Novartis Heart Failure Drug Gains Speedy FDA Approval Reply

Entresto, Novartis’s novel heart failure (HF) drug, gained FDA approval earlier today. The approval arrived 6 weeks ahead of the drug’s action date. Formerly known as LCZ 696, the drug had already received a fast track designation and an expedited review under the FDA’s priority review program.Novartis said the wholesale acquisition cost of Entresto will be $12.50 per day, less discounts.

According to Novartis, the label will state that Entresto is “indicated to reduce the risk of cardiovascular death and heart failure hospitalization in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.”

Entresto is the first of a new class of drugs known as Angiotensin Receptor Neprilysin Inhibitors, or ARNIs. It consists of the well-known angiotensin receptor blocker valsartan and a novel compound, the neprilysin inhibitor sacubitiril. Inhibition of neprilysin is intended to held reduce the neurohormonal activation that helps drive common heart failure (HF) processes like vasoconstriction, sodium retention, and remodeling. This specific combination was designed to avoid angioedema, a side effect which doomed a similar earlier drug, omapatrilat, which combined an ACE inhibitor and a neprilysin inhibitor.

The drug will be available in three dosage strengths: 24/26 mg, 49/51 mg and 97/103 mg (sacubitril/valsartan). The label recommends that most patients should start with the middle dose and move to the higher dose after 2-4 weeks. The lower dose may be preferred for some patients.

Excitement about Entresto began last year following the impressive results of the PARADIGM pivotal trial, in which 8,442 HF patients with reduced ejection fraction (EF) were randomized to the ACE inhibitor enalapril or Entresto. As I’ve reported previously, the study was stopped early, though enrollment in the trial had been completed, following an interim analysis performed by the data and safety monitoring committee, which found “that the prespecified stopping boundary for an overwhelming benefit had been crossed.” After a mean followup of 27 months, Entresto was superior to enalapril in most of the major outcomes. There were significant reductions in the primary endpoint (the combination of cardiovascular death or hospitalization for HF), the individual components of the endpoint, all-cause mortality, and HF symptoms.

Entresto is the first HF drug that has been shown to have a significant mortality benefit when compared to an ACE inhibitor, the current standard of treatment.

The FDA said the most common side effects in patients receiving Entresto were hypotension, hyperkalemia, and renal impairment. Black patients and patients with a history of angioedema are more likely to develop angioedema. In PARADIGM angioedema occurred in 19 Entresto patients and 10 enalapril patients. Entresto should not be used while patients are also taking an ACE inhibitor as this increases the risk of angioedema.

Although there have been previous concerns that Entresto might increase the risk of developing dementiaNovartis said there is no mention of dementia in the label.

“Despite the uncertainty and high financial risk we designed the world’s largest heart failure trial to compare Entresto to the previous gold standard. As a result millions of people diagnosed with reduced ejection fraction heart failure now have a much greater opportunity to live longer and stay out of hospital,” said David Epstein, Division Head, Novartis Pharmaceuticals, in a press release. “We recognize our responsibility to ensure Entresto reaches US patients and prescribers as soon as possible and will begin shipping in the US in the coming week.”

“The very meaningful survival advantage of Entresto seen in the PARADIGM-HF trial should persuade physicians to consider Entresto for all appropriate patients, in place of traditional ACE inhibitors or angiotensin receptor blockers,” said Dr. Milton Packer, Professor and Chair for the Department of Clinical Sciences at University of Texas Southwestern Medical Center, Texas, USA. “Entresto is expected to change the management of patients with HFrEF for years to come.”

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Novartis’ Summer Blockbuster LCZ696 Gains A Name, Skips An Advisory Panel Reply

Entresto. That’s the brand name Novartis has chosen for LCZ696, its new heart failure drug that is expected to be a blockbuster. The name won’t be final until official confirmation, which comes with FDA approval. But Novartis will introduce the name for the first time this weekend in presentations at the European Society of Cardiology Heart Failure meeting in Seville, Spain.

FDA approval of Entresto is expected to occur by August at the latest. There are no apparent roadblocks to approval since Novartis has stated that it doesn’t expect an FDA advisory panel. Approval might well come earlier this summer.

At the ESC heart failure meeting this weekend Entresto investigators will also deliver some supporting secondary information about the drug….

Click here to read the full post on Forbes.

