Report on New Patented Drugs — Tysabri

Under its transparency initiative, the PMPRB publishes the results of the reviews of new patented drug products conducted by Board Staff for purposes of applying the Board's pre-2010 Guidelines for all new active substances introduced in Canada after January 1, 2002.

Brand Name: Tysabri

Generic Name: natalizumab

DIN: 02286386 (20 mg/mL)

Patentee: Biogen Idec Canada Inc.

Indication – as per product monograph: Indicated as monotherapy (i.e., single disease-modifying agent) for the treatment of patients with the relapsing–remitting
form of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations, to decrease the number and volume of active brain lesions identified on magnetic
resonance imaging (MRI) scans and to delay the progression of physical disability. Tysabri is generally recommended in MS patients who have had an inadequate
response to, or are unable to tolerate, other therapies for multiple sclerosis.

Date of Issuance of First Patent Pertaining to the Medicine: June 29, 2004

Notice of Compliance: September 28, 2006

Date of First Sale: November 21, 2006

ATC Class: L04AA23
Antineoplastic and Immunomodulating Agents; Immunosuppressants; Immunosuppressants; Selective immunosuppressants

Application of the Guidelines

Summary

The introductory price of the Tysabri was found to be within the pre-2010 Guidelines because the price in Canada did not exceed the median of the prices of the same drug product sold in the comparator countries listed in the Patented Medicines Regulations (Regulations) in which Tysabri was sold.

Scientific Review

Tysabri is a new active substance and the PMPRB's Human Drug Advisory Panel (HDAP) recommended that Tysabri be classified as a category 3 new medicine (provides moderate, little or no therapeutic over comparable drug products). The HDAP did not recommend any comparators for the conduct of a Therapeutic Class Comparison (TCC) test.

Price Review

The TCC of the pre-2010 Guidelines provides that the price of a category 3 new drug product cannot exceed the prices of other drug products that are clinically equivalent in treating the same disease or condition. Comparators are generally selected from among existing drug products in the same 4th level of the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) Classification System. However, when it is inappropriate or impossible to conduct a TCC test, Board Staff will give primary weight to the median of the international prices identified in an International Price Comparison (IPC) test. See the Board's Compendium of Guidelines, Policies and Procedures “up to 2009” for a more complete description of the Guidelines and the policies on TCCs.

As no comparators were identified for purposes of conducting a TCC test, an IPC test was conducted. The introductory price of Tysabri was considered within the pre-2010 Guidelines as it did not exceed the median of the international prices identified in the IPC test. Tysabri was sold in six countries listed in the Regulations, namely, Germany, Italy, Sweden, Switzerland, United Kingdom and the United States.

Introductory Period (November to December 2006)

Sources:

1. No public price available until 2008. La Régie de l'assurance maladie du Québec, 2008, listed a price of $159.1876/mL.
2. Publicly available price as per the Patented Medicines Regulations.

The publication of Summary Reports is part of the PMPRB's commitment to make its price review process more transparent.

Where comparators and dosage regimens are referred to in the Summary Reports, they have been selected by the HDAP for the purpose of carrying out the PMPRB's regulatory mandate, which is to review the prices of patented drug products sold in Canada to ensure that such prices are not excessive.

The PMPRB reserves the right to exclude from the therapeutic class comparison test any drug product it has reason to believe is being sold at an excessive price.

In Summary Reports under the pre-2010 Guidelines, the PMPRB refers to the publicly available prices of comparators, provided that such prices are not more than 10% above a non-excessive price, in which case no price will be made available. Publication of these prices is for information only and should not be construed as indicating that the public prices are considered to be within the pre-2010 Guidelines.

The information contained in the PMPRB's Summary Reports should not be relied upon for any purpose other than stated and is not to be interpreted as an endorsement, recommendation or approval of any drug product, nor is it intended to be relied upon as a substitute for seeking appropriate advice from a qualified health care practitioner.

References

Fiore D. Multiple sclerosis and natalizumab. Am J Ther 2007; 14: 555–60.

Biinquet C et al. The prognostic value of initial relapses on the evolution of disability in patients with relapsing-remitting multiple sclerosis. Neuroepidemiology 2006; 27: 45–54.

Gaillard N et al. Influence of acute aggravations on the development of long-term handicap in relapsing remitting multiple sclerosis: a clinical study in 99 patients. Article in French. Rev Neurol (Paris) 2007; 163: 72–81.

Hirst C et al. Contribution of relapses to disability in multiple sclerosis. J Neurol 2008; 225: 72–81.

Lieu C, Blumhardt LD. Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts. J Neurol Neurosurg Psychiatry 2000; 68: 450–7.

Lublin FD. The incomplete nature of multiple sclerosis relapse resolution. J Neurol Sci 2007; 256 (suppl 1): S14–18.

