Drug Industry Daily - Oct. 19, 2010 Issue

Vol. 9 No. 203

Panel Recommends Keeping Aranesp for Kidney Disease Patients Not on Dialysis

An FDA advisory committee has voted overwhelmingly to recommend keeping Amgen’s Aranesp available to treat anemia associated with chronic renal failure in patients not on dialysis.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 15–1 Monday against withdrawing Aranesp’s (darbepoetin alfa) approval in non-dialysis patients. Several panelists advised Aranesp could be particularly beneficial for certain subpopulations, such as patients with very low hemoglobin.

It would be “a little precipitous and a little aggressive to take it off the market” for non-dialysis patients, Henry Black, clinical professor of internal medicine at New York University, said.

The panel also voted 9–5 with three abstentions against cutting the dose in patients when hemoglobin levels fall below 9 g/dL. It voted 13–2 with two abstentions not to adopt that regimen for dialysis patients as well.

Currently, Aranesp is used to achieve and maintain hemoglobin levels within the range of 10 g/dL to 12 g/dL. Several panelists recommended against setting a hard level for beginning treatment. However, James Neaton, professor of biostatistics at the University of Minnesota, said that a more conservative approach should be taken until there is more certainty about the relationship between hemoglobin increases and mortality.

During the meeting, Amgen proposed changes to the drug’s label that would limit treatment to patients with less than 10 g/dL who are at high risk for transfusion and for whom transfusion avoidance is considered clinically important. 

Recent results for the TREAT trial showed Aranesp not only failed to meet its primary endpoints on mortality, specific cardiovascular events and end-stage renal disease in the chronic kidney disease population, but usage increased the risk of stroke (5 percent Aranesp versus 2.6 percent placebo) (DID, Oct. 15).

The TREAT trial had been designed to demonstrate that achieving a blood hemoglobin level higher than the 12 g/dL target in current labeling would improve outcomes by reducing the risk of death, cardiovascular and renal failure in chronic kidney disease patients.

But the panel Monday voted 10–4 with three abstentions against entirely avoiding use of the drug in chronic kidney disease patients with a prior history of stroke. Several recommended an informed consent document for those patients.

Cardiovascular risks have been reflected in the boxed warning section of erythropoesis-stimulating agent (ESA) labels since 2007 and, in December 2009, Amgen further strengthened the warnings to incorporate the specific stroke risk found in TREAT.

Additionally, the FDA recently approved a classwide risk evaluation and mitigation strategy for the three anemia drugs in one indication, use of the drugs to treat anemia in patients receiving chemotherapy (DID, Feb. 17).

The FDA asked the panel for recommendations on future studies of ESAs and heard several calls for true placebo comparison studies. Another panelist recommended a head-to-head comparison of ESAs, and Judith Kramer, associate professor of medicine at Duke University, noted, “We need to look at the unacceptably high rate of over-shooting with the current regimen.” — April Hollis


Woodcock: FDA to Release Several Drug Safety, REMS Guidances This Fall

The FDA plans to release several drug safety guidances this fall, including one on safety-related labeling changes, a top FDA official says.

Other guidances will cover postmarketing studies and clinical trials, MedGuide-only risk evaluation and mitigation strategies (REMS), and the biomarker qualification process, CDER Director Janet Woodcock said Monday at FDAnews’ Third Annual Risk Management and Drug Safety Summit in Washington.

The FDA hopes to see advancements in the use of biomarkers, which may predict how a patient will respond to a treatment and their likelihood of succumbing to certain adverse events.

“We’re really starting to understand how to screen people so we can screen out the people at high risk for adverse events,” Woodcock said.

REMS Framework

The agency has been developing a framework for improving REMS as it works toward a standardized REMS that can be applied to already-marketed drugs. The FDA will develop criteria for requiring a REMS and determining what elements to use, Woodcock said, noting there will be an opportunity for public comment.

The FDA issued a draft guidance on the format and content of REMS in September 2009, but some stakeholders have argued the document isn’t specific enough and could add additional time to get drugs on the market (DID, Jan. 5).

The FDA will hold a retreat in a few days to work on institutionalizing policies and procedures for multi-disciplinary teams to review and manage postmarketing safety issues. The agency’s recently released five-year strategic plan lists drug safety as a top priority (DID, Oct. 1).

“We’re working on identifying target activities, such as how soon do you initiate data gathering ... and what are the standard timelines,” Woodcock said.

The FDA is using a new functionality in its document archival system to track and manage significant postmarketing drug safety issues, referred to as tracked safety issues (TSIs) she added. As of Oct. 6, active or ongoing TSIs totaled 469.

The agency is also taking a harder look at its ongoing postmarket monitoring efforts, with the Science Board reviewing the FDA’s pharmacovigilance program “to see if we can’t do better.” — April Hollis


FDA Approves New Botox Indication To Treat Chronic Migraine

Allergan has gained FDA approval to market Botox for the preventive treatment of chronic migraine headaches in adults.

The new indication, announced by the company late Friday, is the first clinically studied prophylactic treatment to be approved by the FDA specifically for patients with chronic migraine, Allergan says.

The FDA’s approval was based on the results of two Phase III trials, which showed that patients treated with Botox (botulinum toxin Type A) experienced a significantly greater decrease in the frequency of headache days from baseline compared with patients on placebo, the company says.