 

New Heart Drug From Novartis: Will It Raise The Risk of Alzheimer’s Disease? Reply

LCZ696 is a heart failure drug from Novartis that many observers think will gain FDA approval later this year and go on to become a blockbuster. Perhaps the biggest obstacle to the drug’s success is the fear that it might raise the risk of Alzheimer’s disease. Now a new article in a top cardiology journal lays out the detailed basis for this concern. The authors do not contend that the Alzheimer’s issue will likely ruin the drug’s chances, but they do maintain that the problem needs to be carefully monitored.

I spoke with Milton Packer, the co-principal investigator of PARADIGM-HF, the mega trial that set off the mega excitement about the drug last year. He offers several persuasive arguments that Alzheimer’s disease won’t be the Achilles’ heel of LCZ696.

But first let’s look at the paper…

Click here to read the full post on Forbes.

 

An Emerging Consensus About Novartis’s New Potential Blockbuster Reply

Last year it became clear that Novartis had a potential blockbuster with its new heart failure drug, LCZ696, which is an angiotensin receptor- neprilysin inhibitor (ARNi) consisting of the company’s own well-known angiotensin receptor blocker valsartan (Diovan) and a novel compound, the neprilysin inhibitor sacubitiril. The results of the PARADIGM trial, which was stopped early because of a large and highly significant reduction in cardiovascular mortality, electrified the cardiovascular community. But the trial also sparked a lot of controversy when skeptics raised questions suggesting that the results were not nearly as impressive as the investigators reported.

Following the initial excitement and discussion we are now starting to get a more measured and realistic view of the drug and the trial. In recent days two important secondary PARADIGM papers have been published. A paper in Circulation looks at the experience of trial participants who didn’t die. A paper in European Heart Journal performs some sophisticated statistical wizardry to estimate how LCZ696 would have performed against placebo instead of an active comparator. It will probably come as no surprise that both papers are highly positive. The Circulation paper shows that LCZ696 was effective in preventing progression of heart failure. The EHJ paper concludes that if it had been compared to placebo in a contemporary, otherwise well-treated population LCZ696 would have produced “striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization.”

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…

Click here to read the full post on Forbes.

 

Japanese Research Scandal Involving Novartis Blood Pressure Drug Widens Reply

The Japanese scandal over research using the Novartis blockbuster hypertension drug Diovan (valsartan) continues to widen. The first major figure brought down in the scandal was Hiroaki Matsubara, a prominent cardiologist and researcher at Kyoto Prefectural University in Japan, who  resigned from his position after numerous retractions and investigations. Then last year accusations surfaced about another prominent researcher, Issei Komuro, a professor at Chiba University.

Chiba University has now completed an investigation of one of Komuro’s most important papers, the 2011 report of the Valsartan Amlodipine Randomized Trial (VART), published in Hypertension Research, which is the official journal of the Japanese Society of Hypertension.

Click here to read the full post on Forbes.

 

 

 

PARADIGM-HF Establishes a New Paradigm for Heart Failure Treatment Reply

So far as I can tell the only problem with PARADIGM-HF is that the results are so good that it’s boring. Anyone interested can reasonably assume that what they hear or read about PARADIGM-HF — and cardiologists will be seeing and hearing an awful lot about it —  will be overwhelmingly positive.

Briefly, the trial did everything its sponsor (Novartis) and its investigators (led by Milton Packer and John McMurray) hoped. It met all its major endpoints in all the subgroups without raising any sort of a safety signal. If the findings are confirmed after a rigorous FDA review, then Novartis will likely have a blockbuster on its hand.

All the excitement is over a new drug still known only by its number, LCZ696.

Click here to read the full post on Forbes, including a detailed interview with Milton Packer.

 

Predicting PARADIGM-HF, Or What To Expect When You’re Expecting Reply

The wait is almost over. For the last 5 months the most eagerly awaited trial in the cardiovascular universe has been PARADIGM-HF, the large (8,500 patient) trial of a new and novel heart failure drug from Novartis. If reality lives up to the early hope and hype, the drug, LCZ696, could completely reshape the heart failure landscape and give Novartis that rarest of gems, a new and genuine blockbuster cardiovascular drug.

The main results of the trial will first be presented at a press conference in Barcelona, Spain this Saturday in connection with the annual meeting of the European College of Cardiology.

