Status - taken off U.S. market, then allowed to reenter with restrictions; marketed in EU

Organizations involved:

Biogen Idec – Manuf.; R&D; Tech.; USA mark.

Biogen Corp. – Former

Elan Corporation, plc – Former

Athena Neurosciences, Inc. – R&D; Tech.; Former

Columbia University – Tech.; Patent dispute

PDL Biopharma, Inc. (PDL) – Tech.

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

Description: Tysabri (Antegren) is an aqueous formulation of natalizumab, a recombinant humanized form of murine (mouse) 21.6 IgG monoclonal antibody expressed in transformed murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions (CDR) of a murine antibody that binds with specificity for integrin alpha(4)beta(1) integrin (alpha4b1-integrin or VLA-4) receptors and alpha(4)beta(7) integrin receptors on certain activated lymphocytes, including activated monocytes and CD4+ T-lymphocytes (T-cells). By binding these receptors, natalizumab acts as an alpha-4 integrin receptor antagonist. Natalizumab has a molecular weight of 149 kDa.

Tysabri is packaged in single-dose ials for intravenous (IV) infusion. Each 15 mL dose contains 300 mg natalizumab; 123 mg sodium chloride; 17.0 mg sodium phosphate monobasic monohydrate; 7.24 mg sodium phosphate dibasic heptahydrate; 3.0 mg polysorbate 80 (Tween 80), in Water for Injection at pH 6.1. Vials are stored at 2-8˚C (refrigerated).

Nomenclature: Integrin Mab, rDNA [BIO]; Tysabri [TR assigned to Elan]; Antegren [TR former]; Natalizumab [FDA USAN]; integrin alpha(4) humanized monoclonal antibody, recombinant [SY]; VLA-4 receptor monoclonal antibody [SY]; NDC 59075-730-15 [NDC]

Biological.: Blocking integrin alpha(4) receptors prevents the lymphocytes from contributing to inflammation by preventing their leaving the bloodstream, activation, and migration into chronic locally inflamed tissue where they can cause inflammation, as occurs in a variety of autoimmune inflammatory diseases e.g., multiple sclerosis and Crohn’s disease. This includes interfering with the process that enables white blood cells (leukocytes), particularly lymphocytes, to enter the central nervous system (CNS) from the blood (i.e., cross the blood-brain barrier). The blood-brain barrier consists of two layers. The outer endothelium is a single layer of cells that line the blood vessels that supply the central nervous system. This endothelium layer is similar to the endothelium layer on blood vessels. In response to cytokines expressed by T-lymphocytes (T-cells) already inside the CNS, the endothelial cells express adhesion glycoproteins on their surface that attach to lymphocytes passing through the blood. One of these adhesion molecules, VLA-4 (Very Late Antigen 4), sticks to another adhesion molecule expressed on the surface of lymphocytes, alpha-4-integrin. In multiple sclerosis (MS), activated lymphocytes migrate to the brain where they inflame the myelin sheaths that protect the nerve cells. In 1992, Elan scientists first described a role for alpha-4 integrin in an animal model of MS. (Yednock et al., Nature, vol. 356, pp. 63-66). Interfering with the process by which lymphocytes are able to enter the central nervous system reduces the inflammation-related damage that these cells cause in MS (and Crohn’s disease).

Lymphocyte infiltration into the intestinal tract in Crohn’s disease is mediated by the interaction between alpha(4) integrin expressed on lymphocytes and its ligand, mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1), expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Alpha(4)beta(7) integrin (a receptor on lymphocytes that natalizumab binds) interacts with MAdCAM adhesion receptors, making Tysabri potentially useful for treatment of Crohn’s disease. In Crohn’s disease patients, the goal is to prevent inflammation in the gastrointestinal tract. By inhibiting VLA-4 interactions with VCAM and fibronectin as well as integrin alpha(4)beta(7) receptor interactions with MadCAM, natalizumab may also act to reduce inflammation in joints associated with rheumatoid arthritis.

Based on its mechanism of activity, progressive multifocal leukoencephalopathy (PML) is a potential serious adverse reaction to Tysabri use. As discussed in the Status section, multiple cased of PML and associated deaths have resulted in suspension of trials and are serious affecting sales. PMS results from activation of latent JC virus, which is common in the general population but rarely results in disease, e.g., about 80% of persons are infected by age 14. PML/JC virus infection primarily affects oligodendrocytes, the cells that produce myelin that surround and serves to insulate nerve fiber and facilitate the transmission of nerve impulses. With Tysabri’s efficacy for MS based on its ability to inhibit the formation of new lesions by inhibiting inflammatory cells, particularly lymphocytes, from entering the brain and central nervous system (CNS), this may increase the risk for opportunistic infections and malignancies in the CNS. With PMS/JC virus infection progressing very slowly, it may take months or years for Tysabri-associated cases to become evident. In the worst case, a significant portion of treated patients could develop PML. Another theoretical factor or cause of PML may be Avonex (interferon beta) reactivation of JC virus infection, causing it to migrate from the kidney to the CNS

Companies.: Tysabri was originally developed by Athena Neurosciences, Inc., which was acquired by Elan Corp (acquired in 2013 by Perrigo). Elan partnered with Biogen Corp., now Biogen Idec, in 2000 to complete the product’s development and for large-scale manufacture and co-marketing. The two companies share profits from Tysabri equally in all indications:. Biogen Idec markets Tysabri in the U.S., and Elan markets it internationally. [However, the product insert reports Elan as the U.S. distributor].

Tysabri is manufactured by Biogen Idec at its Davis Avenue facilities in Research Triangle Park, NC, in a new $50 million, dedicated, 42,000-sq.-ft. expansion of one of the two manufacturing plants at the site. Biogen shortened Tysabri’s development by going from producing clinical supplies to 15,000-Liter batches, skipping the typical intermediate step of making ~2,000 L batches.

