Natalizumab (Tysabri)

Number: 0751

Policy

Note: Site of Care Utilization Management Policy applies.  For information on site of service for natalizumab (Tysabri), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

  1. Aetna considers natalizumab (Tysabri) monotherapy medically necessary for the treatment of individuals with relapsing forms of multiple sclerosis (e.g., relapsing‐remitting MS (RRMS), secondary‐progressive MS (SPMS) with relapses, progressive‐relapsing MS (PRMS)) (but not for the treatment of chronic progressive multiple sclerosis) for persons who meet all of the following criteria:

    1. Member is not adequately responsive to three or more of the following least cost medically necessary brands of drugs for relapsing multiple sclerosis: Aubagio, Avonex, Betaseron, Gilenya, Lemtrada, Plegridy, Rebif, Tecfidera, Glatopa 20 mg or Copaxone 40 mg; and

    2. Member has had anti-JCV antibody testing with ELISA prior to initiating treatment with natalizumab and annually thereafter. 

      For purpose of this policy, failure of an adequate trial of multiple sclerosis treatment is defined as follows:

      • The member has increasing relapses (defined as two or more relapses in a year, or one severe relapse associated with either poor recovery or MRI lesion progression); or
      • The member has lesion progression by MRI (increased number or volume of gadolinium-enhancing lesions, T2 hyperintense lesions or T1 hypointense lesions); or
      • The member has worsening disability (sustained worsening of Expanded Disability Status Scale (EDSS) score or neurological examination findings).

      Intolerance is defined as intolerable side effects despite optimized management strategies.

      Aetna considers use of natalizumab in combination with other disease modifying treatments (interferons, Copaxone, Glatopa, Gilenya, Aubagio, or Tecfidera) experimental and investigational because there is a lack of reliable evidence that use of natalizumab in combination with other disease modifying treatments is more effective than use of natalizumab alone.

      See also CPB 0264 - Multiple Sclerosis.

  2. Crohn's disease:

    1. Active Crohn's disease

      Aetna considers natalizumab medically necessary for the treatment of moderate to severe active Crohn's disease in adult members 18 years of age and older, where active Crohn's disease is manifested by one or more of the following signs and symptoms:

      • Abdominal pain;
      • Bleeding;
      • Diarrhea;
      • Extra-intestinal manifestations: arthritis or spondylitis;
      • Internal fistulae;
      • Intestinal obstruction;
      • Megacolon;
      • Perianal disease; or
      • Weight loss; and

      Member has had an inadequate response to, or are unable to tolerate, conventional Crohn's disease therapies including anti-inflammatory drugs (e.g., sulfasalazine), corticosteroids, immunosuppressive agents (e.g., 6-mercaptopurine or azathioprine), and inhibitors of tumor necrosis factor-alpha (e.g., adalimumab or infliximab); and

      Member has had anti-JCV antibody testing with ELISA prior to initiating treatment with natalizumab and annually thereafter; and

      Member has failed to adequately respond to one or more of the least-cost medically necessary targeted immune modulators for Crohn's disease: Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Remicade (infliximab), or Stelara (ustekinumab).

    2. Fistulizing Crohn's disease

      Member is 18 years of age and older and has fistulizing Crohn's disease for at least 3 months, and

      Member has had anti-JCV antibody testing with ELISA prior to initiating treatment with natalizumab and annually thereafter; and

      Member has failed to adequately respond to one or more of the least-cost medically necessary targeted immune modulators for Crohn's disease: Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Remicade (infliximab), or Stelara (ustekinumab).

      Note: continuation criteria for either active or fistulizing Crohn's disease requires a documented diagnosis (as per above), clinical documentation indicating there is disease stablity or improvement, and the member has had documented anti-JCV antibody testing with ELISA within the last 12 months. 
  3. Aetna considers use of natalizumab in combination with immunosuppressants or tumor necrosis factor inhibitors (e.g., adalimumab (Humira), infliximab (Remicade) experimental and investigational because the safety and effectiveness of these combinations has not been established. Note: According to the Product Insert, in Crohn's disease, natalizumab should not be used in combination with immunosuppressants or inhibitors of tumor necrosis factor-alpha (e.g., adalimumab, infliximab).

  4. Aetna considers natalizumab experimental and investigational for all other indications (e.g., acute ischemic stroke, chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, Rasmussen encephalitis, stem cell mobilization, and ulcerative colitis) because its effectiveness for indications other than the ones listed above has not been established.

  5. Aetna considers testing for anti-natalizumab antibodies medically necessary for individuals with a suboptimal clinical response.  Note: Repeat testing at 3 months after the initial positive result is recommended in individuals in whom antibodies are detected to confirm that antibodies are persistent.  Prescribers should consider the overall benefits and risks of natalizumab in persons with persistent antibodies.

  6. Aetna considers anti-JCV antibody testing with ELISA medically necessary prior to initiating treatment with natalizumab and annually thereafter to assess risk of developing progressive multifocal leukoencephalopathy.  Aetna considers polymerase chain reaction (PCR) testing of cerebrospinal fluid for John Cunningham (JC) polyomavirus, for diagnosis of progressive multifocal leukoencephalopathy in persons before initiating natalizumab treatment not medically necessary.  For indications for PCR testing for JC polyomavirus, see CPB 0650 - Polymerase Chain Reaction - Selected Indications.

  7. Aetna considers pro-angiogenic factor matrix metalloproteinase 9 (MMP9) as a biomarker for predicting PML risk in natalizumab-treated individuals experimental and investigational because the effectiveness of this approach has not been established.

Note: There are several brands of targeted immune modulators on the market. There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Otezla (apremilast), Remicade (infliximab), Renflexis (infliximab-abda), Simponi (golimumab), Simponi Aria (golimumab intravenous), Stelara (ustekinumab), Tremfya (guselkumab), Xeljanz and Xeljanz XR (tofacitinib) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because Actemra (tocilizumab), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab), and Tysabri (natalizumab) brands of targeted immune modulators are more costly than the least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, these brands of targeted immune modulator will be considered medically necessary only if the member has a contraindication, intolerance or incomplete response to the following numbers of trials of least cost brands of targeted immune modulators by indication:

  • Ankylosing spondylitis – two least cost brands
  • Crohn’s disease – one least cost brand (not including Renflexis)
  • Juvenile idiopathic arthritis – trial of Enbrel (etanercept)
  • Plaque psoriasis – three least cost brands
  • Psoriatic arthritis – three least cost brands
  • Rheumatoid arthritis – three least cost brands
  • Ulcerative colitis – one least cost brand (not including Renflexis)

Note that Cimzia (certolizumab), Cosentyx (secukinumab), Ilaris (canakinumab), Ilumya (tildrakizumab-asmn), Kevzara (sarilumab), Olumiant (baricitinib), Siliq (brodalumab), and Taltz (ixekizumab) brands of targeted immune modulators do not require a trial of a least cost brand of targeted immune modulator; there may, however, be a higher copayment where these brands are covered under pharmacy plans with a tiered formulary. Please check benefit plan descriptions. If the least costly targeted immune modulators do not have the labeled indication (see Appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication. Also note that Renflexis is not a least cost brand for Crohn’s disease and ulcerative colitis indications.