Click here to read the full post on Forbes.

 

FDA Rejects Novel Novartis Drug For Acute Heart Failure Reply

Novartis said today that the FDA had issued a complete response letter for the biologics license application for RLX030. The drug, also known as serelaxin, is a recombinant form of the naturally occurring human hormone relaxin-2, which has been found to help women adjust to the cardiovascular changes that occur during pregnancy.

Click here to read the full post on Forbes.

 

 

A New Novartis Heart Failure Drug Might Be A Blockbuster Reply

I try to avoid using words like “blockbuster” and “breakthrough” when writing about new drugs and treatments. I’ve been disappointed too many times. But, though they’ve been in short supply lately in cardiovascular medicine, sometimes there really are breakthroughs and blockbusters. In my career writing about cardiovascular medicine I’ve seen the introduction of the ACE inhibitors, statins, stents, ICDs, and clopidogrel, among others. All of these became multibillion-dollar products. Now there’s a new candidate that just might join this group. I’ll tell you why, but I can’t emphasize strongly enough that right now we only have extremely preliminary information. So be warned. And don’t be completely surprised if it does bomb out. We’ve been down this road before.

As I reported previously (here and here), early on Monday Novartis disclosed that the PARADIGM-HF trial testing LCZ696, a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor (ARNI), had been stopped early. As I later found out, the news was even better than Novartis had said in its press release. I spoke with the co-principal investigator of the trial, Milton Packer, who told me that the trial had been stopped because of a highly statistically significant reduction in cardiovascular mortality in patients taking LCZ696 instead of the current gold standard of treatment, an ACE inhibitor. Marc Pfeffer, a cardiologist at the Brigham and Women’s Hospital with long experience in heart failure, told me that he interprets “the stopping of a major clinical outcome trial for effectiveness by an experienced DSMB [Data and Safety Monitoring Board] as indicating that the final results will be both definitive and important.”

The first thing to know is that a reduction in cardiovascular mortality is a really big deal….

Click here to read the full post on Forbes.

 

 

Novartis Trial Was Stopped Early Because Of A Significant Drop In Cardiovascular Mortality 1

The largest-ever trial in heart failure was stopped early because of a highly statistically significant reduction in cardiovascular mortality, according to one of the trial’s two primary investigators.

Earlier today I reported that the PARADIGM-HF trial testing LCZ696, a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor (ARNI), had been stopped early because the trial had demonstrated a significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization. This information was taken from a Novartis press release.

But it turns out that the press release wasn’t entirely accurate. For once, a company appears to have actually downplayed a positive finding in its trial….

Click here to read the full post on Forbes.

English: Mohawk Stop Sign

English: Mohawk Stop Sign (Photo credit: Wikipedia)

Early Success For Novel Novartis Heart Failure Drug Reply

A large clinical trial testing a novel compound from Novartis for chronic heart failure has been stopped early for efficacy. In a press release Novartis said the Data Monitoring Committee had recommended early closure of the PARADIGM-HF trial because the trial had demonstrated a significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization.

PARADIGM-HF randomized patients with heart failure and reduced left ventricular ejection fraction to either the ACE inhibitor enalapril or LCZ696, an Angiotensin Receptor Neprilysin Inhibitor (ARNI) that is the first in its class.

Click here to read the full post on Forbes.

 

 

FDA Advisory Panel Recommends Against Approval Of Novartis Heart Failure Drug Reply

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted unanimously (11-0) against approval of the biologics license application (BLA) for serelaxin (proposed trade name Reasanz). The novel drug from Novartis was intended to be used in patients with acute heart failure. The once highly-promising drug, which received a ”breakthrough therapy” designation from the FDA last year, was also turned down for approval in Europe earlier this year.

Click here to read the entire post on Forbes.

 

 

FDA Reviewers Recommend Against Approval For Novartis Heart Failure Drug 1

Ahead of an important advisory panel FDA reviewers have recommended against approval of a novel drug for acute heart failure from Novartis. The once highly-promising drug, which received a ”breakthrough therapy” designation from the FDA last year, was turned down for approval in Europe earlier this year.

On Thursday the FDA’s Cardiovascular and Renal Drugs Advisory Committee will discuss the biologics license application (BLA) for serelaxin injection (proposed trade name Reasanz) from Novartis.

Click here to read the full post on Forbes.

