Natalizumab

Number: 0751

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses natalizumab for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of natalizumab (Tysabri) or natalizumab-sztn (Tyruko) is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

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

1. Prescriber Specialties

   The medication must be prescribed by or in consultation with one of the following:

   1. Crohn's disease: gastroenterologist;
   2. Multiple sclerosis: neurologist.

2. Criteria for Initial Approval

   Aetna considers natalizumab (Tysabri) or natalizumab-sztn (Tyruko) medically necessary for the following indications:

   1. Crohn’s disease (CD)

      For adult members who have received any other biologic indicated for the treatment of moderately to severely active Crohn’s disease and who have been tested for anti-JCV antibodies;

   2. Relapsing forms of multiple sclerosis (MS)

      For members who have been diagnosed with a relapsing form of multiple sclerosis (including relapsing-remitting and secondary progressive disease for those who continue to experience relapse) and those who have been tested for anti-JCV antibodies;

   3. Clinically isolated syndrome (CIS)

      For the treatment of members with clinically isolated syndrome and those who have been tested for anti-JCV antibodies.

   Aetna considers all other indications as experimental, investigational, or unproven. 

3. Continuation of Therapy

   Aetna considers continuation of natalizumab (Tysabri) or natalizumab-sztn (Tyruko) therapy medically necessary for the following indications:

   1. Crohn’s disease (CD)

      1. For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain remission; or
      2. For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:
         
         
         1. Abdominal pain or tenderness; or
         2. Diarrhea; or
         3. Body weight; or
         4. Abdominal mass; or
         5. Hematocrit; or
         6. Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), magnetic resonance enterography (MRE), or intestinal ultrasound; or
         7. Improvement on a disease activity scoring tool (e.g., Crohn’s Disease Activity Index [CDAI] score);

   2. Relapsing forms of multiple sclerosis (MS) or clinically isolated syndrome (CIS)

      For all members (including new members) who achieve or maintain a positive clinical response with the requested drug as evidenced by experiencing disease stability or improvement.

4. Related Policies

   1. CPB 0249 - Inflammatory Bowel Disease: Serologic Markers and Pharmacogenomic and Metabolic Assessment of Thiopurine Therapy
   2. CPB 0264 - Multiple Sclerosis
   3. CPB 0285 - Plasmapheresis/Plasma Exchange/Therapeutic Apheresis
   4. CPB 0341 - Infliximab
   5. CPB 0404 - Interferons
   6. CPB 0655 - Adalimumab

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information.

Natalizumab is branded as Tysabri (Biogen Inc) and Tyruko (Sandoz Inc). They are supplied as an injections of 300 mg/15 mL (20 mg/mL) solution in a single-dose vials for dilution prior to infusion. Tysabri is to be administered as an intravenous infusion within 8 hours of preparation and should not be given as an intravenous push or bolus. Tyruko must be administered within 4 hours of preparation.

Multiple sclerosis (MS): Only prescribers registered in the MS TOUCH® Prescribing Program may prescribe Tysabri, or registered in the MS TYRUKO REMS Program to prescribe Tyruko for MS. The recommended dose of natalizumab for MS is 300 mg via intravenous infusion over one hour every 4 weeks. 

Crohn's disease (CD): Only prescribers registered in the CD TOUCH® Prescribing Program may prescribe Tysabri, or registered in the CD TYRUKO REMS Program to prescribe Tyruko for CD. The recommended dose of natalizumab for CD is 300 mg administered by intravenous infusion over one hour, every 4 weeks. Natalizumab should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α. Aminosalicylates may be continued during treatment with natalizumab. 

Per the label, if the person with CD has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue natalizumab. For persons with CD who start natalizumab while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of natalizumab has occurred; if the person with CD cannot be tapered off of oral corticosteroids within 6 months of starting natalizumab, discontinue natalizumab. Other than the initial 6-month taper, prescribers should consider discontinuing natalizumab for persons who require additional steroid use that exceeds 3 months in a calendar year to control their CD.