Biogen Idec constructed a new large-scale facility in Oceanside, CA, expected to substantially increase Tysabri manufacturing capacity. However, not needing this capacity, in June 2005, Biogen Idec sold the facility to Genentech for $408 million (taking a loss of ~$50 million).

On Aug 6, 2009, Elan Corp. filed suit against Biogen Idec Inc. in federal court in New York seeking declaratory and injunctive relief that certain aspects of Elan's recent transaction with affiliates of Johnson & Johnson comply with Elan's Collaboration Agreement with Biogen Idec for the development and marketing of Tysabri. In early Sept. 2009, the U.S. District Court for the Southern District of New York ruled in favor of Biogen Idec. In Sept. 2009, Elan Corp. confirmed it would receive $115 million less than previously agreed from Johnson & Johnson (J&J) as part of a revised deal designed to save its existing collaboration with Biogen Idec for Tysabri. Elan had closed a deal with Johnson & Johnson which would give J&J all the assets and rights related to its Alzheimer's therapeutics. Biogen Idec sued, alleging that deal represented a material breach of the Tysabri deal. In order not to forfeit its own rights to Tysabri and complete the deal with J&J, Elan was forced to revise its pact with J&J. As a result, Elan received just $885 million instead of the origianal $1 billion from J&J in exchange for 18.4% of its shares. The near-term loss of $115 million would likely be offset by even a single quarter's profits from sales of Tysabri.

In April 2013, Biogen-Idec paid Elan $3.3 billion (plus will pay contingent royalty payments ranging from 18-25% beginning in 2014) to acquire its share and gain full control of Tysabri.

FDA class: Biologic BLA

Approvals: Date = 20041123; original BLA

Date = 20060605; BLA supplement; Indication = market reentry allowed, with multiple restrictions

Date = 20080114; BLA supplement; Indication = approval for for the treatment of moderate-to-severe Crohn’s disease in patients with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies.

Date = 20090416; supplemental BLA; Indication = approval of new high titer manufacturing process

Date = 20091109; supplemental BLA; Indication =changes to the label to reflect the increased risk of PML when taken over a longer period of time, noting that “Risk of developing progressive multifocal leukoencephalopathy increases with longer treatment duration, and for patients treated for 24 to 36 months is generally similar to the rates seen in clinical trials. There is limited experience beyond three years of treatment”.

Date = 20120120; supplemental BLA; Indication = medical device approval of Quest Diagnostics' Stratify JCV companion JC virus infection (i.e., detection of JC virus antibodies) diagnostic test to reduce the risk for those patients who are particularly susceptible to PML; Separately, FDA has revised Tysabri's label with new language explaining that patients who test positive for the John Cunningham (JC) virus are more likely to develop PML. FDA warned that the test shouldn't be used alone in making a clinical decision about the risks and benefits of continuing on natalizumab treatment, and that it is not diagnostic of PML. Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 7/2012]:

1.1 Multiple Sclerosis (MS)

TYSABRI is an integrin receptor antagonist indicated for treatment of: Multiple Sclerosis (MS)
As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy.)
Crohn’s Disease (CD) )
Inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α.)
Important Limitations:)
In CD, TYSABRI should not be used in combination with immunosuppressants or inhibitors of TNF-α.

Status: In Feb. 2004, Biogen Idec and Elan announced that they would submit (and that FDA agreed to accept) a BLA for Tysabri for treatment of multiple sclerosis (MS) using one-year data (rather than waiting for 2-year data, as originally planned) from their two ongoing 2-year Phase III trials (see “Trials” section below). All prior FDA approvals of MS therapeutics involved two-year trials. A BLA for acellerated approval for MS was filed on May 25, 2004, and accepted for filing with priority review (6 month approval target date) on July 26. Accelerated approval was granted in Nov. 23, 2004, based on one year data from two ongoing two-year Phase III trials – AFFIRM and SENTINEL. This approval was somewhat sooner than many had expected. With its U.S. approval, the trade name “Tysabri” was adopted (in place of Antegren).

An MAA for European Union approval for MS was filed in June 2004. This included one-year data from two ongoing 2-year Phase III trials in about 2,100 patients. On Sept. 29, 2004, Elan submitted a MAA for approval of Tysabri for treatment for Crohn’s disease (based on ENACT-II trial data).

On Feb. 28, 2005, Biogen and Elan halted sales of Tysabri (pulled it off the market) and halted (temporarily suspended) their two ongoing Phase III trials of Tysabri after two cases of progressive multifocal leukoencephalopathy (PML) were identified in patients in the Phase III AFFIRM trial for MS receiving Tysabri plus Avonex, with one of the patients having died from this rare viral brain infection. Tysabri’s official approval status was not modified. At the time, with product launch in late Nov. 2004, Tysabri had already been used in over 5,000 patients. In late March, analysis of Phase III trial data resulted in a case of malignant astrocytoma being revised to a diagnosis of PML (i.e., a third caes of PML was reported). This patient, who died in Dec. 2003, had received Tysabri monotherapy. Biogen and Elan went back and reviewed existing MRIs for early signs of PML in other patients in Tysabri trials; performed physical exams and new MRIs on each patient in clinical trials; and further studied possible links between PML and Tysabri.

On Sept. 26, 2005, Biogen Idec and Elan submitted a supplemental BLA to the FDA seeking reentry of Tysabri into the U.S. market. FDA granted the BLA priority peview. The companies also submitted a similar application to the European Union. These were filed after an independent study of over 3,000 patients having received Tysabri reported no evidence of new cases of PML. Results from this study were published in the March 2, 2006, issue of the New England Journal of Medicine. The sBLA included results from this study, a revised label and risk management plan, and two-year data from the AFFIRM Phase III monotherapy trial and the SENTINEL Phase III trial of Tysabri plus interferon beta-1a (Avonex).

