BlueCross and BlueShield of Montana Medical Policy/Codes
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases
Chapter: Drugs - Medical Benefit
Current Effective Date: February 15, 2014
Original Effective Date: October 25, 2013
Publish Date: January 15, 2014
Revised Dates: January 15, 2014
Description

Six biologic therapies are currently approved for the treatment of RA and other chronic inflammatory conditions.  Three of them, Humira, Enbrel and Remicade, work in different ways to inhibit an inflammatory cytokine called tumor necrosis factor (TNF).  Remicade is used in combination with methotrexate.  The fourth, Kineret, blocks the action of another inflammatory cytokine called interleukin-1.  The fifth is Orencia, and it is approved for use in patients who have failed prior treatment with disease-modifying anti-rheumatic drugs (DMARDs) or TNF antagonists.  Orencia is a T-cell inhibitor, and T-cells are part of the inflammatory process in RA.  These drugs can treat symptoms of RA and also slow or prevent damage to joints.  The sixth and most recent is Rituxan.  This drug is approved for use in combination with methotrexate to reduce signs and symptoms in patients who have failed prior treatment with one of the anti-TNF agents.  Rituxan targets certain B cells that are also part of the inflammatory process in RA.  There have been serious side effects noted with these therapies, and risks and benefits should be discussed and its use monitored carefully by a physician.   The currently available biologic therapies must either be injected under the skin (Enbrel, Humira, and Kineret) or infused through an intravenous infusion (IV) (Remicade, Orencia and Rituxan).   

Tumor Necrosis Factor (TNF) Alpha Inhibitors

Infliximab (Remicade)

Remicade, generic name infliximab, is an IV injectable antibody that blocks the effects of tumor necrosis factor alpha (TNF alpha).  By blocking the action of TNF-alpha, Remicade reduces the signs and symptoms of inflammation.   This anti-TNF drug is classified as one of the BRMs (biologic response modifiers).   TNF alpha has been found in the joints of RA patients and in stools of patients with Crohn's disease and correlates with elevated disease activity.   Infliximab (Remicade) is supplied as a sterile lyophilized powder for intravenous infusion.   Elevated levels of TNF have also been implicated in many inflammatory diseases.   Remicade is given under medical supervision and is often prescribed in combination with the DMARD methotrexate. 

Etanercept (Enbrel)

Enbrel is a genetically engineered protein and represents a class of drugs for the treatment and management of RA.   Enbrel binds to TNF, a naturally occurring protein in the body, and inhibits its action.   TNF, which promotes inflammation in the body, is found at elevated levels in the fluid surrounding the affected joints of RA patients.  

Although many patients with RA respond well to currently available treatments, many are also disabled and suffer severe pain from the disease.   It is estimated that RA, an autoimmune disease, affects more than two million Americans, with as many as one third to one half of these people estimated to have moderate to severe RA.  

First approved for RA, Enbrel is now approved for five typically chronic inflammatory diseases.  Besides RA the inflammatory diseases are polyarticular-course juvenile RA, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.  

Humira (adalimumab)

Humira is a human-derived antibody that binds to human TNF alpha.   TNF is naturally produced by the body and is involved with normal inflammatory and immune responses.   By working against the inflammatory process, Humira, like other TNF blockers has been shown to be effective in controlling symptoms of the disease.

Cimzia (certolizumab pegol)

Cimzia is the first and only PEGylated Tumor Necrosis Factor alpha antibody (anti-TNFa) indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderate to severe active disease who have an inadequate response to conventional therapy.   In May 2009, the FDA approved Cimzia to treat moderately to severely active RA.

Cimzia is administered by subcutaneous injection.  The initial dose of CIMZIA is 400 mg given as two subcutaneous injections of 200 mg.   For Crohn’s Disease, Cimzia may be administered at 400 mg initially and at weeks two and four.   If response occurs, follow with 400 mg every four weeks.   For RA, Cimzia may be administered 400 mg initially and at weeks two and four, followed by 200 mg every other week.   For maintenance dosing, 400 mg every four weeks may be considered. 