Source: Biogen, 2023; Sandoz, 2023

Experimental and Investigational or Not Medically Necessary

1. Aetna considers Tysabri used concomitantly with any other disease-modifying MS agents (Note: Ampyra and Nuedexta are not disease-modifying), immunosuppressants, or TNF inhibitors (e.g., adalimumab, infliximab) as experimental and investigational.

2. Aetna considers natalizumab experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

   1. Acute ischemic stroke
   2. As adjunctive therapy for drug-resistant epilepsy
   3. Chronic inflammatory demyelinating polyneuropathy
   4. Neuromyelitis optica
   5. Rasmussen encephalitis
   6. Stem cell mobilization
   7. Ulcerative colitis.

3. Aetna considers polymerase chain reaction (PCR) testing of cerebrospinal fluid for John Cunningham (JC) polyomavirus, for diagnosis of progressive multifocal leukoencephalopathy in members before initiating natalizumab treatment not medically necessary. For indications for PCR testing for JC polyomavirus, see CPB 0650 - Polymerase Chain Reaction - Selected Indications.

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

5. Aetna considers serum neurofilament light chain levels experimental and investigational as a prognostic biomarker for multiple sclerosis treatment with natalizumab.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
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 natalizumab 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 natalizumab treatment]
Other CPT codes related to the CPB:
86790	Antibody; virus, not elsewhere specified [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
Q5134	Injection, natalizumab-sztn (tyruko), biosimilar, 1 mg
Other HCPCS codes related to the CPB:
Plegridy, Aubagio, Gilenya, Tecfidera, Mavenclad and Mayzent - 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
J2350	Injection, ocrelizumab, 1 mg
J3245	Injection, tildrakizumab, 1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
Q5131	Injection, adalimumab-aacf (idacio), biosimilar, 20 mg
Q5132	Injection, adalimumab-afzb (abrilada), biosimilar, 10 mg
ICD-10 codes covered if selection criteria are met:
G35	Multiple sclerosis [relapsing, not chronic progressive]
G37.8	Other specified demyelinating diseases of central nervous system [clinically isolated syndrome]
K50.00 - K50.919	Crohn's disease [Adults only]
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 hematopoietic 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

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Indicated 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 tumor necrosis factor alpha (TNF-α). Tysabri and Tyruko should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α. 
• Indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Tysabri and Tyruko increase the risk of progressive multifocal leukoencephalopathy (PML). When initiating and continuing treatment with Tysabri or Tyruko, physicians should consider whether the expected benefit of Tysabri or Tyruko is sufficient to offset this risk.

Natalizumab is available as Tysabri (Biogen Inc.) and Tyruko (Sandoz Inc.). Natalizumab 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.

Tysabri and Tyruko carry a black box warning for risk of progressive multifocal leukoencephalopathy (PML). PML is an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing Tysabri therapy. Because of the risk of PML, Tysabri and Tyruko are available only through a restricted distribution program called the TOUCH® Prescribing Program (Biogen, 2023).

Three factors that are known to increase the risk of PML in natalizumab‐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.

Other labeled warnings and precautions include the following:

• Herpes infections: Life-threatening and fatal cases have occurred with herpes encephalitis and meningitis infections; blindness has occurred in patients developing acute retinal necrosis;
• Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, has occurred;
• Hypersensitivity reactions (e.g., anaphylaxis);
• Immunosuppression/Infections
• Thrombocytopenia.
  

The most common adverse reactions (incidence of 10% or more) include the following:

• MS - headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash;
• CD - headache, upper respiratory tract infections, nausea, and fatigue.

Tysabri was initially FDA-approved in 2004. Tyruko, a biosimilar to Tysabri, was FDA-approved in August 2023 for all indications of the reference medicine, with same dosing and administration schedule.

Crohn's Disease

Natalizumab has 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.

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, internal fistulae, intestinal obstruction, megacolon, perianal disease, 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), immunosuppressive 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:

• 2 infusions of placebo;
• 1 infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo;
• 2 infusions of 3 mg of natalizumab per kilogram; or
• 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 cannot be fully tapered within 6 months.

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.

Multiple Sclerosis and Clinically Isolated Syndrome

Natalizumab was approved by the U.S. Food and Drug Administration (FDA) on November 23, 2004 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.