See also CPB 0249 - Inflammatory Bowel Disease: Serologic Markers and Pharmacogenomic and Metabolic Assessment of Thiopurine TherapyCPB 0341 - Infliximab, and CPB 0655 - Adalimumab (Humira).

Background

Natalizumab (Tysabri, Biogen-Idec, Cambridge, MA) is a recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells. The antibody has a human framework region and a murine complement region that binds to alpha4‐integrin. The specific mechanism by which natalizumab exerts its effects in multiple sclerosis (MS) and Crohn’s disease (CD) is not yet fully defined. In MS, natalizumab may produce a clinical effect by binding to alpha4β1‐integrin and preventing activated inflammatory cells from entering the blood brain barrier. These inflammatory cells are thought to produce lesions. In CD, natalizumab may produce a clinical effect by binding to alpha4β7‐integrin and preventing the recruitment of leukocytes to the gut mucosa. Leukocyte recruitment is implicated in the inflammatory response that is characteristic of CD.

Natalizumab has been approved by the U.S. Food and Drug Administration (FDA) as monotherapy for the treatment of patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations.The safety and efficacy of natalizumab beyond two years is unknown. Because Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), natalizumab is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies.

Natalizumab has also been approved by the FDA for inducing and maintaining clinical response and remission in adult patients with moderately to severely active CD with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF‐alpha.Natalizumab should not be used in combination with immunosuppressants or inhibitors of TNF‐alpha.

It was initially approved by the FDA in November 2004 for the treatment of patients with relapsing forms of multiple sclerosis (MS) who have not responded adequately, or can not tolerate, other treatments for MS.  However, Tysabri was withdrawn from the market in February 2005, after 3 patients in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML).  Two of the cases were fatal.  The FDA allowed a clinical trial of natalizumab to resume in February 2006, following a re-examination of the patients who had participated in the previous clinical trials, confirming that there were no additional cases of PML.  To decrease the possibility of patients developing PML in the future, the manufacturer, Biogen-IDEC, submitted to the FDA a Risk Management Plan, called the TOUCH Prescribing Program, to ensure safe use of the product (Baker, 2007).  The FDA has determined that natalizumab can be made available under the TOUCH Prescribing Program with the following main features:

  • Natalizumab will only be administered to patients who are enrolled in the program.
  • Patients on natalizumab are to be evaluated at 3 and 6 months after the first infusion and every 6 months after that, and their status will be reported regularly to the product’s manufacturer.
  • Prior to initiating the therapy, health care professionals are to obtain the patient's magnetic resonance imaging (MRI) scan to help differentiate potential future MS symptoms from PML.
  • The drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program.

An assessment of the use of natalizumab for MS by the American Academy of Neurology (AAN, 2008) reached several conclusions.  The AAN found that natalizumab reduces measures of disease activity such as clinical relapse rate, gadolinium (Gd)-enhancement, and new and enlarging T2 lesions in patients with relapsing MS.  The AAN also found that natalizumab improves measures of disease severity such as the Expanded Disability Status Scale (EDSS) progression rate and the T2-hyperintense and T1-hypointense lesion burden seen on MRI in patients with relapsing MS.  The AAN reported that the relative efficacy of natalizumab compared to other available disease-modifying therapies is unknown.  In addition, the AAN found that the value of natalizumab in the treatment of secondary progressive multiple sclerosis (SPMS) is unknown.  The AAN stated that the SENTINEL trial provides evidence for the value of adding natalizumab to patients already receiving interferon-beta-1a (IFNbeta-1a,) 30 micrograms, intra-muscularly (IM) once-weekly.  The AAN found that it provides no information either about the value of adding IFN-beta therapy to patients already receiving natalizumab in the treatment of relapsing-remitting multiple sclerosis (RRMS) or about the value of continuing IFN-beta therapy once natalizumab therapy is started.  The AAN assessment found that there is an increased risk of developing PML in natalizumab-treated patients.  The 2 cases seen in MS were treated with a combination of natalizumab and IFN-beta-1a, but the fact that PML occurred only with combination therapy may be a chance development.  The AAN reported that there may also be an increased risk of other opportunistic infections.  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.  The AAN reported that, since the development of their guideline, 2 cases of PML have been reported in patients receiving natalizumab monotherapy, 1 of whom had never previously received any immunomodulatory or immunosuppressive treatment.  The AAN noted that this observation indicates that natalizumab, by itself, is a risk factor for PML.  However, the evidence has not been formally reviewed by the Therapeutics and Technology Assessment Subcommittee (TTA).

The AAN assessment of natalizumab for MS recommended: "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.  "The AAN assessment also concluded: "Similarly, because combination therapy with IFN-beta 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."

Crohn's disease (CD), also known as enteritis or ileitis, is a chronic inflammatory bowel disease that affects men and women equally.  The etiology of CD is unknown, but evidence suggests that a genetic predisposition combined with an abnormal interaction between the gastrointestinal (GI) tract and enteric microorganisms may play a role in the pathogenesis.  About 20 % of patients with CD have a blood relative with some form of inflammatory bowel disease.  While the ileum and the colon are most commonly affected, any area of the GI tract from the mouth to the anus may be involved.  The ileum is affected in approximately 33 % of patients, the colon in 20 to 30 % of patients, and combined affliction of the ileum and the colon is observed in 40 to 50 % of patients.  The severity of symptoms, frequency of complications, and likelihood of intestinal resection as a consequence of CD are usually greater in patients with ileo-colic involvement than in those with disease limited to the ileum or the colon alone (Huprich et al, 2005; NDDIC, 2006).

Crohn’s disease can occur in all age groups, but it is more often diagnosed in people aged 20 to 30 years.  Moreover, individuals of Jewish heritage have an increased risk of developing CD, whereas African Americans are at decreased risk for developing CD.  The most common symptoms of CD are abdominal pain and diarrhea.  Other symptoms include abscesses, arthritis, cramping, fever, rectal bleeding, skin problems, and weight loss/malnutrition (NDDIC, 2006).