On Feb. 15, 2006, FDA removed the hold on clinical trial dosing with Tysabri, allowing trials to resume. FDA primarily based its decsion on having observed no additional deaths due to PML. Biogen Idec and Elan subsequently started an open-label, international safety extension study of Tysabri enrollling patients from prior Phase III MS trials. The results from this trial formed the basis for the later reapproval of Tysabri.

In March 2006, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 7-5 to support reintroduction of Tysabri as a first-line therapy for relapsing multiple sclerosis (MS) in conjunction with a strict risk management plan. The committee voted unanimously against allowing market reentry for non-relapsing forms of MS and also voted against co-administration of Tysabri with other approved chronic MS therapeutics. On March 22, 2006, FDA announced that the review decision target (PDUFA) date regarding returning Tysabri to the market was delayed another 90 days from March 29 to June 28.

On June 5, 2006, FDA approved the supplemental BLA allowing reentry of Tysabri into the U.S. market as monotherapy for relapsing forms of multiple sclerosis (MS) to slow the progression of disability and reduce the frequency of clinical relapses. The approval included revised labeling with enhanced safety warnings; and a risk management plan (TOUCH Prescribing Program; mandatory for patients) designed to inform physicians and patients of the benefits and risks of Tysabri treatment and minimize potential risk of PML. Tysabri was (re)launched in the U.S. on July 24, 2006. In making its the rare decision to allow a withdrawn product back onto the market, FDA was influenced by calls from patients who said they were willing to take the risk of contracting PML, because of the potential benefits of Tysabri.

The TOUCH Prescribing Program in the U.S. includes revised labeling with a prominent boxed warning of the risk of PML; warnings against concurrent use with chronic immunosuppressant or immunomodulatory therapies, and by patients who are immunocompromised due to HIV, hematological malignancies, organ transplants or immunosuppressive therapies; mandatory enrollment for all prescribers, central pharmacies, infusion centers and patients who wish to prescribe, distribute, infuse, or receive, respectively, Tysabri; controlled, centralized distribution only to authorized infusion centers; FDA review of educational tools for patients and physicians, including a patient medication guide, TOUCH enrollment form and a monthly pre-infusion checklist; ongoing assessment of PML risk and overall safety, including regular imaging tests to check for PML; and a 5,000 patient cohort observational study over five years, the TYSABRI Global Observation Program in Safety (TYGRIS).

Because of the increased risk of PML, after its FDA reapproval, Tysabri monotherapy is only “generally recommended” for patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies. Some debate whether this means that Tysabri lost its original approval as a first-line therapy.

In March 2006, the Europe the Committee on Proprietary Medicinal Products for Human Use (CHMP), European Union (EU), concluded that Tysabri should return to the market. On June, 29, 2006, the MAA was approved for treatment of relapsing remitting multiple sclerosis (MS) patients for the purpose of delaying the progress of disability and reduction of the frequency of relapses. This was Tysabri’s first approval in the EU (with all of its problems with PML occurring in the U.S.).

On Dec. 15, 2006, Biogen-Idec and Elan jointly filed a supplemental BLA seeking approval of Tysabri for treatment of moderately to severely active Crohn’s disease, based primarily on three Phase III trials of Tysabri as both an induction and maintenance therapy. A related supplemental MAA had previously been filed for European Union approval. The Biogen-Idec CEO conceded that Tysabri is unlikely to receive European Union approval for Crohn’s disease, with an additional trial likely to be required, which would take years. However, Biogen-Idec and Elan filed for U.S. approval for Crohn’s disease largely based on Tysabri’s induction of remissions. However, the minimal pattern of Tysabri in terms of PML suggest an increased risk in patients receiving immune suppressing drugs or otherwise with compromised immune systems, likely making approval for Crohn’s unlikely or difficult.

On May 3, 2007, Biogen Idec reported to FDA that there have been no new cases of PML associated with Tysabri since it was allowed to reenter the U.S. market.

In July 2007, the Committee for Medicinal Products for Human Use (CHMP), EMEA, European Union (EU), ruled that the benefits of using Tysabri for Crohn’s disease did not outweigh the risks, and that there was “insufficient evidence” of its effectiveness for the disease, along with concerns over potentially serious side effects, including PML. Elan and Biogen Idec promptly initiated an appeal of this supplemental MAA rejection.

On July 31, 2007, the Gastrointestinal Drugs Advisory Committee and Drug Safety and the Risk Management Advisory Committee jointly reviewed Tysabri for the treatment of Crohn’s disease. The members voted voted 12 in favor to 3 opposed, with 2 abstaining, to recommend approval of Tysabri for treatment for moderate-to-severe Crohn’s disease in patients having failed tumor necrosis factor inhibitor treatment and not on immunosuppressive therapy (a narrower indication than sought by Biogen Idec and Elan), pending finalization of an appropriate risk management plan.

In early Oct. 2007, FDA announced a three month delay in ruling on approval of Tysabri for Crohn's disease, with a new PDUFA date of Jan. 13, 2008.

In Nov. 2007, the CHMP, EMEA, European Union (EU), adopted a negative opinion on the marketing authorization for Tysabri for treatment for Crohn's disease. This decision followed the appeal filed by Biogen Idec and Elan of a previous negative opinion adopted by the CHMP.

On Jan. 14, 2008, Tysabri received FDA approval for the treatment of moderate-to-severe Crohn’s disease in patients with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies (Humira and Remicade). Crohn's disease patients must be enrolled in a special restricted distribution program called the Crohn's Disease–Tysabri Outreach Unified Commitment to Health (CD TOUCH) Prescribing Program. Patients, prescribers, pharmacies, and infusion centers must all be enrolled in CD-TOUCH and agree to comply with the company's strict monitoring guidelines; and they must participate in an extensive educational program to inform people about the risks of Tysabri. Under CD-TOUCH, health care providers evaluate Crohn's disease patients after three months of treatment to determine if they have improved on Tysabri. If not, patients should discontinue treatment.

