BlueCross and BlueShield of Montana Medical Policy/Codes
Tysabri (Natalizumab)
Chapter: Drugs - Medical Benefit
Current Effective Date: February 01, 2014
Original Effective Date: July 18, 2013
Publish Date: January 15, 2014
Revised Dates: January 15, 2014
Description

Tysabri® is a monoclonal antibody bioengineered in the laboratory and designed to hamper the movement of potentially damaging immune cells from the bloodstream, across the “blood brain barrier,” and into the brain and spinal cord. The monoclonal antibody was first approved by the FDA in November 2004 for the treatment of relapsing forms of MS and later withdrawn by the manufacturer in February 2005 after three patients developed progressive multifocal leukoencephalopathy (PML) during clinical trials. PML is a rare and frequently fatal demyelinating disease of the central nervous system that primarily affects immunocompromised patients and is caused by the activation of a polyomavirus, which is latent in 80% of healthy adults. Tysabri® was re-approved by the FDA in June 2006 and is indicated for the treatment of patients with relapsing forms of MS to reduce the frequency of clinical exacerbations. In January 2008 the FDA approved Tysabri for the treatment of moderate-to-severe CD in patients with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies.

Tysabri® is given intravenously every four weeks and is only available to prescribing physicians and patients through a distribution program known as TOUCH® administered by Biogen Idec, Inc. TOUCH® is a distribution program designed to assess the risk of progressive multifocal leukoencephalopathy (PML) associated with Tysabri, minimize the risk of PML, minimize death and disability due to PML, and promote informed risk-benefit decisions regarding Tysabri use. The risks of Tysabri treatment are addressed through the distribution program, along with education of prescribers, pharmacists, infusion center staff, and patients about potential PML infection associated with Tysabri treatment. Safety and efficacy of treatment with Tysabri beyond two years are not known.

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, often disabling disease of the brain and spinal cord. According to the MS Association of America, approximately 350,000 individuals have been diagnosed with MS in the U.S., with an estimated 10,000 diagnosed each year. The most common form of MS at the time of initial diagnosis is a relapsing-remitting form (RRMS), in which acute symptoms or worsening of neurologic function (referred to as “relapses”, “attacks”, or “exacerbations”) occur intermittently.

Prior to receiving treatment for MS with Tysabri, a MRI brain scan must be obtained for each patient to aid in the differentiation of potential MS symptoms from PML. To enable early identification of potential cases, periodic follow-ups are required at three and six months after the initial infusion and then every six months thereafter.

NOTE: Patient must be enrolled in and meet all the criteria of the MS TOUCH Prescribing Program.

Crohn’s disease

Crohn's disease (CD) is a chronic, inflammatory bowel disease that affects both men and women. There is no cure. CD can cause diarrhea, fever, rectal bleeding, malnutrition, narrowing of the intestinal tract, obstructions, abscesses, cramping, and abdominal pain. The disease also can lead to abnormal connections (fistulas) leading from the intestine to the skin or internal organs. Its cause is unknown. There are more than one million people with CD worldwide.

In CD patients, a baseline brain MRI may be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on Tysabri therapy are uncommon.

NOTE: Patient must be enrolled in and meet all the criteria of the CD TOUCH Prescribing Program.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

This medical policy includes guidelines based on current standards of practice derived from peer reviewed, evidence-based literature. These references include, but are not limited to, FDA labeling, Milliman, Hayes, DrugDex, NCCN, AAP, Transfusion Medicine, Biologics Compendium, Infectious Disease Society of America, American Society of Hematology, and CMS coverage policy. A requested therapy must be proven effective for the diagnosis, procedure, drug dose, frequency and duration, if applicable, and also be consistent with recommendations in at least one authoritative source. The coverage positions in this medical policy is supported by FDA labeling, nationally recognized societies and evidenced base guidelines.

Tysabri® (natalizumab) may be considered medically necessary as monotherapy for the treatment of adult patients (18 years of age and older) with relapsing forms of multiple sclerosis (MS) to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations in patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies AND when meeting ALL the following criteria:

  • Medical record documentation (by a neurologist) with a diagnosis of a relapsing form of MS. Note:  Relapsing forms of MS include Relapsing-Remitting MS (RRMS), Secondary Progressive MS (SPMS) with relapses, and Progressive-Relapsing MS (PRMS).
  • Documentation of a magnetic resonance imaging (MRI) brain scan prior to initiating Tysabri therapy. Note: The MRI scan may be helpful in differentiating subsequent MS symptoms from Progressive Multifocal Leukoencephalopathy (PML).
  • Medical record documentation of a patient’s: 
    1. Inadequate response to alternative MS therapies  (i.e., continued relapses with resulting disability) OR
    2. Inability to tolerate alternative MS therapies (i.e., severe side effects such as severe flu like symptoms, severe fatigue, etc.).

