Drug Industry Daily - Dec. 27, 2010 Issue

Vol. 9 No. 249

Amphastar Amends Lawsuit Against FDA to Gain Generic Lovenox Approval

Amphastar Pharmaceuticals has amended a lawsuit against the FDA and is now asking a federal court to force the agency to approve its ANDA for generic Lovenox, which the company says has been unfairly delayed.

In an amended complaint filed Wednesday in the U.S. District Court for the District of Columbia, Amphastar, which claims it is the first company to file an ANDA for generic Lovenox (enoxaparin sodium), argues that the FDA has continually denied its application without proper justification.

 “Amphastar has repeatedly met the standards set by the FDA, only to see those standards shift or to have new standards arbitrarily and capriciously created,” Amphastar says in its complaint. “Every time Amphastar clears the agency’s latest obstacle to approval, a new one is created.”

The most recent delay came Nov. 30 when the FDA informed Amphastar that its raw heparin supplier in China would need to be inspected again, Jason Shandell, vice president and general counsel for Amphastar, told DID. The supplier has been cited for good manufacturing practice violations in the past.

Although the letter also showed a path to approval, the company has not yet decided whether it will proceed with the reinspection, Shandell added.

Amphastar filed suit against the FDA in October accusing the agency of unfairly detaining two shipments of semi-purified heparin earlier this year, saying the holdup was part of arbitrary regulatory treatment that has delayed approval of its ANDA (DID, Oct. 27).

However, in November, the FDA released the detained heparin, just days after Amphastar filed for an injunction to force the agency to do so (DID, Nov. 15).

Amphastar’s desire to have its application quickly approved has been buoyed by the huge sales Sandoz and Momenta have seen from their generic version of Lovenox, approved earlier this year.

The generic brought in about $292 million in sales and captured more than half of the brand drug’s market share in its first nine weeks on the market (DID, Nov. 2).

In its complaint, Amphastar also accuses the agency of showing favoritism to Sandoz and Momenta. Shandell told DID he believes the FDA is “manipulating” the company’s application and that CDER Director Janet Woodcock is to blame.

“While Amphastar’s enoxaparin ANDA has languished, the FDA’s favored competitor, which filed its enoxaparin ANDA more than two years after Amphastar, has been allowed to be the exclusive producer of a generic enoxaparin sodium injection product in the United States, reaping a financial windfall in the process,” the complaint says.

The FDA declined to comment on the lawsuit.

Amphastar’s amended complaint is available at www.fdanews.com/ext/files/AmendedComplaint.pdf. — David Belian, Jonathan Block


FDA OKs Anal Cancer Prevention Indication for Merck’s Gardasil

The FDA has approved Merck’s Gardasil to prevent anal cancer and anal intraepithelial neoplasia (AIN) in males and females age 9 to 26.

Gardasil (human papillomavirus (HPV) quadrivalent (Types 6, 11, 16, 18) vaccine, recombinant), previously approved as an HPV vaccine, is now indicated to prevent anal cancer caused by HPV types 16 and 18 and for the prevention of AIN grades 1, 2 and 3 caused by HPV types 6, 11, 16 and 18, Merck said Wednesday.

In November, an FDA advisory panel supported Gardasil’s new indication (DID, Nov. 19).

Approximately 2,000 men and more than 3,000 women will be diagnosed with anal cancer this year, according to the American Cancer Society.

Gardasil’s efficacy against HPV-related anal disease was studied in men who have sex with men because of the known high risk of anal infection and disease in that population.

The drug could now be looked at again by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) to recommend whether routine vaccination in the new indication is warranted.

ACIP has previously recommended routine Gardasil vaccination of females at age 11 or 12 and as catch-up vaccination for females between the ages of 13 and 26. However, in October 2009, the committee did not endorse routine vaccination of males between 9 and 26 to reduce their likelihood of acquiring genital warts.

The vaccine brought in $316 million for Merck in the third quarter, up 2 percent from the same quarter last year. — April Hollis


FDA Probes Increased Death Risk Associated With Human Growth Hormone

The FDA has issued a MedWatch alert on recombinant human growth hormone as the treatment may be associated with a slightly elevated risk of death based on a French study.

According to the Sante Adulte GH Enfant study, people with certain kinds of short stature treated with recombinant human growth hormone, known as somatropin, during childhood and followed over a long period of time had a slightly increased risk of death compared to the general population.

While the FDA has begun an ongoing review to investigate potential risks associated with taking somatropin, the agency is urging patients not to stop taking the treatment without consulting their physician.

The FDA currently believes the benefits of somatropin outweigh related risks. Any new recommendations will be released following the completion of its review.

Somatropin is a protein used to replace naturally occurring human growth hormone by stimulating tissue growth and height as well as improving protein, carbohydrate, lipid and mineral metabolism.

Somatropin is available in the U.S. under brand names including Genotropin from Pfizer, Humatrope from Eli Lilly, Norditropin from Novo Nordisk, Nutropin and Nutropin AQ from Ipsen, Omnitrope from Sandoz, Saizen from Merck Serono and Tev-Tropin from Savient Pharmaceuticals. — Molly Cohen


Gilead Halts Ambrisentan Trial for Pulmonary Fibrosis

Citing a lack of efficacy, Gilead Sciences has terminated its Phase III ARTEMIS-IPF trial of ambrisentan to treat idiopathic pulmonary fibrosis (IPF).