Simponi (golimumab)

Simponi is a human monoclonal antibody that targets and neutralizes excess TNF-alpha.   The first once-monthly subcutaneous anti-TNF-alpha therapy, Simponi was FDA approved in May 2009 for the treatment of moderately to severely active RA, active psoriatic arthritis and active ankylosing spondylitis, and is available either through the Simponi SmartJect autoinjector or through a prefilled syringe.  Simponi is also being studied as an intravenous infusion therapy for the treatment of RA

T-Cell Costimulation Modulator

Orencia (Abatacept)

Orencia, a selective costimulation modulator, inhibits T-cell activation by binding to CD80 and CD86, thereby blocking interaction with CD28.   This interaction provides a co-stimulatory signal necessary for full activation of T lymphocytes, implicated in the pathogenesis of RA.   Activated T lymphocytes are found in the synovium of patients with RA.  

Monoclonal Antibody

Rituxan (Rituximab)

Rituxan is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.   B-cells are believed to play a role in the pathogenesis of RA and associated chronic synovitis.   In this setting, B-cells may be acting at multiple sites in the autoimmune/inflammatory process including rheumatoid factor and other autoantibody production, antigen presentation, T cell activation, and/or proinflammatory cytokine production.  Rituxan is administered in two 1000 mg IV infusions separated by two weeks.  It is given in combination with methotrexate.

The FDA expanded the approved indications for Rituxan in April 2011 to include the treatment of two forms of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, (1) Wegener’s granulomatosis (WG) and (2) microscopic polyangiitis (MPA).  Vasculitis is a family of 15+ rare autoimmune diseases that can affect people of all ages, according to the Vasculitis Foundation (VF).  WG mostly affects the respiratory tract (sinuses, nose, trachea, and lungs) and kidneys, while MPA commonly affects the kidneys, lungs, nerves, skin, and joints.  Both are considered orphan diseases because they each affect less than 200,000 people in the United States.

Stelara™ (Ustekinumab)

Stelara is a fully human IgG1κ monoclonal antibody to interleukin (IL)-12/23 produced in a murine myeloma cell line using recombinant DNA technology.   Stelara™ is administered by subcutaneous injection for patients:

  • Weighing <100 kg (220 lbs) - recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
  • Weighing >100 kg (220 lbs) - recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.   In subjects weighing >100 kg, 45 mg was also shown to be efficacious.  However, 90 mg resulted in greater efficacy in these subjects

Stelara reduces the immune systems ability to fight infections.  Infections can be caused by viruses, fungi, or bacteria that have spread throughout the body.   There may also be an increased risk of developing cancer.   In addition, patients being treated with Stelara should not receive live vaccines.  BCG vaccines should not be given during treatment with Stelara or for one year prior to initiating treatment or one year following discontinuation of treatment.  Caution is advised when administering live vaccines to household contacts of patients receiving Stelara because of the potential risk for shedding from the household contact and transmission to patient.

Actemra (tocilizumab)

Actemra is a humanized anti-human IL-6 receptor monoclonal antibody that works by competitively blocking the binding of IL-6 to its receptor. Thus, it inhibits the proliferative effects of IL-6, which lead to synovial thickening and pannus formation in RA.

The FDA approved Actemra on January 8th 2010 for adult patients with RA who have failed other approved therapies because of serious safety concerns that were noted in clinical studies. These safety concerns include elevated liver enzymes, elevated Low-density lipoprotein (LDL) or bad cholesterol, hypertension, and gastrointestinal perforations.  In April 2011 the FDA approved Actemra for patients two years of age and older with active systemic juvenile idiopathic arthritis (SJIA).

The recommended dose of Actemra for adult patients is once every 4 weeks as a 60-minute single intravenous drip infusion.  When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response.   Reduction of dose from 8 mg/kg to 4 mg/kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.  Doses exceeding 800 mg per infusion are not recommended.

Actemra for SJIA patients is given once every two weeks as a 60-minute single intravenous drip infusion.  The dose is dependent on kilogram of body weight. 

