DID - April 7, 2008 Issue

Vol. 7 No. 68

Grassley Investigating Amgen’s Aranesp Rebates and Discounts

Sen. Chuck Grassley (R-Iowa) is continuing to investigate Amgen’s rebates and discounts to doctors for Aranesp.

As the ranking Republican member of the Senate Committee on Finance, which oversees Medicare and Medicaid, Grassley says he is concerned about doctors “profiting through rebates they receive from purchasing … ESA directly from Amgen … and then collecting payments from Medicare and private insurers, often above the price they paid for the drugs.” Aranesp (darbepoetin alpha) is an erythropoiesis-stimulating agent (ESA) used to treat anemia in cancer patients and patients on dialysis.

Grassley also is concerned that the drug may be used by patients with cancers for which ESAs do more harm than good.

“Some oncology practices in some states are receiving unusually high rebates for purchasing Aranesp…. Patients deserve to know what’s going on as they make decisions about their health and safety based on the advice of their doctors,” Grassley says.

In Indiana, rebates for Aranesp paid to a 10-oncologist practice “increased more than fourfold from about $1.5 million in calendar year 2004 to about $6.5 million in calendar year 2006,” which resulted in about $650,000 in rebates per doctor in 2006, according to Grassley.

He is asking the company for information on the factors it used to make decisions about rebates paid to physicians, group practices and physician clinics. He asks whether the purchase of another drug or product from Amgen “in certain time frames” is taken into account.

Other lawmakers have investigated the company’s marketing practices for the drug. Reps. John Dingell (D-Mich.) and Bart Stupak (D-Mich.) asked Amgen to explain marketing practices involving the bundling of or discounts on Neupogen (filgrastim) and Neulasta (pegfilgrastim) when their sales were linked to Aranesp (DID, April 2). They requested copies of ads, Amgen’s contracts with oncologists and other documents.

At the same time, ESAs have come under scrutiny by the Oncologic Drugs Advisory Committee, which last month recommended substantial labeling changes for ESAs, including Aranesp (DID, March 14).

Over the past 12 months, labeling for the anti-anemia drugs has been updated with boxed warnings instructing physicians not to target patients’ hemoglobin levels greater than 12 g/dL because, under those circumstances, the drugs may shorten overall survival and the time-to-tumor progression in several cancer types (DID, Nov. 9, 2007).

Amgen told DID it would continue to cooperate with Sen. Grassley’s inquiry and provide the requested information. Amgen denied that its marketing practices “have led to inappropriate or excessive off-label use of ESAs” and said that “to avoid even the appearance of such concerns, earlier this year, Amgen restructured the rebates of its Aranesp contracts to be based on share of sales rather than sales volume.”

Grassley’s letter is available at grassley.senate.gov/public/index.cfm?FuseAction=PressReleases.Detail&PressRelease_id=15a22e96-fa36-ed1b-a5f6-5bc5d01d6776&Month=4&Year=2008  — Yuliya Melnyk


Rotarix Launch Set for Second Half of 2008

GlaxoSmithKline (GSK) plans to launch its recently approved rotavirus vaccine in the second half of the year after the Centers for Disease Control and Prevention (CDC) considers the product in June.

The FDA last week approved GSK’s Rotarix (rotavirus vaccine, live) to prevent rotavirus infection, which causes severe diarrhea and is responsible for more than 400,000 doctor visits in the U.S. and 55,000–70,000 hospitalizations annually. Rotarix is the second such vaccine approved for marketing in the U.S.

The agency’s Vaccines and Related Biological Products Advisory Committee recently voted that Rotarix was safe and effective (DID, Feb. 21).

Merck’s RotaTeq (rotavirus vaccine, live), which had worldwide sales of $525 million in 2007, was approved by the FDA two years ago (DID, Feb. 6, 2006). It is approved to protect against rotavirus serotypes G1, G2, G3 and G4 while Rotarix is approved to prevent types G1, G3, G4 and G9 but not G2. G1 is the most prevalent type.

GSK told DID it was confident Rotarix would secure a recommendation from the CDC’s Advisory Committee on Immunization Practices to be scheduled as a recommended pediatric vaccine. The committee is set to meet June 25-26 in Atlanta. Rotarix already is approved outside of the U.S and generated $182 million in sales for GSK last year.

According to data presented by GSK at FDA’s advisory committee meeting, the G1 rotavirus serotype represented 73 percent of the cases in North America between 1973–2003, with G2 and G3 at 11 percent each. The G9 type accounted for less than 2 percent.

Physician labeling for Rotarix carries a claim that the vaccine has statistically significant efficacy against combined non-G1 types, GSK noted. In addition, the product has a favorable dosing profile when compared with RotaTeq.

Rotarix is administered orally in a two-dose series to infants 6 weeks to 24 weeks of age, with a minimum-dosing interval of four weeks. Merck’s product is a three-dose oral series given to infants between 6 weeks and 32 weeks of age, dosed at four-week and 10-week intervals, respectively.

