Status: approved; marketed

Organizations involved:

Genentech, Inc. – Manuf.; R&D; Tech.; Patent dispute; USA mark.; Parent; Patent dispute

Tanox, Inc. – R&D; Tech.; Patent dispute; Former

Novartis Pharmaceutical Corp. – R&D; USA mark.

Novartis AG – Manuf.; Intl. mark.; Parent

Ciba-Geigy Ltd. – R&D; Tech; Former

Protein Design Labs., Inc. – Tech.; Patent dispute

University of Colorado – Tech.

Columbia University – Tech.; Patent dispute

Akin Gump Strauss Hauer & Feld – Patent dispute

Amgen Inc. – Tech.

Cross ref.: See the Monoclonal Antibodies entry (#300).

Description: Xolair is a lyophilized (freeze-dried) formulation of omalizumab (E25), a recombinant humanized monoclonal antibody glycoprotein, with binding specificity for human immune globulin E (immunoglobulin E; IgE), associated with allergic responses and asthma, expressed by a transformed Chinese hamster ovary (CHO) cells. A murine monoclonal antibody with desired IgE-binding characteristics was humanized, with the gene sequence for the IgE binding site excised and engrafted into a human IgG1 frame work, with less than 5% of the resulting monoclonal antibody being of murine origin. Version 25 of humanized variants was selected for development, resulting in the name rhuMab-E25. Omalizumab has a molecular weight of ~149 kDa.

Xolair inhibits the binding of IgE to high-affinity IgE receptor, particularly Fc.epsilon.RI, on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcRI-bearing cells limits the release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcRI receptors on basophils in atopic patients. Omalizumab binds to the C.epsilon.3 domain of free IgE, the site of high-affinity IgE receptor binding. This neutralizes circulating IgE by preventing IgE from binding to its high-affinity receptor on the surface of mast cells, and down-regulates further production of IgE by blocking binding of antigens to IgE expressed on the surface of B-cells. The monoclonal antibody was designed not to bind to IgE already complexed Fc-epsilon-RI receptor on basophils and mast cells, which could lead to inflammatory and allergic reactions; and not to bind to IgE complexed with Fc-epsilon-RII receptors on various cells including platelets, which could also lead to adverse effects.

Xolair is packaged in single-use vials for reconstitution with Sterile Water for Injection, USP, and administration by subcutaneous (SC) injection. Each vial contains 202.5 mg of omalizumab, 145.5 mg sucrose, 2.8 mg L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20 (Tween 20) for delivery of 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI. The product is stored at 2-8° C (refrigerated) with a dating period of 18 months from the date of manufacture (defined as the date of final sterile filtration of the formulated drug product). Xolair should be shipped at controlled ambient temperature (≤86˚F). Xolair contains no preservatives.

Nomenclature: Immunoglobulin E Mab, rDNA [BIO]; omalizumab [FDA USAN INN]; Xolair [TR]; immunoglobulin G, anti-(human immunoglobulin E FC region) (human-mouse monoclonal E25 clone PSVIE26 gamma-chain), disulfide with human-mouse monoclonal E25 clone PSVIE26 kappa-chain, dimer [CAS]; 242138-07-4 [CAS RN]; rhuMab-E25 [SY]; immunoglobulin E25 monoclonal antibody [SY]; MaE11, recombinant humanized [SY]; NDC 50242-040-62 [NDC]

Biological.: Immunoglobulin E (immune globulin E; IgE) is a member of the immunoglobulin family that mediates allergic responses, such as asthma, food allergies, type 1 hypersensitivity, and sinus inflammation. IgE is expressed on the surface and secreted by B-cells or B lymphocytes. IgE binds to B-cells (as well as to monocytes, eosinophils and platelets) through the Fc region of an IgE receptor, Fc.epsilon.RI (FcRI)

Allergy is a hypersensitive state induced by an exaggerated immune response to a foreign agent (allergen). Immediate (type I) hypersensitivity, characterized by allergic reactions immediately following contact with allergen, is mediated via B cells and is based on antigen-antibody reactions, whereas delayed hypersensitivity is mediated via T cells and based on mechanisms of cellular immunity. In recent years, the term “allergy” has become more and more synonymous with type I hypersensitivity. This immediate hypersensitivity is based on the production of IgE-type antibodies by B cells.

Upon initial exposure to an allergen, B-cells bearing a surface-bound IgE antibody specific for the antigen/allergen are “activated” and develop into IgE-secreting plasma cells. Locally-produced IgE first sensitizes local mast cells. The constant regions of the IgE (antibodies) bind with Fc receptors on the surface of the mast cells, and “spill-over” or remaining IgE enters the circulation and binds to receptors on both circulating basophils and tissue-fixed mast cells throughout the body. The resulting allergen-specific IgE circulates through the bloodstream and becomes bound to the surface of mast cells in tissues and basophils in the blood through Fc receptors.

