Medications that slow or stopthe progression of multiplesclerosis (MS) are difficult tocome by?so difficult, in fact, that only5 other such disease-modifying agentswere available in the United Stateswhen the FDA licensed Biogen Idecand Elan's natalizumab (Tysabri) inNovember 2004 (Table 1).1
The FDA had moved quickly onTysabri after receiving preliminary datafrom placebo-controlled clinical trialsshowing that the new biologic wasvery effective and generally well-toleratedwhen used alone or in combinationwith Biogen Idec's interferon beta-1a (Avonex). Any excitement orchanges in MS treatment that Tysabri'sintroduction may have generated werequickly muted, however.
Biogen Idec and Elan voluntarilywithdrew Tysabri from the market onFebruary 28, 2005, when the rareopportunistic infectious disease progressivemultifocal leukoencephalopathy(PML) was reported in 2 MSpatients receiving the drug. Tysabridosing in ongoing studies also was suspendedat that time, but a third case ofPML was found in a participant in aCrohn's disease trial.2
Following an extensive review ofadverse events with Tysabri and thepublication of 2-year data from MStreatment studies, the FDA relicensedthe medication in July 2006 with a narrowedindication and a strict risk managementprogram.
A TOUCH of Infection Prevention
Key to the reintroduction of Tysabriwas Biogen Idec and Elan's collaboratingwith the FDA to develop the TysabriOutreach: Unified Commitment toHealth (TOUCH) prescribing program.This program is designed primarily tominimize patients' risk for PML, but italso will facilitate the tracking of alladverse events associated with theuse of Tysabri.
PML is caused by the typically harmlessJC virus and is marked by clumsiness,progressive weakness, and visual,speech, and sometimes personalitychanges. There is no treatment, andPML nearly always is fatal.
Any pharmacist, pharmacy, prescriber,wholesaler, or patient involvedin the distribution or administration ofTysabri must register with TOUCH andcomplete educational and reportingrequirements. Patients taking Tysabrimust be given a Medication Guide eachtime they receive an infusion.
For now, Tysabri will be available onlythrough 13 specialty pharmacies (Table2). A Web site (www.tysabri.com), callcenter (800-456-2255), pregnancy registry,5-year postmarketing safetystudy, and ongoing TOUCH evaluationalso are elements of Tysabri's risk managementprogram.
Tysabri is the first selective adhesionmolecule inhibitor. It binds to T cellsand prevents them from migratingacross the walls of blood vessels. Researchersbelieve that such migrationcauses inflammation and the resultingdamage to nerve fibers that producesMS symptoms.3
Tysabri generally should be reservedfor adults with relapsing-remitting MSwho have not responded to or cannottolerate other therapies. It should notbe used in patients with compromisedimmune systems, and it should not begiven concomitantly with medicationsthat alter or weaken immune response.These cautions are necessarybecause Tysabri is itself an immunomodulatorthat increases patients' risk for PML and other opportunisticinfections.
More frequently, patients receivingTysabri experience headaches, fatigue,urinary tract infections, depression, jointpain, rash, and urinary urgency/frequency.Fewer than 1% of patients have hadserious allergic reactions to Tysabri.Such reactions appear to be most commonamong patients who have developedantibodies to the medication,which is a recombinant version of theIgG molecule that is produced in mousecells. When an allergic reaction occurs,Tysabri administration should bestopped immediately, symptoms shouldbe treated, and the patient should notbe restarted on the medication.
Tysabri is administered via intravenousinfusion once every 4 weeks ina TOUCH-certified clinic. The product issupplied in single-use vials that contain300 mg of natalizumab in 15 mL ofclear solution. The concentrated drugmust be mixed with 100 mL of 0.09%Sodium Chloride Injection, USP, beforebeing infused over the course of anhour. Tysabri vials must be kept refrigeratedat between 2?C and 8?C andshould not be shaken.
In the AFFIRM trial, patients receivingTysabri were 42% less likely thanpatients receiving placebo to experiencesustained disability progression.The active-treatment patients also hadsignificantly fewer new or enlargedlesions on brain tissues.4 AddingTysabri to ongoing Avonex therapyproduced significant positive results.Compared with patients receiving justAvonex, those receiving both Tysabriand Avonex had a 24% lower risk fordisability progression.5
Tysabri has been found to improvecognitive function in MS patients andto reduce their need for steroids andhospital care.6,7 Although the medicationis not indicated for Crohn's diseasetherapy, data presented at theAmerican College of Gastroenterologyshow that Tysabri is effective for maintainingCrohn's remission for up to 2years.8
Mr. Lamb is a freelance pharmacywriter living in Virginia Beach,Va, andpresident of Thorough Cursor Inc.
1. National Multiple Sclerosis Society. The Disease-Modifying Drugs. New York, NY: National Multiple Sclerosis Society; 2006.
2. Keely KA, Rivey MP, Allington DR. Natalizumab for the treatment of multiple sclerosis and Crohn's disease. Ann Pharmacother. 2005;39:1833-1843.
3. Tysabri (natalizumab) prescribing information. Cambridge, Mass, and San Diego, Calif: Biogen Idec Inc and Elan Pharmaceuticals Inc; 2006.
4. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899-910.
5. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911-923.
6. Fisher E, O'Connor PW, Havrdova E, et al. The effects of natalizumab on brain atrophy and cognitive function: results from the AFFIRM study. Paper presented at: Congress of the European Committee for Treatment and Research in Multiple Sclerosis; Madrid, Spain; September 28, 2006.
7. Lanker S. Natalizumab reduces corticosteroid use and hospitalizations and increases the proportion of disease-free multiple sclerosis patients. Poster presented at: Academy of Managed Care Pharmacy Educational Conference; Chicago, Ill; October 6, 2006.
8. Panaccione R, Colombel JF, Enns R, et al. Natalizumab maintains remission for 2 years in patients with moderately to severely active Crohn's disease and in those with prior infliximab exposure: results from an open-label extension study. Paper presented at: UnitedEuropean Gastroenterology Week; Berlin, Germany; October 24, 2006.