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The stand-out session at this year’s European Society of Cardiology Congress in Paris, France was the presentation of results from AstraZeneca PLC’s DAPA-HF Phase III study of Forxiga/Farxiga (dapagliflozin) in heart failure with reduced ejection fraction. The study paves the way for the SGLT-2 inhibitor’s approval – likely in the first half of 2020 – to treat heart failure in both diabetic and non-diabetic patients.

Already approved to treat type 2 diabetes, with a label expansion for cardiovascular outcomes expected imminently, Forxiga can expect a sizable sales boost from an approval in heart failure. The product is also in ongoing trials for heart failure for preserved ejection fraction, in additional studies looking at other measures in heart failure, and in chronic kidney disease. Fellow SGLT-2 inhibitor Jardiance (empagliflozin) from Eli Lilly & Co. and Boehringer Ingelheim GmbH has been ahead of AstraZeneca as a preventive for cardiovascular outcomes, but is trailing in the heart failure indication. 

Nevertheless, Jardiance is being put through similar paces in its ongoing clinical trial program and is likely to provide robust competition across the board.

Boehringer reported net sales of Jardiance of about €1bn in the first half of 2019, with Lilly reporting its 50% share of the gross margin on Jardiance at $436m, while Forxiga's first-half sales were $726m.

Mene Pangalos, executive vice-president of biopharmaceuticals R&D at AstraZeneca, spoke to Scrip about the findings.

Scrip: I’d like to start with DAPA-HF, which studied dapagliflozin in a mixed population of diabetics and non-diabetics. I hear there were standing ovations during the presentation.
Mene Pangalos: It was fun. You don’t go to conferences very often and get a response like that. You get it once in your career if you’re lucky, a few times if you’re really lucky. It was really nice, actually.
What can you say about that fact that there didn’t seem to be a difference between diabetics and non-diabetics?
There wasn’t a difference, and that’s the really exciting piece for us. This is now moving beyond being a diabetes medicine. It’s the first outcome study with an SGLT-2 inhibitor looking at patients with and without diabetes – and that was obviously a question mark – and the data I think are very compelling that there is absolutely no difference in effect size whether you are diabetic or not diabetic in terms of the benefit on heart failure risk and heart failure progression.
What does that mean for the way we think about SGLT-2 inhibitors? We have thought about them as diabetes drugs primarily, but it sounds like there’s more to them.
Well we haven’t been thinking about them as a diabetes drug, we’ve been thinking about them as a class of drug that has got very broad and significant potential. If you look at the studies that we have ongoing, obviously DAPA-HF has read out now, but behind that we have the trial that’s ongoing in heart failure with preserved ejection fraction as well as reduced ejection fraction and that’s going to read out in the next year or so, and that’s also in diabetic and non-diabetic patients. We also have a trial running in chronic kidney disease which should be reading out in the next 12 months or so as well, and that is also in patients with and without diabetes. So we look at this molecule not just as a diabetes medicine but as a medicine that’s going to be useful for patients with cardiovascular disease and heart failure but also for patients with chronic kidney disease as well.
And that fact that there isn’t anything at the moment for heart failure with preserved ejection fraction (HFpEF) – what hope do you have that dapagliflozin might change that?
I think we are very encouraged by the data we have seen so far, both in terms of the data we’ve seen from our DECLARE study, which was in diabetics but included patients with preserved ejection fraction, but also from the data that we’ve seen and the scientific hypothesis we feel we’ve got a good chance of hitting the HFpEF population as well in a positive way, but obviously the data need to read out before we can be confident.
What is it about the scientific hypothesis that means there is more hope for this?
It’s an interesting question and I don’t want to get into too much detail because we’re still trying to get to the bottom of understanding fully the mechanism of action, there are a number of different hypotheses, but when you look at the impact that this has on not just glucose but sodium and overall volume, the impact it has on the metabolic state of cells in terms of being able to create a starvation-like phenotype in cells that actually then stimulates pathways that are important in regeneration: I think there’s some interesting biology here that we’re digging into which takes it beyond just being something that enables you to excrete glucose in the urine.
The other interesting thing was that even when patients were on Entresto [Novartis AG’s approved angiotensin receptor-neprilysin inhibitor sacubitril/valsartan] already, there was a benefit. What does that mean for the drug?
To be clear what we’ve showed was that in the 500 or so patients in the trial that were on Entresto, the efficacy of dapagliflozin was the same in terms of benefit whether you were on or not on Entresto. Mechanistically there’s no reason to think anything other than these two drugs would be complementary to one another. So we view this as being additive: if a patient is on Entresto you can put Forxiga on top of that, and it’s a very easy drug to use, it’s a once a day, and if you’re not on Entresto that’s also fine. I think it’s a nice simple option for physicians to use in patients with heart failure with reduced ejection fraction.
But what would that mean for uptake and pricing given that neither drug is all that cheap?
I don’t really want to comment on the pricing or on the uptake – given the data we have, and that this is reimbursed for diabetes today, I don’t think being reimbursed for heart failure should be a challenge.
How about differentiation over other SGLT-2 inhibitors or indeed other products in development for heart failure that work in different ways?
Yes, obviously I think this is very likely to be a class effect. I think what is very good about the data is that we have it in hand, it was very compelling, and we’ve got a very clean safety profile, which I think is really pleasing. We have no imbalances on things like lower limb amputations, gangrene, all of the things we have in terms of safety profile are very clean. Major hypoglycemic events is the same in both treatment groups, renal adverse events is the same, volume depletion is the same, so this is going to be a relatively simple drug for physicians to use. Obviously other companies will have to get their data readouts and look at their data – we can concentrate on ours and we have a head start. But I would not be surprised if ultimately we see good data with other SGLT-2 inhibitors as well. But I’m very happy to have our data in hand and ready to go, and have our conversation with the regulators and get this hopefully approved as fast as possible.
How quick do you think that could be?
Filing second half this year, there’s not that much of the second half of this year left, and hopefully approved in the first half of next year.
Have you already started having conversations with insurers, or reimbursement authorities?
No. People are acutely aware of the data now given that it’s been presented, and Forxiga is already on many formularies around the world, so this is really about expanding its label. Nothing is straightforward in the commercial world and I’m an R&D person, so I’m the last person that should be talking about it, but the fact that this is a well-established brand, mechanism of action, used widely in diabetes around the world, what we’re saying now is that we can expand it into the cardiology population.
What was the reaction amongst that cardiology physician population – because these people are going to have to get used to prescribing something that is not in their normal armamentarium?
I think they’re thrilled actually – they’re thrilled because the data were highly compelling, and however we cut the data it was highly significant in terms of the benefit, and it’s a very simple once-a-day drug to use with a relatively benign side-effect profile, so I think the cardiologists in the room – there was a reason why we were getting spontaneous applause for the data set, and why it’s on the front page of the Congress News today, because it’s being viewed as a landmark study and a breakthrough therapy for these patients.
So – again, you’re in R&D, but what does this mean for the additive sales potential of the drug?
This should increase our forecast for Forxiga considerably in terms of the heart failure population. There are 64 million people globally with heart failure and I would say about half of them have HFrEF. So this is a very big opportunity.
Can you comment on how it squares up against Jardiance?
No, I would say we have the data and they don’t! I think this puts us in a really good spot now in terms of cardiology and heart failure. They’ve had for some time the advantage with their data because we haven’t had our CV outcomes data in our label, which we should have before the end of the year, we both have studies running in HFrEF and HFpEF, we both have studies running in kidney disease, this is a large opportunity, it’s good to grow the class. I think the other big opportunity for us is to start to displace much more dramatically the DPP-IVs [dipeptidyl peptidase-IV inhibitors Januvia (sitagliptin), Galvus (vildagliptin), Onglyza (saxagliptin) and Tradjenta/Trajenta (linagliptin)], because given the data we have now, the DPP-IVs should be moving backwards in terms of proportion of patients being prescribed those for diabetes relative to SGLT-2. I think there’s a lot of opportunity for both of us to do well here, with a very important drug class now for both diabetes and non-diabetic patients.