The mast cells and basophils then become sensitized for the allergen, with subsequent exposure to the same allergen causing a cross linking of the basophilic and mast cellular Fc.epsilon.RII. This results in a release of histamine, leukotrienes, platelet activating factors, eosinophil and neutrophil chemotactic factors, and the cytokines IL-3, IL-4, IL-5 and GM-CSF. These substances are responsible for the clinical symptoms typical of immediate hypersensitivity – contraction of smooth muscle in the respiratory tract or the intestine, the dilation of small blood vessels and associated increase in their permeability to water and plasma proteins, the secretion of mucus resulting, e.g., in rhinitis, atopic eczema and asthma, and the stimulation of nerve endings in the skin resulting in itching and pain. Also, the reaction upon second contact with the allergen is intensified because some B cells form a “memory pool” of surface IgE positive B cells (sIgE+ B cells) after first contact with the allergen by expressing IgE on the cell surface. Common environmental allergens which induce anaphylactic hypersensitivity are found in pollen, foods, house dust mites, animal danders, fungal spores, and insect venoms. Atopic allergy is associated with anaphylactic hypersensitivity and includes the disorders, e.g., asthma, allergic rhinitis and conjunctivitis (hay fever), eczema, urticaria and food allergies. In asthma, when allergen binds surface-bound IgE, this induces rapid release of a variety of mediators that collectively induce bronchial constriction and inflammation.

Omalizumab inhibits allergic reactions by down-regulating the IgE immune response, the earliest event in the induction of allergy. Other antibody classes are not affected. Omalizumab is capable of neutralizing IgE by binding free circulating IgE, and inhibiting the binding of IgE to cells bearing Fce receptors I or II, particularly mast cells and basophils. This reshaped human antibody also activates host cellular immune mechanisms resulting in specific killing of the sIgE+ B cells. Omalizumab recognizes and binds IgE expressed on the surface of surface IgE positive B cells (sIgE+ B cells), with resulting cellular immune reactions depleting the population of these cells which form the “memory pool” resulting in IgE production after a second exposure to the allergen.

Antibodies to IgE, in principle, may also induce mediator release from IgE-sensitized mast cells by cross-linking the Fce receptors, antagonizing the beneficial effects they exert on the serum IgE and sIgE+ B-cell levels. Thus, antibodies for treatment of allergy, e.g., omalizumab, must not be capable of reacting with IgE bound on sensitized mast cells and basophils, but should retain the capability to recognize sIgE+ B cells. Since omalizumab does not recognize cytophilic IgE on cells bearing Fce receptors I or II (mast cells and basophils), it does not induce mediator release by these cells. Omalizumab has a long lasting therapeutic effect, because it has a significant inhibitory effect on the formation of IgE in the immune response.

Omalizumab interferes early in the underlying causation of allergy by removing IgE antibodies and surface IgE positive B-cells, eliminating or reducing the potential for an allergic response, and inhibiting IgE formation. Thus, Xolair treatment does not require ongoing/repeated doses, and Xolair can be used for prophylactic treatment by administration prior to symptoms of allergy. A course of treatment is expected to last about six months or longer. Treatment of patients with moderate-to-severe allergic asthma can reduce symptoms, while decreasing or even completely eliminating the need for steroids and other medications. Omalizumab does not bind to or induce histamine release from basophils, nor does it bind to or recognize IgG. The immune complexes formed between IgE and omalizumab in vivo are relatively small (m.w. <1 million) and are unlikely to cause organ damage.

Companies.: Xolair was developed by a collaboration of Tanox, Inc., Genentech, Inc., and Novartis Pharmaceuticals Corp., the U.S. subsidiary of Novartis AG. Genentech and Novartis co-market Xolair in the U.S., and Novartis AG handles European and international marketing. In Nov. 2006, Genentech acquired Tanox for ~$919 million, with this eliminating Genentech paying patent royalties to Tanox and Genentech now also receiving royalties in Novartis sales outside the U.S.

Omalizumab is manufactured by Genentech, CBER/FDA est. no. 1048. Eventually, manufacturing will be shared with Novartis (which will presumably manufacture product for its international markets). Omalizumab was originally approved for manufacturing by Genentech at two facilities, in S. San Francisco, CA, and a site redacted (censored) by FDA. Genentech has subsequently reported that omalizumab is manufactured at its new large-scale facilities in Vacaville, CA. The final formulated product is filled, lyophilized, labeled and packaged at S. San Francisco, CA, facilities.

Novartis AG has constructed new manufacturing facilities in Huningue, France. These facilities are expected to manufacture assume manufacture of all the supply of Xolair after FDA approval, expected in early-mid 2006.