Conventional therapies for patients with CD include nutritional supplements, drugs, surgery, or a combination of these options.  Currently, there is no cure for CD.  The goals of treatment are to control inflammation, correct nutritional deficiencies, and relieve symptoms.  Pharmacotherapy entails antibiotics (e.g., ampicillin, sulfonamide, and tetracycline), anti-diarrheal agents (e.g., codeine, diphenoxylate, and loperamide), anti-inflammatory drugs/disease modifying anti-rheumatic drugs (e.g., sulfasalazine and methotrexate), corticosteroids (e.g., budesonide and prednisone), immunosuppresssive agents (e.g., 6-mercaptopurine and azathioprine) as well as biologics such as tumor necrosis factor (TNF) inhibitors (e.g., infliximab and adalimumab) (NDDIC 2006; Lichtenstein et al, 2006). 

Another biologic that has been used in the treatment of CD is natalizumab (Ghosh et al, 2003; Sanborn et al, 2005; Targan et al, 2007; Akobeng, 2008).  In a double-blind, placebo-controlled trial, Ghosh and colleagues (2003) examined the effectiveness of natalizumab in 248 patients with moderate-to-severe CD.  Subjects were randomly assigned to receive 1 of 4 treatments: (i) 2 infusions of placebo; (ii) 1 infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; (iii) 2 infusions of 3 mg of natalizumab per kilogram; or (iv) 2 infusions of 6 mg of natalizumab per kilogram.  Infusions were given 4 weeks apart.  Outcomes included changes in scores for the CD Activity Index (CDAI; higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein (CRP) levels.  The group given 2 infusions of 6 mg of natalizumab per kilogram body weight did not have a significantly higher rate of clinical remission (defined by a score of less than 150 on the CDAI) than the placebo group at week 6 (the prospectively defined primary end point in the effectiveness analysis).  However, both groups that received 2 infusions of natalizumab had higher remission rates than the placebo group at multiple time points.  Natalizumab also produced a significant improvement in response rates (defined by a reduction of at least 70 points in the score on the CDAI).  The highest remission rate was 44 % and the highest response rate was 71 % (at week 6 in the group given 2 infusions of 3 mg per kilogram).  Overall, the 2 infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects.  The quality of life improved in all natalizumab groups; CRP levels improved in groups receiving 2 infusions of natalizumab.  The rates of adverse events were similar in all four groups.  The authors concluded that treatment with natalizumab increased the rates of clinical remission and response, improved the quality of life and CRP levels, and was well-tolerated in patients with active CD.

Sandborn and associates (2005) performed 2 controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active CD.  In the first study, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8.  The primary outcome was response, defined by a decrease in the CDAI score of at least 70 points, at week 10.  In the second study, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every 4 weeks through week 56.  The primary outcome was a sustained response through week 36.  A secondary outcome in both trials was disease remission (a CDAI score of less than 150).  The first study showed that the natalizumab and placebo groups had similar rates of response (56 % and 49 %, respectively; p = 0.05) and remission (37 % and 30 %, respectively; p = 0.12) at 10 weeks.  Continuing natalizumab in the second study resulted in higher rates of sustained response (61 % versus 28 %, p < 0.001) and remission (44 % versus 26 %, p = 0.003) through week 36 than did switching to placebo.  Serious adverse events occurred in 7 % of each group in the first trial and in 10 % of the placebo group and 8 % of the natalizumab group in the second trial.  In an open-label extension study, a patient treated with natalizumab died from PML.  The authors concluded that induction therapy with natalizumab for CD resulted in small, non-significant improvements in response and remission rates.  Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every 4 weeks.

In a randomized placebo-controlled trial, Targan et al (2007) evaluated the effectiveness of natalizumab induction therapy in patients with CD.  Patients (n = 509) with moderate-to-severe active CD and active inflammation characterized by elevated CRP concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at weeks 0, 4, and 8.  The primary end point was induction of response (greater than or equal to 70-point decrease from baseline in the CDAI score at week 8 sustained through week 12).  Additional effectiveness end points included the proportion of patients with sustained remission (CDAI score less than 150 points) and response or remission over time.  Response at week 8 sustained through week 12 occurred in 48 % of natalizumab-treated patients and 32 % of patients receiving placebo (p < 0.001).  Sustained remission occurred in 26 % of natalizumab-treated patients and 16 % of patients receiving placebo (p = 0.002).  Week 4 response rates were 51 % for natalizumab and 37 % for placebo (p = 0.001).  Responses remained significantly higher at subsequent assessments (p < 0.001) in natalizumab-treated patients.  Natalizumab-treated patients also had significantly higher remission rates at weeks 4, 8, and 12 (p < or = 0.009).  The frequency and types of adverse events were similar between treatment groups.  The authors concluded that natalizumab induced 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 effectiveness of natalizumab as induction therapy in patients with elevated CRP and active CD.  This is in agreement with a Cochrane review on the use of natalizumab for induction of remission in CD (MacDonald and McDonald, 2007), which concluded that pooled data suggest that natalizumab is effective for induction of clinical response and remission in some patients with moderate-to-severe active CD.

In a single-arm study, Hyams and colleagues (2007) evaluated the safety, tolerability, and effectiveness of natalizumab in adolescent patients with moderate-to-severe active CD (n = 38; aged 12 to 17 years; pediatric CDAI [PCDAI] greater than 30).  Patients received 3 intravenous infusions of natalizumab (3 mg/kg) at 0, 4 and 8 weeks.  The primary analysis was safety, assessed by adverse events, laboratory results, and vital signs.  Pharmacokinetic and pharmacodynamic measurements and formation of anti-natalizumab antibodies also were analyzed.  Effectiveness outcomes were assessed by changes in PCDAI, quality of life (IMPACT III), and levels of CRP and serum albumin.  Thirty-one patients (82 %) received 3 natalizumab infusions.  The most common adverse events were headache (26 %), pyrexia (21 %) and CD exacerbation (24 %).  Clinical response (greater than or equal to 15-point decrease from baseline PCDAI) and remission (PCDAI less than or equal to 10) rates were greatest at week 10 (55 % and 29 %, respectively).  Three patients (8 %) tested positive for anti-natalizumab antibodies.  The peak level (61.0 and 66.3 microg/ml) and half-life (92.3 and 96.3 hours) of natalizumab were comparable after the first and third infusions.  Mean [alpha]4 integrin receptor saturation was 93 % at 2 hours and less than 40 % at 4 weeks after the first and third infusions.  Increase from baseline in circulating lymphocytes ranged from 106 % to 122 % at 2 weeks and 45 % to 65 % at 4 weeks after each infusion.  The authors concluded that natalizumab (3 mg/kg) was well-tolerated in these adolescent patients with active CD, with a safety and effectiveness profile similar to that of adult natalizumab-treated CD patients.  They noted that future studies should evaluate long-term safety and effectiveness.