In Jan. 2008, with its approval for Crohn's disease, the product insert/labeling for Tysabri was updated to include information about risks of liver damage. A letter was sent to physicians in Feb. 2008.

In Aug. 2008, Tysabri had received approval in the U.S., European Union, Switzerland, Canada, Australia and Israel.

On March 20, 2008, EMEA/EU ruled that that warnings about liver injury must be added to the product information for Tysabri.

In Aug. 2008, FDA informed healthcare professionals of two new cases of progressive multifocal leukoencephalopathy (PML) in European patients receiving Tysabri monotherapy for MS for more than one year. Previous PML cases in patients with MS were seen in combination with other immunomodulators. At this time,~39,000 patients had received treatment with Tysabri worldwide, with ~12,000 patients receiving treatment for a least one year. No new cases had been seen in the U.S., where about 7,500 patients have received the drug for greater than one year and ~3,300 patients have received the drug for at least 1.5 years. The FDA still believed that Tysabri monotherapy may confer a lower risk of PML than when Tysabri is used with other immunomodulators . Prescribing information for Tysabri was revised to include information informing prescribers and patients that cases of PML have occurred in patients taking Tysabri as monotherapy.

In Sept. 2009, the U.S Securities and Exchange Commission (SEC) subpoenaed Elan in connection with two events: its July 31, 2008, announcement of two cases of PML in patients taking its multiple sclerosis drug Tysabri (and its release two days earlier of data from a clinical study of its experimental drug for Alzheimer's disease, bapineuzumab).

In Oct. 2009, FDA issued a notice that from July 2006, (when Tysabri marketing resumed) to Sept. 8, 2009, 13 reported cases of Tysabri-related PML were confirmed worldwide in patients being treated for MS with Tysabri monotherapy. There had been no postmarketing reports of PML in patients treated with Tysabri for Crohn’s disease. Less than 2% of Tysabri use in the U.S. has been in patients with Crohn's disease. Based on available data from the U.S. and outside of the U.S., the current rate of PML in patients who have received at least 24 infusions was reported to range from 0.4 to 1.3 per 1,000 patients. The risk for developing PML appeared to increase with the number of Tysabri infusions received.

In Oct. 2009, the Committee for Medicinal Products for Human Use (CMPH), EMA, European Union, began a review of Tysabri safety after the report of the 23rd patient developing PML. The last time Biogen Idec had provided an update on the number of PML cases was in July, when it said 11 cases had been reported. Later, a presentation by a researcher at a medical conference revealed two more cases, bringing the total to 13. Biogen Idec stopped updating investors on the number of PML cases at the end of July, saying it wanted to focus on the drug's benefits, and would update the medical community at scientific meetings.

In Dec. 2008, Biogen Idec received European Union approval for Tysabri manufacture using a new higher titer (yield) process expected to increase yield by 400%.

In April 2009, Biogen Idec received FDA approval for Tysabri manufacture using its new higher titer process. Biogen Idec failed to respond to the author's inquiries regarding the new process.

In late 2009, it was noted that a disproportionate number of PML cases had occurred in Germany. Oversight isn't is not as rigorous there as it is in the U.S., where Tysabri use is governed by a strict risk-management program. By contrast, European distribution goes largely unrestricted. Also, Germany has been accused of being lax about making sure patients get completely free of other immunosuppressants before going on Tysabri, among other things. Biogen Idec was working with German clinics and academic medical centers to change that.

In Jan. 2010, Committee for Medicinal Products for Human Use (CHMP), EMA, European Union, identified 31 cases of progressive multifocal leukoencephalopathy (PML) brain infection in patients taking Tysabri and recommended new measures for dealing with its risks. Of the 31 cases worldwide, 23 patients had been taking Tysabri for more than two years -- roughly one case of PML for every 1,000 patients treated for two years. This rate was consistent with the risk noted in the insert/labeling. However, CHMP said the benefits of Tysabri continued to outweigh risks for patients with highly active relapsing-remitting multiple sclerosis. Recommendations included updating prescribing information about the increase in the risk of PML after two years of treatment, and providing additional advice on how to manage patients who show signs of PML. CHMP/EMA also recommended that forms be signed by patients at the beginning of treatment with Tysabri, and again after two years of treatment.

In Jan 2010, Biogen Idec Inc. announced it would communicate with U.S. doctors once a month on the occurrence of new cases of a rare brain infection in patients using Tysabri, as the biotech firm strived to find the right balance in keeping the medical and financial communities updated on that number. The situation has been closely watched because Tysabri was previously pulled from the market because of its association with progressive multifocal leukoencephalopathy (PML). Biogen Idec updates physicians mid-month and provides information through a password-protected Web site. Investors can get the same information from Investor Relations, although the company will not be posting it on a public Web site or making announcements. Patient Services provides Tysabri users with information upon request, although not with the level of detail given to physicians, or even to investors.

On Feb. 10, 2010, FDA notified U.S. healthcare professionals and patients that the risk of developing progressive multifocal leukoencephalopathy (PML) increases with the number of Tysabri infusions received. This was based on reports of 31 confirmed cases of PML received by the FDA as of January 21, 2010,which would now be included in the Tysabri drug label and patient Medication Guide. Information about the occurrence of Immune Reconstitution Inflammatory Syndrome (IRIS) in patients who have developed PML and subsequently discontinued Tysabri wa also added to the drug label. IRIS is a rare condition characterized by a severe inflammatory response that can occur during or following immune system recovery, causing an unexpected decline in a patient’s condition after return of immune function. FDA asserted that the clinical benefits of Tysabri continued to outweigh the potential risks. Revisions to the drug label and patient Medication Guide, with the continued use of the TOUCH Prescribing Program, were intended to maximize the safe use of Tysabri and the identification of new PML cases.

