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.

 

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FDA Panel Recommends Approval Of Mipomersen For Familial Hypercholesterolemia 1

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, an antisense oligonucleotide inhibitor manufactured by Genzyme, for use in homozygous familial hypercholesterolemia (FH). With its relatively close 9-6 vote, and with its comments, the committee expressed concerns about both the efficacy and safety of the drug, but ultimately the severity of homozygous FH led the panel to recommend approval.

“We need a toolkit, we need as many options as possible for these patients,” said one panel member.

On Wednesday the same committee voted 13-2 in favor of  a similar indication for lomitapide capsules, manufactured by Aegerion. On both days, panel members strongly urged the FDA to restrict use of lomitapide and mipomersen to patients with homozygous FH and “avoid the slippery slope” of using the drugs in heterozygous FH or in patients with resistant hypercholesterolemia.

Some panel members voiced concern that the clinical trials with mipomersen excluded patients with apheresis. During the section for public comments Sidney Wolfe said that the trials were unethical for this reason, since apheresis represents the gold standard of treatment for these patients. One panelist responded that though it was an unfortunate exclusion it was not unethical. A Genzyme spokesperson reported that a trial is now underway looking at mipomersen on top of apheresis.

The panel agreed that mipomersen was effective in lowering cholesterol but felt the reduction was “modest” and that most patients would not reach LDL levels under 100. As with lopitamide, trials were not powered for clinical endpoints. Panelists wondered about the clinical effect of lowering LDL cholesterol from 400 to 300.

The committee did not appear to be greatly concerned about the possibility of a cancer signal brought up in the FDA review. Several panelists thought that the cancer signal may have reflected an ascertainment bias, and, further, that a young homozygous FH population would be less susceptible to an elevated cancer risk. Most of the cancers observed in the clinical trials occurred in elderly patients who did not have homozygous FH.

The biggest obstacle to mipomersen was the question over liver safety. Committee members wrestled with the issue without reaching a consensus, perhaps reflecting their faith (or hope) that the FDA’s proposed Risk Evaluation and Mitigation Strategies (REMS) will work as intended. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

 

 

FDA Reviewers Recommend Approval For Lomitapide For Homozygous Familial Hypercholesterolemia 2

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 13-2 to recommend approval of Aegerion Pharmaceuticals’ cholesterol-lowering drug lomitapide for use in patients with homozygous familial hypercholesterolemia (FH).

The lopsided vote does not completely reflect the views of many of the panel members, who expressed considerable concern  that the drug might be used in lower risk populations, in particular, patients with heterozygous FH. The committee also expressed concern about the use of lomitapide in children with homozygous FH, since they were not included in clinical trials, but might be considered candidates for therapy in clinical practice.

Panel members appeared to largely agree with one panel member, who explained that his yes vote was “specific for this condition” (homozygous FH) only. He said he could accept the “trade-off between a near-certain early demise versus the possibility of liver disease.”

Aegerion estimates that there are about 6,000 homozygous FH patients in the US and Europe.

The committee expressed support for the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would  require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

On Thursday the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Following the release of a highly critical FDA review, many observers believe the mipomersen panel will be much more contentious.

FDA Review Raises Safety Concerns About Mipomersen 1

An FDA review raises a number of potentially significant safety concerns about the cholesterol-lowering drug mipomersen. The review appears ahead of a Thursday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to evaluate Genzyme’s new drug application (NDA) for use of the drug as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce LDL, apolipoprotein B, total cholesterol, non-high density lipoprotein-cholesterol and lipoprotein (a) in patients with homozygous familial hypercholesterolemia (FH). Mipomersen is an antisense oligonucleotide inhibitor which targets apoB-100. (On Wednesday the same committee will meet to discuss a similar indication for lomitapide capsules, manufactured by Aegerion.)

FDA reviewers said that mipomersen was generally effective in lowering LDL cholesterol. More than half of patients in clinical trials had more than a 20% decrease in LDL levels. In the pivotal trial with homozygous FH patients mipomersen reduced LDL by 24.7%. As expected, mipomersen also resulted in significant reductions in app B, total cholesterol, and non-HDL cholesterol.