On January 14, 2008, the FDA approved natalizumab for the treatment of moderate-to-severe CD in adults with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-alpha.  Moreover, as in the use of this drug for relapsing forms of MS, CD patients using natalizumab must be enrolled in a special restricted distribution program called the Crohn's Disease - Tysabri Outreach Unified Commitment to Health (CD-TOUCH) Prescribing Program.  Under CD-TOUCH, health care providers evaluate CD patients after 3 months of treatment to determine if they have improved on natalizumab.  If not, patients should discontinue treatment.  Individuals who are taking corticosteroids for CD should begin tapering steroid doses while on natalizumab.  Treatment should be discontinued if steroids can not be fully tapered within 6 months.

In addition to PML, serious side effects of natalizumab include hypersensitivity reactions (e.g., anaphylaxis and liver injury).  Other atypical infections have also been seen in patients receiving immunosuppressive agents while on natalizumab; serious herpes infections have also been observed.  Common side effects of natalizumab include fatigue, headache, rash, infusion reactions, urinary tract infections, as well as joint and limb pain.

A small number of of patients receiving natalizumab developed detectable antibodies at least once during treatment.  Calabresi et al (2007) ascertained the incidence and clinical effects of antibodies that develop during treatment with natalizumab.  In 2 randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing MS, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab.  Antibodies to natalizumab were measured using an ELISA.  Patients were categorized as "transiently positive" if they had detectable antibodies greater than or equal to 0.5 microg/ml) at a single time point or "persistently positive" if they had antibodies at 2 or more time points greater than or equal to 6 weeks apart.  In the AFFIRM study, antibodies were detected in 57 of 625 (9 %) of natalizumab-treated patients: 20 (3 %) were transiently positive and 37 (6 %) were persistently positive.  Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p less than or equal to 0.05), relapse rate (p = 0.009), and MRI (p less than or equal to 0.05) compared with antibody-negative patients.  In transiently positive patients, full efficacy was achieved after about 6 months of treatment, the time when patients were becoming antibody negative.  The incidence of infusion-related adverse events was significantly higher in persistently positive patients.  Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant.  The authors concluded that the incidence of persistent antibody positivity associated with natalizumab is 6 %.  Reduced clinical efficacy is apparent in persistently positive patients.  They noted that patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing.

In an editorial that accompanied the study by Calabresi et al, Freedman and Pachner (2007) stated that "routine NAb testing for anti-natalizumab antibodies is unwarranted, but clinicians need to reconsider the effect of a treatment when patients continue to have an increased level of disease activity.  Whether this is due to the development of NAb against the treatment or some other biologic reason, it still might be in the best interest of the patient to consider a change in therapy that will produce a better clinical response".

Indeed the FDA-approved labeling for natalizumab (Tysabri) states that testing for antibodies should be performed if they are suspected.  Antibodies may be detected and confirmed with sequential serum antibody tests.  Antibodies detected early in the treatment course (e.g., within the first 6 months) may be transient and disappear with continued dosing.  Repeat testing at 3 months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent.

Neumann and colleagues (2009) stated that natalizumab is approved by the DFA for the treatment of patients with MS and Crohn's disease.  These investigators focused on its role in the context of hematopoietic stem cell transplantation and stem cell diseases.  The use of natalizumab alone or in combination with either cytotoxic drugs or other antibodies might be a new modality for stem cell mobilization and a therapeutic option for patients with hematologic malignancies.

Wolf et al (2010) presented the clinical and para-clinical effects of natalizumab (300 mg)in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) who did not respond to standard therapies.  Main outcome measures included clinical disability, MRI, and saturation of the alpha(4) integrin on T lymphocytes.  T cells expressing the alpha(4) integrin were found in the inflamed peripheral nerve.  Natalizumab bound with high affinity to the alpha(4) integrin on T lymphocytes in the patient.  However, the patient's clinical condition deteriorated and as seen on MRI without any measurable effect after treatment with natalizumab.  The authors concluded that although experimental evidence suggests that natalizumab could theoretically be effective in immune-mediated disorders of the peripheral nervous system, this patient with CIDP did not benefit from this therapeutic approach.  They stated that natalizumab can not be recommended in CIDP at present and should only be explored in controlled clinical trials.

In a retrospective case-series study, Kleiter and colleagues (2012) described their first experiences with natalizumab, given to patients with suspected RRMS who were later diagnosed with aquaporin 4-positive neuromyelitis optica (NMO).  Main outcome measures were relapses and accumulation of disability.  These investigators identified 5 patients (1 male and 4 females; median age of 45 years) who were initially diagnosed with MS and treated with natalizumab before diagnosis of NMO was established.  Natalizumab was given as escalation therapy after failure of 1st- or 2nd-line immunomodulatory therapies for MS.  During natalizumab therapy (median duration of 8 infusions; range of 2 to 11 infusions), all 5 patients displayed persisting disease activity; a total of 9 relapses occurred (median duration to relapse, 120 days; range of 45 to 230 days) after the start of treatment.  Four patients had an accumulation of disability and 1 patient died 2 months following cessation of natalizumab treatment.  The authors concluded that these findings suggested that natalizumab fails to control disease activity in patients with NMO.

Barnett and associates (2012) noted that auto-antibody mediated astrocyte injury is implicated as a primary event in NMO by biomarker, post-mortem and experimental studies that differentiate the condition from MS.  These researchers described the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies.  These findings supported autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease.  The authors stated that adherence to current NMO diagnostic criteria may delay treatment, or lead to inappropriate therapy with beta-interferon or natalizumab.

In a review on "Monoclonal antibodies in the treatment of neuroimmunological diseases", Rommer et al (2014) stated that over the past 25 years, monoclonal antibodies (MAbs) have become important elements in the therapeutic concepts for numerous clinical specialities, including oncology, gastroenterology, hemostaseology and endocrinology.  One of the most dynamic fields of their use is the treatment of autoimmune diseases.  Although the number of existing MAbs interfering with the immune system has increased remarkably and many studies have yielded encouraging results in the treatment of neuroimmunological diseases, their clinical use is still limited compared with standard treatments.  The only MAb that has been approved for a neuroimmunological disease by now is natalizumab for the treatment of RRMS.  The authors provided an overview on MAbs that are currently in use or under investigation for treating neuroimmunological diseases like MS, NMO, CIDP, inclusion body myositis, dermatomyositis, polymyositis, opsoclonus-myoclonus syndrome, multi-focal motor neuropathy, anti-myelin-glycoprotein neuropathy, stiff person syndrome, and myasthenia gravis.