 

 

European Setback For Novartis Heart Failure Drug Reply

European regulators have dealt a setback to a novel heart failure drug under development by Novartis.

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended against giving market approval to serelaxin (Reasanz) for the treatment of acute heart failure. The recommendation is based largely on the committee’s analysis of the RELAX-AHF trial, which was published in the Lancet in 2012. Here is CHMP’s explanation for their decision:

Click here to read the full post on Forbes.

 

 

 

FDA Advisory Panel To Review New Heart Failure Drug From Novartis Reply

A novel acute heart failure drug from Novartis will be evaluated next month by an FDA advisory committee, perhaps countering a long string of crash-and-burn cardiology drugs. On February 13 the FDA’s Cardiovascular and Renal Drugs Advisory Committee will discuss the biologics license application (BLA) for serelaxin injection from Novartis. The indication is for the improvement of the symptoms of acute heart failure through reduction of the rate of worsening of heart failure. (The meeting notice has been posted in the Federal Register but has not yet appeared on the FDA website.) Last year the drug received a “breakthrough therapy” designation from the FDA.

Click here to read the full post on Forbes.

 

Saying Sorry May Not Be Good Enough For Novartis Reply

Novartis has issued a formal apology over misconduct relating to valsartan (Diovan) research in Japan, but that apology does not appear likely to satisfy the Japanese Health, Labor and Welfare Ministry, which plans to fully investigate the company’s role in the scandal. If necessary, ministry officials are prepared to raid the company’s offices in Japan.

A Novartis official apologized to the Japanese public for the apparent manipulation of data. David Epstein, the head of the pharmaceutical division at Novartis, met with the Japanese health minister. “We express our deep regret for the concern that the issue has brought to patients, to the medical society as well as the ministry,” Epstein was quoted by Reuters after the meeting. He said the company was “willing to work with” Japanese investigators and will “take additional actions and potential sanctions in order to bring the issue to a good conclusion.”

Click here to read the full post on Forbes.

Lancet Formally Retracts Jikei Heart Study Of Valsartan Reply

The Lancet has formally retracted the Jikei Heart Study paper, originally published in 2007. The retraction had been widely anticipated for more than a month, after a series of news reports in Japan made it clear that the long-simmering controversy over scientific misconduct involving the Novartis blood pressure lowering drug valsartan (Diovan) had come to a full boil. (See our earlier story here.)

As reported previously, the current scandal first began to unfold in late 2011 when a Japanese blogger pointed to a number of apparent errors in publications authored by Hiroaki Matsubara. This ultimately led to a series of retractions of Matsubara’s papers and the retraction of the main paper of the Kyoto Heart Study itself by the European Heart Journal.

In the notice of retraction

Click here to read the full story on Forbes.

More Bad News For Novartis Blood Pressure Drug Reply

In the last few days more bad news about valsartan (Diovan, Novartis) has emerged in Japan. Another major study conducted in Japan– the Jikei Heart Study– will be retracted and Japanese health authorities said they were investigating severe skin reactions associated with use of the drug.

The new events are only the latest problems for the drug and Novartis…

Click here to read the full story on Forbes.

 

Diovan Data Was Fabricated, Say Japanese Health Minister And University Officials Reply

Following a long series of accusations, retractions, and the resignation of a prominent professor, it now is clear that data from a large Japanese study of valsartan (Diovan, Novartis) was fabricated. On Thursday officials at Kyoto Prefectural University of Medicine said that “had patient records been used in their entirety,” the Kyoto Heart Study “would have had a different conclusion,” reported AFB.

In 2009 the Kyoto Heart Study investigators, including the chief investigator, Hiroaki Matsubara, reported that treatment with valsartan resulted in significant cardiovascular benefits independent of the drug’s blood-pressure lowering effect. Now officials at the university say the drug had no such effect.

On Friday Norihisa Tamura, Japan’s health minister, said data had been “fabricated and falsified.” Tamura said he would set up a committee to prevent episodes like this from happening again.

Click here to read the full story on Forbes.

 

Norihisa Tamura

Novel Heart Failure Drug From Novartis Gains ‘Breakthrough Therapy’ Designation From FDA 1

Serelaxin, the novel therapy under development for the treatment of acute heart failure, has received a “breakthrough therapy” designation from the FDA, according to Novartis, the company developing the drug. The designation, the FDA explains, “is intended to expedite the development and review of drugs for serious or life-threatening conditions” and requires “preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.” In addition to getting a speedier review process, the sponsor of a drug with the designation receives “more intensive FDA guidance” on the development program.

