Clinical UM Guideline
This document addresses natalizumab (Tysabri), a recombinant humanized monoclonal antibody known as an alpha-4 integrin antagonist.
Tysabri has received U.S. Food and Drug Administration (FDA) approval with limited distribution as monotherapy for the treatment of individuals with relapsing forms of multiple sclerosis (MS). Tysabri is also approved for adults with moderately to severely active Crohn's disease (CD) who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of tumor necrosis factor-alpha (TNF-α). Tysabri is available only for prescribers and individuals enrolled in a restricted distribution program focused on safety, the TOUCH Prescribing Program.
Note: Please see the following related documents for additional information:
Treatment with natalizumab (Tysabri) is considered medically necessary for either of the following uses:
Not Medically Necessary:
Treatment with natalizumab (Tysabri) is considered not medically necessary for all other uses and for individuals with any of the following:
The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
|J2323||Injection, natalizumab, 1 mg [Tysabri]|
|K50.00-K50.919||Crohn's disease [regional enteritis]|
Tysabri was initially approved by the FDA in November 2004 for the treatment of relapsing forms of MS. However, it was withdrawn by the manufacturer, Biogen Idec, Inc. in February 2005, after 3 subjects in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML). The drug was allowed to return to the market in 2006, following a re-examination of those who had participated in clinical trials, confirming there were no additional cases of PML. In January 2008, the FDA also approved Tysabri for the treatment of moderate-to-severe CD in persons with evidence of inflammation, who have had an inadequate response to, or are unable to tolerate, conventional CD therapies.
The FDA determined that Tysabri can be made available only under the TOUCH Prescribing Program. The TOUCH prescribing program facilitates the safe and appropriate use of Tysabri and ensures that persons are monitored very closely for any new sign or symptom suggestive of PML. Under the program, Tysabri can only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies authorized by the TOUCH Prescribing Program. Furthermore, those receiving the drug must be educated about the risks and benefits of Tysabri and enrolled in the TOUCH Prescribing Program.
The FDA also alerts clinicians and the public that a positive test result for anti-John Cunningham virus (JCV) antibodies is a risk factor for the development of PML in individuals treated with natalizumab. Additional risk factors include a longer duration of treatment (especially greater than 2 years) and a history of immunosuppressant medication use (for example, mitoxantrone, azathioprine, methotrexate, cyclophosphamide or mycophenolate mofetil). Those demonstrating all three risk factors have an estimated PML risk of 11/1000. As of January 4, 2012, the FDA was aware of 201 confirmed worldwide cases of PML related to the use of natalizumab.
Anti-JCV antibody status is determined by performing an anti-JCV antibody detection test such as the Stratify JCV Antibody ELISA test. A positive result indicates prior exposure to JCV. Anti-JCV antibody detection testing should be considered prior to natalizumab treatment (or during treatment if status is unknown). When assessing the risk for PML using anti-JCV antibody status, a positive test at any time is considered a risk factor regardless of prior or future test results. The risks and benefits of continued natalizumab treatment should be weighed in an individual with a history of a positive anti-JCV antibody test. Those with a negative JCV antibody result may still be at risk for PML as new JCV infection or false negative result are possible and as such, periodic retesting may be warranted.
Natalizumab treatment should be discontinued immediately at the first sign or symptom of PML (for example, progressive weakness on one side of the body, limb clumsiness, visual disturbance, changes in thinking, memory, personality or orientation). Individuals should be counseled to contact their prescriber if symptoms occur. Adverse events should be reported to the FDA through the MedWatch program.
Published studies support the usage of natalizumab in certain individuals with relapsing forms of MS. Due to the significant risk factors of natalizumab, it has been generally reserved for individuals with relapsing forms of MS who have had an inadequate response to or are unable to tolerate alternate MS therapies. In 2006, the National MS Society expert opinion paper "Patient Access to Tysabri" reported that the term relapsing MS includes: Relapsing-Remitting MS (RRMS), Secondary-Progressive MS (SPMS) and Progressive-Relapsing MS (PRMS).