NOTE:  The U. S. Food and Drug Administration (FDA) recommends that anyone who has been taking an immune-modifying MS drug (such as Copaxone, Betaseron, Avonex, or Rebif) should not begin Tysabri for two weeks after the last dose, and that anyone who has been taking an immune-suppressing drug (such as Novantrone, Cytoxan, or Imuran) should not begin Tysabri for three to six months after the last dose. Other drugs which weaken the immune system are monthly intravenous steroids.

Tysabri (natalizumab) may be considered medically necessary for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease (CD) with evidence of inflammation who have had an inadequate response to, or are unable to tolerate conventional CD therapies and inhibitors of TNF-a, AND when meeting ALL the following criteria:

  • Medical record documentation of a patient’s inadequate response to conventional CD therapies and inhibitors of TNF-a; 
  • Documentation that patient is not receiving chronic immunosuppressant or immunomodulatory therapy; and
  • Documentation that patient has no systemic medical conditions resulting in significant compromised immune system function.

NOTE:  The FDA, commenting on CD patients without a complicating neurologic condition, stated "...a baseline brain MRI may also be helpful to distinguish preexistent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on Tysabri therapy are uncommon."

NOTE:  The FDA recommends discontinuing Tysabri for CD in patients who have not experienced therapeutic benefit by twelve weeks of induction therapy, and in patients who cannot discontinue chronic concomitant steroids within six months of starting therapy. Other than the initial six-month taper, prescribers should consider discontinuing Tysabri for patients who require additional steroid use that exceeds three months in a calendar year to control their CD.

NOTE:  In CD, Tysabri should not be used in combination with immunosuppressants or inhibitors of TNF-a.

Tysabri® (natalizumab) is considered experimental, investigational and/or unproven for all other indications including but not limited to, Non-relapsing MS, Rheumatoid Arthritis, or Ulcerative Colitis.

Rationale

Multiple Sclerosis

The FDA approved the reintroduction of Tysabri as a monotherapy treatment for relapsing forms of MS in June 2006 and is currently available only under a special restricted distribution program, TOUCH®. A black box warning is included in the FDA labeling mentioning the risk of PML and outlining the TOUCH program.  The FDA notes that there is no known treatment, prevention, or cure for PML. Although the risk for PML may be higher for patients receiving concurrent immunosuppressive therapy, the potential for lower risk with natalizumab monotherapy and the potential effects of extended duration of treatment remain unclear.

In March 2006 results were presented from the two-year studies of Tysabri alone (AFFIRM study) and Tysabri added to Avonex® (interferon beta-1a, the SENTINEL study). The AFFIRM study authors report that Tysabri reduced the risk of sustained progression of disability and the rate of clinical relapse in those with relapsing MS. The SENTINEL study authors report that adding Tysabri to Avonex therapy was significantly more effective than Avonex alone in relapsing MS. However, two of the cases of PML occurred in patients who had been taking this drug combination. The safety profile of Tysabri taken as monotherapy for up to two years appears to be acceptable. However, its combination with other immune-modulating or immune-suppressing agents appears to enhance the risk of PML, an often fatal disease.

AFFIRM Study:

The AFFIRM study involved 942 individuals with relapsing MS, who received either Tysabri or inactive placebo by intravenous infusions every four weeks for more than two years. The established primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability as measured by the Expanded Disability Status Scale (EDSS) at two years. The paper, written by Chris H. Polman, M.D. (Vrije Universities Medical Center, Amsterdam) and colleagues, reports that the study achieved its primary outcome by slowing the risk of progression of disability by 42 percent. The drug reduced the rate of clinical relapses by 68% over two years, and reduced the development of new or newly enlarging MRI-detected brain lesions by 83%. The drug also reduced the mean number of enhancing (active) MRI lesions by 92% after the first and second year.

SENTINEL Study:

The SENTINEL study involved 1171 people with relapsing MS who were on Avonex but had experienced at least one relapse during the previous 12 months. All participants continued on Avonex, in combination with either Tysabri or inactive placebo given by intravenous infusions every four weeks for up to 116 weeks. The established primary end points were the rate of clinical relapse at one year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the EDSS (a standard disability scale), at two years.

A recent study published in the New England Journal of Medicine cites the possibility of one patient in a thousand having the risk of PML if they take Tysabri.  Allan H. Ropper, M.D. (Caritas St. Elizabeth’s Medical Center, Boston) notes, “It seems that less than two years of treatment with natalizumab alone is relatively safe, but the possibility remains that PML will develop in 1 in 1000 patients. At the moment, it is doubtful that neurologists will chance using natalizumab in conjunction with other immunosuppressive agents, with the possible exception of corticosteroids when they are required for acute relapses.”  Of the three confirmed cases of PML, two had occurred in a study of Tysabri combined with Avonex (interferon beta-1a) and the patient with CD had received other immunosuppressive treatment.

A 5,000 patient cohort observational study, “Tysabri Global Observation Program in Safety (TYGRIS)” will be conducted over the next five years to further assess PML risk and overall safety of Tysabri.