Tanox originally approached Genentech about joint development of an IgE antibody therapeutic in 1989, but Genentech wanted to develop it on its own, and Tanox rejected the offer. Tanox soon found a partner in Ciba-Geigy AG, now Novartis AG. Genentech later initiated a patent suit against Tanox, and other disputes arose among Tanox, Ciba-Geigy and Genentech. This including Tanox filing suit against Genentech in 1993 alleging patent infringement by omalizumab, Genentech’s monoclonal antibody, contending that Genentech had stolen its idea and trade secrets, with Genentech countersuiing.

Tanox, Ciba-Geigy (now Novartis AG) and Genentech settled their disputes and formed a collaboration in July 1996, agreeing to combine their IgE monoclonal antibody Phase II trials and subsequent development efforts, and settle all patent disputes. This included Genentech paying Tanox $16 million and agreeing to certain royalty payments. Two candidate products, a chimeric monoclonal antibody (CGP 5190, TNX-901; manufactured by Tanox) developed by Tanox and Ciba-Geigy, and a humanized monoclonal antibody (E25; omalizumab) developed by Genentech were both tested through Phase II trials. The Genentech product, omalizumab, was selected for further development, with Genentech’s succesfull scale-up of omalizumab manufacturing figuring in this decision. Hoffmann-La Roche AG, the majority owner of Genentech, passed on its option rights for involvement in omalizumab development and marketing. Tanox had originally manufactured omalizumab for studies/trials in its own facilities, planned to manufacture it at commercial-scale, and started to develop large-scale manufacturing facilities. However, Genentech obtained exclusive manufacturing rights. [Note, large (bio)pharmaceutical companies generally prefer to manufacture their products in-house or totally control their manufacture].

Xolair was jointly developed by Genentech, Ciba-Geigy/Novartis and Tanox, under their 1996 agreement. Genentech records all U.S. sales, and Novartis records international (ex-U.S.) sales. Genentech and Novartis share profits about 50-50, with Genentech receiving slightly less than half. Tanox receives a 10% royalty on U.S. and European sales.

However, after the 1996 agreement and during development of Xolair, Tanox also began its own development of a similar IgE monoclonal antibody, TNX-901, for treatment of peanut allergy, an indication too small to be of interest to Genentech and Novartis. Genentech and Novartis filed suits alleging that their original agreement with Tanox did not permit development of another IgE monoclonal antibody. In Oct. 2001, a U.S. District Court ruled that Tanox did have the right to develop TNX-901. A subsequent court decision forced the dispute into binding arbitration, which Tanox lost.

In Feb. 2004, Tanox, Inc., Novartis Pharma AG, and Genentech, Inc. settled all litigation and finalized the terms of their three-party collaboration (from the 1996 agreement) to develop and commercialize IgE antibodies, including Xolair (omalizumab) and TNX-901. Genentech and Novartis each reimbursed Tanox $3.3 million for a portion of its TNX-901 development costs. Tanox relinquished all rights to manufacture Xolair and, in exchange, receives royalty payments tied to the quantity of Xolair produced by Genentech. Tanox reports the net amount it receive from Xolair sales is in the range of 8-12% of the net sales, depending on the sales level achieved and geographic distribution of the sales. Tanox also benefited from accelerated forgiveness of a loan it used to finance the construction of its biologics manufacturing plant in the mid-1990s. As in the 1996 agreement, Genentech and Novartis share U.S. marketing rights for Xolair and other collaboration products, while Novartis has marketing rights outside the U.S. Other existing royalty and profit-sharing percentages remained unchanged. Committees with representatives from all three companies were set up to cooperatively oversee further development and commercialization of Xolair, and any other collaboration products. The partners also committed to developing Xolair for the treatment of peanut allergy.

Tanox is involved in a dispute with its former lawyers, led by Akin Gump Strauss Hauer & Feld, that represented it in its initial suit against Genentech that resulted in the 1996 settlement, including Tanox receiving a $16 million licensing fee and future royalties on Xolair. Tanox had (mistakely, in hindsight) hired the lawyers on a contingency basis. The law firms allege Tanox tried to conceal its initial $16 million payment from Genentech to avoid having to pay half of it as legal fees. An arbitration panel ruled in favor of the lawyers, saying that Tanox was involved in “machinations” to avoid its payments to its lawyers. Tanox was ordered to pay $3.5 million to the lawyers, plus 33.3-40% of all milestone payments from Genentech plus 10% of the royalties Tanox receives from sales of Xolair. Two courts have upheld the arbitrators’ decision. With the law firms essentially receiving 10% of Tanox’s ~10% royalties on Xolair, or 1% of sales, and with Xolair sales to projected to eventually exceed $1 billion/year, the law firms could receive substantial income (e.g., $10 million on sales of $1 billion).

Some articles about Tanox’s involvement in Xolair portray it as being forced to halt development of a product for peanut allergy have appeared widely in the popular press, with many of these stories portraying Genentech (and Novartis) as stealing Tanox’s innovations, and interfering with Tanox and stopping/delaying a much-needed product from development by its inventors. This includes an article in the New York Times, March 13, 2003.

