Status: withdrawn from U.S. and EU markets in 2009

Organizations involved:

Genentech, Inc. – Manuf.; R&D; Tech.; USA mark.; Japan mark.

Xoma Corp. – Manuf. other; R&D; Tech.; USA mark.; Former

Merck Serono S.A. – Europe mark.; Asia mark,

Merck KGaA – Parent

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

Columbia University – Tech.; Patent dispute

Amgen Inc. – Tech.

Serono International S.A. – Former

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

Description: Efalizumab or Raptiva is a lyophilized (freeze-dried) formulation of recombinant humanized IgG1-kappa isotype murine monoclonal antibody expressed by transformed Chinese hamster ovary (CHO) cells that selectively binds to the lymphocyte (T-cell) surface CD11a receptor. Efalizumab has a molecular weight of ~150 kDa.

Raptiva is a sterile, white to off-white powder packaged in single-use glass vials for subcutaneous (SC) injection. Each Raptiva package (4-dose pack carton) contains four trays, with each containing one single-use vial, one single-use prefilled diluent syringe containing 1.3 mL Sterile Water for Injection (non-USP; not in compliance with USP requirement for pH), two 25 gauge x 5/8 inch needles and two alcohol prep pads. Each single-use vial of Raptiva contains 150 mg of efalizumab (to deliver 125 mg), 123.2 mg of sucrose, 6.8 mg of L-histidine hydrochloride monohydrate, 4.3 mg of L-histidine and 3 mg of polysorbate 20 (Tween 20), and is designed to deliver 125 mg of efalizumab in 1.25 mL. Reconstitution of the single-use vial with 1.3 mL of the supplied sterile water for injection yields approximately 1.5 mL of solution to deliver 125 mg per 1.25 mL (100 mg/mL) of efalizumab. After reconstitution, Raptiva is a clear to pale yellow solution with a pH of approximately 6.2. Raptiva is stored at 2–8°C (36–46°F; refrigerated). The expiration date is printed on each vial’s label.

Biological.: Efalizumab binds to CD11a, a subunit of leukocyte function antigen-1 (LFA-1), which is expressed on all leukocytes, and decreases cell surface expression of CD11a. The binding of LFA-1 and ICAM-1 inhibits the adhesion of leukocytes to other cell types. Efalizumab inhibits the binding of T lymphocytes (T-cells) to other cell types by inhibiting the binding of the LFA-1 T-cell surface receptor to the intercellular adhesion molecule-1 (ICAM-1) surface receptor on other cell types. Depending on the cell type (e.g., interactions between LFA-1 and ICAM-1), efalizumab contributes to the initiation and maintenance of multiple processes, including inhibition of T lymphocytes, T-cell proliferation, cytokine release, adhesion of T lymphocytes to endothelial cells, and migration of T lymphocytes to sites of inflammation including psoriatic skin. CD11a is also expressed on the surface of B lymphocytes, monocytes, neutrophils, natural killer cells, and other leukocytes. Therefore, the potential exists for efalizumab to affect the activation, adhesion, migration, and numbers of cells other than T lymphocytes.

Lymphocyte activation and trafficking to skin plays a role in the pathophysiology of chronic plaque psoriasis. In psoriatic skin, ICAM-1 cell surface expression is upregulated on endothelium cells and keratinocytes. Efalizumab targets three key processes in the cascade of events that lead to psoriasis: (1) binding of T-cells through interactions with adhesion molecules (CD11a) on the endothelial cell surface; (2) trafficking of T-cells into the skin; and (3) activation of T-cells. These actions are linked to psoriasis with its abnormal growth of skin cells and painful skin lesions.