In Feb. 2011, 10 more PML cases and 4 more deaths were reported, bringing the total number of confirmed cases to 95 and deaths to 20 since Tysabri was reintroduced into the market in July of 2007. Biogen-Idec reported the overall rate of PML cases per 1,000 patients has edged slightly higher to 1.16, up from 1.0 in Nov. 2010.

In April 2011, FDA reported that the risk for PML appears highest during the third year of treatment, with PML occurring in an estimated 1.5 per 1,000 patients treated with Tysabri during months 25 to 36. The PML risk was 0.3 per 1,000 patients during the first two years of treatment. After three years, the rate was 0.9 per 1,000. Limited data are available beyond four years. This data was added to product insert.

On June 11, 2011, EMA/EU approved the inclusion of anti-JC virus (JCV) antibody status as an additional factor to aid in stratifying patients at risk for developing progressive multifocal leukoencephalopathy (PML) in the Summary of Product Characteristics (SPC) for TYSABRI. In addition, as part of a standard review process, the EC concluded the quality, safety and efficacy of TYSABRI continue to be adequately demonstrated and renewed the EU five-year MAA. The new SPC language states that patients who are anti-JCV antibody positive are at an increased risk of developing PML compared to patients who are anti-JCV antibody negative. Recent studies indicated that irrespective of MS treatment, approximately 55% of MS patients are anti-JCV antibody positive. The SPC language also states that patients who are anti-JCV antibody positive, have received prior immunosuppressant (IS) therapy, and received treatment with TYSABRI for more than two years have the highest risk of developing PML. The addition of anti-JCV antibody status to previously-established risk factors further stratifies the potential risk of developing PML.

Tech. transfer: U.S. patents cited on the product insert in 2009 were 5,840,299; 6,033,665; 6,602,503; 5,168,062; 5,385,839; and 5,730,978. Patent cited in July 2012 were 5,840,299 and 6,602,503. U.S. 5,840,299, “Humanized antibodies against leukocyte adhesion molecule VLA-4,” assigned to Athena Neurosciences, Inc., now Elan, claims natalizumab and other recombinant humanized monoclonal antibodies (immune globulins) and use for treatment of various autoimmune diseases. U.S. 6,602,503 and 6,602,503, “Recombinant anti-VLA-4 antibody molecules,” assigned to Biogen Idec, claim recombinant humanized alpha4b1-integrin-binding monoclonal antibodies, fragments, vectors and methods of manufacture.

The patents, licensing, cross-licensing and patent disputes concerning humanized recombinant monoclonal antibodies are complex. See the “Tech. transfer” section of the Monoclonal Antibodies entry (#300) for further information. Genentech currently has a very strong position, with its broad “New Cabilly” patent (cross-licensed with similar Celltech Group patents) providing U.S. patent protection into 2018. Protein Design Labs. (PDL) also has a strong patent position concerning recombinant humanized monoclonal antibody design and expression.

Biogen was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Biogen Idec 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.

Biogen-Idec licensed the Queen patents (see the Tech. transfer section of the Monoclonal Antibodies entry) from Protein Design Labs., now PDL Biopharma, Inc. (PDL). The EP patent, EP0451216. expired in (or by) 2010. However, PDL filed a number of SPCs, including one granted in the U.K. extending patent coverage to but December 27, 2014.

Trials: Over 2,800 MS patients have received natalizumab in clinical studies. Very encouraging Phase II trial results were reported in early 2003, with relapse rates reduced by about 50%, compared to 30-35% reduction for existing therapeutic regimens. In this six-month, double-blind, international Phase II trial in 213 patients with relapse-remitting multiple sclerosis (RRMS; secondary progressive MS) reported in Feb. 2003, the mean number of new lesions was 0.7 per patient in the 3 mg/kg Tysabri group and 1.1 in the 6 mg/kg Tysabri group, compared to 9.6 in the placebo group (p <0.001 at both doses). A total of 13 patients in the 3 mg/kg group and 14 patients in the 6 mg/kg group had relapses, compared to 27 patients in the placebo group (p=0.02). Tysabri also reduced by about 90% the formation of brain lesions, which correlate to problems with walking that can necessitate using a wheelchair. Tysabri appeared to be fairly well tolerated. Certain events such as infection, urinary infection, pharyngitis and rash occurred more frequently, but there was no statistical difference compared to placebo. There were also infrequent hypersensitivity reactions. Tysabri is also in two other ongoing Phase II trials for MS treatment, with results expected in early 2005.

Tysabri entered Phase III trials for MS in Sept. 2001. Two Phase III clinical trials evaluating natalizumab in multiple sclerosis are ongoing. The AFFIRM trial is a 2-year, randomized, multi-center, placebo-controlled, double-blind study in ~900 relapsing-remitting MS patients, evaluating the ability of Tysabri to slow the progression of disability in MS and reduce the rate of clinical relapses. The SENTINEL trial is a 2-year, randomized, multi-center, placebo-controlled, double-blind study of ~1,200 patients with relapsing-remitting MS, evaluating the effect of the combination of natalizumab and Avonex vs. Avonex monotherapy in slowing the progression of disability and reducing the rate of clinical relapses. Both trial protocols included a planned one-year analysis of the data (which now will be used to support filing for approval). The primary endpoint for both trials is based on the Expanded Disability Status Scale (EDSS) and relapse rates. The pre-specified primary endpoint of the one-year analyses is relapse rates.

Tysabri was reported in 2003 to effective in Crohn’s disease in a Phase II, randomized, controlled trial. It has also shown promise in a pilot study for treatment of active ulcerative colitis.