In Jan. 2006, Tanox received a $12.8 million milestone payment from Genentch under its 2004 cross-licensing agreement concerning IgE antibodies including Xolair.

In early 2006, Novartis AG was awaiting FDA approval for manufacture of all its supply of Xolair at its facilities in Huningue, France. This indicates that Genentech will no longer manufacture Xolair after this plant comes online.

Manufacture: Omalizumab is produced by transformed Chinese hamster ovary (CHO) cells in suspension culture in a medium containing the antibiotic gentamicin, which is not detectable in the final product. The CHO cell line used was originally developed by Dr. T. Puck, University of Colorado, from a biopsy sample from an adult Chinese hamster. Formulation changes made during clinical development included changing from an aqueous to lyophilized formulation, and changes in manufacturing “during terminal development.” Biochemical comparability and clinical pharmacokinetic/pharmacodynamic studies demonstrated that product used for clinical trials and commercialization were comparable/identical.

In a Sept. 2006 presentation by Novartis staff (the Lean Steering Committee), it was disclosed that Xolair’s target manufacturing throughput time is 75 days (from unfreezing of the manufacturing strains to final Xolair release), reduced from 96 days, with a throughput rate of three batches/week, with Overall Asset Effectiveness (OAE) of ≥64%, and production yield ≥80%. This includes testing by Genentech. Current and target times (manufacturing phases), respectively, are cultivation (42/39 days), purification (8/4 days), batch review P (7/5 days), batch review QA (7/5 days), deviation (30/20 days), release (2/1 days) and Genentech testing (49/35 days). Various minor changes in the manufacturing process were proposed. Novartis looks to increase Q-Sepharose purification yield from 89% to 95%. Current and target yields, respectively, are clarification (96/96%), ProSepA (Protein A purification; 99/99%), SP-Sepharose (96/96%), Q-Sepharose (89/95%), UF/DF formulation (92/94%), and filling (99/99%), with total yield increasing from 74% to ≥80%. Besides this, “DS quantity target [is] ≥ 11.5 Kg DS/Batch (Xolair Lyo).” Changes are expected to be implemented through the end of 2007. Key changes cited include “Dedicated CIP system for harvest phase; Reduce CIP / SIP time for buffer and preparation tank; New sequence of production / CIP / Buffer preparation; and New autoclave and washing machine.”

FDA class: Biologic BLA

CBER class: Blood And Blood Derivatives

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 20030620; BLA (BL 103976/0)

Date = 20070702; BLA supplement; Indication = addition of black box warning anaphylaxis has been reported in about two out of 1,000 patients.

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Xolair (Omalizumab) is indicated for adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Xolair has been shown to decrease the incidence of asthma exacerbations in these patients. Safety and efficacy have not been established in other allergic conditions.

Status: Genentech and Novartis filed a BLA on June 2, 2000 for asthma and seasonal allergic rhinitis (hay fever) in adults and pediatric patients. In Sept. 2000, FDA requested suspension of new trials of omalizumab, while allowing ongoing long-term trials to continue. The hold on new trials was due to concerns about the preclinical toxicity of omalizumab and a follow-up antibody, E26; and thrombocytopenia was reported in studies in monkeys for omalizumab at 5-27 times the maximum clinical dose. Novartis and Genentech conducted additional preclinical studies. With this data and no thrombocytopenic events having occurred in the completed Phase III clinical trials, the clinical hold was lifted in Nov. 2000.

On July 5, 2001, FDA issued a Complete Response Letter, including requests for further preclinical, clinical and pharmacokinetic data, and detailed information concerning prolonged use. On Dec. 18, 2002, the companies amended the BLA by restricting the proposed indication to moderate-to-severe allergic asthma in adults (totally dropping the seasonal allergic rhinitis indication, severely restricting the potential market), with data from Phase III trials expected to satisfy FDA requests. The electronic filing included test results from more than 6,000 patients in 26 different studies. The only new clinical data was from an open-label Phase IIIb study that doubled the size of the safety database from the initial filing.

A major concern at the time was that Xolair may increase cancer risk. Genentech reported that malignant neoplasms occurred in 20 of 4,127 (0.5 percent) of Xolair patients compared to five of 2,236 (0.2%) of control patients. Most, about 60%, of Xolair-related cancers were found within six months, a latency time so short (for cancer) that Xolair was considered unlikely to be the cause, and there was no other evidence linking Xolair as a carcinogen.

On May 15, 2003, the Pulmonary-Allergy Drugs Advisory Committee, FDA, reviewed Xolair. At the meeting, FDA reported that although showing a robust and statistically significant effect on primary endpoints in well-controlled trials, the efficacy of Xolair was “small.” The review committee was not particularly concerned about the theoretical increased risk for cancer associated with IgE immune response suppression by Xolair, and voted unanimously (11-0) to recommend its approval in those ages 12-65 (including the upper age limit, due to limited clinical trial enrollment of patients over 65).