The FDA-approved labeling for natalizumab (Tysabri) states that 300 mg of natalizumab (Tysabri) should be infused intravenously over approximately 1 hour, every 4 weeks.  In CD patients, natalizumab should be discontinued in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in patients that can not discontinue chronic concomitant steroids within 6 months of starting therapy.

Bittner et al (2013) presented the first case of Rasmussen encephalitis (RE) treated with natalizumab.  This therapy was initiated under the rationale that peripheral lymphocytes invading the central nervous system contribute to disease activity and seizure generation.  Leukocyte-endothelial interaction has been proposed as a potential target for the treatment of epilepsy in pre-clinical studies.  Interestingly, treatment with natalizumab in a patient with MS and refractory epilepsy improved both MS condition and seizure frequency previously.  In this patient, these investigators observed a reduction of seizure frequency early after treatment initiation with natalizumab.  The effect lasted for more than 1 year.  It should be kept in mind that interpretation of these data is limited by an additional co-administration of varying anti-epileptic medications.  The authors concluded that treatment strategies for RE that target specific immune cell subtypes (such as B cells with rituximab and CD4+ T cells with natalizumab) remain to be clarified in future clinical studies. 

Bright et al (2014) prospectively reviewed the literature to determine the effectiveness of therapies for CIDP.  Articles published from January 1990 to December 2012 were searched for studies to treat adults with CIDP; peer-reviewed full-text articles published in English were included.  A total of 9 placebo-controlled double-blinded randomized trials were reviewed to treat subjects with CIDP exhibiting various degrees of effectiveness.  The most effect treatments were; 3 randomized controlled trials (RCTs) using intravenous immunoglobulin (IVIG), a study comparing pulsed dexamethasone and short-term prednisolone and rituximab all showed promising results and were well-tolerated.  The authors concluded that IVIG and corticosteroids remain first line treatments for CIDP.  Therapies using monoclonal antibodies, such as rituximab and natalizumab offer the most promise for treatment of CIDP; however they also need further research, as does the use of stem cell therapy for treating CIDP.  Moreover, they stated that large RCTs and better patient selection are needed to address responsiveness of CIDP patients to conventional treatments to elucidate mechanisms of action and future directions for therapeutic improvement.

An UpToDate review on “Natalizumab for treatment of Crohn disease in adults” (Korzenik, 2014) states that “Natalizumab is intended for use as monotherapy.  It should not be used in patients who may have impaired immunity, are taking immunosuppressants, or are taking TNF inhibitors.  We suggest stopping glucocorticoids within a few months of initiation of natalizumab.  A two-month washout is reasonable for azathioprine/6 mercaptopurine, methotrexate, anti-TNF agents, and mycophenolate.  Leukocyte and neutrophil counts should be within or close to the normal range prior to starting therapy”.

Furthermore, the product labeling warns against concurrent use of Tysabri and TNF inhibitors because of the potential for increase in risk of progressive multifocal leukoencephalopathy.  The product labeling also states that, in clinical studies of natalizumab for CD, concurrent use of TNF inhibitors was not permitted, and it states that subgroup analysis showed that persons who failed to respond to a prior course of TNF inhibitors had a lower response rate than other CD patients.

Warnings and Precautions

  • Natalizumab carries a black box warning regarding PML and requires physicians, pharmacies, and patients to be enrolled in the risk management TOUCH program for access to therapy.
  • The safety and efficacy of natalizumab in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established.Patients receiving such therapies should not ordinarily be treated with natalizumab.
  • The TOUCH program requires patient follow up every six months for continued enrollment in the program.
  • Natalizumab has been associated with significant liver injury in the post‐marketing setting and should be discontinued in patients with jaundice or other evidence of significant liver injury.

Progressive Multifocal Leukoencephalopathy (PML)

Three factors that are known to increase the risk of PML in TYSABRI‐treated patients have been identified:

  • Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 4 years of TYSABRI treatment.
  • Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil).
  • The presence of anti‐JCV antibodies. Patients who are anti‐JCV antibody positive have a higher risk for developing PML.

Consideration should be given to testing patients for anti‐JCV antibody status prior to treatment or during treatment if antibody status is unknown. Infection by the JC virus is required for the development of PML. Anti‐JCV antibody negative status indicates that exposure to the JC virus has not been detected. Patients who are anti‐JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Therefore, patients with a negative anti‐JCV antibody test result should be retested every 6 months. For purposes of risk assessment, a patient with a positive anti‐JCV antibody test at any time is considered anti‐JCV antibody positive regardless of the results of any prior or subsequent anti‐JCV antibody testing. When assessed, anti‐JCV antibody status should be determined using an analytically and clinically validated immunoassay.

Natalizumab versus Fingolimod for Patients with Relapsing-Remitting Multiple Sclerosis

In a multi-center, observational study, Barbin and associates (2016) compared natalizumab (NTZ) and fingolimod (FGD) on both clinical and MRI outcomes in patients with RRMS from 27 MS centers participating in the French follow-up cohort Observatoire of Multiple Sclerosis.  Patients with RRMS included in the study were aged from 18 to 65 years with an EDSS score of 0 to 5.5 and an available brain MRI performed within the year before treatment initiation.  The data were collected for 326 patients treated with NTZ and 303 with FGD.  The statistical analysis was performed using 2 different methods:
  1. logistic regression and
  2. propensity scores (inverse probability treatment weighting). 

The confounder-adjusted proportion of patients with at least 1 relapse within the 1st and 2nd year of treatment was lower in NTZ-treated patients compared to the FGD group (21.1 % versus 30.4 % at 1st year, p = 0.0092; and 30.9 % versus 41.7 % at 2nd year, p = 0.0059) and supported the trend observed in non-adjusted analysis (21.2 % versus 27.1 % at 1st year, p = 0.0775).  Such statistically significant associations were also observed for gadolinium (Gd)-enhancing lesions and new T2 lesions at both 1st year (Gd-enhancing lesions: 9.3 % versus 29.8 %, p < 0.0001; new T2 lesions: 10.6 % versus 29.6 %, p < 0.0001) and 2nd year (Gd-enhancing lesions: 9.1 % versus 22.1 %, p = 0.0025; new T2 lesions: 16.9 % versus 34.1 %, p = 0.0010) post-treatment initiation.  The authors concluded that the findings of this observational suggested the superiority of NTZ over FGD to prevent relapses and new T2 and Gd-enhancing lesions at 1 and 2 years.  This study provided Class IV evidence.

 

This study had several drawbacks:
  1. these investigators chose MRI data as secondary outcomes but there was no central read-out, no central quality control, and no standard acquisition protocol for MRI data, 
  2. differences were also observed when comparing patients with MRI missing data (not included) and patients without (included).  As expected, patients with missing data had less active disease than the others, for whom the disease monitoring was probably more appropriate,
  3. the observational nature of the study, reflecting clinical practice with data representative of the MS population.  

