Recently in FDA Category

First Jeffrey Kindler, then Lipitor, and now this: Pfizer announced today that it's* its dependency on the FDA's approval is over.

* Bloody hell.

Yesterday the FDA announced that it will evaluate postmarketing reports of "serious" bleeding in patients taking the anticoagulant Pradaxa (dabigatran); although the agency doesn't say how many reports of serious bleeding have been received since the drug was approved a little more than a year ago.* The FDA is basing its analysis on data from its own pilot program, the Mini-Sentinel system, as well as submitted information to its standard reporting system, AERS.

Currently Pradaxa is only available in the United States in the form of 150- and 75-mg pills, the latter approved for renally compromised patients (CrCL 15-30 mL/min) and solely on the basis of pharmacokinetic studies. The FDA has been criticized for failing to approve the 110-mg pill, which was shown to be comparable (ie, nonsuperior) to warfarin in the large RE-LY trial (for background, start here). According to SDI's proprietary national tracking services, cited by the FDA, about 1.1 million prescriptions for Pradaxa were dispensed in the United States between October 2010 and August 2011, and 371,000 patients received Pradaxa from outpatient retail pharmacies. Not a huge population, but not insignificant either.

The FDA also advises, wisely, that comparing postmarketing reports of bleeding with Pradaxa and those with warfarin is probably not helpful, because "warfarin has been marketed for over 50 years and is well known to cause bleeding, [consequently] patients and healthcare professionals are not likely to report bleeding in association with warfarin." The agency concludes, "Thus, a simple comparison between Pradaxa and warfarin...is of limited value." The FDA also says that it's working with Pradaxa's manufacturer, Boehringer Ingelheim, to assess a range of potentially adverse postmarketing events.

AERS = Adverse Events Reporting System.

* For the prevention of stroke and other cases of systemic embolism in patients with nonvalvular a-fib.

Today marks the generic availability of Pfizer's Lipitor, the blockbuster drug to beat all blockbuster drugs.

Duff Wilson of the NYT lays out how Pfizer is leveraging its short-term losses (for instance, it will get 70% of generic maker Watson's profits).

And Forbes's Matthew Herper gets nostalgic for the era of the widely prescribed money maker ("Why There Will Never Be Another Drug Like Lipitor"). Specifically he provides a concise history of Lipitor's rise and plateau; but he unfortunately omits one of the most interesting and important points of the early Lipitor campaign.

When first approved by the FDA in 1996, Lipitor was only indicated to reduce LDL cholesterol; it had not been shown to prevent clinical vascular events like its 4 existing statin competitors at the time. Nevertheless, trial data showed that Lipitor reduced LDL cholesterol by a relatively greater percentage than the other statins. And because clinicians believed (and still do) that LDL cholesterol is directly linked to the risk of vascular events, Pfizer was able to leverage this belief into ever-escalating sales during the next several years without having data to show that Lipitor actually reduced the risk of vascular events.* Clinicians made the a-to-b-to-c connection with prescription-writing alacrity.

Oh BTW, the generic name of Lipitor: atorvastatin.

* Lipitor wasn't approved by the FDA for this indication until 2004.

Delayed update (12/10/11): In an intriguing NEJM Perspective piece, Jackevicius et al expect that atorvastatin will "dominate" the statin market as a result of switching from generic simvastatin and branded Crestor. Specifically, in 3 years, they expect the market share of atorvastatin to reach 44%. They also estimate, on the basis of experience with simvastatin (which went generic in 2006), that the price of generic atorvastatin will be about 50% of the price of branded Lipitor, after the 6-month exclusivity period ends for the first generic manufacturer.

The projected overall cost savings by 2014, owing to the generic availability of atorvastatin: $4.5 billion annually; when factoring in the aging of the population, add another $30 million. These projections assume the "rapid availability and timely uptake of generic atorvastatin," which may be delayed thanks to industry maneuvers between Pfizer and generic drug makers (which are designed to limit competition). Pfizer is also reportedly planning to ask the FDA to approve an OTC version of Lipitor at some unspecified date.

On Friday, the FDA approved Xarelto (generic name, rivaroxaban) for the prevention of stroke in patients with nonvalvular a-fib.* Approval of the direct factor Xa inhibitor, a product of Janssen Ortho (essentially JNJ) and Bayer Healthcare AG, was based on the mammoth-sized (N > 14,000) ROCKET-AF trial, in which Xarelto was found to be noninferior (ie, comparable) to warfarin for the prevention of stroke and other systemic embolic events in patients with nonvalvular a-fib and other stroke risks (mean CHADS2 score = 3.5).

Xarelto is the second anticoagulant to seriously compete with the old-as-dirt warfarin for the prevention of stroke in patients with a-fib. In October of last year, the FDA approved Boehringer Ingelheim's Pradaxa (dabigatran), a direct thrombin inhibitor. Neither medication requires the usually cumbersome protime monitoring, but Pradaxa, unlike Xarelto, was shown to be superior (at the 150-mg BID dosage) to warfarin for the prevention of stroke in a similar patient population.