Rotarix labeling carries a warning against administering the product to patients with hypersensitivity to latex. Labeling for Rotarix and RotaTeq warns that they have not been tested in children with gastrointestinal disorders.

Wyeth pulled its rotavirus vaccine, RotaShield, from the market in 1999 due to reported incidences of intussusception, a condition in which one section of intestine falls into another, causing intestinal blockage.

When the FDA’s advisory committee considered the drug, both the agency and committee Chairman John Modlin, professor of medicine at Dartmouth-Hitchcock Medical Center, were comfortable with Rotarix’s intussusception safety profile. — Christopher Hollis


Takeda Wins in Patent Infringement Appeal

The U.S. Supreme Court has upheld a June 2007 decision by the U.S. Court of Appeals for the Federal Circuit in favor of Takeda’s patent for Actos, denying Australia-based Alphapharm’s petition for a writ of certiorari.

Actos (pioglitazone HCl) was approved in 1999 as an adjunct to diet and exercise to improve glycemic control in Type 2 diabetes patients as a monotherapy and in combination with other treatments.

The dispute began after Alphapharm, Mylan Pharmaceuticals, Ranbaxy Laboratories and Watson Pharmaceuticals filed ANDAs to sell generic versions of Actos. Alphapharm and Mylan were the only two to challenge the ’777 patent, which covered the drug’s active ingredient, pioglitazone, as invalid for obviousness.

Takeda challenged the companies in court. In early 2006, the U.S. District Court for the Southern District of New York ruled in favor of Takeda in its case against Alphapharm.

In its submission to the appeals court, Alphapharm based part of its case for the patent’s invalidity due to obviousness on the Supreme Court ruling in KSR International Co. v. Teleflex Inc.

Because of available prior art, “compound b” — which Takeda eventually developed into pioglitazone — was an obvious choice as the next diabetes drug, said Andrew Berdon, partner at Quinn Emanuel Urquhart, which represented Alphapharm (DID, July 3, 2007).

The appellate court did not agree with Alphapharm’s arguments and affirmed the lower court’s ruling.

Based on the Supreme Court’s decision, the FDA will not approve a generic version of pioglitazone until the ’777 patent expires in 2011. — Elizabeth Jones


AMAG Says Iron Replacement Therapy Results Positive

AMAG Pharmaceuticals reported positive efficacy and safety results from four separate Phase III clinical trials of its intravenous iron replacement therapy ferumoxytol.

Three of the studies evaluated the drug’s safety and efficacy in 875 patients with all stages of chronic kidney disease. Patients received either two 510-mg doses of intravenous ferumoxytol within approximately one week or 200 mg of oral iron daily for three weeks. Both groups were followed for 35 days.

“The aggregate results demonstrated that there was a statistically significant greater mean increase in hemoglobin from base line to day 35 in patients receiving ferumoxytol compared to patients receiving oral iron,” the company said. Patients’ hemoglobin increased approximately 1 g/dL during this period for each stage of the disease.

The fourth study was a randomized, double-blind, placebo-controlled crossover safety study enrolling 40 peritoneal dialysis patients, 255 hemodialysis patients and 413 patients not dependent on dialysis. Patients got one intravenous injection of either 510 mg ferumoxytol or saline placebo on day zero and a second treatment on day seven.

Overall adverse events rates were lower for those on the drug — 12.5 percent compared with 20.5 percent for those on placebo — and drug-related adverse event rates were similar for those on the drug (5 percent) as for those on the placebo (7.7 percent).

AMAG presented the results of the trials Thursday at a meeting of the National Kidney Foundation in Dallas. President and CEO Brian Pereira said the company wants to commercialize ferumoxytol to treat iron deficiency anemia in patients with chronic kidney disease and expects the FDA to rule on its NDA in late October. — Martin Gidron


Taro Gets Tentative Approval for Generic Lamictal

Taro Pharmaceutical received tentative approval for its lamotrigine ANDA. When marketed, the seizure treatment would compete with GlaxoSmithKline’s (GSK) blockbuster drug Lamictal.

Taro’s application covers Lamotrigine tablets in 25-, 100-, 150- and 200-mg strengths. Patents for these strengths are expected to expire next January, Taro said. The company must receive final approval before it begins marketing the product.

Caraco Pharmaceutical Laboratories also has tentative approval for generic Lamictal and likely will begin marketing its tablets next January, and Teva Pharmaceuticals is expected to launch its version in the middle of this year. GSK and Teva settled Lamictal patent litigation two years ago, and Teva currently distributes generic Lamictal chewable tablets in the U.S. in 5- and 25-mg strengths (DID, Feb. 21, 2005).

Lamictal tablets have annual U.S. sales of approximately $2.6 billion, Taro said. It is indicated in the treatment of partial seizures and for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes.

Last September, GSK received an approvable letter from the FDA for Lamictal XR, a once-daily, extended-release formulation of the drug. GSK said it was discussing its next steps with the FDA (DID, Nov. 14, 2007). — April Astor

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Reporters: Martin Gidron, April Astor, Christopher Hollis, Elizabeth Jones, Yuliya Melnyk

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