The authors stated that the choice of the treatment not only depended on the effectiveness of the molecule, but also various factors including JCV testing and individual PML risk, the necessity for recurrent hospitalizations, or child-bearing potential.  They stated that considering these weaknesses, interpretation of the results should be made with caution until RCTs are available to compare NTZ and FGD.

Tsivgoulis and colleagues (2016) noted that although FGD and NTZ appear to be effective in the treatment of RRMS, they have never been directly compared in a RCT.  These researchers evaluated the comparative effectiveness of FGD versus NTZ using a meta-analytical approach.  Data from placebo-controlled RCTs were used for indirect comparisons and observational data were used for head-to-head comparisons.  These investigators identified 3 RCTs (2,498 patients) and 5 observational studies (2,576 patients); NTZ was associated with a greater reduction in the 2-year annualized relapse rate (ARR; SMDindirect = -0.24; 95 % confidence interval [CI]: -0.44 to -0.04; p = 0.005) and with the probability of no disease activity at 2 years (ORindirect = 1.82; 95 % CI: 1.05 to 3.15) compared to FGD, while no differences between the 2 therapies were found in the proportion of patients who remained relapse-free (ORindirect = 1.20; 95 % CI: 0.84 to 1.71) and those with disability progression (ORindirect = 0.76; 95 % CI: 0.48 to 1.21) at 2 years.  In the analysis of observational data, these researchers found no significant differences between NTZ and FGD in the 2-year ARR (SMD = -0.05; 95 % CI: -0.26 to 0.16), and 2-year disability progression (odds ratio [OR]: 1.08; 95 % CI: 0.77 to 1.52).  However, NTZ-treated patients were more likely to remain relapse-free at 2-years compared to FGD (OR: 2.19; 95 % CI: 1.15 to 4.18; p = 0.020).  The authors concluded that indirect analyses of RCT data and head-to-head comparisons of observational findings indicated that NTZ may be more effective than FGD in terms of disease activity reduction in patients with RRMS.  However, they stated that head-to-head RCTs are needed to independently confirm this preliminary observation.

Extended Interval Dosing of Natalizumab

Zhovtis Ryerson and colleagues (2016) evaluated the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.  These researchers performed a retrospective chart review in 9 MS centers to identify patients treated with extended interval dosing (EID) regimens of NTZ.  Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centers:
  1. early extended dosing (EED; n = 249) every 4 weeks 3 days to 6 weeks 6 days;
  2. late extended dosing (LED; n = 274) every 7 weeks to 8 weeks 5 days; and
  3. variable extended dosing (n = 382) alternating between EED and LED.  

These groups were compared with patients on standard interval dosing (SID; n = 1,093) every 4 weeks.  A total of 17 % of patients on SID had new T2 lesions compared with 14 % in EID (p = 0.02); 7 % of patients had enhancing T1 lesions in SID compared with 9 % in EID (p = 0.08); ARR was 0.14 in the SID group, and 0.09 in the EID group.  No evidence of clinical or radiographic disease activity was observed in 62 % of SID and 61 % of EID patients (p = 0.83).  No cases of PML were observed in EID group compared with 4 cases in SID cohort.  The authors concluded that dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy.  Moreover, they stated that further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Natalizumab Discontinuation: Tapering Protocol

In a phase IV, 12-month, randomized, single-blinded study, Weinstock-Guttman and colleagues (2016) compared 2 modes of NTZ cessation interventions:
  1. immediate, and
  2. tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period. 

A total of 50 relapsing patients with (MS who had been on NTZ therapy for greater than or equal to 24 months and were contemplating NTZ discontinuation were enrolled.  Participants were randomized to either the immediate discontinuation group (IDG) or the tapered group (TG); IDG discontinued NTZ at once and initiated another disease modifying therapy (DMT) following the last NTZ infusion, while the TG received 2 more NTZ infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT.  Standardized MRI was performed at baseline, 6 and 12 months from the last NTZ infusion.  A higher rate of relapses in the IDG (n = 28) compared to the TG (n = 8) over 12 months from the last infusion (p = 0.007) was observed, most relapses occurred within 3 months of discontinuation (20 versus 7 relapses, p = 0.012).  The IDG showed a higher number of new T2 lesions within 6 to 12 months of discontinuation (p = 0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 versus 0.1 ml, p = 0.024) and a higher number of new T1-hypointense lesions over 0 to 12 months (p = 0.005) as well as from baseline to 6 months (p = 0.026) compared to the TG.  The authors  concluded that NTZ discontinuation therapy was associated with development of new disease activity; the authors’ tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.

Pro-Angiogenic Factor Matrix Metalloproteinase 9 (MMP9) as a Biomarker for Predicting PML Risk in Natalizumab-Treated Patients

Fissolo and colleagues (2017) identified biomarkers associated with the development of PML in MS patients treated with NTZ.  Patients with RRMS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study.  Cryo-preserved PBMC and serum samples collected at baseline, at 1- and 2-year treated time-points, and during PML were analyzed for gene expression by RNA-sequencing and for serum protein levels by LUMINEX and ELISA assays, respectively.  Among top differentially expressed genes in the RNA-sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: pro-angiogenic factors (matrix metalloproteinase 9 [MMP9], VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD).  Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients.  Only MMP9 was validated and, in pre-PML patients MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients and levels remained lower at later time-points during NTZ treatment.  The authors concluded that the findings of this study suggested that the pro-angiogenic factor MMP9 may play a role as biomarker associated with the development of PML in MS patients treated with NTZ.  These preliminary findings need to be validated by well-designed studies.