Benlysta (belimumab)

Benlysta is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF).  Benlysta was FDA approved on March 9, 2011 for treatment of systemic lupus erythematosus (SLE).  The recommended dosage regimen is 10 mg/kg at 2-week intervals for the first three doses, and at four-week intervals thereafter.

Interleukin 1 Blocker

Kineret® (Anakinra)

Kineret is a recombinant, non glycosylated form of the human interleukin-1 receptor antagonist (IR-1Ra).   Kineret acts by blocking the biological effects of the chemical messenger IL-1.  IL-1 (a protein) is produced by many cells in the body and is found, in increased amounts within joints that are inflamed by RA.   IL-1 promotes the inflammation and destruction of cartilage and bone in RA.

Ilaris® (canakinumab)

Ilaris is an interleukin-B blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPs), in adults and children four years of age and older.  CAPS are a group of rare inherited auto-inflammatory conditions.  Signs and symptoms include recurrent rash, fever/chills, joint pain, fatigue, and eye pain/redness.  In more severe forms, additional symptoms occur, such as deafness, systemic amyloidosis (protein accumulation in tissues and organs, such as the kidneys), significant central nervous system disabilities, including mental retardation/intellectual disability and vision loss, and substantial joint and bone deformities.

The recommended dose of Ilaris is 150 mg for CAPS patients with body weight greater than 40 kg.  For CAPS patients with body weight between 15 kg and 40 kg the recommended dose is 2 mg/kg.  For children 15 to 40 kg with an inadequated response, the dose can be increased to 3mg/kg.  Ilaris is administered every eight weeks as a single dose via subcutaneous injection. 

Krystexxa (pegloticase)

Krystexxa is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout.  Krystexxa achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid.   Krystexxa was FDA approved September 14, 2010, and is indicated for the treatment of chronic gout in adult patient’s who are refractory to conventional therapy.

The recommended dose and regimen of Krystexxa for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks.  The optimal treatment duration has not been established.

Amevive (alefacept)

Amevive is a dimeric fusion protein that consists of the extracellular CD2 binding portion of the human leukocyte function antigen -3 (LFA-3) linked to the Fc portion of IgG1. Amevive interferes with lymphocyte activation by specifically binding to CD2 on lymphocytes thereby inhibiting LFA-3/CD2 interaction.  Amevive was FDA approved January 2003 for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

The recommended dose of Amevive is 7.5 mg given once weekly as an IV bolus, or 15 mg given once weekly as an IM injection.  The recommended schedule consists of 12-weekly injections. Retreatment with an additional 12-week schedule may be initiated provided that CD4+ T lymphocyte counts are within the normal range, and a minimum of a 12-week interval has passed since the previous course of treatment. Data on retreatment beyond two cycles are limited.

Special Note Regarding Severity of Psoriasis

The National Psoriasis Foundation Medical Board has described criteria to assist medical professionals in distinguishing between mild, moderate, and severe disease based on body surface area (BSA) and impact on quality of life.  Affected BSA has been frequently used to assess disease severity.  One percent of BSA is approximately equal to the patients open hand with fingers tucked together and thumb tucked to the side.  In clinical trials, severe disease often is commonly defined as more than 10% affected BSA and the FDA has used 20% BSA to indicate severe disease.  In 2002, the American Academy of Dermatology published a consensus statement on psoriasis therapies that also used the mild, moderate, and severe criteria to guide treatment plans.  In this system, patients with mild disease have limited BSA involvement and may be treated with topical therapies.  Although moderate and severe disease categories my overlap, patients with moderate to severe disease generally have greater than 5% affected BSA, and appropriate therapies include phototherapy or systemic therapy.

Policy

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

Coverage

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

Biologic Response Modifiers (BRMs) when utilized for the treatment of rheumatoid arthritis (RA) and other chronic inflammatory diseases may be considered medically necessary for the specific indications as noted under each of the following BRMs:

NOTE:  Certain BRMs are self injectables and therefore may be covered under a pharmacy benefit plan rather than the medical benefits.

