DID - Dec. 23, 2009 Issue

Vol. 8 No. 248

FDA: Vytorin, Zetia ‘Unlikely’ to Increase Cancer Risk

Merck’s cholesterol drugs Vytorin and Zetia aren’t likely to increase the risk of cancer or related deaths, according to an FDA review of data from three clinical trials.

The agency made the determination based in its review of the placebo-controlled SEAS trial data and interim results from two large-scale cardiovascular trials of Vytorin — which combines Zocor (simvastatin) and Zetia (ezetimibe), the FDA said Tuesday.

The review was prompted by some preliminary reports of a potential increased incidence of cancer in SEAS trial patients taking Vytorin.

Based on those reports, the FDA issued an early communication in August 2008 about a possible association between cancer and the use of Zetia or Vytorin. The SEAS trial studied 1,873 patients with narrowed or obstructed aortic heart valves to determine whether Vytorin treatment would reduce the number of major cardiovascular adverse events. A lower overall cardiovascular risk was not found with Vytorin (DID, July 22, 2008).

A review of final SEAS trial data, however, shows the risk of cancer did not increase consistently over time, according to the FDA. To date, no risk pattern has been found in the other Vytorin trials under review, the SHARP and IMPROVE-IT trials, the agency added. — Owen Skoler


Shire Submits BLA for Fabry Drug to Combat Shortage

Less than six months after a shortage of a Fabry disease treatment was announced, Shire has filed a BLA for Replagal to treat the rare illness.

Shire submitted the BLA for Replagal (agalsidase alfa) at the FDA’s request, Jessica Cotrone, a Shire spokeswoman, told DID Tuesday. The request followed Genzyme’s June production suspension of Fabrazyme (agalsidase beta), the only FDA-approved treatment for Fabry disease.

Replagal is currently available to U.S. patients under an FDA-approved treatment protocol, and the company is supporting emergency IND requests, Shire says. The drug is approved in 45 countries outside of the U.S. and has about half the market compared with Fabrazyme, according to Cotrone.

Genzyme told DID that it is shipping about 30 percent of Fabrazyme demand. The company said earlier this month that it would begin shipping 70 percent to 100 percent of demand in the second quarter of 2010 (DID, Dec. 2).

Genzyme’s orphan drug exclusivity for Fabrazyme ends next year, according to Cotrone. The FDA’s request for Shire to submit a BLA for Replagal accelerated the company’s decision to bring the drug to the U.S. market, she said.

Fabry disease is an inherited disorder that results from the buildup of a particular type of fat in the body’s cells. The disease can lead to potentially life-threatening complications such as progressive kidney damage, heart attack and stroke.

Replagal generated $176 million for Shire last year, according to the company’s 2008 annual report. — Owen Skoler


ICH Guidances Aim to Stop Redundant Testing

The FDA has published two final International Conference on Harmonisation (ICH) guidances on sterility and disintegration designed to eliminate redundant testing by industry in the U.S., EU and Japan.

The guidance on sterility tests says drug manufacturers can use three pharmacopoeial texts interchangeably — “Ph. Eur. 2.6.1. Sterility,” “JP 4.06 Sterility Test” and “USP <71> Sterility Tests” — if they also meet certain conditions on rinsing fluids and testing liquid parenteral preparations.

The disintegration test guideline advises makers of tablets and capsules that they can use “Ph. Eur. 2.9.1 Disintegration of Tablets and Capsules,” “JP 6.09 Disintegration Test” and “USP <701> Disintegration” interchangeably, with certain restrictions related to tablet length and enteric-coated dosage forms of products.

The ICH’s sterility guidance is available at www.fdanews.com/ext/files/8923fnl.pdf, and its disintegration guidance is available at www.fdanews.com/ext/files/8922fnl.pdf. — April Hollis


Cephalon Expects Nuvigil Decision by End of March

The FDA has extended its review of Cephalon’s sNDA for the Nuvigil treatment for excessive sleepiness by three months to March 29, 2010.