In August 2019, Biogen updated the FDA approved prescribing information to further clarify that relapsing forms of multiple sclerosis includes clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS (National Multiple Sclerosis Society, 2019).

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 cannot 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."

Other Indications

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.

Chronic Inflammatory Demyelinating Polyneuropathy

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 cannot be recommended in CIDP at present and should only be explored in controlled clinical trials.

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.

Neuromyelitis Optica

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.

Rasmussen Encephalitis

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. 

Stem Cell Mobilization

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.

Monoclonal Antibodies

A small number 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.

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 specialties, 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.

Natalizumab as Adjunctive Therapy for Drug-Resistant Epilepsy

In a phase-II clinical trial, French et al (2021) examined the safety and effectiveness of natalizumab as adjunctive therapy in adults with drug-resistant focal epilepsy.  Subjects with 6 or more seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks.  Primary effectiveness outcome was change from baseline in log-transformed seizure frequency, with a pre-defined threshold for therapeutic success of 31 % relative reduction in seizure frequency over the placebo group.  Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic.  Secondary effectiveness endpoints/safety were also assessed.  Of 32 and 34 subjects dosed in the natalizumab 300-mg and placebo groups, 30 (94 %) and 31 (91 %) completed the placebo-controlled treatment period, respectively (1 subject was randomized to receive natalizumab but not dosed due to IV complications).  Estimated relative change in seizure frequency of natalizumab over placebo was -14.4 % (95 % CI: -46.1 % to 36.1 %; p = 0.51).  The proportion of subjects with 50 % or more reduction from baseline in seizure frequency was 31.3 % for natalizumab and 17.6 % for placebo (OR 2.09, 95 % CI: 0.64 to 6.85; p = 0.22); AEs were reported in 24 (75 %) and 22 (65 %) subjects receiving natalizumab versus placebo, respectively.  The authors concluded that although the threshold to demonstrate effectiveness was not met, there were no unexpected safety findings and further examination of possible anti-inflammatory therapies for drug-resistant epilepsy is needed.  This study provided Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy.

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.

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.

Serum Neurofilament Light Chain Levels as a Prognostic Biomarker for Multiple Sclerosis Treatment with Natalizumab

Bridel et al (2021) examined the potential of serum neurofilament light (Nfl) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with RRMS treated with natalizumab.  Patients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, the Netherlands, including patients with RRMS treated with natalizumab.  Selection criteria included age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation.  Clinical and MRI assessments were carried out on a yearly basis, and serum Nfl was measured at 5 time-points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year, and 2 years after natalizumab initiation, and on last follow-up visit.  Using general linear regression models, these researchers compared the longitudinal dynamics of Nfl between patients with and without confirmed EDSS progression between year 1 visit and last follow-up, and between individuals with and without EDSS+ progression, a composite endpoint including the EDSS, 9-hole peg test, and timed 25-foot walk.  A total of 89 natalizumab-treated patients with RRMS were included.  Median follow-up time was 5.2 years (interquartile range [IQR] 4.3 to 6.7, range of 3.0 to 11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 years (SD 8.5), and median disease duration was 7.4 years (IQR 3.8 to 12.1).  Between year 1 and the last follow-up, 28/89 (31.5 %) individuals showed confirmed EDSS progression.  Data for the EDSS+ endpoint was available for 73 out of the 89 patients and 35/73 (47.9 %) showed confirmed EDSS+ progression.  These investigators observed a significant reduction in Nfl levels 3 months after natalizumab initiation, which reached its nadir of close to 50 % of baseline levels 1 year after treatment initiation.  They found no difference in the longitudinal dynamics of Nfl in progressors versus non-progressors.  Serum Nfl levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up.  The authors concluded that in this cohort of natalizumab-treated patients with RRMS, Nfl failed to capture or predict progression that occurred largely independently of clinical or radiologic signs of acute focal inflammatory disease activity.  These researchers stated that additional biomarkers may thus be needed to monitor progression in these patients.  This study provided Class II evidence that serum Nfl levels were not associated with disease progression in natalizumab-treated patients with RRMS.