Because of their small size the mipomersen trials were not powered to assess cardiovascular outcomes, though cardiovascular benefit is of course the ultimate intended effect of the drug. However, the numbers in the phase 3 studies ran in the wrong direction. Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen  group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”

More troubling is the FDA safety review, mostly centering on liver-related problems. Mipomersen was associated with increases in serum transaminases and hepatic fat. In phase 3 trials, hepatic steatosis occurred in 7.3% (19/261) of mipomersen-treated patients compared with 1.6% (2/129)of  placebo-treated patients. ALT increased in 9.6% of mipomersen treated patients compared with 0.8% of placebo-treated patients. In a long-term extension trial one-quarter of mipomersen-treated patients had an average liver fat fraction greater than 20%. The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.

Other safety issues in the trials included injection site reactions and flu-like symptoms. The committee will also likely spend time discussing the cancer findings. According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that “there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”

The FDA will also ask the panel to evaluate a proposed Risk Evaluation and Mitigation Strategies (REMS) if the drug gains approval. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

Given the severity and rarity of homozygous FH it is difficult to predict how the committee will vote, but the safety concerns raised by the FDA make it extremely unlikely the drug could receive an expanded indication for heterozygous FH anytime in the near future.

FDA Reviewers Raise No New Red Flags Over Lomitapide 1

FDA reviewers have raised no new concerns about lomitapide ahead of a Wednesday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.  The FDA today released briefing documents that evaluate the new drug application (NDA) for lomitapide capsules, the microsomal triglyceride transfer protein (MTP) inhibitor from  Aegerion Pharmaceuticals for use as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and triglycerides in patients with homozygous familial hypercholesterolemia. (On Thursday the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Briefing documents for that meeting will be released on Tuesday.)

The reviewers concluded that lomitapide was effective in lowering LDL cholesterol by about 40%. The drug also effectively reduced total cholesterol, apoB, triglyceride, non-HDL, VLDL, and Lp(a) levels. Lomitapide also lowered potentially beneficial HDL and Apo A1 levels. The reviewers said that “the clinical consequences, if any, of these changes are unknown.”

The committee will likely focus on side effects and safety issues related to lomitapide. Gastrointestinal side effects are common with the drug. More troubling are concerns about possible liver damage associated with the drug. In the pivotal trial 38% of the patients had ALT elevations greater than three times the upper limit of normal, and 24% had elevations five times the ULN. Most patients in the trials also had significant elevations in hepatic fat. The reviewers also noted that lomitapide might induce deficiencies in fat-soluble nutrients.

To address the safety issues related to lomitapide the FDA will ask the committee to evaluate a Risk Evaluation and Mitigation Strategies (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would  require special certification for health care professionals and pharmacies that prescribe and dispense the drug.

FDA Advisory Panel Recommends Expanded Indication For Sapien Transcatheter Heart Valve Reply

The FDA’s Circulatory System Devices Panel voted overwhelmingly on Wednesday to recommend an expanded indication for the Edwards Sapien Transcatheter Heart Valve in patients with symptomatic severe aortic stenosis who have high operative risk. The device is currently approved for use only in patients who are not surgical candidates.

The committee voted 10-2 that the Sapien device was safe, 12-0 that it was effective, and 11-0, with 1 abstention, that the benefits of the device outweigh the risks. Much of the day was spent by committee members wrestling with a number of difficult questions raised by FDA reviewers prior to the meeting, including the possible introduction of bias in the pivotal PARTNER A trial  because some patients randomized to surgery did not undergo surgery, the difficulty of evaluating the transapical approach due to the small number of patients randomized in that stratum of PARTNER, and the higher incidence of stroke and aortic regurgitation in the Sapien group.