Tumor Necrosis Factor (TNF) Alpha Inhibitors

  • Remicade® (Infliximab)
  1. For the reduction of the signs and symptoms, and inducing and maintaining clinical remission in adult and pediatric patients (six to seventeen years old) with moderately to severely active Crohn’s disease, who have had an inadequate response to conventional therapy.  
  2. Patients with fistulizing Crohn's disease for the reduction in the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure.  
  3. In combination with methotrexate, for use in the reduction of signs and symptoms, inhibiting the progression of structural damage, and improving physical function of patients with moderately to severely active RA .  Exception:  Infliximab (Remicade) used alone for the reduction of signs and symptoms of RA is allowed as an off-label use for those patients who cannot tolerate Methotrexate.  
  4. Patients with ankylosing spondylitis or psoriatic arthritis who are refractory to conventional therapies.  
  5. Reducing signs and symptoms, achieving clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
  6. Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. 
  7. The treatment of adult patients (18 years of age or older) with chronic severe plaque psoriasis (i.e., extensive and/or disabling) who are candidates for systemic therapy or phototherapy AND when other systemic therapies are medically less appropriate.    Remicade should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.  

All other uses of Remicade are considered experimental, investigational, and unproven.

  • Enbrel® (Etanercept)
  1. Enbrel is indicated for reduction in signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderate to severe active RA, Enbrel can be used in combination with methotrexate or used alone.
  2. Enbrel is indicated for reducing signs and symptoms of moderate to severe active polyarticular-course juvenile idiopathic arthritis (JIA) in patients ages 2 and older.
  3. Enbrel is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA).    Enbrel can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.
  4. Enbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
  5. Enbrel is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

All other uses of Enbrel are considered experimental, investigational, and unproven.

  • Humira® (Adalimumab)
  1. Indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active RA.   Humira can be used alone or in combination with methotrexate or other DMARDs. 
  2. Indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 4 years of age and older.  Can be used alone or in combination with methotrexate.
  3. Indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function of active arthritis in patients with psoriatic arthritis.   Humira can be used alone or in combination with disease-modifying anti-rheumatic drugs (DMARDs)..  
  4. Indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.
  5. Indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. 
  6. Indicated for reducing signs and symptoms and inducing clinical remission in adult patients with moderately to severely active Crohn’s disease if they have also lost response to or are intolerant to infliximab.
  7. Indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.
  8. Indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP).

All other uses of Humira are considered experimental, investigational, and unproven 

  • Cimzia® (certolizumab pegol)
  1. Reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
  2. Indicated for the treatment of adults with moderately to severely active RA.
  3. Treatment of adult patients with active psoriatic arthritis.
  4. Treatment of adults with active ankylosing spondylitis

All other uses of Cimzia are considered experimental, investigational, and unproven.

  • Simponi® (golimumab)
  1. Moderately to severely active RA in adults, in combination with methotrexate.
  2. Active Psoriatic Arthritis (PsA) in adults, alone or in combination with methotrexate.
  3. Active Ankylosing Spondylitis in adults.
  4. Active Ulcerative Colitis, moderate to severe in patients who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine for:
  • Inducing and maintaining clinical response
  • Improving endoscopic appearance of the mucosa during induction
  • Inducing clinical remission
  • Achieving and sustaining clinical remission in induction responders.

All other uses of Simponi are considered experimental, investigational, and unproven.

  • Simponi Aria®  (golimumab)
    • Indicated for the treatment of adult patients with moderately to severely active Rheumatoid Arthritis (RA) in combination with methotrexate

All other uses of Simponi Aria are considered experimental, investigational, and unproven.

T-Cell Co-stimulation Modulators

Orencia® (Abatacept):

  1. Orencia is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA.   Orencia may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.
  2. Orencia is indicated for reducing signs and symptoms in pediatric and adolescent patients aged six years and older with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). 

The use of Orencia for other treatments of RA or for other chronic inflammatory diseases is considered experimental, investigational, and unproven.