Wednesday’s decision followed an interim review of unblinded trial data from a data monitoring committee, which found no added benefit to patients randomized to the treatment. The primary endpoint of the study was time to death or disease progression.

Ambrisentan is an endothelin-receptor agonist (ERA) marketed as Letairis and approved by the FDA to treat pulmonary arterial hypertension (DID, June 19, 2007).

Although Gilead has not yet thrown in the towel on the IPF indication, the results didn’t surprise anyone. According to Baird analyst Thomas Russo, “we are unsurprised by this news, given the previous failure of Actelion’s Tracleer [bosentan], a drug from the same …. class in a similarly designed study, and our own doctor checks indicating low expectations for ERAs in IPF.”

Gilead “is conducting a thorough review of the data and will communicate the full results of this analysis to the medical community when they are available,” company spokesman Nathan Kaiser told DID.

“Gilead continues to evaluate the drug in Phase III for patients with pulmonary hypertension associated with idiopathic pulmonary fibrosis,” Kaiser added.

In other Gilead news, the company said Monday it would pay $225 million to acquire Arresto Biosciences, a biotechnology company that develops monoclonal antibodies for fibrotic diseases and cancer. Gilead expects the deal to close in the first quarter of 2011. — Molly Cohen


AstraZeneca, Abbott Drop Development of Cholesterol Drug Certriad

AstraZeneca and Abbott are discontinuing development of Certriad, a cholesterol-lowering combination drug, after a March complete response letter for the drug.

The companies decided that development of Certriad (rosuvastatin calcium and fenofibric acid) is no longer commercially attractive after they reviewed the complete response letter, AstraZeneca said Wednesday (DID, March 31). Their codevelopment and license agreement will end Jan. 22.

Certriad is a combination of AstraZeneca’s Crestor (rosuvastatin calcium) and Abbott’s Trilipix (fenofibric acid).

Abbott had believed that Certriad could exceed $1 billion in annual sales, but Wells Fargo analyst Larry Biegelsen had more modest expectations for the drug.

The low expectations were supported by clinical trials results showing the combination did not reduce cardiovascular events, the lengthy regulatory delay following the complete response letter and cheaper generic versions of the most popular statin, Pfizer’s Lipitor and fenofibrate, Abbott’s TriCor, likely becoming available soon, Biegelsen adds in a Wednesday note.

Lipitor (atorvastatin calcium) goes generic in March 2011, while generics of TriCor (fenofibrate) should be available by July 2012.

“The loss of Certriad, while not a real surprise, reinforces the urgency for [Abbott] to find new opportunities in the lipid space,” Biegelsen notes. He expects Abbott to in-license a new fish oil pill, CETP inhibitor or PCSK9 inhibitor.

Amarin and Omthera have fish oil products in the works, while Merck, Eli Lilly, Mitsubishi and Roche have pipeline CETP inhibitors and Amgen is developing a PCSK9 inhibitor. — April Hollis


Cumberland Gets Complete Response Letter for Acetadote sNDA

Cumberland Pharmaceuticals will request a meeting with the FDA after the agency handed the company a complete response letter for its Acetadote sNDA to treat acute liver failure.

The letter follows a three-month review extension from the FDA in August. The sNDA has priority review.

The FDA said that although clinical trial results showed certain coma patients treated with Acetadote (acetylcysteine) experienced a numerically higher rate of transplant-free survival, the data did not show enough efficacy for the proposed indication of increasing survival in all patients with acute liver failure.

Cumberland disagrees, but says it will work closely with the agency to “gain clarity on the pathway to approval for this important indication,” according to CEO A.J. Kazimi. “We continue to believe that the data and literature supporting Acetadote as a treatment for patients suffering from non-acetaminophen acute liver failure are extremely relevant to a critically ill patient population with few treatment alternatives.”

The injectable drug is approved to treat acetaminophen overdose in adult and pediatric patients primarily in hospitals (DID, Aug. 24).

The new indication is likely delayed indefinitely, according to Duncan-Williams analyst Irina Rivkind. She adds she does not expect any additional market exclusivity from the sNDA as the trial failed to show efficacy.

Another concern for the company, Rivkind writes Wednesday in an analyst note, is that the drug’s orphan drug exclusivity expires Jan. 23, and could lead to Acetadote generics hitting the market next month.

One way the company is aiming to stem the potential impact of generics is through a new formulation of the drug. In October, the company also submitted an sNDA for the new formulation. An FDA decision on that application is expected in early January. — Jonathan Block



To clarify a Dec. 22 DID story on a settlement agreement involving Dey Pharma, Merck KGaA will pay the $280 million settlement as the lawsuit was filed prior to Mylan’s 2007 acquisition of Dey from Merck KGaA. Also, the settlement does not constitute an admission of wrongdoing by Dey (DID, Dec. 22).

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