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Novartis Impresses Where Others Have Failed

There is some good news from the clinic today. Novartis reported data on LCZ696, a combination therapy for congestive heart failure, and the results have really grabbed a lot of attention. (The trial had been stopped early back in March, so the news was expected to be good). This is a combo of the angiotensin II antagonist valsartan and a neprilysin (neutral endopeptidase) inhibitor, AHU-377.
Compared to enalapril, the standard ACE inhibitor therapy for CHF, the Novartis combo lowered the risk of cardiovascular death by 20% and the risk of hospitalization by 21%, while having at least as good a safety profile as the generic ACE drug. Those are powerful arguments for the company to make, both to physicians and to insurance payers, so the future of the therapy, barring any sudden misfortunes, looks assured. There’s not a lot that you can do for people with congestive heart failure as it is, and this looks like a real advance.
As Matthew Herper mentions, though, this isn’t the first time that a similar combination has been tried in CHF. A few years ago, Bristol-Myers Squibb had a major failure with a single drug that inhibited both the ACE and neprilysin enzyme pathways, Vanlev (omapatrilat). That compound had a persistent problem with angioedema, as detailed here, and that led to its eventual rejection by the FDA on risk/benefit grounds, after a great deal of expensive Phase III work. Back in 2002, in the early days of this blog, I predicted that no ACE/endopeptidase combination would ever see the light of day again, which shows you how much I know about it. But I wasn’t alone, that’s for sure. It’s very interesting and surprising that LCZ696 has worked out as well as it has, and it’s a very worthwhile question to wonder what the difference could have been. Balance between the two pathways? Having an receptor antagonist on the ACE end rather than an enzyme inhibitor? Whatever it was, it seems to have done the trick.
The only question I have about the new combo is how it would compare to an ACE/diuretic combination, which (from what I know) is also a standard course of therapy for CHF patients. On the other hand, you’d expect that a diuretic might also be added to LCZ696 treatment – it was shown that it could be combined with omapatrilat, since they’re all different mechanisms.
And one other point – I always make this one in these kind of situations. I’m willing to bet that critics of the drug industry, who like to go on about “me-too” drugs and lazy industrial research efforts, would have had LCZ696 on the list of eye-rolling follow-up drugs (that is, if they’d been paying attention at all). I mean, the angiotensin pathway is thoroughly covered by existing drugs, and neprilysin/NEP has been targeted before, too (both by omapatrilat and by Pfizer’s so-called “female Viagra”, UK-414,495). But there’s an awful lot we don’t know about human medicine, folks.
Update: here’s a deep look at the IP and patent situation around the combo.
Update 2: and here’s a detailed exchange about the way the trial was conducted and the drug’s possible impact.

7 comments on “Novartis Impresses Where Others Have Failed”

  1. Just asking... says:

    What is the benefit to the patient of such dual-drug formulations? I can see the advantage to the companies, but aside from improved compliance what’s the point? Or is that sufficient?

  2. John Thacker says:

    If you’ve ever been around someone with CHF, improved compliance is a major, major benefit. Most people in that condition have a whole raft of medications to take, with various interactions. (As Derek says, diuretics are common. Many people with CHF have diabetes, which is a risk factor for CHF.) Simply having the combination tested for interactions in rigorous clincial trials is big too.

  3. anon says:

    Before Vanlev, Aventis (then Marion Merrell Dow) discovered what they called MDL-100240, later named AVE-7688, then named Ilepatril. It was a dual ACE/NEP peptidomimietic. They were slow in developing it and it lagged behind Vanlev. Sanofi-Aventis eventually dropped development at phase 3, but the reason to my knowledge was never disclosed.
    I always suspected that all of the mergers– MMD, to Hoechst, to Aventis, to Sanofi-Aventis– could not have helped.
    #1- the benefit is having two different mechanisms of action that compliment each other, in one pill, so that a certain drug ratio is maintained to maximize the hoped-for synergy, and so compliance is better.

  4. I looked up neprilysin on wikipedia. Is it possible this can increase one’s risk for Alzheimer’s disease since it may interfere with the breakdown of beta amyloid as neprilysin is involved in its breakdown.
    Well, similarly, DPP-4 inhibitors have not be demonstrated to show an increase in cancer, yet.

  5. rab says:

    This is an interesting trial, and a great result for Novartis As a heart failure physician, I’d need to see some more data before I give it to my patients.
    What I find really fascinating is that the LCZ696 group had a *much* lower blood pressure than the control group. Could the simple lowering of BP be the mechanism of the improved mortality. (Almost) without fail, medications leading to a reduction in mortality in heart failure cause a lower blood pressure, and there’s good biological reasoning as to why this could be advantageous in heart failure.
    There is another report saying that the mortality effect and antihypertensive effect of LCZ696 are independent, simply be comparing the onset of effects, but I found this unconvincing to say the least.
    Overall congratulations to Novartis for pushing this through. HF is a very very common condition, and up to now, the state of the art was 20 year old drugs (and HF was beginning to feel like an orphan disease…).

  6. DN says:

    ACE is a dangerous target because it disposes of bradykinin, an excess of which convincingly causes angioedema. My guess is that the angiotensin II receptor antagonist causes reflex upregulation of ACE, which should actually reduce the chances of angioedema. It would be interesting to try combining the dual peptidase inhibitor with a bradykinin receptor antagonist like icatibant. For all we know some bradykinin receptors might be helpful to CHF.

  7. Anon says:

    @DN: Bradykinin also contributes to BP lowering through vasodilation. I am not sure how much BK levels contribute to the effectiveness of ACE inhibitors, but this should be taken into account.

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