FDA approval was granted on June 20, 2003; approval time = ~3 years. Xolair is exempt from CBER/FDA lot release inspection requirements. Approval included requirements for five Phase IV post-approval trials, including a study of cancer incidence in 5,000 Xolair patients over five years (results expected in 2011).

The first approval for Xolair was granted in Australia on June 18, 2002.

Novartis AG applied for European Union approval in June 2000, and withdrew its application after encountering delays with FDA approval. Novartis resubmitted its MAA for allergic asthma inadequately controlled by inhaled steroids in July 2004, including data from new trials. The proposed indication was prevention of asthma exacerbations and control of symptoms in adults and adolescents with severe persistent allergic asthma inadequately controlled despite use of inhaled corticosteroids, long-acting beta-2 agonists, as well as other controller medications.

On Oct. 27, 2005, Xolair received approval in the European Union. Novartis received approval in all 25 European member states as an add-on therapeutic to improve asthma control in adults and adolescents (aged 12 years and above) with severe persistent allergic asthma despite treatment with daily high-dose inhaled corticosteroids plus a long-acting inhaled beta-2 agonist; have a positive skin test or in vitro reactivity to a perennial aero-allergen; have reduced lung function (FEV1 <80 per cent); have frequent daytime symptoms or night-time awakenings; and have multiple documented severe asthma exacerbations. Xolair was approved only for IgE-mediated asthma.

Xolair received U.K. approval on Nov. 7, 2005 for use in patients whose asthma can not be controlled with standard therapy and are at increased risk of hospitalization.

In Feb. 2007, after receiving additional reports of anaphylaxis, FDA issued a warning and called for Lilly to strengthen the warnings on Xolair’s product insert/labeling. FDA notified asthmatic patients and healthcare professionals of the new anaphylaxis reports and noted that reactions generally occur within two hours of receiving a Xolair subcutaneous injection. However, reported cases also include patients who had delayed anaphylaxis, with onset two to 24 hours or even longer, after receiving Xolair. FDA advised health care professionals who administer Xolair to observe their patients for at least two hours after the treatment is given. No deaths had been reported, but FDA has asked Genentech to add a black boxed warning, the strongest possible, to a revised product label and provide a medication guide for patients. The label on Xolair already included warnings about the risk of anaphylaxis after treatment with Xolair being one in 1,000 patients, based on preapproval clinical trials.

In July 2009, FDA was reported to be evaluating interim safety findings from an ongoing study of Xolair, "Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS)," that suggested a disproportionate increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic and thrombophlebitic events in patients treated with Xolair compared to the placebo control group.

On Aug. 24, 2009, Lilly received European Union (EU) approval for Xolair to treat children age 6 to 11 years with severe persistent allergic asthma.

In Nov. 2009, an FDA advisory committte voted 10-4 againt approval of Xolair use in children aged 6 to 11. The committee was concerned about safety and the possibility of a long-term cancer risks. Xolair has been cleared since 2003 for use by adults and adolescents aged 12 and older.

Tech. transfer: See the Companies section above for aspects of the complex relationship, including patent disputes, between Tanox and Genentech, and Genentech licensing Tanox’s patents. 6,699,472

Omalizumab-related patents assigned to Genentech include U.S. 6,037,453, “Immunoglobulin variants,” March 14, 2000 and 6,329,509, “Anti-IgE antibodies,” Dec. 11, 2001. These claim humanized IgE monoclonal antibodies in which a murine antibody, MaE11, directed against human IgE was used to provide CDR (active immunogen-binding) regions which were substituted into a human IgG1 immunoglobulin framework, forming Mabs including rhuMaE25, E25 or omalizumab. Residues were modified by site-directed mutagenesis to form anti-IgE MaE11 variants, which were used as the template to create rhuMaE25 or E25. See also Shields et al., Intl. Arch. Allergy Immunol., 107: 308-312, 1995; and Presta et al., J. Immunology, 151: 2623-2632, 1993. Related U.S. patents assigned to Genentech include 6,290,957; 6,172,213; and 5,994,511, describing methods for improving the affinity of recombinant IgE Mabs, including E25, using affinity maturation with phage display (AMPD). In July 2004, Genentech received U.S. 6,761,889, “Anti-IgE antibodies,” claiming methods for adjusting/optimizing the affinity of a antibodies for their targets, including use of affinity maturation with phage display (AMPD), with this exemplified by recombinant IgE antibodies.

U.S. patents covering aspects of therapeutic use of omalizumab and related humanized IgE monoclonal antibodies assigned to Genentech include 6,699,472, “Method of treating allergic disorders,” March 2, 2004, expired in 2011. The patent claimed use for treatment of asthma, food allergy, hypersensitivity, and anaphylaxis.

