The Real Truth and Potential of LCZ696

Is Novartis' LCZ696 "revolutionary" or just a marginal improvement?
Daniel R. Hoffman, Ph.D., President, Pharmaceutical Business Research Associates
POSTED: WEDNESDAY, SEPTEMBER 10, 2014, 1:02 PM

Over the Labor Day weekend, Novartis presented the results of a trial for its cardiovascular compound, LSC696, at the European Society of Cardiology (ESC) meeting in Barcelona, Spain. Reactions to those results were the number one topic on the pharma blogosphere for several days afterward.
Prior to the presentation, Wall Street's sales projections for the drug were in the vicinity of $1 billion per year by 2020. Immediately afterward the forecasts skyrocketed, especially among the most bullish analysts. Morningstar analyst Damien Conover raised his forecast from an annual peak of just over $1 billion to approximately $6 billion. Leerink Swann's Seamus Fernandez doubled his estimate from $3.2 billion a year to $6.4 billion. Sanford C. Bernstein's Timothy Anderson was especially exuberant, predicting annual sales as high as $8 billion.
So do these enormous sales projections for LCZ696, following its Labor Day splash, indicate that the product is a "revolutionary breakthrough" for treating heart failure, as its lead investigator calls it? Or is this just one more instance where a pharma company promotes a small, tweaked improvement as a breakthrough to justify squeezing payers for premium dollars?
First, a bit of background.
LSC696 actually combines two compounds: valsartan (which is currently sold by Novartis under the name Diovan) and the neprilysin inhibitor, sacubitril.
The valsartan works within a physiological pathway known as the RAAS cascade. Researchers classify it as an angiotensin II receptor blocker (ARB) because it opposes the action of angiotensin II, a naturally occurring substance in the body that raises blood pressure and forces the heart to work harder. ARBs help relax and widen blood vessels, thereby lowering blood pressure and making it easier for the heart to pump blood.
The sacubitril is a neprilisyn inhibitor, which means it decreases the body's neprilysin enzyme that, in turn, helps control blood volume and lower blood pressure. Given this combined mode of action, researchers call LSC696 a RAAS-NEP inhibitor.
Amid all the Wall Street drumbeating, Novartis' design for the study presented in Barcelona was the first thing that aroused skepticism. Novartis compared the new regimen to enalapril. Enalapril acts on the RAAS cascade differently than ARBs. It prevents the conversion of angiotensin I to angiotensin II. As such it is classified as an ACE inhibitor. Within this treatment group, enalapril is actually one of the oldest and weakest ACE inhibitors, having been approved in 1985 as branded Vasotec. Although matching the LCZ696 test drug/regimen against another compound is preferable to pharma's usual approach of comparing something new to placebo, a comparison to something that is less than state of the art seems to stack the deck in favor of the new medication.
Just as importantly, contributing authors in the New England Journal of Medicine pointed out that the enalapril dose used in the trials was lower than the one generally recommended. At the same time, investigators had the liberty to increase dosing on the valsartan portion of LCZ696 to its maximum level. That means Novartis' researchers may have compared a full dose of valsartan to a moderate dose of enalapril, in which case something other than LCZ696's use of a NEP inhibitor is what produced a better result. This observation is part of what led several cardiologists who attended the meeting in Barcelona to ask why LCZ696, if it represents a truly improved level of care, failed to reduce atrial fibrillation, a key characteristic of worsening heart failure.
Some observers question yet another aspect of the LSC696 study design. They point out that patients who received the Novartis test regimen had significantly lower systolic blood pressure before the study than those who received enalapril. The higher ingoing blood pressure among enalapril users may have created a more advanced cardiovascular condition that made their hospitalizations or deaths more likely.
Other cardiologists at ESC questioned the part of Novartis' study plan that included a "washout" period for patients enrolled in the trial. Investigators switched patients from the heart medications they were taking prior to the study and gave them either enalapril or the LSC696 duo before starting the trial. Those patients that could not tolerate the therapies were not enrolled. That means the incidence of side effects and other adverse events in the study was likely lower than what cardiologists would see in real world practice because the enrollment was skewed to favor patients who can tolerate valsartan+sacubitril.