Other important differences between Xarelto and Pradaxa are 1) the package insert for the former contains a so-called black-box warning (against the risks of thrombosis after drug discontinuation and spinal/epidural hematoma); and 2) Xarelto is taken once a day, unlike the twice-daily Pradaxa.

Beyond superior-versus-noninferiority claims, potential drug-related risks, and any convenience of dosing, a distinction between Xarelto and Pradaxa may emerge with respect to pricing. According to destinationrx, a month's supply of Xarelto costs $218.70 (~$7.30 per pill or day).** A month's supply of Pradaxa (60, 150-mg pills) will set you back $236.20 (~$7.87 per day). Much of the cost distinction between these 2 drugs, however, will probably depend on how formularies classify the drugs and exact prescription co-pays on health-plan members. Branded warfarin (ie, Coumadin) is, of course, a fraction of these costs, and the price of generic warfarin (which some cardiologists are loathe to prescribe owing to the unpredictability of protimes) is even lower still.

* As well as for the prevention of deep vein thrombosis (DVT).
** 10 mg daily is the dosage for DVT prophylaxis; for the prevention of stroke in patients without renal dysfunction, the recommended dosage is 20 mg per day.

Has the FDA gone too far this time?

By way of Pharmalot:

Cheng Yi Liang, 57, pleaded guilty yesterday to securities fraud and "making a false statement," after the SEC charged the former FDA chemist in March with insider trading (for background, go here). The maximum sentence for the first count is a 20-year prison term followed by a 5-year supervised release and a fine of $5 million. For count two, Liang could be imprisoned for 5 years and fined $250,000. An alternative fine could also be ordered for Liang, the plea agreement indicates: twice his gross gain or loss—or about $7.5 million by my calculation. A guilty plea also may endanger his immigration status (it is not stated in the agreement what Liang's immigration status is, however).

The plea agreement also argues that Liang's offenses are especially egregious because of the amount of money he earned through insider knowledge, the "sophisticated means" by which he earned it, and the fact that he was in a "position of public trust" as an FDA employee. Liang has evidently agreed to forfeit his $3,776,152 in gains through his TDAmeritrade and other accounts, as well as some vital real estate (eg, his residence in Gaithersburg, Maryland, and the home of his son, "A. L.").

Pharmalot also reports that Cheng Yi Liang's son, Andrew Liang, pleaded guilty last month to one count of possessing child pornography (yeesh), which was discovered in the government's investigation.

It's still not clear what tipped off the feds to the elder Liang's trading activities, but Derek Lowe's original thought about the profits Liang realized from the surprise approval of the antipsychotic iloperidone (Fanapt; Vanda Pharmaceuticals) remains highly plausible.

Laquinimod, Teva's investigational pill for multiple sclerosis, was no better than placebo for reducing relapses in a 2-year phase 3 study (BRAVO) of patients with relapsing-remitting disease. These initial trial results were provided yesterday by Teva in a press release, which also reported that laquinimod-treated patients had a greater burden of disease at baseline, as demonstrated by MR images. When this "imbalance" was corrected, hedged the company, significant reductions in the annualized relapse rate, disability progression, and loss of brain volume were realized.*

But no matter. Company share value dropped precipitously on the news, from about $46.50 to less than $42.50 (~9%), as of this post.

And despite this dismal outcome for the maker of Copaxone (the number-1-selling and most expensive self-injected MS drug in the world), Tevas says that it still plans to submit laquininod for FDA approval at some unspecified time. Claimed Teva's Group VP of Global Branded Products, Yitzhak Peterburg, somewhat disingenuously but expectedly, "We are encouraged by the overall outcomes achieved in the laquinimod Phase III clinical development program...Teva remains committed to the clinical development of laquinimod and is confident that the drug could provide a unique option for the treatment of multiple sclerosis."

Unlike fingolimod (Gilenya; Novartis), the only FDA-approved disease-modifying pill for the treatment of MS, laquinimod appears to exert its anti-inflammatory effects less specifically, through a variety of possible mechanisms. Maybe that fact has something to do with the phase 3 outcome. Who knows?

Other possible oral options for MS in late-phase development include teriflunomide (sanofi-aventis) and BG-12 (dimethyl fumarate; Biogen Idec). In June, Merck KGaA announced that it would cease development of its oral contender, cladribine.

* A separate arm evaluated once-weekly IM interferon beta (Avonex); however, the study was not powered to compare laquinimod with the injectable disease-modifying agent.

A new meta-analysis of 14 Chantix (varencicline) trials raises safety concerns, perhaps rashly, about the short-term (≤1 year) cardiovascular risks of the drug. And while the absolute effect size with Pfizer's smoking-cessation drug, versus placebo, was tiny (1.06% - 0.82% = 0.24%), the potential cardiovascular effects of Chantix at least make more physiologic sense than some other studies proposing a short-term risk of cancer with certain antidiabetic drugs (like Actos and Avandia).