Vollmer T. The natural history of relapses in multiple sclerosis. J Neurol Sci 2007; 256 (suppl 1): S5–13.

Young PJ et al. Relapses and subsequent worsening of disability inr elapsing-remitting multiple sclerosis. Neurology 2006; 67: 804–8.

Update on progressive multifocal leukoencepalopathy (PML) and Tysabri. EMEA Press release. London. 13 August 2008. Available at: http://www.emea.europa.eu

Mullen JT et al. Melanoma complicating treatment with natalizumab for multiple sclerosis (letter). N Eng J Med 2008; 358: 647–648.

Boster A et al. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol 2008; 7: 173–183.

Goodin DS et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008; 71: 766–773.

Rudick RA et al. Health related quality of life in multiple sclerosis: effects of natalizumab. Annals of Neurology; published online 14 August 2007.

Multiple sclerosis-natalizumab: Appraisal consultation document available from: http://guidance.nice.org.uk/page.aspx?o=418937

John T. Mullen, M.D.,Timothy K. Vartanian, M.D.,Michael B. Atkins, M.D. Melanoma Complicating Treatment with Natalizumab for Multiple Sclerosis. NEJM, 358; 6, February 7, 2008, p. 647–48.

Stefan Gattenlöhner, M.D., Eva-Bettina Brocker, M.D., Hans-Konrad Muller-Hermelink, M.D.

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.

Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–23.

Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354: 924–33.

O'Connor P. Key issues in the diagnosis and treatment of multiple sclerosis. Neurology 2002; 59(Suppl 3): S1–S33.

Grima DT, Torrance GW, Francis G, et al. Cost and health related quality of life consequences of multiple sclerosis. Mult Scler 2000; 6: 91–8.

Rice GP, Hartung H, Calabresi PA. Anti-á4 integrin therapy for multiple sclerosis. Mechanisms and rationale. Neurology 2005; 64: 1336–42.

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.

Ropper AH. Selective treatment of multiple sclerosis. N Engl J Med 2006; 354: 965–7.

Natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 2387–9.

Anonymous. The trials and tribulations of Tysabri. Lancet Neurol 2006; 5: 373.

Goodin D. The return of natalizumab: weighing benefit against risk. Lancet Neurol 2006; 5: 375–7.

Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23.

Dalton CM, Miszkiel KA, Barker GJ, et al. Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 2004; 251: 407–13.

O'Connor P, Miller D, Riester K, et al. Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis. Multiple Sclerosis 2005; 11: 568–72.

Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-[alpha]4 integrin antibody on brain lesion activity in MS. Neurology 1999; 53: 466–72.

O'Connor PW, Goodman A, Willmer-Hulme AJ, et al. Randomized multicenter trial of natalizumab in acute MS relapses. Clinical and MRI effects. Neurology 2004; 62: 2038–43.

Randomized multicenter trial of natalizumab in acute MS relapses. Clinical and MRI effects. Neurology 2005; 64: 174–5.

Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–23.

Karussis D, Biermann LD, Bohlega S, et al. A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting. Eur J Neurol 2006; 13: 61–71.

Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy of Neurology and the MS council for clinical practice guidelines. Neurology 2002; 58: 169–78.

Miller A, Cohen J, Eidelman B, et al. Disease management consensus statement. http://www.nationalmssociety.org/pdf/forpros/Exp_Consensus.pdf

Rizvi SA, Agius MA. Current approved options for treating patients with multiple sclerosis. Neurology 2004; 63: S8–14.

Olek MJ. Treatment of relapsing-remitting multiple sclerosis. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2006.

Calabresi PA. Considerations in the treatment of relapsing-remitting multiple sclerosis. Neurology 2002; 58: S10–22.

Doggrell SA. Natalizumab in multiple sclerosis: proceed with caution? Expert Opin Pharmacother 2006; 7: 1675–8.

Adelman B, Sandrock A, Panzara MA. Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med 2005; 353: 432–3.

Kleinschmidt BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353: 369–74.

Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353: 375–81.

Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005; 353: 362–8.

Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab – unforeseen consequences. N Engl J Med 2005; 353: 414–6.

Drazen JM. Patients at risk. N Engl J Med 2005; 353: 417.

Langer-Gould A, Steinman L. What went wrong in the natalizumab trials? Lancet 2006; 367: 708–10.

Progressive multifocal leukoencephalopathy, natalizumab, and multiple sclerosis. N Engl J Med 2005; 353: 1744–6.

Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354: 924–33.

Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. Curr Opin Neurol 2006; 19: 341–9.

Langer-Gould A, Steinman L. Progressive multifocal leukoencephalopathy and multiple sclerosis: lessons from natalizumab. Curr Neurol Neurosci Rep 2006; 6: 253–8.

Olek M. Treatment of progressive multiple sclerosis. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2006.