After considering the study's design, a second reason for skepticism relates to interpreting the results. The press releases tout the fact that LCZ696 confers a 20% relative risk reduction versus enalapril for developing the study endpoints of heart failure hospitalization or death. What that actually means is there was a 26.5% chance for hospitalization/death with enalapril versus a 22% chance with LCZ696. Now a 4.5% smaller risk can make a huge commercial difference, because that was the approximate extent to which Plavix reduced risk versus aspirin. Plavix went on to become the world's second highest selling product behind Lipitor. Clinically and epidemiologically, however, that represents a good but not a great difference. Thirty-two people need to be treated (NNT) with LCZ696 to prevent one death and the rule of thumb is that an NNT of 50 or higher means something is fairly useless. In other words, LCZ696 may represent yet another marginal, incremental improvement rather than any sort of revolutionary breakthrough.
In addition to issues related to the study's design and interpretation, a number of cardiologists and other researchers raise an issue about sacubitril's mode of action: inhibiting the neprilysin enzyme. They fear the process could affect other metabolic pathways and produce harmful consequences. For example, some researchers argue that neprilysin seems to play a role in reducing beta-amyloid in the brain. Beta-amyloid forms the clumps and tangles characteristic of Alzheimer's disease and reducing the neprilysin enzyme may raise the risk of patients developing Alzheimer's. Novartis ended the study reported in Barcelona too early to assess such side effects.
LSC696 is not the first RAAS+NEP inhibitor promoted by its developer as something that will revolutionize the way cardiologists treat the hypertension-to-heart failure process. The same earth-shaking predictions for Bristol-Myers Squibb's omapatrilat (Vanlev) were all over the media a decade ago. Novartis's lead investigator on LSC696 is Dr. Milton Packer from the University of Texas Southwestern in Dallas. Ten years ago the same Dr. Packer, then at Columbia University in New York, was BMS’s lead investigator on Vanlev and he was equally effusive in touting that product as a revolutionary breakthrough. Alas, Vanlev never even made it to the market. The FDA decided against approving it because a number of patients in the studies developed potentially serious angioedema, a swelling of the lips and throat.
Around the same 2004-2005 timeframe, Pharmacia was developing another RAAS-NEP inhibitor, eplerenone (Inspra), one that did receive FDA approval. Nonetheless, its modest benefits led Pfizer to promptly bury Inspra as soon as they bought Pharmacia.
Is LCZ696 sufficiently different from these other RAAS-NEPs to be more effective in controlling heart failure while avoiding their side effects and safety-tolerability problems? The Novartis therapy replaces an ACE inhibitor with an ARB and it uses a different neprilisyn inhibitor. But as often happens in pharmacology, the several different compounds within a chemical class produce the same clinical effect.
Whether LCZ696 lives up to its projections for pulling in $6-8 billion a year will also depend on how Novartis prices the product. In the past, the company has been remarkably tone deaf on that factor, as witness the launch of its MS product Gilenya.
Novartis has about six or seven years all to itself for using this RAAS-NEP inhibitor before a competitor potentially can bring another one to market. That’s both an advantage and a disadvantage. The advantage of working without a competitor is obvious, but the disadvantage is that Novartis will have to generate the primary demand for a RAAS-NEP all alone. Acting by themselves, they will have to provide data that satisfactorily answer all the questions about the study. Without competing RAAS-NEP brands on the market, Novartis will be the only company looking to demonstrate and publicize better long-term outcomes that can justify premium pricing. It remains to be seen how well they will do all of this before a competitor or two come along.
Finally, it seems questionable whether any branded pharma company would pair either omapatrilat or eplerenone with an off-patent ARB and sponsor the studies needed to obtain regulatory approval. Eplerenone is already a generic and omapatrilat will likely lose patent protection this year. Nonetheless, it is worthwhile speculating whether a Teva, an Actavis or a Dr. Reddy's – all of which know how to make good margins on generics – might be willing to sponsor and conduct the studies that test how well one of them, combined with a generic ARB, treats heart failure.
If one or more generics companies did make that play, the sales projections for LCZ696 would likely fall back to what they were before Labor Day or possibly even lower.
When the FDA shot down Vanlev, some observers predicted that it was unlikely another RAAS-NEP would ever see the light of day. Perhaps the public relations Novartis manufactured for LCZ696 might provide its most important benefit if all the talk inspires the development of an all-generic medication for heart failure, one where its slightly better effect is matched by a commensurately modest price.