Ultimately, however, the committee was persuaded by the totality of the data from PARTNER and additional nonrandomized data from patients who received the device under a continued access protocol. An additional strong source of reassurance for the panel was the safeguard provided by the TVT registry, a joint initiative from the Society of Thoracic Surgeons (STS) and The American College of Cardiology (ACC) that will closely monitor the use of TVR in clinical practice.

In sharp contrast to many recent advisory committee meetings, this panel was marked by the absence of drama and tension. A high point of the meeting for many observers was the public comment session. One speaker was a 92-year-old Sapien recipient who was a World War II veteran and prisoner or war who had survived the Bataan Death March. Another patient who spoke in favor of Sapien was the father of well-known Columbia University interventional cardiologist Jeffrey Moses, who helped develop the device. Moses said that he “wisely” chose to stay out of the case, though initially he did help persuade his father to accept the device after he refused to undergo surgery.

Related reading: 

Live Blog: FDA Advisory Panel For Edwards Sapien Transcatheter Heart Valve Reply

Here’s my live-blog of the FDA’s meeting of the Circulatory System Devices Panel to consider the premarket approval (PMA) application for the Edwards Sapien Transcatheter Heart Valve for use in patients with symptomatic severe aortic stenosis who have high operative risk. As reported here earlier this week, FDA reviewers have raised a number of questions about the safety and efficacy of the Sapien heart valve system. Here is a link to the FDA and Edwards briefing documents.

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Meeting adjourned.

6:00– The committee votes 10-2 that Sapien is safe, 12-0 that it is effective, and 11-0 (1 abstention) that the benefits outweigh the risks. 

5:55– Here’s questions 2 and 3:

VOTING QUESTION 2: Is there reasonable assurance that the Edwards SAPIENTM Transcatheter Heart Valve is effective for use in patients who meet the criteria specified in the proposed indication?

VOTING QUESTION 3: Do the benefits of the Edwards SAPIENTM Transcatheter Heart Valve for use in patients who meet the criteria specified in the proposed indication outweigh the risks for use in patients who meet the criteria specified in the proposed indication?

5:54– Wow– computer voting system is broken! They’re going to vote on paper.

5:48– After they finish the legal mumbo jumbo the voting will begin.

5:43– Getting close to the voting questions. Here’s #1:

VOTING QUESTION 1: Is there reasonable assurance that the Edwards SAPIENTM Transcatheter Heart Valve is safe for use in patients who meet the criteria specified in the proposed indication?

5:39– Edwards via Craig Smith giving their summary. He says he’ll be brief.

5:38– Now talking about study data that should be included in the labeling.

5:30– Now talking about post-approval studies to get further insights into stroke, aortic regurgitation, long term effectiveness, valve-in-valve, and gender issues.

5:28– Now discussing the totality of the evidence. Chairman states that the committee agrees that Sapien is safe and effective, with a number of caveats, such as stroke, TA/TF, gender, AR. (Why bother voting now?)

5:20– Committee now discussing informed consent and whether a more detailed informed consent form should be required. An additional piece of paper is not really the ideal solution.

5:15– Chairman summarizes that the FDA is concerned that valve-in-valve use may occur, but there’s no data to support this. Committee strongly encourages getting data on this and it should not be endorsed on the label. Committee wants to motivate the company to perform a separate clinical trial for this indication.
Click to continue reading…

FDA Advisory Committee Recommends Against ACS Indication For Rivaroxaban 1

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against adding an indication for acute coronary syndromes (ACS) to the label  of the anticoagulant rivaroxaban (Xarelto). The vote was 6 to 4 against approval, with 1 abstention.

The advisory panel spent most of the day trying to reconcile diametrically opposed views of the pivotal ATLAS ACS 2-TIMI 51 trial. On the one hand, the sponsor (Johnson & Johnson) and the TIMI investigators (Jessica Mega, C. Michael Gibson, and Eugene Braunwald) portrayed a robustly positive trial that strongly demonstrated the beneficial effects of low dose rivaroxaban in ACS when added to dual antiplatelet therapy. On the other hand, one FDA reviewer, Medical Team Leader Tom Marciniak, raised multiple questions about the validity of the trial and its conclusions because of an alarming amount of early withdrawals and missing data. His view was largely endorsed by several committee members, including Steve Nissen and Sanjay Kaul.