Note:  FDA recommendations:

  • Orencia should not be administered concomitantly with TNF antagonists,
  • Orencia is not recommended for use concomitantly with other biologic RA therapy, such as anakinra,
  • Patients with JIA should be brought up to date with all immunizations prior to Orencia therapy

Monoclonal Antibodies

  • Rituxan® (Rituximab) [NOTE:  See MP RX502.030 for Rituxan for all indications]
  • Stelara® (ustekinumab)
    • Indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.  Note:  Stelara is intended for subcutaneous administration under the supervision of a physician.
    • Indicated for the treatment of adult patients (18 years or older) with active psoriatic arthritis. Stelara can be used alone or in combination with methotrexate (MTX)
  • Actemra® (tocilizumab)
    • Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs)
    • Indicated for treatment of patients two years of age and older with active systemic juvenile idiopathic arthritis (SJIA).  Actemra may be used alone or in combination with methotrexate.
    • Indicated For the treatment of patients two years of age and older with active polyarticular juvenile idiopathic arthritis (PJIA).

NOTE: 

  • Patients treated with Actemra are at increased risk for developing serious infections that may lead to hospitalization or death.  Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.  If a serious infection develops, interrupt Actemra until the infection is controlled.
  • Actemra has not been studied and its use should be avoided in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection.
  • It is recommended that Actemra not be initiated in patients with an absolute neutrophil count (ANC) below 2000/mm3, platelet count below 100,000/mm3, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).

Actemra is considered experimental, investigational and unproven for all other indications.

  • Benlysta® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy (e.g. corticosteroids, antimalarials, immunosuppressives, and nonsteroidal anti-inflammatory drugs).  Note: Benlysta is contraindicated for patients with the following:
    • Severe active lupus nephritis,
    • Severe active central nervous system lupus, or
    • Those taking other biologics or intravenous cyclophosphamide.

Benlysta is considered experimental, investigational and unproven for all other indications.

Interleukin 1 Blocker

Kineret® (Anakinra)

  • Indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active RA, in patients 18 years of age and older who have failed one or more DMARDs. 
  • Kineret is indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) which is a subtype disease of Cryopyrin-Associated Periodic Syndromes (CAPS).

The use of Kineret for other treatments of RA or for other chronic inflammatory diseases is considered experimental, investigational, and unproven.

Ilaris® (canakinumab)

  • Indicated for the treatment of Cryopyrin-Associated Periodic syndromes (CAPs), in adults and children four years of age and older including:
    • Familial Cold Autoinflammatory Syndrome (FCAS), OR
    • Muckle-Wells Syndrome (MWS)
  • Indicated for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 years and older.  

Krystexxa™ (pegloticase)

Krystexxa is indicated for the treatment of chronic gout in adult patients 18 years of age or older who are refractory to conventional therapies as documented in the medical record by:

  • Baseline serum uric acid (SUA) of at least 8 mg/dL; and
  • Symptomatic gout with at least three gout flares in the previous 18 months or at least one episode of gout tophus or gouty arthritis; and
  • Medical history of failure to normalize uric acid (to less than 6 mg/dL) with at least three months of allopurinol treatment at the maximum medically appropriate dose or a medical contraindication to allopurinol.

Krystexxa is considered experimental, investigational, and unproven for all other indications including but not limited to treatment of asymptomatic hyperuricemia.

Amevive® (alefacept)

Amevive is indicated for the treatment of adult patients (18 years of age or older) with moderate to severe chronic (> 1 year) plaque psoriasis who are candidates for or had previously received systemic therapy or phototherapy (unless contraindicated) and meet both the following criteria:

  • Normal CD4+ T lymphocyte counts (>250 cells/μL ) prior to an initial or a subsequent course of treatment; and
  • Plaque psoriasis involvement of more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals.

Note: Amevive is contraindicated for patients with any of the following:

  • Infected with human immunodeficiency virus (HIV);
  • History of systemic malignancy;
  • Chronic infections or a history of recurrent infection; OR
  • Receiving other immunosuppressive agents or phototherapy.

Amevive is considered experimental, investigational and unproven for all other indications.

