Assessment: The use of natalizumab Tysabri for the treatment of multiple sclerosis an evidence-based review

1. 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 D. S. Goodin, B. A. Cohen, P. O’Connor, L. Kappos, and J. C. Stevens

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3. Presentation Objectives

4. Overview

5. Background

6. Background, cont.

7. Gaps in Care

8. Gaps in Care, cont.

9. Gaps in Care, cont.

10. AAN Guideline Process

11. Clinical Questions

12.

13. AAN Classification of Evidence

14. AAN Level of Recommendations

15. Translating Class to Recommendations A = Requires at least two consistent Class I studies.)* B = Requires at least one Class I study or at least two consistent Class II studies. C = Requires at least one Class II study or two consistent Class III studies. U = Studies not meeting criteria for Class I through Class III.

16. Translating Class to Recommendations * In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval is > 2).

17. Applying This Processto the Issue We will now turn our attention to the guidelines.

18. Clinical Questions Does treatment with natalizumab reduce disease activity in RRMS by clinical and MRI measures? Does treatment with natalizumab reduce disease severity in RRMS by clinical and MRI measures? How does the efficacy of natalizumab compare with currently available disease-modifying therapies? Is natalizumab effective in other clinical types of MS such as secondary progressive MS (SPMS)?

19. Clinical Questions, cont. 5. In patients with RRMS, does the combination of natalizumab with other disease-modifying therapies improve efficacy? In patients with MS, how safe is natalizumab, either alone or in combination with other immune-modulating agents?

20. Methods MEDLINE and EMBASE 1966 to October 2006 Search terms natalizumab and multiple sclerosis Relevant, fully published, peer-reviewed articles

21. Methods, cont. Each panel member reviewed each article for inclusion. Risk of bias was determined using the classification of evidence for each study (Classes I–IV). Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). Conflicts of interest were disclosed.

22. Literature Review

23. Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required: a) concealed allocation, b) primary outcome(s) clearly defined, c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias. Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a RCT in a representative population that lacks one criteria a-d. AAN Classification of Evidencefor Therapeutic Intervention

24. AAN Classification of Evidencefor Therapeutic Intervention, cont. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.* Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report. *Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

25. Analysis of Evidence Question 1: Does treatment with natalizumab reduce disease activity in RRMS by clinical and MRI measures? Question 2: Does treatment with natalizumab reduce disease severity in RRMS by clinical and MRI measures? Question 3: How does the efficacy of natalizumab compare with currently available disease-modifying therapies?

26. Analysis of Evidence, cont. Question 4: Is natalizumab effective in other clinical types of MS such as SPMS? Question 5: In patients with RRMS, does the combination of natalizumab with other disease-modifying therapies improve efficacy? Question 6: In patients with MS, how safe is natalizumab, either alone or in combination with other immune-modulating agents?

27. Conclusions Natalizumab reduces measures of disease activity such as clinical relapse rate, Gd-enhancement, and new and enlarging T2 lesions in patients with relapsing MS (Class I studies, Level A). Natalizumab improves measures of disease severity such as the EDSS progression rate and the T2-hyperintense and T1-hypointense lesion burden seen on MRI in patients with relapsing MS (Class I studies, Level A). The relative efficacy of natalizumab compared to other available disease-modifying therapies is unknown (Level U).

28. Conclusions, cont. The value of natalizumab in the treatment of SPMS is unknown (Level U). The SENTINEL trial provides evidence for the value of adding natalizumab to patients already receiving IFN-1a, 30 g, IM once weekly (one Class I study, Level B). There is an increased risk of developing PML in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy). The two cases seen in MS were treated with a combination of natalizumab and IFN-1a, but the fact that PML occurred only with combination therapy may be a chance development.

29. Conclusions, cont. There may also be an increased risk of other opportunistic infections (Level C). On the basis of clinical trial data, the PML risk has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this estimate could change in either direction with more patient-years of exposure. Since the development of this guideline, two cases of PML have been reported in patients receiving natalizumab monotherapy, one of whom had never previously received any immunomodulatory or immunosuppressive treatment.

30. Conclusions, cont. This observation indicates that natalizumab, by itself, is a risk factor for PML. However, the evidence has not been formally reviewed by Therapeutics and Technology Assessment (TTA) Subcommittee.

31. Recommendations Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the FDA. Similarly, because combination therapy with IFN and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials.

32. Future Research The true risk of PML in patients receiving natalizumab monotherapy needs to be established in large longitudinal postmarketing surveys of patients on treatment for several years. A large-scale postregistration study (the TYGRIS study) is now under way to address this issue. It is currently possible to monitor a patient’s specific cellular immunity to JC virus. If such a test were commercially available, studies to determine its value in predicting the risk of developing PML would be strongly recommended. Testing to assess different dosing regimens to improve efficacy and/or reduce risk should be done.

33. Future Research, cont. Assessment of the safety and efficacy of combinations of treatments should be made. Study of ways to reverse immediately the effects of natalizumab if PML or other serious side effects occur should be done. Head-to-head comparative studies are needed to define the relative value and safety of natalizumab, both compared to our current therapies and to those under development. The effectiveness of natalizumab in other disease types of MS such as SPMS needs to be studied.

34. References Bar-Or A, Oliviera EML, Anderson DE, Hafler DA. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999;100:252–259. Conlon P, Oksenberg JR, Zhang J. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol Dis 1999;6:149–166. Davis LS, Oppenheimer-Marks N, Bednarczyk JL, McIntyre BW, Lipsky PE. Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. J Immunol 1990; 145:785–793. Chan PY, Aruffo A. VLA-4 integrin mediates lymphocyte migration on the inducible endothelial cell ligand VCAM-1 and the extracellular matrix ligand fibronectin. J Biol Chem 1993;268:24655–24664. O’Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS. Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J Immunol 1999;162:1024–1031.

35. References, cont. 6. Chabas D, Baranzini SE, Mitchell D, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001;294:1731–1735. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against 41 integrin. Nature 1992;356:63–66. Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747. Niino M, Bodner C, Simard ML, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 2006;59:748–754.

36. References, cont. For a complete list of references, please access the full guidelines at www.aan.com/guidelines

37. Questions/Comments

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