued priority review. Then you even saw that the FDA, with this DAPA‑HF indication, issued their own press release. The combination of our DECLARE indication along with this DAPA‑HF data is really an indication it's really going to be paradigm‑shifting in the medical community.
Julie: Were any of the findings from the study that the approval was based on particularly surprising?
Kiersten: The part of the data that was most surprising to us in a very good way is that when we actually looked at...We talk about the primary endpoint as the composite of the entire patient population for reducing cardiovascular death or hospitalization of heart failure in patients both with and without type 2 diabetes.
When you actually look at the sub‑cut of the patient populations, what we found was that the result in the patients with type 2 diabetes as well as those without type 2 diabetes were remarkably consistent.
Naeem: I completely agree with that, but what I found very intriguing was that the benefit started early and it continued to accrue over time. In fact, we did an analysis to check when did the benefit actually occur first. It was significant at day 28. That's when it became statistically significant. Then, obviously, the benefit continued to accrue over time.
In addition to just looking at the overall benefit that was showing a 26% relative risk reduction, if you broke it out by was it driven by worsening heart failure or CV death, we saw that both drove the primary endpoint. We saw a 30% relative risk reduction for worsening of heart failure events. We saw an 18% relative risk reduction for CV death.
To add to that, even looking at the latest medication that's been out there ‑‑ that's an ARNI ‑‑ you saw a benefit for DAPA that was showing a 25% relative risk reduction with the use of an ARNI and a 26% benefit when you did not use an ARNI.
Whether you used an ARNI or not, the benefit was seen with this molecule. That was absolutely phenomenal. That was, in my mind, quite surprising and put this in a realm of its own.
Julie: What are some of the real‑world applications for this approval in clinical practice?
Kiersten: If you think about it today, there's about 6.5 million Americans who have heart failure. That number is increasing. It is growing as the population gets older and as medicines in other cardiovascular diseases treat things like heart attacks and so forth.
When you actually look at the treatment of heart failure, the mortality rate has only really slightly improved in the last 10 years. In the mortality rate specifically, patients who diagnose with heart failure, within five years, the mortality rate is about 50%. About 10% of those patients are living after 10 years after diagnosis.
Not only is this a very serious condition for the patient, but then you look at the health care costs associated with treating heart failure. It's quite a significant burden. If you actually look at it, it's about $30 billion worth of cost put on the US every year to treat these patients.
An average cost of a hospitalization for a heart failure is about 23,000 and with about 50% of patients being hospitalized at least twice a year. It's just a significant cost burden to our health care system also.
A medicine like this that potentially treats hospitalization of heart failures and can reduce cardiovascular death not only has meaning to the patient in improving their longevity and quality of life, but it also has a real potential economic benefit to the health care system overall. That's why we are seeing such a significant amount of interest specifically in the cardiology community.
What we've also been really happy to see is that it's not just at the point of treatment. What we also have with our DECLARE indication and what you're seeing in both primary care and in the endocrinology space is that the prevention of hospitalization of heart failure in patients with type 2 diabetes is also extremely important.
We know that hospitalization of heart failure and heart failure is probably the first and most frequent complication of type 2 diabetes. The ability to both be able to prevent hospitalization of heart failure in patients with type 2 diabetes and then also treat patients, regardless of their type 2 diabetes status, in the heart failure space is quite meaningful that we have one medicine that does both.
Julie: What are each of you most excited about in regards to this approval?
Kiersten: Maybe I'll start. Then, Naeem, I'll throw it to you. What I just said is what I'm most excited about, that we really can span the continuum of prevention of hospitalization heart failure in type 2 all the way through treatment and that we can do this specifically in the treatment space on top of the standard of care.
It's a medicine that doesn't need to get titrated. You can use it depending on what other medicines you have a heart failure patient on. It will be extremely meaningful to not just cardiologists, but really, it will change the way that type 2 diabetes is treated, as well as heart failure.
To have one medicine that can do that across multiple specialty groups is really paradigm‑shifting and important not only to the medical community but also to the many, many patients who suffer from these cardiovascular metabolic diseases.
Naeem: With this approval for Farxiga, we have reached the point where we can potentially transform heart failure treatment for the millions of people living with heart failure with reduced ejection fraction.
Farxiga should provide a much‑needed treatment option to reduce this disease burden and also help people live longer. That's the whole crux that we are looking to do. We can actually now help prevent heart failure. Now we can help treat it as well.
We, as Kiersten said, go from prevention to treatment. That's a very, very, very good option. That's a very simple option for physicians to incorporate into their treatment paradigm for these patients.
Julie: Excellent. Then just overall, is there anything else that you would like to add?
Kiersten: The only thing that I would add is that this is just the new beginning of the beginning for Farxiga. The DECLARE DAPA‑HF data is really very compelling. As we've talked about, it's paradigm‑shifting.
You probably also saw, just in the last few weeks, our DAPA‑CKD study was stopped early due to overwhelming efficacy. Here's where we're studying Farxiga in chronic kidney disease patients both with and without type 2 diabetes.
After that, we also have another heart failure study in preserved ejection fraction. I really think that the future of Farxiga will live into our vision that Farxiga can provide cardio‑renal protection not only to type 2 diabetic patients but to patients who also suffer both heart disease as well as renal disease.
To me, that's what's most exciting about the beginning of this next phase of Farxiga's journey that we're on.