In a company press release, issued July 4th,* Pfizer said it "stands behind the benefit/risk profile of Chantix" and "expressed concerns about the reliability of the meta-analysis." Specific concerns related to the "appropriateness of the authors' measure of cardiovascular risk...which combines events that do not share a common biological cause." The probable main objection here is the inclusion of arrhythmias in the composite endpoint, which may not have anything to do with the process of vascular disease. Pfizer also stressed the small absolute difference between Chantix- and placebo-treated patients. The company reported that it plans to conduct its own meta-analysis to assess the potential cardiovascular risks of Chantix.

In June, the FDA posted a warning about the potential, albeit small, cardiovascular risks of Chantix. The warning was based on data from a 1-year, randomized, placebo-controlled trial of 700 smokers. Both the efficacy and safety results are tabulated here. Clearly Chantix improves the chances of quitting (which should lower tobacco-related cardiovascular and cancer risks—!), but short-term cardiovascular risks may also exist with use of the drug.

Outcome	Chantix (n = 350)	Placebo (n = 350)	P Value
Continuous quit rate, % (4 weeks)	47	14	<.0001
Continuous abstinence rate, % (weeks 9-52)	19	7	<.0001
Nonfatal MI, %	2.0	0.9	Not calculated
Need for coronary revascularization, %	2.3	0.9	Not calculated
Angina requiring hospitalization, %	2.3	2.3	Not calculated
New diagnosis of PVD or PVD procedure, %	1.4	0.9	Not calculated

N.B.--For the safety analysis, the n value in the Chantix arm was 353.

Notably this trial was not powered to detect statistically significant differences in the safety analysis portion of the study. The FDA affirmed that, on the basis of these data, it was "requiring the manufacturer to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials" to further define the potential, short-term cardiovascular risks of Chantix.

* No holiday for public relations.

Merck KGaA (the US subsidiary of which is Merck Serono) announced yesterday that it will cease late-stage development of oral cladribine for the treatment of multiple sclerosis. The company cites the FDA's safety (probably cancer-related) concerns about the drug. In addition, Merck KGaA will pull oral cladribine from markets in Russia and Australia, where the compound has been available under the ridiculous trade name Movectro.

Merck KGaA implies in a press release that its decision to kill oral cladribine has something to do with forthcoming safety data (or lack thereof) from continuing trials of the drug—namely, the extension phase of the CLARITY trial, the ORACLE MS study, and/or the ONWARD study. In March, the FDA issued a complete response letter, indicating that it would not approve oral cladribine on the basis of the drug's safety profile; but Merck KGaA put an exceptionally rosy spin on the news...which it has evidently now rescinded.

Oral cladribine was, at one time, in a nail-biting horse race for FDA approval with fingolimod (Gilenya), Novartis's orally administered challenger. Fingolimod was approved by the FDA for the treatment of relapsing-remitting MS in September of last year and is expected to take a sizable chunk of the market* from other disease-modifying drugs, like frontrunners interferon beta (eg, Avonex; Biogen Idec) and glatiramer acetate (Copaxone; Teva).

* Despite its staggering cost.

A new post-hoc analysis of the RE-LY trial—the pivotal trial of Boehringer Ingelheim's Pradaxa (dabigatran)—suggests that the lower, 110-mg tablet should be available for elderly patients. In a recent online report at the Circulation website, reported yesterday by heartwire, the risk of extracranial bleeding was found to be significantly higher with the 150-mg bid dosage in patients older than 74 years of age (table below adapted from heartwire).

Endpoint	Warfarin, %	Pradaxa 110 mg bid, %	Pradaxa 150 mg bid, %	P
Major bleeding
All ages	3.57	2.87	3.31	.002*
Age <75	3.04	1.89	2.12	—
Age ≥75	4.37	4.43	5.10	<.001*
Extracranial bleeding
Age <75	2.44	1.76	1.91	—
Age ≥75	3.44	4.10	4.68	.001*
Intracranial bleeding
Age <75	0.61	0.14	0.26	—
Age ≥75	1.00	0.37	0.41	.28*

* P for interaction.

Consequently the lead author of the analysis, Eikelboom, concludes to heartwire that these new data "support the need for both doses of dabigatran to be made available in the US. The 150-mg dose will be the dose of choice in the under-75s but in older patients clinicians will want to consider the 110-mg dose to reduce the risk of extracranial bleeding."

In October of last year, the FDA approved only the 150-mg bid dosage of Pradaxa, and the agency attempted to justify its perplexing decision by providing a not-terribly-convincing argument in an April issue of the NEJM. Beasley et al rationalized that the FDA approval "was based on our inability to identify any subgroup in which use of the lower dose [110 mg bid] would not represent a substantial disadvantage." However, Eikelboom's subanalysis provides a compelling reason for approving the lower dosage (which is already available in Canada) in the United States.