Click here to read the full story on Forbes.

 

Novartis Acknowledges Employees Participated In ‘Independent’ Trials Reply

Novartis has acknowledged that employees of the company participated in five “independent” investigator-initiated post-registration trials without disclosing their relationship to the company. The company said that a broader “comprehensive investigation with independent third party experts is ongoing” but that it has “provided an update” to Japanese medical societies and to the principal investigators of the five trials.

The new statement from Novartis admits that “one of our former employees [presumably Shirahashi] had varying levels of involvement in five investigator initiated valsartan trials in Japan.” The statement also disclosed that “a second former employee (who reported to the first former employee) had involvement which was limited to one of these trials.” Novartis said that independent investigation is continuing but that so far there has been no indication of a “specific company strategy to integrate the first former employee into the five valsartan investigator initiated trials.” However, the investigation has revealed

that some of this former employee’s superiors in Japan knew of his participation in these trials and were supportive of him in these activities. They believed that employees of a business that had academic titles could perform clinical research support as academics, without any conflict of interest issues arising. In addition, there is no indication that any of his supervisors knew or approved of the incomplete disclosure of his affiliation in the published papers for these studies.

Click here to read the full story on Forbes.

 

İsviçre Basel'deki Novartis binası

 

 

Japanese Research Scandal Expands To A Second Trial And A Novartis Employee Reply

A Japanese research scandal, which has so far centered on actions taken by the once-prominent cardiologist Hiroaki Matsubara, has now expanded. As has been previously reported, several papers authored by Matsubara have been retracted, including, most notably, the main publication of the Kyoto Heart Study in the European Heart Journal.

Now, however, questions have been raised about  another clinical trial, the Jikei Heart Trial, which was published in the Lancet in 2007.  (Matsubara was not involved in this trial.) Novartis, which manufactures valsartan (Diovan), the drug studied in both trials, has announced that it is investigating both trials in response to new allegations that a Novartis employee worked on the trials without any disclosure of his company affiliation.

Click here to read the full story on Forbes.

Another One Bites the Dust: Diovan Patent Expires But Generic Valsartan Is MIA 1

Although the patent on valsartan (Diovan, Novartis) expired last Friday, a generic version of the popular antihypertensive drug has yet to make it to market. By contrast, a generic version of Diovan HCT, the combination of valsartan and hydrochlorothiazide, was recently launched by generic drugmaker Mylan.

As reported on Pharmalot, Ranbaxy, the embattled generic drugmaker, holds the exclusive rights to market generic valsartan for 180 days, but has so far been unable to gain FDA approval. The delay, according to Pharmalot, “only adds to the uncertainty surrounding Ranbaxy’s ability to recover from its long-standing manufacturing woes and haggling with the FDA over its ability to resume operations on regular basis in the US.”

According to the Wall Street Journal, the Diovan franchise generated $5.7 billion worldwide in 2011.
Click here to read the Mylan press release…

Novartis Announces Top Line Results For Phase 3 Trial Of New Acute Heart Failure Drug Reply

Novartis announced preliminary results from the RELAX-AHF trial, a phase 3 study of a novel drug, RLX030 (serelaxin), for patients hospitalized with acute heart failure. The company said the trial met one of its two primary endpoints in reducing dyspnea.

Novartis also reported a reduction in all cause mortality at 6 months. However, it should be noted that the predefined secondary endpoint on ClinicalTrials.Gov was mortality at 60 days, not 6 months. (CardioBrief has requested clarification from Novartis about this point.)

In the trial, 1,161 patients hospitalized with acute heart failure were randomized to placebo or an IV infusion of RLX030 for up to 48 hours.   By design, the trial had 2 primary efficacy end points measuring dyspnea,but only one of them reached statistical significance, according to the company.

The full results of RELAX-AHF are scheduled to be presented as a late-breaking clinical trial at the American Heart Association meeting in Los Angeles in November.

RLX030 is a recombinant form of the naturally occurring human hormone relaxin-2. The drug was originally developed by Corthera, Inc, which was acquired by Novartis in February 2010.
Click here to read the press release from Novartis…