Read more at http://www.philly.com/philly/blogs/healthcare/Is-Novartis-LCZ696-revolutionary-or-just-a-marginal-improvement.html#CbilwoKvtFcTlQO1.99

 

nobody at Novartis with an insight into the unmassaged data believes that LCZ is a "breakthrough"

 

Unless you lack honesty, humility, intelligence, are naive or are from Management!

 

or you're some money grubbing soulless sack of ____ that gets paid a kings ransom by many pharma co's to run these types of stacked trials

regardless...(cue circus music in 5,4,3,2,1
"hurry hurry, step right up, get your speaker fees now ! only __#'s of RX's & you will earn thousands in honoraria !! "
(cue fast narrator disclaimer voice in 3,2,1....) Limited time offer , see your local CV 'x-pert' rep for details , act now, don't delay !!!! , company not responsible side effects of the sunshine law.

Our experts include bonus knowledge from a new syllabus !

 

Some of this post makes sense and some of it does not. Inspra is an aldosterone antagonist, and in all my years in medicine, have I ever heard it referred to as a naprilysin inhibitor. Inspire failed because the data wasn't as robust as that seen with its counterpart, spironolactone. Both affect mineralocorticoids, which drive sodium and water retention-all hallmarks of heart failure. The RALES trial showed direct benefit of spironolactone when added to standard of care. Inspire came along after this trail gained traction, with more marginal data. Cardiologists didn't have as much faith in it, so it failed. So, that part of the above article is completely inaccurate.

With regards to this whole thing around plaques and so forth...let's just wait. Alzheimers is a very sophisticated confluence of multiple factors that drive its pathology. Who's to say that naprilysin is the tipping point, until we have more data. Just enjoy the ride right now...you're getting paid to sit around and learn something! What can be better that that?!??!?!?!?

 

Yes, different classes of drugs, but they all have the intended purpose of augmenting the natriuretic peptide system pathways in heart failure. LCZ's longer term data demonstrating durable, clinically significant efficacy and extended safety that currently is the question mark relative to more established therapies. LCZ may only be relevant in a niche population and at some potential cost. Both from a financial and safety perspective!

 

There's a very good reason LCZ696 received huge attention from all the US TV networks as a "blockbuster." Nearly all the advertising on national network news programs is for prescription medicines. The free promotional "stories" made perfect sense.

 

I'm glad I stayed at a Holiday Inn and left my home study at home:

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of hypertension and heart failure. This is accomplished through long-term regulation of sodium and water balance, blood volume, and arterial pressure.
ACE inhibitors, angiotensin receptor II blockers (AT-II blockers) and aldosterone antagonists have been used to tackle the RAAS in the past, but combined ACE or AT-II and neutral endopeptidase (NEP) inhibitors (also called neprilysin) have been shown to be more potent in reducing blood and especially pulse pressure in patients with hypertension. Conceptually, NEP inhibition alone should increase salutary natriuretic peptide actions in CVD. However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond standard pharmacotherapy.

NEP is an endothelial cell surface zinc metalloproteinase which is involved in the degradation of several regulatory peptides including the natriuretic peptides (Atrial natriuretic peptide [ANP], Brain natriuretic peptide [BNP], C-type natriuretic peptide [CNP] and Dendroaspis natriuretic peptide [DNP] and augments vasodilatation. By inhibiting the RAS and potentiating the natriuretic peptide system at the same time, combined inhibitors so called ‘Vasopeptidase inhibitors’, reduce vasoconstriction and enhance vasodilatation and in turn decrease peripheral vascular resistance and blood pressure.

Different ACE/NEP inhibitors have been tested, but omapatrilat is the most widely studied in the setting of hypertension, heart failure and chronic angina. Historically, the incidence of angioedema is more frequent in patients taking combined ACE and NEP inhibitors and this has prevented these medications from finding a widespread use. One factor that may give vasopeptidase the edge over ACE inhibitors as antihypertensives may be their greater potentiation of bradykinin, but this may also be their Achilles heel.

In the LCZ696 PARADIGM-HF Study, there was a higher rate of angioedema with the investigational product LCZ696 than enalapril, which is a potential concern.

 

Thank God for Google! Ok, Dr. Who. Omaprilat is a vasopeptidase inhibitor and has nothing to do with naprylisin. Its MOA has more to do with preservation of endogenous nitric oxide production, than preserving naturetic peptides in advanced CV disease. It failed due to angioedema and increased liver enzyme levels. If you don't have training in medicine, don't post what you read online. Especially if you don't have the training to appropriately dissect the information.

 

Here's all you need to know about LCZ's potential

https://www.youtube.com/watch?v=j3Cn7slInGo

 

Cold!

 

Sorry, I'm the same Doctor Who representing Novartis at various FDA Ad Com Meetings. You obviously are a limited capacity CV Rep (likely getting fired), who likes to think they have comprehension and reading skills. The post in question never states that omaprilat is a naprylisin inhibitor. The post raises questions about using RAS targeting compounds in combination with NEPs to potentially increase bradykinin levels that may trigger angioedema.

 

I doubt this very seriously.

