Natalizumab

Natalizumab is a prescription drug co-marketed by Biogen Idec and Élan as Tysabri. It was previously named Antegren. Natalizumab is administered by infusion and has proven effective in the treatment of multiple sclerosis and Crohn's disease. Three months after its approval by the FDA, the drug was voluntarily withdrawn after being linked to adverse events including one death. After an intensive safety evaluation, the drug was re-approved by the FDA as a potentially significant advancement over existing therapies and returned to the marketplace under a program of restricted distribution and regular patient evaluations.

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Description

Natalizumab is a humanized monoclonal antibody against integrin-α4 that has proven efficacy in the treatment of two serious autoimmune disorders: multiple sclerosis (MS) and Crohn's disease (CD).

In MS, natalizumab was shown to reduce relapses by 67% vs. a placebo. It slowed the progression of disability (as measured by EDSS) by 42%. While it is impossible to compare results across different clinical trials, the older generation drugs, interferons and glatiramer acetate (Copaxone), are generally acknowledged as demonstrating about a 30-35% decrease in relapse rate vs. placebo; and only two drugs have been shown to decrease the progression of disability, but again only by around 20-40%.

In Crohn's, a randomized controlled trial found that natalizumab increased the rate of remission ^[1].

Mechanism of action

The mechanism of action of natalizumab is believed to involve the inhibition of immune cells from crossing blood vessel walls to reach various tissues, including the brain.

Link to a rare brain disease

While the drug was shown to be powerfully effective for preventing relapses of MS, just three months after natalizumab was initially approved for MS by the FDA, the companies announced on February 28, 2005 that one fatal and one non-fatal case of a rare, often lethal brain disease known as progressive multifocal leukoencephalopathy (PML) were found in patients given natalizumab in combination with interferon beta-1a (Avonex) over a two year period.^[2][3] Natalizumab was voluntarily withdrawn from the market that day,^[4] after the first two confirmed cases, so that an intensive safety evaluation could be conducted to determine the prevalence of PML and what actions might be taken to minimize the likelihood of PML. During the safety review, a second PML death was attributed to natalizumab in March of 2005, in a Crohn’s disease patient who had died in December 2003 from what was thought at that time to be a brain tumor, but the diagnosis was subsequently re-evaluated as having been PML. The Crohn’s disease patient who had received eight doses of natalizumab over an 18-month period had a prior medication history which included multiple courses of immunosuppressant agents, which are thought to have contributed significantly to the PML.^[5]

Biogen Idec and Élan were both affected financially by the reports of PML.

The companies announced in the fall of 2005 that they had resubmitted it to the U.S. Food and Drug Administration (FDA) and were also resubmitting to the European Medicines Agency (EMEA), for approval in Europe. The FDA again granted natalizumab "Priority Review" status, a designation granted to products considered to be potentially significant advancements over existing therapies. Under this designation, the FDA commits to render a decision within six months of submission rather than the standard ten months.

Return to the market

On June 5, 2006, after reviewing two years of safety and efficacy data and an Advisory Committee hearing ending in a unanimous recommendation for reapproval, FDA re-approved it for patients with relapsing forms of MS under certain conditions (the FDA Advisory Committee recommended the return of the treatment as a first line therapy but the FDA did not follow completely the recommendation).

They also included a special restricted distribution program known as the TOUCH Prescribing Program ("TOUCH" stands for "Tysabri Outreach: Unified Commitment to Health"). Under this program, only prescribers, infusion centers, and specialty pharmacies trained and enrolled in the TOUCH program can prescribe and administer Tysabri. Additionally, patients must also be enrolled in the TOUCH program, so that they may be educated on Tysabri as well as periodically evaluated while being treated with Tysabri.

In April of 2006 the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), issued a positive opinion recommending marketing authorization for natalizumab as a treatment for relapsing-remitting multiple sclerosis. Several weeks later on June 29, the EMEA also approved natalizumab in the European Union for relapsing forms of MS, but not subject to the TOUCH restrictions.^[6]

Price and marketing issues

The wholesale price of Tysabri is US$2184.62 per vial. Given that natalizumab is generally administered 13 times a year, the annual costs for Tysabri is approximately US$28,400 (not including costs associated with infusion services), priced at a premium to the older generation drugs.

References

1. ^ Ghosh S, Goldin E, Gordon F, Malchow H, Rask-Madsen J, Rutgeerts P, Vyhnálek P, Zádorová Z, Palmer T, Donoghue S (2003). "Natalizumab for active Crohn's disease". N. Engl. J. Med. 348 (1): 24-32. PMID 12510039.
2. ^ Kleinschmidt-DeMasters BK, Tyler KL; Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005 Jul 28;353(4):369-74.
3. ^ Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D; Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005 Jul 28;353(4):375-81.
4. ^ PHARMACEUTICALS: RESTRICTIONS IN USE AND AVAILABILITY. World Health Organization. Retrieved on 2007-07-23.
5. ^ Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts; Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med. 2005 Jul 28;353(4):362-8.
6. ^ Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW, Jager HR, Clifford DB. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006 Mar 2;354(9):924-33.