In Feb. 2005, two-year data from the AFFIRM trial of Tysabri monotherapy of MS were reported. Tysabri met the trial’s primary endpoint of slowing the progression of disability in this trial of 942 patients with relapsing-remitting multiple sclerosis (RRMS). Tysabri reduced by 42% the risk of disability progression relative to placebo as measured by the Expanded Disability Status Scale (EDSS), and reduced by 67% the rate of clinical relapse. These results were sustained and consistent with previously reported one-year results. Other data, including MRI measures, adverse event profile and immunogenicity, were similar to previously reported results. The incidence of infections in Tysabri-treated and placebo-treated patients was similar, 3.2% and 2.6%, respectively. These included bacterial infections, such as pneumonia and urinary tract infection, which responded appropriately to antibiotics. Tysabri has also been associated with hypersensitivity reactions, including serious systemic reactions that occurred at an incidence of less than 1% in this trial. The trial results were hailed by Biogen Idec as “a major milestone in the treatment of MS.. These two-year data strengthen our belief that TYSABRI will become the leading therapy for MS patients.” This was shortly before PML was associated with Tysabri (and/or Avonex).

Elan and Biogen/Biogen Idec have also conducted several Phase III clinical trials in Crohn’s disease. One Phase III trial, ENACT-I (Evaluation of Natalizumab as Continuous Therapy-1), reported in summer 2003, reflected results of a prior Phase II trial in which Tysabri missed the primary endpoint of induction of remission, primarily due to unexpected efficacy in the placebo arm. [MLM02, an integrin alpha(4)beta(7) monoclonal antibody, from Millennium Pharmaceuticals and Genentech had previously similarly failed to meet its primary endpoint in a Phase II trial]. In ENACT-I, the primary endpoint of “response,” defined by a 70-point decrease in the Crohn’s Disease Activity Index (CDAI) at week 10. was not met, with comparable side effect profiles in the treated and placebo group. In the other Phase III trial, Tysabri met the primary endpoint of reducing flare-ups [a 70-point decrease in the Crohn’s Disease Activity Index (CDAI) at week 10]. Among 72% of those enrolled with evidence of active inflammation, a statistically significant clinical response and improved remission rates were seen at week 10 and other time points compared to placebo, suggesting that Tysabri will be useful in treating immune-mediated diseases, Crohn’s disease, and/or this subset of Crohn’s patients.

A Phase III trial (ENACT-II) may support Tysabri approval for moderate to severe Crohn’s disease maintenance therapy. This double-blind international Phase III is testing Tysabri in 339 patients. Results at one year were reported in fall 2004 showed that 54% of Tysabri patients had a sustained response compared to 20% for the placebo group; and 39% of Tysabri patients maintained clinical remission compared to 15% for the placebo

In Dec. 2004, Biogen Idec and Elan began the STARS (Study of Tysabri Against Rebif in relapsing multiple Sclerosis) trial, a randomized, assessor-blinded, parallel-group international study enrolling more than 1,000 MS patients comparing Tysabri and Rebif (Interferon beta-1a from Meck Serono). Patients receive either Rebif subcutaneously at 44 µg three times per week or Tysabri 300-mg intravenous infusion once every four weeks. The primary endpoint will be the rate of clinical relapses. Secondary endpoints include analysis of the proportion of patients remaining relapse free, MRI brain scans, safety, tolerability and quality of life. Phase II trials of Tysabri for treatment of rheumatoid arthritis began in Feb. 2004.

In June 2005, it was reported that ENCORE, the second Phase III induction trial of Tysabri for the treatment of moderately to severely active Crohn’s Disease in patients with evidence of active inflammation, had met its primary endpoint of clinical response as defined by a 70 point decrease in baseline Crohn’s Disease Activity Index (CDAI) score at both weeks 8 and 12. Encore also met all of its secondary endpoints, including clinical remission (achieving a CDAI score of equal to or less than 150 at both weeks 8 and 12) at both weeks 8 and 12. There were no notable differences in the overall rates of adverse events or serious adverse events between the Tysabri and placebo treatment groups.

In July 2005, two-year results were reported from the SENTINEL Phase III trial of Tysabri plus with Avonex (interferon beta-1a) for relapsing forms of multiple sclerosis (MS). The trial met its two-year primary endpoint of slowing the progression of disability, with the addition of Tysabri to Avonex resulting in a 24% reduction in the risk of disability progression compared to that of Avonex alone. The addition of Tysabri to Avonex also led to a 56% relative reduction in the rate of clinical relapses compared to that provided by Avonex alone. The reduction in relapse rate was statistically significant and sustained over the entire two-year study period. The rate of infection was 1.6 per patient-year in both Avonex plus Tysabri-treated patients and Avonex plus placebo-treated patients. Serious infections occurred in 2.9% of Avonex plus placebo-treated patients and 2.7% of Avonex plus Tysabri-treated patients.

On March 1, 2006, three studies reporting the relative safety and effectiveness of Tysabri were published in the New England Journal of Medicine (a few days before FDA advisory committee hearings on whether to resume sales of Tysabri). Tysabri alone or with standard interferon treatment reduced the rate of relapse by as much as two-thirds after two years and reduced the number of patients whose MS progressed, compared to those on a placebo or interferon-beta alone. In one study of 942 people, nearly twice as many on placebo treatment progressed over two years., while the Tysabri group had 68% fewer relapses. In the second study of 1,171, the rate of relapse was reduced in half when Tysabri was added to interferon-beta. A quarter more patients got worse on interferon alone. An independent committee reported finding no additional cases of PML brain infection in other study volunteers, and estimated the incidence/risk of PML at 1 in 1,000. An accompanying editorial article stated that the studies “confirm that this drug is a significant advance for MS treatment.”

