Compound Name:NatalizumabMolecular Target:?4-subunit of ?4-?1 and ?4-?7 integrins; blocks binding of VLA4 to VCAM-1 and binding of ?4-?7 to MADCAM-1Molecular Structure:humanized IgG4?Licensed Indication:Relapsing forms of MS, Crohn's DiseaseManufacturer and/or Distributor:Elan Pharmaceuticals & Biogen IdecInitial FDA Approval2004SummaryNatalizumab (Tysabri) is a recombinant humanized IgG4k monoclonal antibody directed at the α4 subunit of the integrins α4β1 (VLA-4) and α4β7, which bind respectively to the adhesion molecules VCAM-1 and MAdCAM-1. Thus, natalizumab can prevent the transmigration of leukocytes across endothelial surfaces to sites of inflammation. Natalizumab is indicated for the treatment of both Crohn's disease (CD) and relapsing forms of multiple sclerosis (MS). It is administered as an intravenous infusion every four weeks.

 Natalizumab monotherapy in the treatment of patients with relapsing forms of multiple sclerosis (MS) delays the accumulation of physical disability and reduces the frequency of clinical exacerbations. It also decreases the development of lesions detected on brain MRI. Due to the concerns regarding progressive multifocal leukoencephalopathy (PML; see below), natalizumab is indicated only for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy. Similarly, for adults with moderately to severely active Crohn’s disease (CD), it is used for inducing and maintaining clinical response and remission only in patients who have had an inadequate response to, or are unable to tolerate conventional CD therapies and inhibitors of tumor necrosis factor-alpha (TNF-a). Natalizumab should not be given in combination with other immunosuppressants or anti-TNF therapy. Other significant safety concerns are hypersensitivity, hepatotoxicity, and infections.

 The FDA has issued a black box warning regarding the risk of progressive multifocal leukoencephalopathy (PML) in patients receiving natalizumab. The drug was withdrawn from the market soon after being introduced in 2004 based on reports of several cases of PML developing in patients with MS or CD initially treated in clinical trials. The incidence of this complication was about 1/1000. It was reintroduced in 2006 following persistent demand from MS sufferers for better treatment options. Due to the severity of this adverse event, patients who receive natalizumab for either indication must be enrolled in and meet the criteria of a special restricted distribution program, the TOUCH Prescribing Program, sponsored by the manufacturer (Biogen-Idec). It is also recommended to test patients for antibodies to the JCV, as an indication of the presence of the virus. In May 2015, new risk factor for progressive multifocal leukoencephalopathy is added to drug safety labelling.References

Package Insert:

1. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006 Mar 2;354(9):924-933.

2. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):911-923.

3. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899-910.

4. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, et al. Natalizumab for active Crohn's disease. N Engl J Med. 2003 Jan 2;348(1):24-32.

5. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003 Jan 2;348(1):15-23.

6. Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, et al. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol. 2011 Aug;10(8):745-758.

7. Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011(10):CD007621.

8. Baldwin KJ, Hogg JP. Progressive multifocal leukoencephalopathy in patients with multiple sclerosis. Curr Opin Neurol. 2013 Jun;26(3):318-323.

9. Fox RJ, Cree BA, De Sèze J, Gold R, Hartung HP et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology. 2014 Apr 29;82(17):1491-8.

10. Kornek B. An update on the use of natalizumab in the treatment of multiple sclerosis: appropriate patient selection and special considerations. Patient Prefer Adherence. 2015 May 19;9:675-84.