Nomenclature: CD11a Mab, rDNA [BIO]; efalizumab [FDA USAN INN]; Raptiva [TR]; Xanelim [TR former]; immunoglobulin G1, anti-(human antigen CD11a)(human-mouse monoclonal hu1124 gamma1-chain), disulfide with human-mouse monoclonal hu1124 light chain, dimer [CAS]; immunoglobulin G1, anti-(human CD11a (antigen)) (human-mouse monoclonal hu1124 gamma1-chain), disulfide with human-mouse monoclonal hu1124 light chain, dimer [CAS]; 214745-43-3 [CAS RN]; CD11a monoclonal antibody, recombinant [SY]; hu1124 [SY]; 50242-058-04 [NDC]

Companies.: Genentech began work on Raptiva in the early 1990s. Raptiva was commercially developed through a collaboration of Genentech, Inc. and Xoma Corp., starting in April 1996. In 1998, Genentech loaned Xoma $10 million to fund research on the humanized monoclonal antibody hu1124 (now Raptiva). Xoma performed nearly all development and testing up to Phase III for psoriasis and manufactured product through Phase III using one (or both) of its 2,750 L CHO bioreactors. Genentech performed Phase III trials and filed for approvals.

Under their original deal (until early 2005), both Genentech and Xoma co-marketed Raptiva in the U.S. Genentech (CBER/FDA est. no. 1048) manufactures the product. Genentech holds exclusive marketing rights in Japan. Xoma receives 25% of profit from sales of Raptiva, with Genentech having paid 87.5% of R&D expenses and loaning Xoma its 12.5% share of R&D expenses.

In Jan. 2005, Xoma restructured its deal with Genentech. Xoma now receives midsingle-digit royalties on worldwide sales and an additional royalty on U.S. sales above a certain level; and a $40 million development loan from Genentech wa eliminated. Xoma previously could have received a higher royalty, but it would have had to pay back the development loan immediately. Xoma relinquished its rights to co-promote Raptiva in the U.S., granting Genentech exclusive U.S. marketing rights, and halted all involvement with Raptiva. Xoma will receive royalties from Genentech on its sales.

In Aug. 2002 and Feb. 2003, Serono International S.A., now Merck Serono S.A., exclusively licensed international marketing rights (outside of the U.S.) and later extended these to include China, South Korea, Taiwan, Hong Kong, Singapore and other Asian countries, in addition Europe. Genentech, Xoma (formerly), and Merck Serono may collaborate on developing new indications: for Raptiva, e.g., rheumatoid arthritis, and share certain global development costs. Merck KGaA acquired Serono in Jan. 2007, and the new company was renamed Merck Serono S.A.

Manufacture: Efalizumab is produced in a Chinese hamster ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

When GenenTech. transferred production Raptiva from a 2,000-liter tank at Xoma to a 12,000-liter tank at its Vacaville, CA, facilities, tests showed that the resulting purified efalizumab was not the same, even though the same cell lines and conditions were used. FDA required clinical trials to prove comparabilty of the two products, delaying approval by about two years.

FDA class: Biologic BLA

Approvals: Date = 20031027; first approval, BLA

Date = 20050700; BLA supplement; Indication = updated the label to include post-marketing reports of thrombocytopenia and serious infections

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

RAPTIVA (efalizumab) is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Status: A BLA was filed in late Dec. 2002, with a supplemental data amendment in May 2003, for treatment of adults with moderate to severe plaque psoriasis. This included results from two pivotal Phase III clinical trials in over 1,000 patients. FDA granted the application priority review, and approval was granted on Oct. 27, 2003 (approval time = ~.83 years). The product was launched in the U.S. on Nov. 17, 2003. The approval of Raptiva was the second therapeutic approved for psoriasis in 2003 (along with Amevive from Biogen Idec).

Genentech and Xoma had expected to finish filing the BLA in summer 2002. However, pharmacokinetic clinical studies comparing product manufactured by Xoma (used in clinical trials) did not show bioequivalence/comparability with product manufactured in large scale by Genentech. The Genentech product attained a higher serum concentration. This caused a delay in filing. [This demonstrates the potential difficulties in achieving manufacture of a “generic” recombinant protein, even when the companies involved fully collaborated in product development and have considerable experience with recombinant protein manufacture].

Serono filed for European Union approval (MAA) in Feb. 2004, and received approval on Sept. 23, 2004, for treatment of moderate-to-severe chronic plaque psoriasis in patients with inadequate or inappropriate respons to other systemic treatments or phototherapy. Raptiva was the first biopharmaceutical to receive EU approval for psoriasis. On March 14, 2004, Serono received approval of Raptiva in Switzerland. Raptiva is also approved in Switzerland, Australia, Argentina, Mexico and Brazil, and is available in 15 countries (as of 2/2005).

