Does Steve Nissen, an outspoken critic of inappropriate industry influence in medicine, have his own conflict of interest problem?
This week Nissen, the chief of cardiology at the Cleveland Clinic, was widely quoted in news reports about the FDA advisory panels evaluating two new highly promising cholesterol drugs from Amgen and Sanofi/Regeneron.
Nissen was broadly supportive of the drugs. Although he has been one of the leading voices against approving and using drugs based solely on their effect on surrogate outcomes, he was much more liberal about these drugs than some other experts and many of the panel members. Here’s what he told CNBC:
“I am somebody who generally is opposed to approving drugs on the basis of surrogate endpoints without the outcome data,” Nissen said by telephone Wednesday, referring to lowering of LDL cholesterol already shown by the medicine. “However, in this case, I actually support approval and I actually think the concerns of the committee are not on target.”
On the NBC Nightly News program he was even more effusive:
“These drugs are breakthrough drugs, they are blockbuster drugs that are very likely going to have a big impact.”
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….
The ill-fated Light trial, which was supposed to examine the cardiovascular outcomes of the weight loss drug Contrave, a combination of naltrexone and bupropion marketed by Orexigen and Takeda, came to a spectacular halt today. The action was probably inevitable given the extreme controversy generated earlier this year when it became known that Orexigen had widely disseminated results from an early interim analysis of the study.
The news about the trial was announced in a press release from the companies and a press release from the Cleveland Clinic, the home institution of Steve Nissen, the trial’s chairman.
A confidential letter sent by top Amarin executives to doctors clearly demonstrates that the primary motive for the lawsuit the company filed yesterday against the FDA has far more to do with marketing than free speech. Amarin said it is suing the FDA to gain the right to disseminate information about Vascepa that would support use of the drug beyond its current highly restricted FDA-approved indication (see reports in Forbes, the New York Times, and the Wall Street Journal.)
Late Monday afternoon Merck released the top line results of TECOS, the cardiovascular outcomes trial with its blockbuster diabetes drug Januvia (sitagliptin). The company said that the trial “achieved its primary endpoint of non-inferiority for the composite cardiovascular (CV) endpoint.” Merck announced only one additional detail: “Among secondary endpoints,” they reported, “there was no increase in hospitalization for heart failure in the sitagliptin group versus placebo.”
On Wednesday the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-2-1 to recommend approval of cangrelor during PCI to reduce the risk of periprocedural thrombotic events such as MI, stent thrombosis, and ischemia driven revascularization.
Two diabetes drugs survived a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on Tuesday. Rejecting recommendations from critics that the drugs should either be withdrawn or get new restrictions on use, the committee voted against any harsh measures, recommending only that information from two neutral clinical trials with the drugs be added to the drugs’ labels.
The two trials were the first large large cardiovascular outcomes trials of any diabetes drugs. SAVOR-TIMI 53 studied saxagliptin (Onglyza, AstraZeneca) and EXAMINE studied alogliptin (Nesina, Takeda Pharmaceuticals).
The FDA said today that it had approved Abiomed’s Impella 2.5 System. According to the company it is is the first hemodynamic support device to gain FDA premarket approval for use during high risk PCI procedures.
The miniature blood pump is designed for temporary use in patients with severe symptomatic coronary artery disease and diminished (but stable) heart function who are undergoing high risk PCI but who are not candidates for surgical revascularization.
On Tuesday morning the members of the Data Monitoring Committee of Orexigen’s Light study began a planned meeting in a hotel in Chicago. They had no way of knowing that in a few hours their routine duties would be completely interrupted by the news that data from the trial– which they thought was known only to them and a very few other people within the company and the FDA– had been revealed to the world by Orexigen. When the news sank in the meeting broke into a scene of high drama and emotion. “I’ve never seen anything like this in 20 years,” said one participant. At one point, I’ve been told, the DMC members were reading my initial story about the data release on a monitor in the meeting room.
The disclosure of the data unleashed a firestorm of criticism directed at Orexigen but also a dramatic 40% increase in the company’s stock, adding about $400 million to Orexigen’s market capitalization. But some believe that despite the short term gain ultimately there may be important negative consequences for the company and its leaders. Certainly the company hasn’t made any friends this week at the FDA or among the doctors and statisticians who perform clinical trials.
The Tuesday meeting was extraordinarily eventful, but in truth the DMC’s activities throughout the trial had never been a day at the beach.
On Tuesday Orexigen sparked a firestorm by disclosing the interim results of an ongoing clinical trial of its weight loss drug Contrave. Takeda, which markets the drug in the US, has released a statement in which it states that it does not support the release of the interim data.
Here is the Takeda statement:
“Pursuant to the Collaboration Agreement between Takeda and Orexigen, Orexigen has the sole right and responsibility for the drafting, prosecution and issuance of Orexigen patent filings. Takeda respects the need to vigorously protect intellectual property relating to pharmaceutical products; however, Takeda does not support the issuance of patents that contain and disclose interim data results of an ongoing clinical trial. Takeda is working with the academic leadership of the Light trial (Data Monitoring Committee, Executive Steering Committee) and the FDA to determine the most appropriate next steps for the LIGHT trial.”
And here is Orexigen’s mildly updated statement about the events:
Orexigen conducted a large cardiovascular outcomes trial in order to file for approval, with the study planned to continue after approval to serve a postmarketing regulatory requirement for additional risk exclusion. We observed an unexpected result in the interim analysis. We filed patent applications based on the results in order to preserve the potential for additional intellectual property. Prior to approval in September 2014, the FDA informed us it had determined that the Light Study would not serve as the postmarketing requirement for Contrave; an entirely new trial would be required. At that point, the company decided to continue with the patent prosecution. The second cardiovascular outcomes trial is expected to start later this year. We are confident that this trial can be enrolled and conducted successfully and we look forward to the results, which are expected by 2022.