In March 2006, Biogen Idec and Elan restarted an open-label, international safety Phase III extension study of Tysabri in about 1,500 MS patients. Patients ho participated in prior Phase III trials and subsequent safety evaluations will be followed for at least a year/

In April 2006, analysis of Tysabri Phase III multiple sclerosis (MS) studies (AFFIRM and SENTINEL) showed significant effects on pre-specified health-related quality of life (QoL) measures, and also showed a significant impact on additional pre-specified measures of disability progression, including visual and cognitive function. This was in addition to previously reported effects on disability progression, relapse rate and MRI.

In April 17, 2007, issue of Neurology, it was reported that Tysabri is associated with significant reductions in the likelihood of sustained vision loss due to inflammatory demyelination of nerve fibers that connect to the eye. Vision loss is one of the most common and disabling symptoms of MS. Researchers analyzed data from two randomized, double-blind, placebo-controlled, parallel group, Phase III trials involving 2,138 patients with relapsing MS. More than half of the participants received Tysabri every four weeks for two years, while the remaining patients received placebo. Visits were conducted every 12 weeks and visual function testing was performed at each visit. Researchers found vision loss -- a worsening of vision defined as a two-line (10-letter) reduction in letter chart scores -- was reduced by as much as 47% among people taking Tysabri, compared to those taking placebo. Despite vision loss being a common and important cause of disability in MS, these Tysabri trials were the first to test visual function.

In Sept. 2008, Biogen Idec and Elan began the first clinical trial of Tysabri in oncology -- to evaluate the safety and potential anti-tumor activity in patients with relapsed or refractory multiple myeloma.

In Jan. 2009 (end of 2008), Biogen Idec reported, "Cumulatively, in the post-marketing setting: Approximately 48,300 patients have been treated with TYSABRI; and of those patients, approximately 20,000 have received at least one year of TYSABRI therapy, approximately 10,700 patients have received at least 18 months of TYSABRI therapy, and 4,300 patients have received at least 24 months of TYSABRI therapy." Also, "To date, the safety data continues to support a favorable benefit-risk profile for TYSABRI."

In April 2009, results were reported from a study showing that Tysabri promoted regeneration and stabilization of damage done to the myelin sheath, as measured by advanced MRI technology. Damage to the myelin sheath causes the symptoms of multiple sclerosis (MS). T he imaging study, which included a total of 110 subjects, used an advanced MRI technology called the Voxel-Wise MTR to measure lesions and normal brain tissue. The study showed that Tysabri promoted remyelination when compared to those receiving interferon beta-1a IM and normal controls.

Medical: Premedication with an H1 antagonist (e.g., 50 mg of diphenhydramine I.V.) is recommended. Appropriate medical resources for the treatment of severe infusion reactions should be available during infusions.

Tysabri is administered as a monthly infusion, while Avonex (interferon beta from Biogen Idec) is injected intramuscularly once a week for MS. Compared to Rebif, with which Tysabri will compete, Tysabri is lacking in long-term efficacy, disability and safety data, which may slow its adoption.

The most frequently reported serious side effects with Tysabri are infections, severe or life threatening allergic reactions, depression (including thoughts of suicide) and gallbladder problems. In trials, these serious side effects occurred at a rate of 0.8% for serious depression and gallbladder problems, at a rate of 2.1% for serious infections. Common side effects include headache, fatigue, depression, and joint pain.

As discussed in the Status and other sections, cases of progressive multifocal leukoencephalopathy (PML) have been reported among Tysabri recipients having started treatment in clinical trials. The incidence of PML in the general population is 1:200,000, and it generally occurs only in severely immunocompromised patients. However, to date, three PML cases have been confirmed among 3,000 patients having received Tysabri in clinical trials.

Disease: There are ~350,000 individuals diagnosed with MS in the U.S., with 10,000 new cases diagnosed each year. The elapsing-remitting form is the most common form of MS., in which acute symptoms or worsening of neurologic function (referred to as “relapses,” “attacks,” or “exacerbations”) occur intermittently. These symptoms can diminish or disappear for months or years between relapses. Crohn’s disease affects over 500,000 persons in the U.S. For further discussion of MS epidemiology and markets, see the entries for interferon beta products (Avonex and Betaseron) used for MS treatment.

There are an estimated >550,000 patients in major markets (U.S., France, Germany, Italy, Spain, United Kingdom, and Japan) diagnosed with Crohn’s disease.

Market: TYSABRI is available only through registered infusion centers participating in the TOUCH® Prescribing Program.

Total 2012 sales (U.S.) reported by Biogen-Idec were about $1.1 billion.

Total worldwide sales/revenue were $1.6 billion in 2012; $1.5 billion in 2011; $1.23 billion in 2010; $1.06 billion in 2009; $815 million in 2008; $378 million in 2008 (Biogen Idec reporting $343 million). Total 2006 revenue reported by Biogen Idec was $48 million; and 2006 revenue reported by Elan was $38.1 million ($28.2 million in the United States and $9.9 million in the European Union; with the product reentering the market in July). Presumably, total worldwide 2006 revenue (sales) for Tysabri is the sum, $78.2 million. Biogen Idec’ revenue included about $36 million in the U.S., and about $12 million internationally. Total sales/revenue reported by Biogen-Idec were $393 million in 2011; $293 million in 2010; $222 in 2009; 222 million in 2009; $129.4 millin in 2008 and $30.4 million in 2007.

The 2012 supplemental approval for use with a PML risk (JC virus infection) companion diagnostic was heralded at the time as expected increase annual sales by $1-1.5 billion. MS patients clamored for Tysabri when it went on sale, with about 7,000 receiving treatment in the first three months (before it was pulled from the market). Biogen Idec reported sales of $3 million in 2004 (4th quarter).