U.S patents jointly assigned to Novartis and Tanox include 6,072,035, “Reshaped monoclonal antibodies against an immunoglobulin isotype,” May 23, 2000; and 6,066,718. These describe development of an antibody having an antigen binding affinity at least 90% of that of the murine CDR-donor TES-C21 monoclonal antibody (not omalizumab).

Dr. Tse Wen Chang, a founder of Tanox, is generally attributed as the inventor of IgE antibodies for treatment of asthma and allergies, having thought of this and recording some notes in the middle of the night in 1988. Tanox has received various patents covering use of IgE monoclonal antibodies for treatment of asthma. U .S. patents assigned to Tanox include 5,614,611 concerning humanized monoclonal antibodies binding to IgE-bearing B cells but not basophils; 5,543,144 concerning treatment of hypersensitivities with anti-IgE monoclonal antibodies which bind to IgE-expressing B cells but not basophils; 5,449,760 concerning monoclonal antibodies that bind to soluble IgE but do not bind IgE on IgE-expressing B lymphocytes or basophils; and 5,428,133 concerning chimeric IgE monoclonal antibodies binding to secreted IgE and membrane-bound IgE expressed by IgE-expressing B cells but not to IgE bound to Fc receptors on basophils; 5,422,258; 5,420,251; 5,260,416; 5,252,467; 5,231,026; and 5,091,313.

Monoclonal antibody humanization technology was nonexclusively licensed from Protein Design Labs., Inc. (PDL). Based on a Jan. 2003 CIBC World Markets Report on PDL, the PDL receives royalties of 3%. See the “Tech. transfer (rDNA)” section of the Monoclonal Antibodies entry (#300) for discussion of the complex patent, licensing, cross-licensing and patents disputes involving humanized recombinant monoclonal antibodies. This includes discussion of humanized recombinant monoclonal antibody technologies developed by Genentech, PDL, and other companies, including Genentech’s own rather broad “New Cabilly” patent (cross-licensed with related patents assigned to the Celltech Group) providing U.S. patent protection into 2018. In March 2000, Tanox paid PDL a $2.5 million fee (including a $1.5 million credit for a prior license) to obtain four licenses for humanized monoclonal antibodies, upon payment of at least $1 million/product, plus unspecified royalties on sales.

On Dec. 22, 2003, Genentech and PDL “conclusively” resolved their disputes concerning PDL’s recombinant humanized monoclonal antibody design/construction patents (and three humanized antibodies from Genentech), as described in the Monoclonal Antibodies entry (#300). This dispute included Xolair, with Genentech refusing the pay PDL royalties for this and other products. Under their new agreement, PDL would receive fees of $1 million for each of Genentech’s recombinant antibody products, including Xolair; and PDL would receive royalties on Genentech’s sales, including for 2003 sales of Xolair (and Raptiva). In exchange, PDL agreed to royalty rate reductions for certain high levels of aggregate sales by Genentech products.

On Aug. 18, 2004, Genentech filed for an extension of the expiration date for U.S. 6,267,958, based on regulations (U.S.C. 9 156) allowing the U.S. Patent and Trademark Office (PTO) to extend patent expiry for pharmaceuticals based on their time in clinical trials and FDA regulatory review. U.S. 6,267,958, “Protein formulation,” assigned to Genentech, claims formulations for stable isotonic solutions from lyophilized proteins, e.g., anti-IgE antibodies, e.g., using “lyoprotectants,” such as sucrose or trehalose, with histidine or succinate buffers. In a Jan. 2004 letter to PTO, FDA requested PTO’s assistance, particularly in determining whether the patent’s claims cover s Xolair or its method of manufacture.

Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Genentech and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the Tech. transfer section of the Recombinant DNA Products entry (#100) for further information.

In Jan. 2006, Genentech and Amgen cross-licensed their respective enabling recombinant monoclonal antibody techologies.

          In Aug. 2010, Genentech, now fully part of Hoffmnn-La Roche, informed PDL BioPharma Inc. it believes that four of its marketed products, including Xolair, are not covered by patents that had been licensed by Genentech from PDL. Genentech/Roche plans to continue to pay patent royalties (while presumably trying to renegotiate of get out of its prior licensing agreement). PDL will surely appeal any actions by Genentech/Roche, since is receives 30% of its revenue from these licenses.

Trials: FDA approval of Xolair was primarily based on two Phase III trials in adults and adolescents with moderate-to-severe asthma and skin test-based sensitivity to common allergens. Both trials were randomized, double blinded trials conducted for 7 months with 5 month blinded extensions. The primary endpoints were reduction in exascerbations of asthma (i.e., requiring treatment with oral or intravenous corticosteroids or a doublinh of inhaled steroid dosage from baseline) during a period of stable steroid use and a steroid-reduction phase. Patients received 150-375 mg Xolair or placebo every 2 or 4 weeks, based in their body weight and total serum IgE level upon trial entry.