The agency delayed the Prescription Drug User Fee Act action date after Cephalon provided additional information on the application for Nuvigil (armodafinil) to treat excessive sleepiness associated with jet lag, company spokeswoman Candace Steele Flippin told DID Tuesday. The treatment is approved for sleepiness associated with sleep apnea/hypopnea, narcolepsy and shift work.

The information was given to the FDA within 90 days of the original action date, according to Cephalon. Steele Flippin could not provide details on the data submitted. The company says it does not expect any further delays.

Cephalon plans to file an sNDA for Nuvigil each year for the next five years, beginning in 2009, Steele Flippin said. She noted the company is studying the drug to treat bipolar depression, excessive sleepiness associated with traumatic brain injury, symptoms of schizophrenia and cancer treatment-related fatigue.

The sNDA received priority review earlier this year (DID, Sept. 25). — April Hollis


Mylan Sued Over Generic Cholesterol Drug ANDA

Schering and MSP Singapore have filed a patent infringement lawsuit against Mylan Pharmaceuticals, which submitted an ANDA for a generic version of Schering’s cholesterol drug Vytorin.

The lawsuit, filed in the U.S. District Court for the District of New Jersey, follows Mylan’s request for FDA approval of generic Vytorin (ezetimibe/simvastatin) formulations in the following strengths — 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg, the generic-drug maker said Tuesday.

Vytorin is a combination of Merck and Schering’s cholesterol drug Zetia (ezetimibe) and Merck’s Zocor (simvastatin). Merck bought Schering-Plough, which owned Schering, in March, but the company is not named in the lawsuit. MSP Singapore is the exclusive licensee for Vytorin, according to court documents.

Mylan says it is the first company to have filed a substantially complete ANDA containing a Paragraph IV certification for generic Vytorin tablets and the company expects its generic to qualify for 180 days of marketing exclusivity if it wins FDA approval.

In the lawsuit, Schering alleges Mylan knew its generic Vytorin and proposed labeling would infringe the brand drug’s ’966 and ’721 patents, and Schering seeks an injunction preventing the company from selling the product.

Mylan asserts that the two patents are invalid, unenforceable and/or will not be infringed by its generic versions.

Vytorin tablets in the same strengths for which Mylan is seeking approval had worldwide sales of about $1.6 billion for the 12 months ended Sept. 30, Mylan says.

Schering Corporation, and MSP Singapore Company LLC, v. Mylan Pharmaceuticals Inc. and Mylan Inc. was filed Dec. 16. — David Belian


Boehringer Seeks to Dismiss Mirapex Antitrust Lawsuit

Boehringer Ingelheim has filed a motion to dismiss an antitrust lawsuit in which Mylan Pharmaceuticals contends the drugmaker took unlawful action to protect an invalid patent on its Parkinson’s disease drug Mirapex.

The motion to dismiss was filed in the U.S. District Court for the Western District of Pennsylvania, according documents posted recently on the court’s website. Boehringer contends that its defeat in a previous Mirapex (pramipexole dihydrochloride) patent case is not enough to prove it is guilty of an antitrust violation.

The antitrust case stems from a lawsuit filed by Mylan in which the company alleges that Boehringer obtained the ’812 patent on Mirapex that it knew or should have known was invalid.

The judge in the antitrust case, Gary Lancaster, has ordered Mylan to file a response to Boehringer’s motion to dismiss by Jan. 20, 2010.

Boehringer unsuccessfully sued Barr and Mylan, claiming the two generic-drug makers infringed the patent.

Boehringer appealed the decision in the U.S. District Court for the District of Delaware to the U.S. Court of Appeals for the Federal Circuit and reached a settlement agreement with Barr that delayed the launch of a generic version of Mirapex until at least 2010, Mylan says (DID, June 30, 2008).

“Boehringer’s actions have injured the market and consumers by eliminating choice and preventing lower cost pharmaceuticals from reaching the market,” Mylan says in its complaint.

Mirapex has FDA approval to treat Parkinson’s disease and restless legs syndrome. Mylan received tentative approval to market a generic Mirapex in November 2006.

Mylan Inc. and Mylan Pharmaceuticals Inc. v. Boehringer Ingelheim International GmbH and Boehringer Ingelheim Pharmaceuticals, Inc. was posted Dec. 17.— David Belian

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