FDA reviewers agree that Genentech Inc.'s first-in-class monoclonal antibody for allergic asthma is associated with lower asthma exacerbation rates in clinical trials, but raised questions about certain safety issues that might arise when introducing the product into a large patient population.
Genentech and its partners, Novartis Pharma AG, of Basel, Switzerland, and Tanox Inc., of Houston, will present the biologics license application for Xolair today to the FDA's Pulmonary-Allergy Drugs Advisory Committee. Decisions reached by such committees are forwarded to the FDA as recommendations. The FDA is not bound by the recommendations, but most industry watchers consider them an insight into the agency's opinion.
Xolair (omalizumab), a once- or twice-monthly injection, would be used as maintenance therapy for the prophylaxis of asthma exacerbations and control of symptoms in adults and adolescents (12 years and above) with moderate to severe allergic asthma that is inadequately controlled despite the use of inhaled corticosteroids.
In the briefing document released Wednesday, the FDA said, "omalizumab treatment was associated with a reduction in exacerbations in subjects whose asthma was managed with moderate to high doses of inhaled corticosteroids."
Furthermore, the document said, "while statistically significant, the effect size in absolute terms was small and was seen in a minority of subjects in the trials, as the large majority of placebo subjects had no exacerbations in any trial."
Regarding the document, Shelley Schneiderman-Ducker, spokeswoman for South San Francisco-based Genentech, told BioWorld Today company officials would not respond, except to say they look forward to productive discussions with the FDA.
Wall Street apparently views the product favorably, as several analysts are forecasting approval.
Patrick Flanigan, analyst with Adams, Harkness & Hill in Boston, told BioWorld Today he expects approval.
"The question really is, who is going to be the appropriate patient for this drug and it would likely be those patients who do not respond to antihistamines," he said. "There's nothing else out there for those patients. It's going to be a very small patient population - it's a niche market."
Flanigan estimates peak (year 2008) worldwide sales to reach $600 million. Others have estimated that Xolair will cost $7,500 to $10,000 per patient per year.
Xolair works by targeting the antibody IgE, an underlying cause of allergic asthma. In allergic patients, the binding of IgE and allergens to inflammatory cells (called mast cells triggers the mast cells to release inflammatory chemical mediators), such as histamine and leukotrienes, which in turn can lead to the symptoms of allergic asthma.
Safety issues associated with Xolair are especially noteworthy due to the potentially large numbers of patients exposed to a product marketed for allergic asthma. "Even small differences in adverse event rates within the controlled studies suggest that many patients may ultimately experience drug-related adverse events," the FDA said.
In clinical trials alone, Xolair has been tested in about 6,000 people.
A reported increased malignancy rate in the clinical trials caught the attention of analysts and the media Wednesday. The FDA said the rate suggests, but does not definitively establish, an increased rate for the Xolair-exposed patients. The FDA said the companies did not exclude patients with a history of malignancy from the trials.
According to the briefing document, malignant neoplasms occurred in 20 of 4,127 (0.5 percent) of Xolair-exposed patients, compared to 5 of 2,236 (0.2 percent) of control patients. Excluding non-melanoma skin cancer, malignancies were detected among 16 (0.4 percent) of Xolair patients and 2 (0.1 percent) of control participants.
Other adverse events noted by the FDA were anaphylaxis and rash.
Concerns about safety are not new to Genentech and its partners. In fact, the Xolair BLA has been on the table since June 2000 when the companies initially filed for a treatment of both asthma and seasonal allergic rhinitis. The FDA responded a year later and requested additional safety data, which the companies provided. Also, the companies dropped seasonal allergic rhinitis as an indication. (See BioWorld Today, Dec. 20, 2002; July 11, 2001; and June 6, 2000.)
Flanigan said the safety data he's reviewed indicates that Xolair is as safe as placebo.
"The biggest concern a couple of years ago was that there could be some thrombocytopenia associated with the drug, but a larger study showed no increased risk associated with Xolair," he said.
The BLA is largely based on two Phase III pivotal trials, both of which hit their respective primary endpoints of reducing asthma exacerbations.
Study 008 involved 525 adolescents and adults (12 to 75 years of age) with moderate to severe allergic asthma that was uncontrolled despite treatment with inhaled corticosteroids and frequent use of beta-agonist rescue medication. The trial lasted 52 weeks. Genentech said patients treated with Xolair had significantly fewer asthma exacerbations per patient than patients receiving placebo. The most frequent adverse events were viral infections, sinusitis, upper respiratory infection and headache.
The other trial is called Study 009. It included 546 patients (12 to 75 years of age) with moderate to severe persistent allergic asthma that was uncontrolled despite treatment with inhaled corticosteroids and frequent use of beta-agonist rescue medication. It also lasted 52 weeks. Genentech said patients treated with Xolair had significantly fewer (58 percent) exacerbations per patients than patients receiving placebo. Adverse events were similar to those in Study 008.
The collaboration between Genentech and Tanox follow breach of contract and patent infringement battles that began in 1993. They settled in 1996 by deciding to combine their resources, as each had an anti-IgE antibody in Phase II trials. (See BioWorld Today, July 10, 1996.)
Under terms of the agreement, Tanox would receive a 10 percent royalty on U.S. and European sales. Genentech and Novartis would not release financial details about the agreement. The companies shared development costs.
Novartis and Genentech would co-promote Xolair in the U.S., where each will have a sales force. Novartis will market it outside the U.S. Novartis received approval for Xolair in Australia, but withdrew its European application in favor of submitting more data. The application is expected to be resubmitted in the first half of 2004.