 

It's future is as bright as Valturna or Tekamlo
Well perhaps not that bright but pretty darn close !

 

Your probably right! It's what we don't know that is the real potential nail in the coffin.

 

1/07/2015 @ 8:00AM 379 views Forbes
The Emerging Consensus About Novartis's New Potential Blockbuster Heart Drug LCZ696


Far more important than these papers, in my view, are the accompanying editorials. The Circulation editorialist, Henry Krum, is an influential Australian cardiologist and the EHJ editorialist, Duke University cardiologist Rob Califf, is one of the most influential and respected cardiologists in the world. Although both editorials are quite positive about LCZ696, they also each emphasize significant limitations of the study and the drug, limitations which the trial investigators have not sought to highlight. This is all the more significant since both editorialists are consummate insiders who disclose that they have consulted for Novartis. In my opinion these editorials represent a broad emerging consensus about the drug and the trial.

Both editorialists write that the most serious limitation of PARADIGM is the use of a run-in phase which excluded patients who could not tolerate either LCZ696 or its comparator, the ACE inhibitor enalapril. A run-in phase is often necessary, and certainly doesn’t invalidate the trial, but, writes Califf, it does diminish “the generalizability of the results, especially when extrapolating to clinicians and patients who are considering whether to initiate LCZ696 in practice. At present, it is not possible to know whether the patient will tolerate this drug at the time treatment is initiated, and the key toxicities (hyperkalaemia and hypotension) tend to occur early and thus would be screened out in the run-in phase.” Krum writes that the incidence of hypotension and angioedema will likely be greater in the real world than in the trial and will need to be carefully monitored.


Califf writes that ”the question is not whether the effect is real; instead,… we should consider the extent to which the size of the effect can be believed and what it means for the future of clinical therapeutics for heart failure.”

Califf seems less disturbed by another issue that has been raised, the early stopping of the trial by the Data Monitoring Committee. In general stopping a trial early is likely to yield an exaggerated estimate of a drug’s effect, but Califf notes that the trial was not stopped until it had already reached its projected number of events and that the magnitude of benefit remained constant after the trial was stopped, with no narrowing of the differences between the groups occurring.

Califf acknowledges other potential reasons why the real world results may not be quite as good as in the trial, including varying patterns of health care utilization in different countries and communities. For instance, in much of the trial population the use of ICDs and biventricular pacing was significantly below current US standards in the heart failure population.

Califf concludes:

Although I believe the effect in practice will be smaller than estimated in this trial with its run-in phase, deficits in use of ICDs and biventricular pacing, and early stopping by a diligent DMC, I also believe that the result is sufficiently large to merit early and widespread adoption in practice.

The big remaining question then is how LCZ696 should be incorporated into clinical practice:

Should LCZ696 replace generic ACE-Is in patients who meet the criteria used in PARADIGM-HF? Should the results be extrapolated beyond the exact population enrolled in the trial? For health systems, the cost-effectiveness calculations are likely to estimate that LCZ696 will be a bargain, but pricing and reimbursement may prove contentious.

Open Data?

Novartis could take one additional step that might give a real boost to LCZ696. A commitment to make all the LCZ696 clinical trial data available to outside researchers would demonstrate its full faith and confidence in the drug. This would be an unprecedented step for a new drug, but the claims and expectations for the drug are also unprecedented.
I asked Harlan Krumholz, the head of the Yale Open Data Access Project, to comment about this:

This is one of the most important advances in heart failure in a decade. The investigators are already harvesting much important knowledge from the trial. It would be a powerful statement by Novartis endorsing open-science, transparency, and responsible conduct of research to immediately make the dataset available for other members of the scientific community to examine and leverage for new knowledge. Eliminate the information asymmetry between those who hold the data and everyone else. Invite the world to learn from what was done.

 

Business is hard enough without giving your competitors the dataset early plus a head start in destroying profit. There scientific community has decades to study this, but we only get a few short years until our growth curve flattens. There's zero upside to early exposure unless we're talking early FDA approval for "Compassionate Use".

 

Keep in mind that there are a great many displaced people that have nefarious purpose with all this product bashing and calls for full information disclosure, knowing full well that this only serves to excite and inflame. By replying to this crap, you just give power to those that would rather try and bring harm to Novartis than really help people.

 

Watch out!! a drug rep pulling out his kick your butt with science stick!!! Funny.

 

Yes a well respected Duke Cardiologist & a Published Influential Australian Cardiologist as well as Forbes have 'nefarious' motives but greedy money grubbing hacks paid stupid $ to do absurd stacked trials with a joke comparator are out for the people !
Do you sleep with your red clown nose on ?