In a press release, J&J said it “will ensure the questions raised today are addressed with the FDA.”

See my previous post for a detailed live account of the advisory committee meeting.

Live Blog: The FDA Advisory Panel For Rixaroxaban for ACS 1

Here’s my live-blogg of the FDA’s Cardiovascular and Renal Drugs Advisory Committee meeting to consider the supplemental new drug application (sNDA) for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. Here is a link to the FDA briefing documents.

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4:48: Meeting adjourned! J&J has just issued a press release saying they will “ensure the questions raised today are addressed with the FDA.”

4:45: Temple is raising the possibility that the FDA might ultimately approve rivaroxaban for ACS. I would not be shocked if this were to happen.

4:38: Now discussing whether the FDA should say about the use of rivaroxaban with thienopyridine. All agree that people should be on a thienopyridine. What about prasugrel and ticagrelor? Nissen says the reality is that rivaroxaban will be given with these drugs, even though there’s no evidence. This was part of his reasoning in voting no. Sager said he would be more concerned about prasugrel, because of the excess risk of bleeding associated with prasugrel. But he notes there is no evidence to support use with either drug.

4:33: Moving on to questions about what to do if rivaroxaban is approved. Everyone agrees that the 2.5 dose is the dose that would get approved.

4:30: Kaul said he wished he had had the courage to abstain (to general laughter) and said he agrees with Fleming that he’d rather advise than vote, and that there was a very fine line between yes and no today.

4:24: Nissen thinks the decision to use mITT– which is counting events at 30 days after stopping treatment– is what doomed ATLAS. With mITT, he says, you’re telling the investigators and the patients that you don’t care so much about what happens to them long term. Nissen thinks the drug could be approvable if there were a second trial, but he also says its possible that the mortality benefit would not be replicated. He’s worried about exposing hundreds of thousands of patients to a three-drug regimen and causing lots of bleeding complications.

4:18: Results: Yes 4, No 6, 1 Abstain!

Voting breakdown:
Click to continue reading…

Rivaroxaban For ACS Gets Positive FDA Review, But Questions About ATLAS Trial Conduct Persist 2

The FDA will offer generally positive but also highly mixed advice to the FDA’s Cardiovascular and Renal Drugs Advisory Committee  when it meets on Wednesday to consider the supplemental new drug application for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. The FDA posted the briefing documents on its website this morning.

Although the primary clinical review and the statistical review support approval for the new indication (the drug is already approved for venous thromboembolism prophylaxis and stroke prevention in AF), one reviewer, Thomas Marciniak, the Medical Team Leader, issued a blistering memorandum suggesting that the supporting data, plagued by missing and inconsistent records in the pivotal ATLAS ACS 2-TIMI 51 trial, “may not support the favorable statistical results.”

The primary clinical reviewer, Karen Hicks, recommended approval for the 2.5 mg BID dose (but not the 5 mg dose) of rivaroxaban for ACS. She noted that the lower dose reduced the combined endpoint of CV death, nonfatal MI, or nonfatal stroke  in the ATLAS trial, with most of the benefit driven by a reduction in CV death, with little or no difference in MI or stroke. The higher 5 mg dose increased bleeding risk in the trial without providing additional efficacy, she concluded. She did not recommend a mortality indication for the label. Her views generally coincide with the reception of the ATLAS trial following its presentation and publication in the New England Journal of Medicine.

It should be noted that Hicks hedged her endorsement with a potentially significant caveat:
Click to continue reading…

FDA Advisory Panel Gives Green Light To HeartWare Ventricular Assist System Reply

The FDA’s Circulatory System Devices panel voted 9-2 on Wednesday to recommend approval of the HeartWare Ventricular Assist System as a bridge to heart transplantation for patients with end-stage heart failure. The panel agreed unanimously (11-0) that the new device is effective. The panel was more divided about safety but ultimately voted  8-3 that the device was safe.