Key dapagliflozin trials in cardiovascular and renal indications

  • DAPA-HF: type 2 diabetics and non diabetics with heart failure: time to death or worsening heart failure event. Estimated filing 2019.

  • DELIVER: dapagliflozin in patients with HFpEF: worsening HF or CV death. Estimated filing 2020+.

  • DETERMINE: dapagliflozin's effect on exercise capacity in patients with HFpEF or HFrEF. Estimated filing: US H2 2020.

  • DAPA-CKD: renal outcomes and cardiovascular mortality in patients with chronic kidney disease. Estimated filing 2020+.

  • DECLARE-TIMI examined cardiovascular outcomes (hospitalization for heart failure or cardiovascular death vs placebo) in patients with type 2 diabetes. MACE didn't meet significance. Label updated in EU in August 2019, pending in US.

Key empagliflozin trials in cardiovascular and renal indications

  • EMPERIAL: heart failure symptoms and exercise ability in patients with HFrEF and HFpEF, regardless of whether they have diabetes. Top-line results expected 2019.

  • EMPEROR: time to first event of cardiovascular death or heart failure hospitalization in patients with HFrEF and HFpEF. Estimated completion 2020.

  • EMPA-KIDNEY: cardiorenal outcomes in type 2 diabetes patients with chronic kidney disease. Top-line results expected 2022.

  • EMPA-REG OUTCOME: cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease. Approved in this population to reduce cardiovascular death risk in 2016.



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