In a systematic review and meta-analysis, Liu et al (2022) examined the prognostic value of Nfl levels in MS treatment with natalizumab.  Relevant studies published before January 2022 were retrieved from the PubMed, Web of Science, and clinicaltrials.gov databases.  Qualitative analysis and meta-analysis were included in 7 of the 46 papers.  Differences in the Nfl levels were used as the main effectiveness measures, and the meta-analysis was carried out using Review Manager version 5.3 software.  A total of 7 studies were selected.  Neurofilament light chain levels were lower in the 947 patients on natalizumab treatment than the 959 patients before therapy, with a moderate effect size of 0.73 (p < 0.00001).  Mean Nfl levels showed no significant difference between the remitting and relapsing phase of MS before and after natalizumab treatment.  The EDSS scores of 41 MS patients in the relapsing phase after natalizumab treatment were significantly lower than those in 102 MS patients without therapy (MD = -0.45; 95 % CI: -0.85 to -0.05; p < 0.001).  However, the EDSS scores in the remitting phase demonstrated no difference.  The comparison of Nfl across multiple groups showed the potential of Nfl as a non-invasive biomarker of neurodegeneration, examining the effectiveness of natalizumab in MS patients.  Furthermore, these investigators examined the relationship between different phases of relapsing-remitting MS with Nfl levels.  However, the value of Nfl as a biomarker was hard to evaluate because of the limited number of studies.  The authors concluded that for clinical application, a comprehensive understanding of Nfl concentrations in disease subtypes is needed, and disease stages should be defined to develop standardized criteria.

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Appendix

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.

Table: Expanded Disability Status Scale (EDSS)

Score	Status
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 transferring. Can wheel self but cannot carry on in standard wheelchair for a full day and may require a motorized 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

Examples of Conventional Therapy Options for CD

1. Mild to moderate disease – induction of remission: a. Oral budesonide; b. Alternatives: metronidazole, ciprofloxacin, rifaximin
2. Mild to moderate disease – maintenance of remission: a. Azathioprine, mercaptopurine; b. Alternatives: oral budesonide, methotrexate intramuscular (IM) or subcutaneous (SC), sulfasalazine　
3. Moderate to severe disease – induction of remission: a. Prednisone, methylprednisolone intravenously (IV); b. Alternatives: methotrexate IM or SC
4. Moderate to severe disease – maintenance of remission: a. Azathioprine, mercaptopurine; b. Alternative: methotrexate IM or SC
5. Perianal and fistulizing disease – induction of remission a. Metronidazole ± ciprofloxacin, tacrolimus
6. Perianal and fistulizing disease – maintenance of remission a. Azathioprine, mercaptopurine; b. Alternative: methotrexate IM or SC

Table: Brands of Targeted Immune Modulators and FDA-approved Indications (not an all-inclusive list):

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	COVID-19 in hospitalized adults Cytokine release syndrome (CRS) Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
Arcalyst	rilonacept	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Recurrent pericarditis
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis or axial spondyloarthritis Enthesitis-related arthritis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira (for Humira biosimiliars, see CPB 0655 - Adalimumab)	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Adult-onset Still's disease Periodic fever syndromes Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Kevzara	sarilumab	Polymyalgia rheumatica Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Rheumatoid arthritis
Olumiant	baricitinib	Alopecia areata COVID-19 in hospitalized adults Rheumatoid arthritis
Orencia	abatacept	Acute graft versus host disease Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behcet’s Disease Plaque psoriasis Psoriatic arthritis
Remicade (for Remicade biosimilars, see CPB 0341 - Infliximab)	infliximab	Ankylosing spondylitis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Ankylosing spondylitis or axial spondyloarthritis Atopic dermatitis Crohn's disease Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Rituxan (for Rituxan biosimilars, see CPB 0314 - Rituximab)	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis Various subtypes of non-Hodgkin's lymphoma
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Juvenile idiopathic arthritis  Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Crohn's disease Plaque psoriasis Psoriatic arthritis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis Ulcerative colitis
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis Psoriatic arthritis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Ankylosing spondylitis Polyarticular Course Juvenile Idiopathic Arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Xeljanz XR	tofacitinib, extended release	Ankylosing Spondylitis Polyarticular Course Juvenile Idiopathic Arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis

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References