There are no clinical scientific studies that support the use of Tysabri for non-relapsing forms of MS.  In contrast to trials in patients with multiple sclerosis, results from the clinical trials of Tysabri in CD patients have proved unclear. While early trials suggested that Tysabri was effective in inducing remission in patients with active CD, this was not supported by data from the phase III “Evaluation of Natalizumab as Continuous Therapy (ENACT) -1 trial” which failed to meet its primary efficacy endpoint. However, more encouraging data have since emerged from the ENACT-2 trial, which suggest that Tysabri is effective in maintaining remission once an acute flare-up has been brought under control.  Results from the two phase III trials conducted to date present the companies with a dilemma, as it appears that while not effective in inducing remission in patients with active disease, Tysabri is nonetheless effective in maintaining remission. Following discussion with the FDA an additional induction trial is planned. The outcome of this trial will be important in determining whether Tysabri can one day be marketed as a treatment for Crohn's disease.

Crohn’s Disease

The FDA's approval was based primarily on two clinical studies, ENCORE and ENACT-2.

Data from the ENCORE trial showed that TYSABRI induced response and remission among patients with moderately to severely active Crohn’s disease, and objective evidence of inflammation, as measured by elevated C-reactive protein. After 12 weeks of therapy, 60% of TYSABRI-treated patients attained response, compared to 44% of placebo treated patients, and 48% of patients had sustained response at both weeks 8 and 12, compared to 32% of placebo treated patients (p<0.005 for both). Among the patients who had inadequate response to prior treatment with inhibitors of TNF-alpha, 38% achieved sustained response at weeks 8 and 12.

ENACT-2 showed that an additional year of Tysabri therapy sustained response and remission among patients with an initial response to Tysabri after three months in ENACT-1. Of patients with response in ENACT-1, sustained response during ENACT-2 was seen in 61% of patients treated with TYSABRI at every visit through an additional six months of therapy, compared to 29% for placebo. This treatment difference was also sustained through 12 months of additional therapy (54% vs. 20%). Remission was sustained at every visit with an additional six months or 12 months of TYSABRI in 45% and 40% of patients, respectively, compared to 26% and 15% of placebo treated patients (p<0.005 for all comparisons). Among the patients that had previously failed TNF-inhibitors, response and remission was sustained at every visit through an additional six months of TYSABRI in 52% and 30% of patients, respectively. Among patients on steroids and in whom a clinical response was achieved, approximately two-thirds were able to discontinue steroids within 10 weeks of beginning to taper steroids.

2010 Update

A search of peer reviewed literature through October 2010 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.

2013 Update

A search of peer reviewed literature through October 2013 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

340, 555.0-555.9

ICD-10 Codes

G35, K50-K50.919

Procedural Codes: J2323
References
  1. Food and Drug Administration (FDA). FDA approves resumed marketing of Tysabri under a special distribution program. FDA News. (June 5, 2006) P06-75. Rockville, MD.
  2. Biogen Idec. Tysabri (natalizumab) information center [website]. Cambridge, MA: Biogen Idec; (2006). Available at: http://www.biogenidec.com .
  3. Langer-Gould A., Steinman L. What went wrong in the natalizumab trials?  Lancet. (2006) 367(9512):708-10.
  4. Polman, C.H., O'Connor, P.W., et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine (2006) 354:899-910.
  5. Rudick, R.A., Stuart, W.H., et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. New England Journal of Medicine (2006) 354:911-23.
  6. Yousry, T.A., Major, E.O., et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. New England Journal of Medicine (2006) 354:924-33.
  7. Ropper, A.H. Selective treatment of multiple sclerosis. New England Journal of Medicine. (2006) 354:965-67.
  8. National Multiple Sclerosis Society, Research/Clinical Update:  Frequently asked questions and their answers concerning Tysabri. www.nmss.org  (2006 July 25).
  9. Phillips, T., Kappos, L., et al. The effects of natalizumab monotherapy on multiple measures of disability progression in MS patients. Program and abstracts of the American Academy of Neurology 58th Annual Meeting; April 1-8, 2006, San Diego, California Abstract S02.005.
  10. Stuve O, Marra C, et al. Immune surveillance in multiple sclerosis patients treated with Natalizumab. Program and abstracts of the American Academy of Neurology 58th Annual Meeting; April 1-8, 2006, San Diego, California Abstract S32.001.
  11. FDA – FDA News – FDA Approved Tysabri to Treat Moderate-to-Severe Crohn’s Disease. (January 2008) www.fda.gov .
  12. Product Information: TYSABRI(R) IV injection, natalizumab IV injection. Biogen Idec Inc, Cambridge, MA, 2009.
  13. Thomson Reuters - Micromedex Healthcare Series. Drugdex Evaluations: Natalizumab. www.thomsonhc.com .  Last accessed November 2013.
  14. FDA - Department of Health and Human Services - Tysabri- Approval Labeling. Last accessed November 2013.
History
April 2013  New 2013 BCBSMT medical policy.  Considered possibly investigational.
February 2014 Document updated with literature review. Coverage unchanged.
BCBSMT Home
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Tysabri (Natalizumab)