In March 2005, Biogen and Elan halted all sales and trials with Tysabri after its use, including in combination with Avonex, was associated with a few cases of progressive multifocal leukoencephalopathy (PML) and deaths (see the Status section). Total 2005 sales have been reported to have been only about $1 million.

Even after reintroduction into the market, most physicians will be very hesitant to prescribe Tysabri for other than severe salvage treatment of MS. This could effectively reduce the long-term potential market to the ~150,000 MS patients worldwide failing on their current MS treatments. Some analysts have optimistically reported that 50% market share of MS patients currently failing therapy could still result in sales Tysabri over $500 million/year.

Worldwide 2009 revenue from Tysabri was $1.06 billion. This included $509 million sales in the U.S and $551 million outside of the U.S. Total 2008 revenue was $815 million [a healthy increase, particularly considering concerns over PML].

In 2009, Tysabri achieved "blockbuster" status with more than $1 billion in sales as the number of patients on therapy grew by 30% over the prior year. Based upon data available to Biogen Idec through the TOUCH prescribing program and other third-party sources as of the end of Dec. 2009, the company estimated that approximately 48,800 patients were on commercial and clinical Tysabri therapy worldwide. This included approximately 24,500 on therapy commercially in the U.S.; approximately 23,700 on therapy commercially in the rest of the world; and approximately 600 clinical trial patients. In 2009, Tysabri was approved in more than 45 countries.

As of mid-2011, Approximately 61,500 MS patients were being treated with Tysabri, and an estimated 238 MS patients per week were starting treatment with Tysabri. As of Jan. 2009, approximately 37,600 patients were on commercial and clinical Tysabri therapy worldwide. At the end of 2008, in the U.S., ~20,200 patients were on Tysabri therapy commercially; outside the U.S., ~16,900 patients were on TYSABRI therapy commercially; and in global clinical trials, ~600 patients were on Tysabri therapy. Also according to Biogen Idec, " To date, the safety data continues to support a favorable benefit-risk profile for TYSABRI."

In June 2006, with the reapproval and relaunch of Tysabri after its withdrawal, Biogen Idec/Elan raised its U.S. price by 20% to $2,185 per single-use 300mg vial (administered every 4 weeks) or $28,400/year, up from the $23,500/year. Biogen Idec attributed its price increase to inflation and the additional costs of studies used to support reintroduction of Tysabri.

In July 2007, Biogen Idec and Elan reported that ~14,000 patients were receiving Tysabri worldwide, including ~8,600 in the U.S. receiving prescriptions from 1,800 physicians; ~4,300 patients in Europe; and ~1,000 in clinical trials. Biogen Idec had also reported the worldwide market for MS therapeutics to be ~$3 billion/year and growing.

In Dec. 2006, analysts with Leerink, Swann & Co. projected worldwide sales of ~$150 million in 2006, $474 million in 2007 and over $1 billion in 2008 (achieving blockbuster status).

In Jan. 2006, with the product then off the market and likely facing restrictions when reentering the market, the CEO of Elan stated he expected Tysabri would break even with around 20,000 patients/year on therapy and “We can break even with revenue of around $500 million.” Biogen Idec has the manufacturing capacity to produce Tysabri for 100,000 patients and had been working to increase this to about 300,000 over 2-3 years.

With the product back on the U.S. market and with EU approval, depending on perceptions of longer-term safety and efficacy, Tysabri could still become a leading treatment for multiple sclerosis and achieve blockbuster sales status. About 190,000 MS patients in the U.S. are currently receiving treatment. About 12,500 have been prescribed Tysabri. Many are confident Tysabri will continue to penetrate the MS market. However, safety concerns will hinder Tysabri’s sales and adoption by physicians and patients for quite some time. More cases of PML associated with Tysabri could significantly reduce or kill sales, even if the product were allowed to remain on the market. Tysabri had been hoped to replace monotherapy with beta interferon (e.g., Avonex; see related entry) and copolymer-1 (Copaxone glatiramer from Teva) for treatment of MS.

Illustrating its difficulties in reentering the U.S. MS market, in Oct. 2006, a survey of 63 neurologists conducted by Reuters Primary Research showed that in 2006 Tysabri will be used in less than 1% of MS patients (translating into revenue of under $30 million; rather close to the actual amount). Since July, only 47 of more than 8,500 patients treated by the physicians surveyed had used Tysabri, even though more than 700 patients had discussed using it with their physicians; and >75% of the patients who had used Tysabri prior to its 2005 suspension had decided not to use it since its reintroduction. Changing patient and physicians perceptions and gaining back sales and market share will be difficult.

After Tysabri’s U.S. relaunch, under the TOUCH Prescribing Program, only prescribers, infusion centers and pharmacies associated with infusion centers registered in the TOUCH program are able to prescribe, infuse or distribute Tysabri. Elan has contracted with a single distributor, ICS, a division of AmerisourceBergen Specialty Group, and 12 specialty pharmacies -- Caremark, CuraScript, PharmaCare, PrecisionRx Specialty Solutions, Medmark, BioScrip, McKesson Specialty, Option Care, Cigna Tel-Drug Specialty Pharmacy, Aetna Specialty Pharmacy, Prescription Solutions, and Accredo NovaFactor. ICS and the 12 specialty pharmacies have been trained on the TOUCH Prescribing Program and are obligated to follow the requirements of the program in order to purchase and distribute Tysabri to authorized infusion sites and central pharmacies.

In Aug. 2007, National Institute for Health and Clinical Excellence (NICE), U.K., which rules on cost-benefit for the U.K. National Health Service, reversed an earlier ruling and supported use of Tysabri for treatment of highly active relapsing-remitting multiple sclerosis, meaning the Tysabri will be reimbursed in the U.K. Tysabri is the first treatment for MS to be recommended by NICE, which currently does no recommend beta interferon or copaxone (glatiramer acetate) as being cost-effective for MS.