Furthermore, the National MS Society stated:
Patients in all three of these groups are considered candidates for Tysabri as long as they continue to have relapses. Patients with Primary-Progressive MS (which is progressive from onset and has no relapses) and those with SPMS and PRMS who are no longer experiencing relapses are not considered candidates for Tysabri.
In 2014, Lublin and colleagues published updated MS disease course descriptions. Three of the original disease courses were retained (RRMS, PPMS and SPMS) with added descriptions. RRMS was further characterized as having active or not active disease and as worsening (defined as increased disability confirmed over a specified time period following a relapse), or stable (defined no evidence of increasing disability over a specified time period following a relapse). PPMS and SPMS were modified to include having active or not active disease and with progression, meaning there is objective evidence of sustained worsening over time, or without progression. Additionally, PRMS was eliminated as a disease course. Individuals who were previously diagnosed with PRMS would now be considered to have PPMS, either active (at the time of relapses or new MRI lesions) or not active. A new disease course was added known as clinically isolated syndrome (CIS). CIS is a single demyelinating episode with consistent MRI findings (indicating inflammation/demyelination in one or more sites in the central nervous system). Individuals with this syndrome are at high risk for developing clinically definite MS.
The Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial (Pohlman, 2006), a randomized, double-blind, placebo controlled study, found that monotherapy with Tysabri (n=627) versus placebo (n=315) significantly reduced by 68% the frequency of clinical exacerbations at 1 year, as well as delayed by 42% the sustained progression of disability over 2 years, as measured by the Kurtzke Expanded Disability Status Scale (EDSS). The cumulative probability of disease progression (on the basis of the Kaplan-Meier analysis) was 17% in the Tysabri group compared to 29% in the placebo group (p<0.001). No cases of PML were reported among subjects participating in the AFFIRM trial.
Miller and colleagues (2007) reported on the effect of natalizumab on MRI measures involving 942 subjects from the AFFIRM trial. In this study, the number and volume of gadolinium-enhancing (Gd), new or enlarging T2-hyperintense lesions, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. When compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (mean of 2.4 versus 0.2, p<0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means of 11.0 versus 1.9, p<0.001), and a 76% decrease in new T1-hypointense lesions (mean of 4.6 versus 1.1, p<0.001) over 2 years. The median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p<0.001); median T1-hypointense lesion volume decrease by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p<0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated group. The authors concluded that natalizumab has a sustained effect in preventing the formation of new lesions in relapsing MS.
Hutchinson and colleagues (2008) performed a sub analysis of the Affirm Study and also the "Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis" (SENTINEL) study. Analysis indicated that natalizumab reduced the risk of disability progression by 64% and relapse rate by 81% in treatment-naïve subjects with highly active disease and by 58% and 76%, respectively, in those with highly active disease in spite of IFNβ-1a treatment. The authors concluded:
Based on its efficacy in treatment-naïve patients with highly active disease, natalizumab may be most effective in early actively relapsing MS, when inflammation is a key contributor to the accumulation of disability. As experience with natalizumab increases and its safety profile is further defined, its full potential in the treatment of MS will be determined.
The American Academy of Neurology (AAN) 2008 evidenced based guidelines (now archived) for the use of natalizumab for the treatment of MS included the following information about the safety of natalizumab:
At the time of this writing, there are no active AAN guidelines pertaining to the use of natalizumab for the treatment of MS.
Recent published literature proposes PML risk stratification according to anti JCV antibody levels prior to natalizumab use. Nicholas and colleagues (2014) proposed an algorithm considering natalizumab for first line treatment of MS in individuals who are anti JCV antibody negative and others stratified by anti-JCV antibody level. The authors stated that, based on its high level of efficacy, natalizumab should be considered for use in individuals with aggressive MS disease courses at least for the first 12-24 months regardless of JCV serum antibody status.