In addition, the trials found that patients treated with Botox experienced a total cumulative reduction in headache hours compared to those taking a placebo.

The drug is given about every 12 weeks as multiple injections around the head and neck to try to dull future headaches, the FDA says.

For Allergan, the indication could contribute as much as $500 million in incremental sales by 2014, Larry Biegelsen, an analyst with Wells Fargo Securities, said in a note Monday.

“The chronic migraine indication will very likely augment [Allergan’s growth] by a greater degree given the low level of incremental investment needed to drive chronic migraine sales,” Biegelsen says. “Allergan already promotes Botox to neurologists for other indications.

The approval will also give official recognition to an off-label use of the drug that Allergan acknowledged promoting in a settlement with the U.S. government last month (DID, Sept. 2).

The company agreed to pay $600 million and plead guilty to a misdemeanor misbranding charge to settle civil and criminal allegations that the company promoted Botox for off-label uses, including the treatment of headaches.

Botox brought in about $1.3 billion in worldwide sales for the company last year. — David Belian


Pfizer Teams With Biocon To Market Biosimilars for Diabetes

Diving into the biosimilars market, Pfizer inked a collaborative deal on Monday with India-based Biocon aimed at gaining an edge on the generics market for diabetes products that will expand after 2014 due to patent expirations.

The agreement gives Pfizer worldwide exclusive rights to market Biocon’s biosimilar versions of top-selling insulins, including recombinant human insulin (Eli Lilly’s Humulin, Novo Nordisk’s Novolin), insulin glargine (Sanofi-Aventis’ Lantus), insulin aspart (Novo’s NovoLog) and insulin lispro (Lilly’s Humalog), except in Germany, India and Malaysia, where Biocon will share marketing rights.

Under the arrangement, Pfizer will pay Biocon $200 million upfront and up to $150 million for development and regulatory milestones. Biocon will also receive payments related to Pfizer’s sales of the four insulin biosimilar products.

In addition, Pfizer gains co-exclusive rights to existing Biocon licenses on some of the products, primarily in a number of developing markets.

Biocon will retain responsibility for clinical development, production and supply as well as securing regulatory approvals of the products. To date, the company’s recombinant human insulin formulations have been authorized in 27 countries in developing markets and are being sold in 23. Glargine is currently available only in India, the companies said. 

Pfizer will begin participating in commercialization of the products “immediately,” spokeswoman Joan Campion told DID.

“Our alliance with Biocon will enable the delivery of biosimilar insulin products, providing attractive, cost-effective treatment options to more diabetes patients,” David Simmons, president and general manager of Pfizer’s Established Products Business unit, said.

Patents on NovoLog, Lantus and HumaLog are set to expire by 2015 and producers of biosimilars hope to grab a significant share of the lucrative diabetes care market.

Pfizer’s participation in the diabetes biosimilars market “raise[s] the bar” for brand-name manufacturers in 2015 and beyond, particularly in developed markets, Leerink Swann analyst Seamus Fernandez said Monday in a research note.

However, the fact that Biocon is pursuing a branded generic strategy via the FDA’s 505(b)2 pathway — meaning it will conduct Phase III trials — could limit the impact of its products in the U.S. market until the agency provides guidance on directly substitutable generics, he added. The FDA is slated to hold a two-day public meeting on Nov. 2 and 3 to gather input on creating the biosimilars pathway mandated by the Patient Protection and Affordable Care Act, which was signed into law in March (DID, Oct. 5).

In the meantime, brand-name insulin manufacturers already are developing new products to ease the impact of generics post-2014, Fernandez says.

According to the World Health Organization, the 2010 market for diabetes drugs and devices is approximately $40 billion. About 35 percent of that segment, or $14 billion, is in insulins. — Meg Bryant


Roche Submits Actemra sBLA for Rare Arthritis in Children

Roche has submitted an sBLA for its rheumatoid arthritis treatment Actemra (tocilizumab) to treat a rare form of arthritis in children.

If granted approval, Actemra would become the first approved therapy for systemic Juvenile Idiopathic Arthritis (sJIA) in the U.S. or EU, Roche said Monday. However, other medications, such as Abbott’s Humira (adalimumab) and Amgen/Pfizer’s Enbrel (etanercept), are approved to treat other forms of JIA.

The Swiss drugmaker also said it submitted an accelerated application for the condition in the EU.

Both applications were supported by data from the Phase III TENDER study, which showed that after three months of treatment, 85 percent of Actemra patients had a 30 percent improvement in the signs and symptoms of sJIA and no fever, compared with 24 percent of those on placebo.

Actemra-treated patients also showed greater improvement from baseline in other areas compared with placebo-treated patients.

The peak age of onset for sJIA is between 18 months and two years, and the disease accounts for two-thirds of all deaths in children with arthritis. About 10 percent to 20 percent of JIA cases are of the systemic variety, according to the Cleveland Clinic.

Actemra, a monoclonal antibody, was approved in the U.S. in January as the first IL-6 receptor inhibitor biologic therapy for rheumatoid arthritis. By blocking the activity of the protein IL-6, tocilizumab is thought to minimize some of the negative characteristics of sJIA, including chronic synovial inflammation, anemia, growth impairment and osteoporosis. — Jonathan Block



To clarify an Oct. 18 DID story on an international effort to stop counterfeit drug sales, the FDA has three or four inspectors at each of the eight international mail facilities nationwide to examine suspicious packages.

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