Rationale

Tumor Necrosis Factor (TNF) Alpha Inhibitors

Remicade

Remicade has demonstrated broad clinical utility in RA, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, ulcerative colitis (UC), and pediatric Crohn’s disease (PCD).   The safety and efficacy of Remicade has been demonstrated in clinical trials over the past fourteen years.   There are currently thirteen FDA approvals across inflammatory diseases in gastroenterology, rheumatology and dermatology, and Remicade has now been used to treat more than 800,000 patients worldwide.

Methotrexate alone for patients with severe RA:

Approximately 50% of people who use Infliximab (Remicade) alone develop antibodies to the medication, which results in loss of clinical response.   Methotrexate impairs this antibody response to negligible levels, so that the therapeutic effect is maintained.   If a patient cannot tolerate Methotrexate it seems appropriate to allow Infliximab (Remicade) alone as an off-label use.   This would be an acceptable benefit for those that do not develop the antibodies.

Off-label use of Etanercept and Adalimumab

In the 2003 BCA TEC Assessment “Off-Label Uses for Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis, Ulcerative Colitis, and Psoriasis”, there is no evidence available to evaluate entanercept or adalimubab for the treatment of ulcerative colitis.   In July 2003, the FDA approved entanercept for the treatment of ankylosing spondylitis.   Therefore ankylosing spondylitis is now an approved FDA indication for entanercept.   In addition, the 2003 TEC Assessment stated that the evidence permits the conclusion that in patients with severe, refractory ankylosing spondylitis the TNF inhibitor etanercept resulted in substantial short-term improvement in the symptoms of axial disease.   The assessment also noted that no conclusions can be drawn about the effects of adalimumab in AS, as there was no published evidence regarding this application.    In the treatment of patients with moderate to severe chronic psoriasis the 2003 TEC Assessment concluded that available evidence is insufficient to permit conclusion concerning the effects of etanercept, or adalimumab on the outcomes of patients with moderate to severe chronic psoriasis.  Therefore, it cannot be determined whether these TNF inhibitors improve net health outcomes for psoriasis patients when compared with conventional therapy.

As of April 30th 2004 Enbrel was approved by the FDA for the treatment of adult patients with chronic, moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.   This approval was based on data from two Phase three studies totaling more than 1200 adults with plaque psoriasis who were treated with Enbrel for up to twelve months.   In one of these Phase three studies, 46 percent of patients receiving 50 mg twice-weekly achieved the primary endpoint of a 75 percent or greater improvement in the psoriasis area severity index (also known as PASI 75) at three months.   These patients were stepped down to half the dose and then continued treatment for an additional three months.   At six months, the percentage of patients achieving a PASI 75 response was maintained following dose reduction.   

T-Cell Co-stimulation Modulator

Orencia (Abatacept)

The safety and efficacy of Orencia have been studied in over 2,600 patients with active RA who have been diagnosed according to the ACR criteria.  The phase III clinical trial program included three double-blind, randomized, placebo-controlled studies: the AIM trial (Abatacept in Inadequate responders to Methotrexate) compared abatacept in combination with methotrexate against methotrexate alone; ATTAIN (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders) compared abatacept in combination with nonbiologic DMARDs against nonbiologic DMARDs alone in patients with inadequate response to TNF antagonists etanercept and infliximab; and ASSURE (Abatacept Study of Safety in Use with other RA Therapies) studied the safety of abatacept compared with placebo when used in combination with biologic and nonbiologic DMARDs.    Orencia is the first approved agent to demonstrate efficacy and safety in patients with an inadequate response to TNF antagonists, as well as those with an inadequate response to methotrexate.

Cimzia

The FDA approved Cimzia on 4/23/2008.  The efficacy and safety of Cimzia were assessed in two double-blind, randomized, placebo-controlled studies in patients aged 18 years and older with moderately to severely active Crohn’s disease, as defined by a Crohn’s Disease Activity Index (CDAI1) of 220 to 450 points, inclusive.  Cimzia was administered subcutaneously at a dose of 400 mg in both studies.  Stable concomitant medications for Crohn’s disease were permitted.  Each study demonstrated that a statistically significant greater proportion of moderate to severe Crohn's disease patients achieved and sustained clinical response with Cimzia for up to six months, compared to placebo.  These data also showed that of the patients who were in remission after initial dosing, the majority maintained remission with no dose escalation.