In briefing documents published online earlier in the week, FDA reviewers  raised a number of questions about the safety of the device and the reliability of the data from the pivotal ADVANCE trial, in which 140 patients received the Heartware device and were compared to historical controls who had received Thoratec’s HeartMate II device. The FDA had not previously permitted historical controls to be used in this fashion. Safety questions focused on stroke and thrombosis.

Unlike the HeartMate II VAS, which is surgically implanted in an abdominal pouch, the HeartWare VAS is implanted next to the heart.

“I think this device is of incredible benefit to patients who are very ill,” said panelist Ralph Brindis, as reported by MedPage Today. Acting panel chair Rick Page said the device represented “a real advance in technology,” as reported by Heartwire.
Click here to read the press release from HeartWare…

Decision on Apixaban (Eliquis) Pushed Back By Three Months 1

Update, March 1, 5 PM: Ramsay Baghadi of the RPM Report says that the Cardiorenal committee will take up the apixaban NDA on Mary 22 and the rivaroxaban supplemental NDA for the ACS indication on May 23, but this information has not been confirmed.

Confirming earlier speculation by a Wall Street analyst, Pfizer and Bristol-Myers Squibb announced on Wednesday evening that the FDA had extended by three months the action date for the new drug application (NDA) for the highly anticipated oral anticoagulant Eliquis (apixaban). The application is for their important indication of stroke prevention in atrial fibrillation. The FDA had previously granted the application a 6-month priority review, resulting in a March 28th decision date. The new decision date is June 28,2012.

Sanford Bernstein research analyst Tim Anderson first raised the idea that the decision date might be delayed back on February 10th. On Tuesday Anderson released another note with additional evidence for the delay, based on the release of the tentative FDA advisory committee calendar for 2012, suggesting that the apixaban NDA will be subject to an advisory panel meeting. According to the calendar, the Cardiovascular and Renal Drugs Advisory Committee is scheduled to meet on March 27 and May 23. The agenda for the March 27 session is already set for a discussion of Replagal for Fabry disease. Recall that yesterday the FDA granted a priority review to the NDA for rivaroxaban for ACS, resulting in a decision date of June 29. One might speculate then that another day might be added to the May 23rd meeting for consideration of the rivaroxaban and apixaban NDAs.

Anderson wonders why the FDA has suddenly put the brakes on the apixaban approval, which had heretofore seemed uncomplicated. He writes:

Our best guess remains that FDA may be seeking cover, given the safety experience following competing drug Pradaxa’s approval in 2010.  Additionally, FDA may be seeking advice on things like product labeling and what claims would be allowed.

We might also note that the approval of rivaroxaban was far more difficult than had been expected. Remember that the ROCKET AF trial had been presented and published with broad approval, but then came under heavy fire from FDA reviewers. It is possible that FDA reviewers may also raise previously unsuspected concerns about the pivotal apixaban trial, ARISTOTLE, though no serious criticisms have been publicly raised so far.
Click here to read the press release from Pfizer and Bristol-Myers Squibb…

2011 in Review: Rivaroxaban, Sapien, Mark Midei, Conflicts of Interest, and Much More 4

Here’s a completely personal review of the past year in cardiology. Please write a comment if you strongly agree, disagree, or think something is missing.

Drug of the Year: Rivaroxaban (Xarelto)– Despite a highly negative review from FDA reviewers, rivaroxaban gained FDA approval for the coveted stroke prevention in AF indication. The drug was approved earlier in the year for VTE prevention after surgery. The biggest surprise, though, was rivaroxaban’s success in ACS in the ATLAS ACS TIMI 51 trial, which may well have an important impact on the field for years to come.

Device of the Year: Sapien Transcatheter Heart Valve– TAVI entered the marketplace this year. It will take another few years before its full impact is completely understood.

Click to continue reading…