In 2014, Plaviana and colleagues investigated whether anti-JCV antibody levels, measured as an index, could define the risk of PML in seropositive subjects with MS treated with natalizumab. Anti-JCV antibody index data were from serum/plasma samples collected more than 6 months prior to PML diagnosis from 71 natalizumab-treated PML subjects and 2522 non-PML anti-JCV antibody-positive subjects. For those with no history of immunosuppressant use, anti-JCV antibody index distribution was significantly higher in PML subjects than in non-PML subjects (p<0.0001). Retrospective analyses of pre-PML samples collected longitudinally from PML subjects demonstrated sustained higher anti-JCV antibody index over time. Although this study demonstrated a higher risk of PML in natalizumab-treated MS subjects with no previous immunosuppressant use in the presence of a higher anti-JCV antibody index, the total number of PML cases included in the analysis was small. Prospective data are necessary to validate the use of an anti-JCV antibody index in the decision-making process using natalizumab in individuals with MS.
Scolding and colleagues (2015) for the Association of British Neurologists, updated their guidelines for prescribing MS disease-modifying treatments. These guidelines divide disease modifiers into two classes: drugs of moderate efficacy (moderate relapse reduction in 30-50% range) and drugs of high efficacy (average relapse reduction more than 50%). Natalizumab was included in the high efficacy group and recommended for individuals with more active disease. The authors stated:
Patients may be classified as having more active MS by frequent clinical relapses and/or MRI activity either when untreated or while on a Category 1 drug. The formal criteria for high-disease activity despite interferon-β or glatiramer requires one relapse in the previous year on interferon-β and either (a) ≥ gadolinium-enhancing MRI lesions or (b) at least nine T2-hyperintensive lesions on cranial MRI. We recommend that patients with more active disease use one of the Category 2 drugs, natalizumab or alemtuzumab.
PML risk and anti-JCV antibody status were not discussed in the guidelines.
McGuigan and colleagues (2016) presented an algorithm to support anti-JCV antibody index testing and MRI monitoring as a part of standard PML protocols, allowing for some JCV positive individuals to begin or continue natalizumab treatment based on individualized analysis of PML risk. In regards to their recommendations, the authors indicated that there was "a lack of high level evidence and several areas of doubt and uncertainty."
The safety and efficacy of natalizumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials of adults (n=1414) with moderately to severely active CD (Crohn's Disease Activity Index [CDAI] ≥ 220 and ≤ 450). Concomitant inhibitors of TNF-α were not permitted, however, concomitant stable doses of aminosalicylates, corticosteroids, with or without immunosuppressants (for example, 6-mercaptopurine, azathioprine, or methotrexate) were permitted, with 89% of subjects continuing to receive at least one of these medications. Although permitted in the clinical trials, combination therapy with immunosuppressants is not recommended (Tysabri Product Information, 2013).
Two of the studies evaluated induction of clinical response as defined as ≥ 70-point decrease in the CDAI from baseline. In Study CD1, known as the ENACT-1 (Efficacy of Natalizumab as Active Crohn's Therapy) trial, 896 subjects were randomized 4:1 to receive 3 monthly infusions of either 300 mg natalizumab or placebo. Clinical results were assessed at Week 10; those with incomplete information were considered as not having a clinical response. At Week 10, 56% of the 717 subjects receiving natalizumab were in response compared to 49% of the 179 subjects receiving placebo (treatment effect, 7%; 95% confidence interval [CI], p=0.067). In a post hoc analysis of the subset of 653 subjects with elevated baseline C-reactive protein (CRP), indicative of active inflammation, 57% of the natalizumab group were in response compared to 45% of those that received placebo (treatment effect, 12%; 95% CI, nominal; p=0.01).