On March 3 2015 the USPTO published an issued patent and supporting documentation, and we believed it was appropriate and necessary to make sure this information was equally available to all investors.
Orexigen proactively discussed the challenges inherent in using interim data from ongoing trials for regulatory approvals, and has been, and continues to be, committed to working with FDA and others to support its regulatory obligations to thoroughly explore Contrave’s therapeutic profile. Just as important, Orexigen is committed to its obligation to patients to fully explore the drug’s profile.
Orexigen is also committed to simultaneously meeting its obligations to other regulatory authorities in the U.S., such as the SEC, and abroad, such as the EMA, which are relevant to, and have authority over, its business. The Company is similarly committed to meeting its fiduciary duties to shareholders.
I will have much more to report about this story soon.
Earlier today Orexigen Therapeutics disclosed positive results from a clinical trial of Contrave, its weight loss pill (a combination of naltrexone and bupropion) that it markets with Takeda. (You can read a good summary of the findings by Adam Feuerstein on TheStreet.)
The surprising thing about the Orexigen disclosure, which was contained in a Form 8-K filed with the SEC, is that it consisted of data derived from an interim analysis of the company’s ongoing Light trial. Normally, interim results are performed by an independent data monitoring committee and the results are known only to the members of the DMC. Occasionally, when important regulatory issues are at stake, the FDA may also be involved. But the detailed results of the analysis are never made public until the trial is stopped.
In this case neither the DMC nor the trial Executive Committee, headed by the Cleveland Clinic’s Steve Nissen, knew about or approved the release of the data. Here’s a statement Nissen sent me:
Medtronic and Boston Scientific have announced plans to start phase 2 clinical trials this year for their updated renal denervation catheters. The once promising new technology is intended to treat hypertension unresponsive to drug therapy. The failure last year of Medtronic’s Symplicity HTN-3, the first large pivotal trial to rigorously test renal denervation, sent manufacturers back to their drawing boards to redesign the devices.
In an article on the Health Affairs blog 4 CVS executives speculate that the new cholesterol lowering PCSK9 inhibitors from Amgen and Sanofi might achieve yearly sales of $150 billion or even higher. I think these numbers are a bit silly. But first let’s take a look at their extremely bullish case….
The FDA announced today that Duke University cardiologist Robert Califf will be the next FDA Deputy Commissioner for Medical Products and Tobacco. The agency said that Califf will be responsible for the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, the Center for Devices and Radiological Health and the Center for Tobacco Products.”
Early on Monday Sanofi and Regeneron leapfrogged their rival Amgen to gain leadership in the race to bring a new class of cholesterol drugs to market. The new development could potentially give Sanofi and Regeneron a month on the market by itself before facing competition from Amgen.
Sanofi and Regeneron announced early on Monday that the FDA had accepted for priority review the Biologics License Application (BLA) for alirocumab, their PCSK9 inhibitor…
And then there were four.
Late Thursday the FDA announced that it had approved edoxaban, the new oral anticoagulant manufactured by Daiichi Sankyo. The drug will be marketed under the brand name of Savaysa and joins three other new drugs in the large and important new oral anticoagulant marketplace…
On Thursday the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 in favor of approval for Daiichi Sankyo’s edoxaban(Savaysa), but the outcome will likely result in a drug that will be on the market but that few physicians will prescribe until further studies are performed.
The FDA today announced that it had approved for use in the US the first drug-coated angioplasty balloon catheter to re-open blocked arteries in the thigh and knee (superficial femoral and popliteal arteries). The Lutonix 035 Drug Coated Balloon Percutaneous Transluminal Angioplasty Catheter (Lutonix DCB) is manufactured by CR Bard and has been available in Europe since 2012.
The FDA’s Circulatory System Devices advisory panel gave an extremely cautious endorsement on Wednesday to Boston Scientific’s Watchman device, a novel catheter-delivered left atrial appendage closure device for people with atrial fibrillation. They signaled that although they thought the device should be made available they also thought that there should be significant restrictions on its use.
On Wednesday Boston Scientific’s Watchman device will once again appear before the FDA’s Circulatory System Devices advisory panel. The Watchman is a novel catheter-delivered left atrial appendage closure device which is intended to be used in place of chronic warfarin therapy to lower the risk of stroke in people with atrial fibrillation. It has been under development for more than a decade and its approval has twice been postponed by the FDA. Briefing documents released ahead of Wednesday’s panel suggest that the third time may not be the charm for Watchman, though close FDA watchers believe the device may ultimately squeak through.
Cholesterol drugs, both new and old, are in the news again. There’s a lot going on now but the picture won’t really become clear until next month, when the results of a decade-old trial will finally be revealed. Briefly, here’s what’s happening:
- Two new trials presented fresh evidence that PCSK9s, the much discussed new class of cholesterol drugs, have powerful LDL-lowering properties.
- A new drug from Esperion, the phoenix of biotech companies, also showed promising results. The drug, ETC-1002, is a few years behind the PCSK9s in development but has some important theoretical advantages that may prove very important down the road.
- At the annual meeting of the American Heart Association in November the results of the IMPROVE-IT trial will be presented. The results of this trial, as I have argued in the past, may have a broad if not decisive impact on the future of the PCSK9s and ETC-1002.