2008 update for Orencia 

ORENCIA JIA Study (AWAKEN Trial)

The AWAKEN trial was a three-part study which included patients with subtypes of JIA that at disease onset included Oligoarticular JIA (16 percent), Polyarticular JIA (64 percent; 20 percent were rheumatoid factor (RF) positive) and Systemic JIA with polyarticular course (20 percent) who had not responded adequately to other JIA therapies.  In the first phase of this study (Period A), a total of 190 patients aged six to 17 years, with disease duration of approximately four years with moderately to severely active disease at study entry, were enrolled in this open-label, four-month, lead-in phase of the study.  The majority (70 percent) of these study patients were new to biologic treatments.  Nearly 30 percent of patients had previously had an inadequate response to a TNF antagonist or anakinra.  Patients received ORENCIA (abatacept) intravenously (10 mg/kg; maximum 1,000 mg) on Days 1, 15, 29 and every month thereafter.   Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as greater than or equal to 30 percent improvement in at least three of the six JIA core set variables and greater than or equal to 30 percent worsening in not more than one of the JIA core set variables.

In Period A of the study, ORENCIA demonstrated consistent improvement in ACR Pedi 30 with similar responses across all JIA subtypes (Oligoarticular extended, 59.3 percent; Polyarticular-RF positive, 68.4 percent; Polyarticular-RF negative 64.3 percent; and Systemic JIA with polyarticular course, 64.9 percent).   In patients who were inadequate responders to DMARDs including MTX and were new to biologic treatment, ORENCIA demonstrated meaningful ACR Pedi response rates with 76 percent of patients achieving an ACR Pedi 30 response rate, 60 percent achieving an ACR Pedi 50 response rate, 36 percent achieving an ACR Pedi 70 response rate and 17 percent achieving an ACR Pedi 90 response rate.   In patients who received prior biological treatment, 38.6 percent achieved an ACR Pedi 30 response rate, 24.6 percent achieved an ACR Pedi 50 response rate, 10.5 percent achieved an ACR Pedi 70 response rate and 1.8 percent achieved an ACR Pedi 90 response rate.

In Period B of the study, patients who completed Period A and achieved an ACR Pedi 30 response were eligible to enter this six-month, double-blind phase.  Patients entering Period B (n=122) were randomized to remain on ORENCIA (n=60) or receive placebo (n=62) for six months.

The primary endpoint of the study was time to occurrence of disease flare.   Disease flare was defined as a greater than or equal to 30 percent worsening in at least three of the six JIA core set variables with greater than or equal to 30 percent improvement in not more than one of the six JIA core set variables; greater than or equal to two centimeters of worsening of the Physician or Parent Global Assessment was necessary if used as one of the three JIA core set variables used to define flare, and worsening in greater than or equal to two joints was necessary if the number of active joints or joints with limitation of motion was used as one of the three JIA core set variables used to define flare.

Efficacy results included:

  • Time difference to occurrence of disease flare was statistically significant based on the log-rank test in patients treated with placebo compared with ORENCIA (abatacept) (p-value equals 0.0002).
  • Patients treated with ORENCIA experienced significantly fewer disease flares compared to placebo-treated patients (20 percent vs.  53 percent, respectively, p-value less than 0.001).
  • The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients who withdrew from ORENCIA treatment [Hazard Ratio: 0.31, 95 percent CI (0.16, 0.59)].

In patients receiving ORENCIA treatment throughout the study (Period A, Period B and the open-label extension Period C), the proportion of ACR Pedi 30, 50 and 70 responders remained consistent through one year.

In both the open-label, lead-in (Period A) and double-blind (Period B) phases of the study, the adverse reactions in pediatric patients were similar in type and frequency to those seen in adult patients.   This was also seen in patients who participated in the open-label (Period C) extension period.