In the CD2 induction trial, known as the Efficacy of Natalizumab in Crohn's disease respOnse and REmission Trial Group (ENCORE) (Targan, 2007), adults (n=509) with at least a 6 month history of moderate to severe CD and active inflammation characterized by elevated C-reactive protein concentrations were randomized 1:1 to receive natalizumab 300 mg or placebo intravenously at weeks 0, 4, and 8. Concurrent therapies for CD were permitted. The primary endpoint was defined as a reduction in the CDAI score from the baseline (≥ 70-point decrease from baseline in the CDAI score at Week 8 sustained through Week 12). Additional efficacy endpoints included the proportion of subjects with sustained remission (CDAI score < 150 points) and response or remission over time. A response was reported at week 8 and sustained through week 12 in 48% of those treated with natalizumab as compared to 32% of those receiving placebo (p<0.001). Sustained remission occurred in 26% of natalizumab-treated subjects compared to 16% of those receiving placebo (p=0.002). Week 4 response rates were 51% for natalizumab compared to 37% for placebo (p=0.001). Responses remained significantly higher at subsequent assessments (p<0.001) in natalizumab-treated subjects. Natalizumab-treated subjects also had significantly higher remission rates at weeks 4, 8, and 12 (p≤0.009). The frequency and types of adverse events were similar between treatment groups. The investigators concluded that natalizumab induced a response and remission at week 8 that was sustained through week 12. Response and remission rates for natalizumab were superior to those for placebo at weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in subjects with elevated C-reactive protein and active CD. Natalizumab was well tolerated in this study.
In Studies CD1 and CD2, for subgroups defined by prior use of, or by inadequate response to prior therapies (i.e. corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of subjects that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Those with inadequate response to inhibitors of TNF-α appeared to have lower clinical response and lower clinical remission in both the treatment and placebo groups. For those subjects in Study CD2 with an inadequate response to prior treatment with inhibitors of TNF-α, clinical response at weeks 8 and 12 was reported in 38% of those randomized to natalizumab, while clinical remission at both weeks 8 and 12 was reported in 17%.
Maintenance therapy was evaluated in Study CD3, where 331 subjects from Study CD1 who had a clinical response to natalizumab at both weeks 10 and 12 were re-randomized 1:1 to treatment with continuing monthly infusions of either 300 mg natalizumab or placebo. Maintenance of response was assessed by the proportion of subjects who did not lose clinical response at any study visit for an additional 6 and 12 months of treatment (month 9 and 15 after initial treatment with natalizumab). The study also assessed the proportion of subjects who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. Requiring maintenance of response or remission at each visit, as opposed to only at month 9 or 15 may have resulted in lower proportions meeting the endpoint criteria.
For subgroups in study CD3, defined by prior use of, or by inadequate response to prior therapies (such as, corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup that was not taking concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Those with inadequate response to inhibitors of TNF-α appeared to have lower maintenance of clinical response and lower maintenance of clinical remission in both the treatment and placebo groups. For those subjects in study CD3 with an inadequate response to prior treatment with inhibitors of TNF-α, maintenance of clinical response through month 9 was observed in 52% of those randomized to natalizumab, with maintenance of clinical remission through month 9 observed in 30%.
Black Box Warnings
The 2016 FDA Product Information label includes the following black box warnings:
Primary progressive MS (PPMS): A clinical course of MS characterized by progression of disability from onset without initial relapses or remissions. The term progressive-relapsing multiple sclerosis or PRMS, previously used to characterize individuals who had progressive disease from onset and clear acute relapses, is no longer preferred. PPMS has now been modified to include having active or not active disease and with progression, meaning there is objective evidence of sustained worsening over time, or without progression. An acute relapse in an individuals with progressive disease from onset is now considered to be PPMS with active disease, whereas those with progressive disease from onset without acute relapses are considered to have PPMS, active but with progression.
Relapsing-remitting MS (RRMS): A clinical course of MS characterized by clearly defined, acute relapses with full or partial recovery; no disease progression or worsening of disability develops between relapses. RRMS is also now characterized as having active or not active disease and as worsening (defined as increased disability confirmed over a specified time period following a relapse), or stable (defined no evidence of increasing disability over a specified time period following a relapse).
Secondary progressive MS (SPMS): A clinical course of MS demonstrating sustained progression of physical disability occurring separately from relapses in individuals who previously had RRMS. SPMS has now been modified to include having active or not active disease and with progression, meaning there is objective evidence of sustained worsening over time, or without progression.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||02/02/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Discussion, References and Definition sections updated.|
|Revised||02/04/2016||MPTAC review. Medically necessary statement clarified to indicate that the Touch Prescribing Program is a requirement for both MS and CD. Discussion and Reference sections updated. Removed ICD-9 codes from Coding section.|
|New||02/05/2015||MPTAC review. Initial document development.|