Omalizumab

Omalizumab (trade name Xolair, Genentech / Novartis) is a humanized antibody drug approved for patients with moderate-to-severe or severe allergic asthma, which is caused by hypersensitivity reactions to certain harmless environmental substances. Omalizumab's cost is high ($10,000 to $30,000 per year), as compared to other drugs used for asthma, and hence omalizumab is mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even with high doses of corticosteroids. Like other protein and antibody drugs, omalizumab causes anaphylaxis (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.^[1]

Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to human immunoglobulin E (IgE). IgE is commonly involved with allergies when present in high amounts in the body.

Medical uses

The primary use of omalizumab is for people with moderate to severe, persistent allergic asthma, uncontrollable with corticosteroids.^[2] The efficacy is more evident among severe asthmatics than among those with moderately severe disease. The response rates among treated severe "allergic" asthma patients are 60-80%, probably depending on the patient screening procedures used by the various clinical groups of different specialties. Because 30-40% of adult asthma cases are not related to allergy and unresponsive to omalizumab, a reliable way to identify treatable patients has been a subject of considerable research interest. The primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements. The other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids.

Due to the lack of sufficient information on the long-term effectiveness and side effects of the drug, omalizumab treatment is not yet very common, and can be expensive. Another barrier to prevalent use is the injectable dosage form, which requires the patient to visit a physician's office or clinic every 2 to 4 weeks during treatment. Additionally, as IgE could be a natural defense against parasitic diseases, treatment is usually not recommended when living in environments where the presence of parasites is common.

Adverse effects

The main adverse effects from omalizumab is anaphylaxis.^[2]

There is a non significant trend to increases in the rate of cancer while taking omalizumab. The increased risk of cancer was 0.5% of people treated for less than one year as opposed to 0.2% of people not treated.^[2] Therefore, it cannot be said for certain whether the increase in cancer was simply random chance or a true adverse effect of omalizumab.

IgE might play an important role in the immune system's recognition of cancer cells,^[3] so indiscriminate blocking of IgE / receptor interaction might have unforeseen problems. There is a possible small increased risk of cancer in those taking omalizumab. Concerns have also been raised about possible induction of Churg-Strauss syndrome, nasal polyps, and adrenal insufficiency.^[4]

Mechanism of action

Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor FcεRI by binding to an epitope on IgE that overlaps with the site to which FcεRI binds. This feature is critical to omalizumab's pharmacological effects because a typical anti-IgE antibody can cross-link cell surface FcεRI-bound IgE and induce mediator release from basophils and mast cells. The epitope to which omalizumab binds is sterically hindered by the receptor when IgE is bound to the receptor and is therefore not accessible to omalizumab binding, preventing an inadvertent anaphylactic reaction. However, by binding to IgE in solution, omalizumab prevents IgE binding to cell surface receptor. Although the binding peptide sequence on IgE that is used to bind to low affinity IgE receptor (FcεRII) is different from the sequence used to bind to FcεRI, omalizumab, by steric hindrance, also prevents binding of IgE to FcεRII. Reduction in surface bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcεRI receptors on basophils in atopic patients.^[5]

History

Tanox, a biopharmaceutical company based in Houston, Texas, started the anti-IgE program, created antibody drug candidates, and filed its first patent application on the anti-IgE therapeutic approach in 1987. In the next year, the company converted one candidate antibody to a chimeric antibody (which was later named CGP51,901 and further developed into a humanized antibody, talizumab). The anti-IgE therapeutic concept was not well received in the early period of the program. In order to seek funding for the anti-IgE program, the two scientist founders of Tanox, Nancy T. Chang, Ph.D. and Tse Wen Chang, Ph.D., visited about 25 pharmaceutical and larger biotech companies in the U.S., Canada, Europe, Japan, and other countries to discuss collaboration throughout 1989. Representatives of Ciba-Geigy (which merged with Sandoz to form Novartis in 1996) thought the anti-IgE program scientifically interesting and executives from Tanox and Ciba-Geigy signed a collaborative agreement in 1990 to develop the anti-IgE program. In 1991-1995, scientists from Tanox and Ciba-Geigy ran a successful Phase I human clinical trial in Southampton, England and a Phase II trial in patients with severe allergic rhinitis in Texas on CGP51,901. In the meantime, representatives of Genentech announced in 1993 that it also had an anti-IgE development program. After a lengthy legal entanglement, Tanox, Novartis, and Genentech formed a tripartite partnership to jointly develop the anti-IgE program in 1996. Omalizumab became the drug of choice for further development, because it had a better developed manufacturing process than TNX-901. Omalizumab, trade-named Xolair, received approval by the U.S. Food and Drug Administration (FDA) in 2003 for treating patients 12 years and older with moderate-to-severe allergic asthma. It has also received approval in many other countries for treating patients 12 years and older with severe allergic asthma. Researchers are also developing Omalizumab for pediatric allergic asthma and several other major allergic diseases, including allergic rhinitis. Major trials have also taken place to evaluate the effects of omalizumab on enhancing the efficacy and safety of allergen-based desensitization immunotherapy. In August 2010, the National Institute for Clinical Excellence in the United Kingdom ruled that Omalizumab should not be prescibed on the NHS to children under 12, causing widespread condemnation from asthma charities. NICE concluded that the high costs of the compound, over £250 per vial, did not represent a sufficiently high increase in quality of life.^[6]

Delivery

The drug is administered subcutaneously once every 2 or 4 weeks. As of May 10, 2008, the company began requiring that the drug be administered by a patient's health care provider, due to a risk of anaphylaxis. Previously, the drug could be self-administered.

Manufacturing

Omalizumab is a glycosylated monoclonal antibody expressed by mammalian cells. The molecule is generated over a long fermentation process in large-scale bioreactors. Once the fermentation is over, the product is purified by successive chromatography steps and finally concentrated by UF/DF (paired ultra filtration / depth filtration). It is considered a highly complicated process in terms of process engineering and automation , which partially explains the drug's high cost.

Currently, Omalizumab is manufactured at the Novartis Huningue manufacturing site (France) through a partnership agreement with Genentech.

Chinese hamster ovary cell suspension culture in a medium containing gentamicin is used to produce omalizumab.

References

External links

• FDA
• AsthmaMatters Every Day
• Xolair