Natalizumab for the Treatment of Acute Ischemic Stroke

In a randomized, placebo-controlled, double-blind, phase II clinical trial, Elkins and colleagues (2017) examined the effect of 1 dose of NTZ in patients with acute ischemic stroke (AIS).  Patients with AIS (aged 18 to 85 years) from 30 US and European clinical sites were randomly assigned (1:1) to 300-mg intravenous NTZ or placebo with stratification by treatment window and baseline infarct size.  Patients, investigators, and study staff were masked to treatment assignments.  The primary end-point was the change in infarct volume from baseline to day 5 and was assessed in the modified intention-to-treat population.  Secondary end-points were the change in infarct volume from baseline to day 30, and from 24 hours to days 5 and 30; the National Institute of Health Stroke Scale (NIHSS) at baseline, 24 hours, and at days 5 (or discharge), 30, and 90; and modified Rankin Scale (mRS) and Barthel Index (BI) at days 5 (or discharge), 30, and 90.   Between December 16, 2013, and April 9, 2015, a total of 161 patients were randomly assigned to NTZ (n = 79) or placebo (n = 82); NTZ did not reduce infarct volume growth from baseline to day 5 compared with placebo (median absolute growth 28 ml [range of -8 to 303] versus 22 ml [-11 to 328]; relative growth ratio 1.09 [90 % CI: 0.91 to 1.30], p = 0.78) or to day 30 (4 ml [-43 to 121] versus 4 ml [-28 to 180]; 1.05 [0.88 to 1.27], p = 0.68), from 24 hours to day 5 (8 ml [-30 to 177] versus 7 ml [-13 to 204]; 1.00 [0.89 to 1.12], p = 0.49), and from 24 hours to day 30 (-5 ml [-93 to 81] versus -5 ml [-48 to 48]; 0.98 [0.87 to 1.11], p = 0.40).  No difference was noted between the NTZ and placebo groups in the NIHSS (score less than or equal to 1 or greater than or equal to 8 point improvement) from baseline at 24 hours, day 5 (or discharge), day 30 (27 [35 %] versus 36 [44 %]; OR 0.69 [90 % CI: 0.39 to 1.21], p = 0.86), and day 90 (36 [47 %] versus 37 [46 %]; 1.10 [0.63 to 1.93], p = 0.39).  More patients in the NTZ group than in the placebo group had mRS scores of 0 or 1 at day 30 (13 [18 %] versus 7 [9 %]; OR 2.88 [90 % CI: 1.20 to 6.93], p = 0.024) and day 90 (18 [25 %] versus 16 [21 %]; 1.48 [0.74 to 2.98], p = 0.18); and BI (score greater than or equal to 95) at day 90 (34 [44 %] versus 26 [33 %]; 1.91 [1.07 to 3.41], p = 0.033) but not significantly at day 5 or day 30 (26 [34 %] versus 26 [32 %]; 1.13 [0.63 to 2.00], p = 0.37).  Natalizumab and placebo groups had similar incidences of adverse events (AEs) (77 [99 %] of 78 patients versus 81 [99 %] of 82 patients), serious AEs (36 [46 %] versus 38 [46 %]), and deaths (14 [18 %] versus 13 [16 %]).  Two patients in the NTZ group died because of AEs assessed as related to treatment by the investigator (pneumonia, and septic shock and multi-organ failure).  The authors concluded that NTZ administered up to 9 hours after stroke onset did not reduce infarct growth.  Moreover, they stated that treatment-associated benefits on functional outcomes might warrant further investigation.

Appendix

Dosing recommendations

Tysabri (natalizumab) injection is available as a solution in a single‐use vial containing 300mg of natalizumab. Tysabri is only available through registered infusion centers participating in the TOUCH prescribing program.

For MS and CD, 300mg of natalizumab is administered by intravenous infusion every four weeks.

In members with CD, natalizumab therapy should be discontinued if therapeutic benefit is not realized by 12 weeks. Tysabri should be discontinued if member cannot be tapered off oral corticosteroids within six months of starting natalizumab therapy.

Table: Expanded Disability Status Scale (EDSS)

The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.

1.0 No disability, minimal signs in one FS
1.5 No disability, minimal signs in more than one FS
2.0 Minimal disability in one FS
2.5 Mild disability in one FS or minimal disability in two FS
3.0 Moderate disability in one FS, or mild disability in three or four FS. No impairment to walking
3.5 Moderate disability in one FS and more than minimal disability in several others. No impairment to walking
4.0 Significant disability but self-sufficient and up and about some 12 hours a day. Able to walk without aid or rest for 500m
4.5 Significant disability but up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance. Able to walk without aid or rest for 300m
5.0 Disability severe enough to impair full daily activities and ability to work a full day without special provisions. Able to walk without aid or rest for 200m
5.5 Disability severe enough to preclude full daily activities. Able to walk without aid or rest for 100m
6.0 Requires a walking aid - cane, crutch, etc - to walk about 100m with or without resting
6.5 Requires two walking aids - pair of canes, crutches, etc - to walk about 20m without resting
7.0 Unable to walk beyond approximately 5m even with aid. Essentially restricted to wheelchair; though wheels self in standard wheelchair and transfers alone. Up and about in wheelchair some 12 hours a day
7.5 Unable to take more than a few steps. Restricted to wheelchair and may need aid in transfering. Can wheel self but can not carry on in standard wheelchair for a full day and may require a motorised wheelchair
8.0 Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the day. Retains many self-care functions. Generally has effective use of arms
8.5 Essentially restricted to bed much of day. Has some effective use of arms retains some self care functions
9.0 Confined to bed. Can still communicate and eat
9.5 Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow
10.0 Death due to MS


Table: Brands of Targeted Immune Modulators and FDA-approved Indications
Brand Name Generic Name FDA Labeled Indications
Actemra tocilizumab

Giant cell arteritis

Juvenile idiopathic arthritis

Rheumatoid arthritis

Systemic juvenile idiopathic arthritis

Cytokine release syndrome (CRS)

Cimzia certolizumab

Ankylosing spondylitis

Crohn's disease

Plaque psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Cosentyx secukinumab

Ankylosing spondylitis

Plaque psoriasis

Psoriatic arthritis

Enbrel etanercept

Ankylosing spondylitis

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthrits

Rheumatoid arthritis

Entyvio vedolizumab

Crohn's disease

Ulcerative colitis

Humira adalimumab

Ankylosing spondylitis

Crohn's disease

Hidradenitis suppurativa

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Uveitis

Ilaris canakinumab

Periodic fever syndromes
 
Systemic juvenile idiopathic arthritis

Ilumya tildrakizumab-asmn

Plaque psoriasis 

Inflectra infliximab

Ankylosing spondylitis

Crohn's disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Kevzara sarilumab

Rheumatoid arthritis

Kineret anakinra

Cryopyrin-associated periodic syndromes

Rheumatoid arthritis

Olumiant baricitinib

Rheumatoid arthritis 

Orencia abatacept

Juvenile idiopathic arthritis

Psoriatic arthritis

Rheumatoid arthritis

Otezla apremilast

Plaque psoriasis

Psoriatic arthritis

Remicade infliximab

Ankylosing spondylitis

Crohn's disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Rituxan rituximab Granulomatosis with polyangiitis

Microscopic polyangiitis

Pemphigus vulgaris

Rheumatoid arthritis
Siliq brodalumab Plaque psoriasis
Simponi golimumab

Ankylosing spondylitis

Psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Simponi Aria golimumab intravenous Ankylosing spondylitis