In Feb. 2005 of Allergy, results were reported from the 28-week, double-blind, international INNOVATE trial in 419 severe persistent asthma patients. All patients were receiving high doses of inhaled corticosteroids plus long-acting beta2-agonists, and two-thirds were receiving additional controller medications including 22% taking oral corticosteroids. All patients had impaired lung function and a history of recent asthma attacks. Xolair (dosage ≥900 µg) significantly reduced asthma exacerbations by 26% vs. placebo (p=0.042; when the baseline was adjusted for asthma exacerbation history prior to randomization. Without adjustment, the reduction was 19% and not statistically significant. Omalizumab also significantly reduced the severe asthma exacerbation rate (p=0.002) and emergency visit rate (p=0.038).

Xolair Phase III trials for treatment of peanut allergy were initiated in the second quarter of 2004, with additional Phase II trials initiated in the third quarter of 2004.

In Dec. 2006, Genentech suspended a placebo-controlled Phase II trial with Xolair for peanut allergy after two patients developed “severe hypersensitivity reactions” after receiving a trace amount of peanut protein as part of screening for peanut allergy. Neither patient had yet received Xolair or placebo. This will further delay development of Xolair for peanut allergy. Genentech reported that it was considering conducting a trial not involving screening for peanut allergy, an observational study that would track patients receiving Xolair or placebo to determine whether fewer accidental peanut reactions take place in the Xolair group.

Genentech is conducting trials to expand the market for Xolair. A Phase III trial in the pediatric setting (ages 6–12) completed enrollment in late 2006. Other ongoing studies include a Phase III trial (EXTRA) in 850 moderate to severe asthma patients failing beta agonists or long-acting corticosteroids, and a post-approval Phase IV trial in 7,500 patients. Novartis is also conducting trials to expand the market for Xolair. These include a Phase III trial in pediatric patients ages 6–12 (with Xolair currently only indicated in patients above 12 years old).

Medical: Xolair, 150-375 mg, is administered subcutaneously once every 2 or 4 weeks. It is generally prescribed to patients with baseline IgE between 30-700 IU/mL and a body weight of not more than 150 kg (330 lb.). The lower IgE restriction is based on the presumption that patients with very low IgE will likely not respond to Xolair, an IgE inhibitor. Because the solution is slightly viscous, the injection may take 5-10 seconds to administer. Dosage size and frequency are determined by serum total IgE level (IU/mL), measured before the start of treatment, and body weight (kg). Doses of more than 150 mg are divided among more than one injection site to limit injections to not more than 150 mg per site. Total IgE levels are elevated during treatment and remain elevated for up to one year after discontinuation of treatment. Re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination. Dose determination after treatment interruptions lasting less than 1 year should be based on serum IgE levels obtained at the initial dose determination. Total serum IgE levels may be (re)tested for dose (re)determination, if treatment with Xolair has been interrupted for one year or more.

Disease: There are an estimated 17 million asthma patients in the U.S., including 12.5 million adults. About 40%-50% of patients are considered to have moderate to severe disease. Of these, only about 5 million seek treatment. Of these, ~80% have elevated IgE. Of these, about 50% have moderate-to-severe disease. This translates into about 2 million potential U.S. patients. Of these, about 500,000 patients are refractory to or continue to present symptoms with other asthma therapeutics. Thus, as originally approved, the indications: for Xolair cover an estimated 500,000 U.S. patients.

Market: Total worldwide revenue was $1.14 billion in 2011; $692 million in 2010; $914 million in 2009; $728 million in 2008; $662 million in 2007; $527 million in 2006; and $227 million in 2005. Genentech accounts for the great majority of Xolair sales (relative to those of Novartis). Total Xolair revenue reported by Genentech (U.S. sales) was $268 million in 2011; $229 million in 2010; $185 million in 2009; $138 in 2009; $137 million in 2008; $129 million in 2007; and $95 million in 2006. Upon the Nov. 2006 acquisition of Tanox by Genentech, it was reported that among the $377 million in sales in the first three quarters of 2006, $310 million (82%) were by Genentech in U.S. and $67 million (18%) were by Novartis ex-U.S., that Xolair then had a 15% share or the asthma market, and that Tanox had received royalties of ~$37 million, indicating it had been receiving royalties of ~10% of sales,

Total Xolair revenue for Novartis was $338 million in 2009 and ~$304 million in 2008. In a Sept. 2006 presentation by Novartis staff (Lean Steering Committee), a slide disclosed Novartis’ worldwide (its own plus Genentech) sales projections of $192 million in 2004, $348 million in 2005, $463 in 2006, $617 in 2007, $741 in 2008, $830 million in 2009 and $920 million in 2010.

In Nov. 2006, Friedman Billings and Ramsey (FBR) analysts, with the acquisition of Tanox by Genentech, projected total Genentech/U.S. sales of Xolair would be $423.1 million in 2006, $574.4 million in 2007, $718.8 million in 2008, $799.0 million in 2009, and $847.9 million in 2010. These are somewhat more conservative than Novartis’s projections.

