After the presentation and publication of the pivotal ARISTOTLE trial, the novel anticoagulant apixaban (Eliquis, Pfizer and BristolMyers Squibb) was widely expected to be a blockbuster. But then it got bogged down at the FDA where initial hopes for a speedy approval were dashed after highly critical reviews. Ultimately approval of the drug was delayed for 9 months past the original deadline as a result of both a PDUFA date extension and a complete response letter from the FDA. Now an article by Sue Sutter in Pharmaceutical Approvals Monthly, based on documents posted by the FDA on its website, offers an inside look at the drug’s roller coaster ride through the FDA.
The article describes in detail the efforts of the FDA to investigate evidence of fraud and dispensing errors in ARISTOTLE. As Sutter writes: “To many looking in from the outside, the apixaban NDA filing seemed like a sure thing.” Initial results of ARISTOTLE suggested that it had “the potential to be best-in-class if the published ARISTOTLE data were to be believed.”
Click here to read the full story on Forbes.
Three studies published in the New England Journal of Medicine provide important new information about the risks and benefits of extended prophylaxis using two of the new oral anticoagulants in patients who have had venous thromboembolism (VTE).
In an accompanying editorial, Jean Connors writes that “deciding how to balance the risks and benefits of extended anticoagulation is difficult” in patients with unprovoked VTE, since the risk of recurrent VTE may reach 40% at 5 years. Patients at low-to-moderate risk of recurrence may benefit from aspirin, which “may be safer than the newer agents,” though “it appears to have less efficacy in reducing recurrent events.” For patients at higher risk, “the new targeted anticoagulants are attractive alternatives to warfarin. The finding that a low prophylactic dose of apixaban has the same efficacy as the full therapeutic dose, with no increased risk of major bleeding, may tip the risk-to-benefit ratio in favor of extended treatment for this patient population. The wide therapeutic window of this agent enables use of a lower dose that retains great efficacy with no or only a minimal increase in bleeding.”
Click here to read the entire post in Forbes.
Don’t miss this very practical discussion about the new generation of anticoagulants and the short term loan costs to cover them over on CardioExchange. Here are a few excerpts.
Christian Thomas Ruff:
I believe the addition of the 3 currently approved novel anticoagulants (dabigatran, rivaroxaban, and apixaban) will eventually translate into a greater proportion of eligible patients being treated; it certainly has in my practice…
Although I think it is important to continue to develop reversal agents for the novel anticoagulants, I don’t think the lack of such an agent is sufficient reason to avoid using a novel anticoagulant.
I think that price is one of the most important factors that has hindered uptake of the novel agents. Although these drugs may well be “cost-effective” in complicated analyses that focused on the costs and benefits to society at large, it is the out of pocket expense for the drugs that really matters to patients…
Andrew E. Epstein:
It is highly unlikely that a direct comparison of the new anticoagulants will ever be done. Thus, we will have to choose between one or another based on pharmacokinetics, convenience, and perhaps formulary availability. Substudy analyses are also important…
I am concerned that although the elderly often have the most to gain from the new anticoagulants, they are also the patients at greatest risk for bleeding, especially if renal function is labile with drugs cleared by the kidneys. For such patients, warfarin should be considered.
A new study suggests that extending anticoagulant therapy for an additional year may be beneficial after patients with venous thromboembolism complete their initial course of therapy. The results of AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment) were presented at the annual meeting of the American Society of Hematology meeting in Atlanta and published simultaneously in the New England Journal of Medicine.
After completing a standard anticoagulation regimen for 6-12 months, 2,486 VTE patients were randomized to either placebo or apixaban (2.5 or 5 mg twice daily) for an additional 12 months. At both doses, apixaban treatment was associated with a large reduction in clinical events and no increase in major bleeding events.
The primary endpoint, the composite of death or symptomatic recurrent VTE, was significantly reduced in the apixaban groups, from 11.6% in the placebo group to 3.8% in the low-dose apixaban and 4.2% in the high-dose apixaban groups (p<0.001 for both comparisons).
There were very few major bleeding events: 4 (0.5%) in the placebo group, 2 (0.2%) in the low dose apixaban group and 1 ((0.1%) in the high dose apixaban group. Clinically relevant non-major bleeds occurred in 2.3% of the placebo group, 3% of the low dose apixaban group, and 4.2% of the high dose apixaban group.
The investigators concluded that the results of the study “provide a rationale for continuing anticoagulation therapy” in VTE patients for whom there is uncertainty about the worth of continued anticoagulant therapy. They calculated that 14 patients would need to be treated to prevent one VTE case.
The FDA will decide the fate of apixaban (Eliquis) by March 17, 2013. The new Prescription Drug User Fee Act (PDUFA) goal date was announced yesterday by the drug’s manufacturers, Pfizer and BristolMyers Squibb.
The new drug application (NDA) for stroke prevention in atrial fibrillation has been delayed twice. Although the pivotal ARISTOTLE trial was highly praised when it was first published, the FDA first extended its review by three months and then issued a complete response letter (CRL) on June 25 requesting “additional information on data management and verification from the ARISTOTLE trial.” According to Pfizer and BristolMyers Squibb, the FDA has now accepted for evaluation their response to the CRL.
In Europe last week the Committee for Medicinal Products for Human Use (CHMP) recommended approval for apixaban for the same indication.
Click here to read the press release from Pfizer and BMS…
The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval for apixaban (Eliquis, Pfizer and BristolMyers Squibb) for atrial fibrillation (AF). The drug is already approved in Europe for the prevention of venous thromboembolic events (VTE) following hip or knee replacement surgery. The drug has not yet been approved in the United States.
Here is the CHMP proposed indication for the existing 2.5 mg dose and a new 5 mg dose:
“Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).”
CHMP proposed that apixaban should be contraindicated in patients at high risk for major bleeding and in patients receiving other anticoagulants.
The CHMP decision was based on data from the ARISTOTLE and AVERROES pivotal clinical trials.
Click here to download the PDF of the CHMP summary of opinion.
Click here to read the press release from Pfizer and BMS…
The FDA has once again delayed approval of apixaban (Eliquis), the much-anticipated oral anticoagulant. Bristol-Myers Squibb and Pfizer announced today that it had received a a Complete Response Letter (CRL) to the New Drug Application (NDA) for the drug for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
The two companies reported that the FDA had asked for “additional information on data management and verification from the ARISTOTLE trial” No new trials were requested by the FDA, according to the companies, who said they “will work closely with the FDA on the appropriate next steps” for the NDA.
Following the widely praised publication and presentation of ARISTOTLE, it was widely anticipated that apixaban would sail through the FDA approval process. This view gained early confirmation when the FDA granted priority review for the NDA last November, but the picture grew cloudier earlier this year when the FDA extended the action date by three months.
Wall Street analyst Tim Anderson speculated that apixaban might still gain FDA approval in 2012, though firm predictions are difficult since Bristol-Myers Squibb and Pfizer have not released details about the questions raised by the FDA in the CRL.
Click here to read the press release from Bristol-Myers Squibb and Pfizer
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…