Psoriatic arthritis

Rheumatoid arthritis
Stelara ustekinumab

Crohn's disease

Plaque psoriasis

Psoriatic arthritis

Taltz ixekinumab

Plaque psoriasis

Psoriatic arthritis

Tremfya guselkumab

Plaque psoriasis

Tysabri natalizumab

Crohn's disease

Multiple sclerosis

Xeljanz tofacitinib Rheumatoid arthritis

Psoriatic arthritis

Ulcerative Colitis
Xeljanz XR tofacitinib, extended release Rheumatoid arthritis

Psoriatic arthritis

Ulcerative colitis
Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

86711 Antibody; JC (John Cunningham) virus

CPT codes not covered for indications listed in the CPB:

Pro-angiogenic factor MMP9 as a biomarker for predicting PML risk - no specific code:

87798 Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; amplified probe technique, each organism [polymerase chain reaction (PCR) testing of cerebrospinal fluid for John Cunningham (JC) polymavirus for diagnosis of progressive multifocal leukoencephalopathy in persons before initiating nataluzumab treatment]
87801 Infectious agent detection by nucleic acid (DNA or RNA), multiple organisms; amplified probe technique [polymerase chain reaction (PCR) testing of cerebrospinal fluid for John Cunningham (JC) polymavirus for diagnosis of progressive multifocal leukoencephalopathy in persons before initiating nataluzumab treatment]

Other CPT codes related to the CPB:

86790 Virus, not elsewhere classified [anti-JCV antibody testing with ELISA]
96365 - 96368 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96379 Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion

HCPCS codes covered if selection criteria are met:

J2323 Injection, natalizumab, 1 mg [not covered in combination with other disease modifying treatments]

Other HCPCS codes related to the CPB:

Plegridy, Aubagio, Gilenya and Tecfidera - no specific code:

J0135 Injection, adalimumab, 20 mg
J0202 Injection, alemtuzumab, 1 mg
J1595 Injection, glatiramer acetate, 20 mg
J1745 Injection, infliximab, 10 mg
J1826 Injection, interferon beta-1a, 30 mcg
J1830 Injection, interferon beta -1b, 0.25 mg
J3245 Injection, tildrakizumab, 1 mg
J7500 Azathioprine, oral, 50 mg
J7501 Azathioprine, parenteral, 100 mg
Q5109 Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg

ICD-10 codes covered if selection criteria are met:

G35 Multiple sclerosis [relapsing, not chronic progressive]
K50.00 - K50.919 Crohn's disease

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

C81.00 - C94.32
C94.80 - C96.4
C96.a - C96.9
D45
Malignant neoplasm of lymphatic and hemtopoietic tissue [for stem cell mobilization]
G04.81 Other encephalitis and encephalomyelitis [Rasmussen encephalitis]
G36.0 Neuromyelitis optica [Devic]
G61.81 Chronic inflammatory demyelinating polyneuritis
I63.00 - I63.9 Cerebral infarction [acute ischemic stroke]
K51.00 - K51.319 Ulcerative colitis

The above policy is based on the following references:

  1. National Horizon Scanning Centre (NHSC). Natalizumab for moderate to severely active Crohn's disease - horizon scanning review. Birmingham, UK: NHSC; 2004.
  2. National Horizon Scanning Centre (NHSC). Natalizumab for multiple sclerosis - horizon scanning review. Birmingham, UK: NHSC; 2002. 
  3. Ghosh S, Goldin E, Gordon FH, et al; Natalizumab Pan-European Study Group. Natalizumab for active Crohn's disease. N Engl J Med. 2003;348(1):24-32.
  4. Huprich JE, Bree RL, Foley WD, et al; Expert Panel on Gastrointestinal Imaging. Crohn's disease. Reston, VA: American College of Radiology (ACR); 2005.  
  5. U.S. Food and Drug Administration (FDA). FDA issues public health advisory on Tysabri, a new drug for MS. FDA News. P05-07. Rockville, MD: FDA; February 28, 2005.
  6. Sandborn WJ, Colombel JF, Enns R, et al; International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) and the Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Groups. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005;353(18):1912-1925.
  7. Scottish Medicines Consortium. Natalizumab 300mg concentrate for solution for infusion. (No. 329/06). Edinburgh, Scotland: NHS Scotland; November 10, 2006.  
  8. National Institutes of Health (NIH), National Digestive Diseases Information Clearinghouse. Crohn's disease. NIH Publication No. 06–3410. Bethesda, MD: NIH; February 2006.
  9. U.S. Food and Drug Administration (FDA). FDA approves resumed marketing of Tysabri under a special distribution program. FDA News. P06-75. Rockville, MD: FDA; June 5, 2006.
  10. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130(3):935-939.
  11. Baker DE. Natalizumab: Overview of its pharmacology and safety. Rev Gastroenterol Disord. 2007;7(1):38-46.
  12. Targan SR, Feagan BG, Fedorak RN, et al; International Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) Trial Group. Natalizumab for the treatment of active Crohn's disease: Results of the ENCORE Trial. Gastroenterology. 2007;132(5):1672-1683.
  13. MacDonald JK, McDonald JW. Natalizumab for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2007;(1):CD006097.
  14. Hyams JS, Wilson DC, Thomas A, et al. Natalizumab therapy for moderate to severe Crohn disease in adolescents. J Pediatr Gastroenterol Nutr. 2007;44(2):185-191.
  15. U.S. Food and Drug Administration. FDA approves Tysabri to treat moderate-to-severe Crohn's disease. FDA News. Rockville, MD: FDA; January 14, 2008.
  16. Akobeng AK. Review article: The evidence base for interventions used to maintain remission in Crohn's disease. Aliment Pharmacol Ther. 2008;27(1):11-18.
  17. Elan Pharmaceuticals, Inc. Tysabri (natalizumab) injection for intravenous use. Prescribing Information. I61061-X. South San Francisco, CA: Elan Pharmaceuticals; January 2008.
  18. National Institute for Health and Clinical Excellence (NICE). Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis. NICE Technology Appraisal Guidance 127. London, UK: NICE; August 2007.
  19. Freedman MS, Pachner AR. Neutralizing antibodies to biological therapies: A "touch of gray" vs a "black and white" story. Neurology. 2007;69(14):1386-1387.
  20. Calabresi PA, Giovannoni G, Confavreux C, et al; AFFIRM and SENTINEL Investigators. The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL. Neurology. 2007;69(14):1391-1403.
  21. No authors listed. Tysabri: Side effects and drug interactions. RxList. 2008. Available at: http://www.rxlist.com/cgi/generic/tysabri_ad.htm#AR. Accessed March 4, 2008.
  22. Goodin DS, Cohen BA, O'Connor P, 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(10):766-773.
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