On July 15, 2005, Genentech issued a “Dear Healthcare Professional” letter and changed the product insert/label for Raptiva to warn of the risk of immune-mediated hemolytic anemia, and updated the label to include post-marketing reports of thrombocytopenia and serious infections. Two cases of hemolytic anemia were reported in trials and two from post-marketing studies.

As of Feb. 2006, Raptiva had been approved in 49 countries and was available in over 40 countries.

On Oct. 16, 2008, FDA added a black box warning to the product insert regarding the risk of progressive multifocal leukoencephalopathy" (PML) in patients taking Raptiva, along with warnings regarding bacterial sepsis, viral meningitis, and invasive fungal disease (opportunistic diseases more common in immune suppressed patients). Raptiva’s label was also updated to include data from juvenile animal studies in mice (age equivalent to a 1-14 year old humans) indicating a potential risk for the permanent suppression of the immune system with repeat administration of Raptiva in this age group. Raptiva is not approved for children under 18 years of age. FDA directed Genentech to develop a Risk Evaluation and Mitigation Strategy (REMS) to ensure that patients receive risk information about Raptiva. A Dear Healthcare Provider letter was issued in early October to inform healthcare providers of the first reported case of PML.

In Nov. 2008, Genentech issued a Dear Healthcare Provider letter to inform U.S. dermatologists and neurologists of a 2nd case of progressive multifocal leukoencephalopathy (PML) which resulted in the death of a 73-year old woman who had received Raptiva for approximately four years for treatment of chronic plaque psoriasis. B.

On Feb. 19, 2009, FDA issued a warning that use of the Raptiva [efalizumab] "poses the risk of developing a rare and often fatal brain infection known as progressive multifocal leukoencephalopathy" (PML)." FDA recommended that healthcare professionals carefully monitor patients on Raptiva, as well as those who have discontinued the drug, for any signs or symptoms of neurologic disease, and that they periodically reassess the benefits of continued treatment. Three patients taking Raptiva were believed to have died of PML, "a known risk with the skin-clearing treatment." FDA repoted a possible fourth case of PML. Two of the patients with confirmed PML and one patient with possible PML died. All the cases had been reported in the last six months. [PML is the same disease that has been linked to the multiple sclerosis therapeutic Tysabri. PML is caused by a typically harmless virus that almost everybody carries (often referred to as JC virus). In patients' whose immune system is weakened, the virus can attack the myelin, or white matter, that surrounds and protects brain cells].

On Feb. 19, 2009, the European Medicines Agency (EMEA), EU, recommended a ban on marketing Raptiva. Raptiva was subsequently taken off the market in European countries.

On April 8, 2009, Genentech withdrew Raptiva from the U.S. market, based on the association of Raptiva with an increased risk of progressive multifocal leukoencephalopathy (PML).

In June 2009, Merck Serono withdrew all remaining Raptiva from European Union countries (due to PML).     

Tech. transfer: See the “Tech. transfer (rDNA)” section of the Monoclonal Antibodies entry (#300) for discussion of the complex patenting, licensing, cross-licensing and patent disputes concerning humanized recombinant monoclonal antibodies. This includes discussion of humanized recombinant monoclonal antibody technologies developed by Genentech, Protein Design Labs. (PDL), and other companies, including Genentech’s broad “New Cabilly” patent (cross-licensed with Celltech Group) providing U.S. patent protection into 2018.

Monoclonal antibody humanization technology for Raptiva was nonexclusively licensed from Protein Design Labs., Inc. (PDL). Based on a Jan. 2003 CIBC World Markets Report on PDL, the company receives royalties of 3%. As described in the Monoclonal Antibodies entry (#300), on Dec. 22, 2003, Genentech and PDL “conclusively” resolved their disputes concerning PDL’s recombinant humanized monoclonal antibody design/construction technology (and three humanized antibodies from Genentech). This dispute included Raptiva, with Genentech refusing to pay PDL royalties for this and other products. Under their new agreement, PDL would receive licensing fees of $1 million for each of Genentech’s licensed recombinant antibody products; including Raptiva; and PDL would receive royalties on Genentech’s sales, including for 2003 sales of Raptiva. In exchange, PDL agreed to royalty rate reductions for certain high levels of aggregate sales of Genentech products.

Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. These patents and licenses expired in 2000, but Columbia received a new 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 technologies. Amgen received nonexclusive licenses to Genentech’s Cabilly II and other patents. Neither company will discuss what Genentech received in exchange. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.

Trials: Raptiva has been extensively studied in 13 psoriasis clinical trials with a total of 2,762 subjects (the largest clinical database for any biologic therapy in psoriasis). These trials followed 2,400 patients treated with Raptiva for 12 weeks, 904 patients for 24 weeks, and 218 patients treated for 1 year. Raptiva was evaluated in four randomized, double-blind, placebo-controlled studies in adults with chronic (>6 months), stable, plaque psoriasis, who had a minimum body surface area involvement of 10% and who were candidates for or had previously received systemic therapy or phototherapy. In these studies, 54–70% of patients had previously received systemic therapy or phototherapy (PUVA) for psoriasis. Patients were randomized to receive doses of 1 mg/kg or 2 mg/kg of Raptiva or placebo once a week for 12 weeks. Patients randomized to Raptiva received 0.7 mg/kg as the first dose prior to receiving the full assigned dose in subsequent weeks. During the studies, patients could receive concomitant low-potency topical steroids. No other psoriasis therapies were allowed during the treatment or follow-up period. Patients were evaluated using the Psoriasis Area and Severity Index (PASI), a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of the psoriatic changes within the affected regions (erythema, infiltration/plaque thickness, and desquamation). Both treatment groups in all four studies had baseline median PASI scores of 17, and baseline median body surface area involvement ranging between 22–28%. Compared with placebo, more patients randomized to Raptiva had at least a 75% reduction from baseline PASI score (PASI-75) 1 week after the 12-week treatment period. The 2 mg/kg dosage was not superior to 1 mg/kg.

In Feb. 2005, Genentech reported final results from a 3-year Phase IIIb open-label study of continuous treatment with Raptiva in adults with moderate-to- severe chronic plaque psoriasis. Sustained improvement in psoriasis symptoms and safety were observed throughout three years. At 36 months, of the 151 patients who completed the study, 75% (113/151) showed a ≥75% or from baseline PASI (PASI 75); and 41% (62/151) showed a ≥90 PASI. Results from a prior 24-week study were reported in the Jan. 2005 issue of Archives of Dermatology.

Raptiva was tested in Phase II trials for moderate-to-severe rheumatoid arthritis, potentially a multi-billion dollar market. However, Raptiva was found to not be effective, and trials were halted in July 2003.

Genentech has been conducting trials to extend the indications: for Raptiva. In late 2003, positive results, particularly prolonging of remission, were reported from the first Phase III trial with Rituxan in previously untreated (frontline) patients with indolent non-Hodgkin’s lymphoma (NHL), and from a Phase III study in combination with chemotherapy as a front-line and maintenance therapy in the treatment of newly diagnosed, diffuse, large, B-cell or aggressive NHL. In March 2004, it was reported that Raptiva failed to show significant benefit in a Phase II trial for treatment of psoriatic arthritis (associated with rheumatoid arthritis). This trial began prior to availability of results from the rheumatoid arthritis trial.

In Oct. 2005, Serono reported results from the multicenter, multinational CLEAR trial evaluating the safety and efficacy of Raptiva in patients with moderate-to-severe psoriasis. Extended treatment of Raptiva patients who did not attain PASI 75 response with 12 weeks of therapy resulted in maintenance and improvement of response. Among Raptiva recipients who showed improvement after 12 weeks, nearly half attained a PASI 75 response at the end of extended treatment. Among patients who had a PGA rating of “good” at week 12, 43.9% had attained a rating of “excellent” or “cleared” by the end of the extended 24-week treatment period. The safety profile of Raptiva was consistent with previous experience, and no new safety concerns were identified with continued treatment or retreatment.

In Feb. 2007, results from a post-approval Phase IV study of Raptiva showed statistically significant improvement in patients with chronic moderate-to-severe plaque psoriasis involving the hands and feet. This 12-week study was the first randomized, double blind, placebo-controlled trial to evaluate a biologic agent in the treatment of this uniquely challenged subpopulation of psoriasis patients. . Plaque psoriasis on the hands and feet has been historically difficult to treat. Raptiva was concluded to be an effective treatment option.