As of Dec. 2009, Xolair was approved in 63 countries and had been used to treat more than 62,000 patients.

The Aug. 2009 European Union approval for use in children age 6-11 expanded the potential market to include nearly 35,000 children in the EU with uncontrolled severe persistent allergic asthma.

The 2007 Average Wholesale Price (AWP) is $620.91/vial (Red Book, 2007). The wholesale acquisition cost (WAC), upon approval, was reported to be $433/vial. The 2005 AWP was $568.31/vial, and $541.25 in 2004. The wholesale acquisition cost, upon approval, was reported to be $433/vial.

Xolair treatment is relatively expensive, with treatment generally costing about $10,000 to $12,000/year. At the maximum dose (two injections every two weeks), the cost can be over $20,000/year. Insurance reimbursement for Xolair has not been a problem.

Xolair’s target U.S. patient population of 500,000 continues to offer significant growth opportunity for Xolair. Genentech faces the challenge of convincing physicians that Xolair should not be their last choice for asthma treatment, and that they should not ignore refractory “moderate” severity patients as Xolair candidates. Many physicians only prescribe Xolair to patients having been hospitalized, with its relatively high cost influencing their view of the product.

Market penetration of just a portion of eligible adult patients provides a potential blockbuster (>$1 billion/year) market (e.g., 100,000 patients paying just $10,000/year provides sales of $1 billion). Other factors affecting the market for Xolair include whether and how it will be used after one year (the length tested in clinical trials), and how to determine whether it is working (since, unlike many other asthma therapeutics, response can not easily be determined by testing pulmonary function). With post-Xolair treatment IgE difficult to measure, physicians face uncertainty in making long-term treatment decisions.

Warnings about Xolair adverse events and its strengthened labeling including these are not expected to affect sales, with prescribing physicians already familiar with Xolair’s adverse effects.      

A variety of therapeutics are available for asthma, and Xolair is likely to contineu to be used primarily in the most severe patients, where its ability to replace multiple therapeutics and reduce hospitalization is most cost-effective and beneficial. Asthma medications include various corticosteroids, adrenergic receptor beta agonists, leukotriene modifiers, and theophylline. Some patients may receive allergy shots, involving injection of low doses of the causative allergen to down-regulate immune response.

In Nov. 2007, the National Institute for Clinical Excellence (NICE), U.K., recommended use of Xolair by the National Health Service (NHS) in patients over the age of 12 with severe and persistent allergic asthma, and only if the allergy was proven by clinical history and skin testing and the attacks are “extremely severe."

In Aug. 2010, NICE recommended against use of Xolair by the National Health Service (NHS) in patients 6-11 years old with severe and persistent allergic asthma. Nice stated Xolair's high cost did not justify its "little extra benefit compared with existing treatments." NICE asserted that Xolair was not cost-effective for those under 12. Thus, NHS treatment of of severe asthma with Xolair must wait until age 12.

In Nov. 2012, NICE reversed its favorable view of Xolair and announced that it no longer believes the National Health Service should prescribe it for adults or children, stating, "After considering new evidence that has become available since the original guidance was published--particularly new mortality data--the NICE draft guidance does not recommend omalizumab for either adults or children." The agency said its reversal also was affected by new dosing recommendations that change the cost of the drug, with costs now ranging from £1,665 ($2,651) per patient per year to as high as £26,640 ($42,384). The ruling "proposes no change to the existing negative recommendation for children aged 6-11 years."

In March 2013, NICE backed down on its draft guidance to withdraw its recommendation for Xolair in the treatment of asthma. Novartis offered Xolair at a discount through a patient access scheme (PAS), convincing NICE to release final draft guidance upholding its original 2007 recommendation. This recommendation also covers adolescents and children aged six years and over with severe, persistent allergic asthma, opening up a new market in England and Wales. Both recommendations cover Xolair's use as an add-on therapy for people whose asthma remains poorly controlled despite receiving optimised standard therapy, such as high-dose inhaled corticosteroids.

In April 2013, NICE formally approved use of Xolair as an option for treating severe, persistent confirmed allergic immunoglobulin E (IgE)-mediated asthma in people aged six years and older. This new guidance removed the requirement of the 2007 NICE guidance for patients aged 12 years and older that all patients should be hospitalized for asthma before being eligible for treatment (meaning more patients should be able to have access to the treatment at an earlier stage). The cost of the treatment was reported to range from £1,665 per patient per year for a 75mg dose administered every month, to £26,640 per patient per year for the maximum 600mg dose given every fortnight. These costs will be lower owing to the PAS, but by just how much lower is uncertain as the Novartis discount remains ‘confidential in confidence’.

Ongoing: Besides ongoing trials (see the Trials section above), Genentech has been reported to be developing a self-injectable liquid formulation of Xolair.