In March 2007, following-up on concerns of anemia as an adverse effect (e.g., FDA having issued a warning letter; see the Status section above), Merck Serono began a post-marketing study in Europe in 7,000 adult patients with moderate to severe plaque psoriasis is to gather additional long-term safety data.

Medical: The recommended dose of Raptiva is a single 0.7 mg/kg subcutaneous (SC) conditioning dose followed by weekly SC doses of 1 mg/kg (maximum single dose not to exceed a total of 200 mg). Sites for injection include thigh, abdomen, buttocks, or upper arm. Injection sites should be rotated. Although intended for use under the guidance and supervision of a physician, if it is determined to be appropriate, patients may self-inject Raptiva after proper training and with medical follow-up. As an immunosuppressive agent, Raptiva may increase the risk of infection and reactivate latent, chronic infections.

Disease: Psoriasis is estimated to affect about 4.5 million persons in the U.S., and about 7 million in Europe.

Market: Note, Raptiva was withdrawn from marketing in early 2009. As a result of the phased withdrawal and resultant excess Raptiva inventories, Genentech reported a one-time cost-of-sales charge (loss) of ~$125 million in its results for the first half of 2009.

The 2007 Average Wholesale Price (AWP) is $432.95/125 mg vial, and $1,731.810/package of four vials (Red Book, 2007). Treatment with Raptiva is reported to generally costs over $14,000/year.

Total worldwide 2008 sales of Raptiva are roughly estimated by the author to be much the same as estimtaed for 2007, about $160 million.

Total worldwide sales of Raptiva were $159.7 million in 2006, $112.6 million in 2005, $56.3 million in 2004; and $1.4 million in 2003 (partial year, launched in Nov.).

Total U.S. Raptiva sales by Genentech were $108 million in 2008; $107 million in 2007, $89.8 million in 2006, $79.2 million in 2005, $52.4 million in 2004, and $1.4 million in 2003. Total sales of outside of the U.S. reported by Serono were $69.9 million in 2006, $33.4 million in 2005, and $3.9 million in 2004

In June 2004, Serono reiterated its projection that total Raptiva sales will eventually peak at $400 million. Serono in Feb. 2003 estimated peak annual sales will reach $250 million/year in Europe and $150 million in Asia (while many analysts forecasted peak Asian sales of $50 million/year). Serono’s forecast presumed it would obtain approval for moderate to severe psoriasis in Europe and most of its other territories by in 2004 (with EU approval granted in Sept. 2004).

In July 2006, National Institute for Health and Clinical Excellence (NICE) issued guidance supporting the use of Raptiva (and Enbrel) to treat adult patients with severe plaque psoriasis lacking other alternatives. NICE provides cost-benefit studies used by the U.K. National Health Service. With this ruling, a major potential block for access to Raptiva in the U.K. was removed.

Competition: Some analysts project the market for recombinant psoriasis therapeutics to reach $5-7 billion in several years. Raptiva was the second therapeutic approved for treatment of psoriasis in 2003, with Amevive from Biogen Idec approved in Jan. 2003. For approved and off-label psoriasis-related indications:, Raptiva ‘s competition now includes Enbrel from Wyeth. Humira from Abbott Labs. and Remicade from Centocor/J&J, both TNF monoclonal antibodies, are showing promise for psoriasis indications:, and may further increase competition. With its wide marketing base and already having attained blockbuster status, Enbrel is serious competition for Raptiva.

The $14,000 annual cost for Raptiva treatment may be compared with Amevive costing $7,000-10,000 for a 12-week course of treatment lasting a reported average seven months. In this context, Genentech considers Raptiva to be priced “competitively.” Many analysts expect Raptiva to outsell Amevive, since it acts more quickly, does not require repeated physician/clinic visits, and Genentech can field a larger marketing and detailing effort. Biogen Idec asserts that Amevive is more convenient after the initial 12-week induction period.

In Europe, Raptiva has not had to contend with competition from Amevive (see related entry), since Biogen (now Biogen Idec) withdrew its European filing for approval in Feb. 2003, and stated it could take several years to generate new data and refile an new application.