Monoclonal Antibody

Rituxan (Rituximab)

On February 28th 2006, the FDA approved the use of Rituxan in combination with methotrexate to reduce the signs and symptoms of moderately to severely-active RA in adults with an inadequate response to one or more TNF antagonist therapies.    Based on the FDA label, efficacy of Rituxan was supported in two well-controlled trials in patients with RA with prior inadequate responses to non-biologic DMARDs.   The use of Rituxan in patients with RA who have no prior inadequate response to one or more TNF antagonists is not recommended.   In addition, the safety and efficacy of re-treatment have not been established in controlled trials.   A limited number of patients have received two to five courses (two infusions per course) of treatment in an uncontrolled setting.   In clinical trials in patients with RA, most of the patients who received additional courses did so 24 weeks after the previous course and none were retreated sooner than 16 weeks.

Interleukin 1 Blocker

Kineret® (Anakinra)

Kineret® was FDA approved on April 23rd 2004.   The safety and efficacy of Kineret® was evaluated in three randomized, double-blind, placebo-controlled trials of 1,790 patients ≥18 years of age with active RA.   An additional fourth study was conducted to assess safety.   In the efficacy trials, Kineret® was studied in combination with other DMARDs other than TNF blocking agents or as a monotherapy. 

2009 Update

Simponi

Safety data was based on five pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS.   These five trials included 639 control-treated patients and 1659 Simponi treated patients including 1089 with RA, 292 with PsA, and 278 with AS.   

Rheumatoid Arthritis (RA)

The efficacy and safety of Simponi were evaluated in three multicenter, randomized, double-blind, controlled trials (Studies RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least three months prior to administration of study agent.  Patients were required to have at least four swollen and four tender joints.  Simponi was administered subcutaneously at doses of 50 mg or 100 mg every four weeks.  Double-blinded controlled efficacy data were collected and analyzed through Week 24.  Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials.

In the three RA trials, a greater percentage of patients treated with the combination of Simponi and MTX achieved ACR responses at Week 14 (Studies RA-1 and RA-2) and Week 24 (Studies RA-1, RA-2, and RA-3) versus patients treated with the MTX alone.  There was no clear evidence of improved ACR response with the higher Simponi dose group (100 mg) compared to the lower Simponi dose group (50 mg).  In Studies RA-2 and RA-3, the Simponi monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses.  Table 2 shows the proportion of patients with the ACR response for the Simponi 50 mg and control groups in Studies RA-1, RA-2, and RA-3.   In the subset of patients who received Simponi in combination with MTX in Study RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at Week 14 were 40%, 18%, and 13%, respectively, in the Simponi 50 mg + MTX group (N = 103) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N = 107).   ACR 20 responses were observed in 38% of patients in the Simponi 50 mg + MTX group at the first assessment (Week 4) after the initial Simponi administration.   In Studies RA-1 and RA-2, the Simponi 50 mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.25 vs.  0.05 in RA-1, 0.47 vs.  0.13 in RA-2, respectively.   Also in Studies RA-1 and RA-2, the Simponi 50 mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 44% vs.  28%, 65% vs.  35%, respectively.

Psoriatic Arthritis (PsA)

The safety and efficacy of Simponi were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Study PsA).   Patients in this study had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter.   Previous treatment with a biologic TNF-blocker was not allowed.  Patients were randomly assigned to placebo (n = 113), Simponi 50 mg (n = 146), or Simponi 100 mg (n = 146) given subcutaneously every 4 weeks.   Patients were allowed to receive stable doses of concomitant MTX (≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial.   The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.   The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14.  Placebo-controlled efficacy data were collected and analyzed through Week 24.   Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%).   The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids.

Simponi ± MTX, compared with placebo ± MTX, resulted in significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Study PsA.   There was no clear evidence of improved ACR response with the higher Simponi dose group (100 mg) compared to the lower Simponi dose group (50 mg).  ACR responses observed in the Simponi-treated groups were similar in patients receiving and not receiving concomitant MTX.  Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes.   However, the number of patients with arthritis mutilans was too small to allow meaningful assessment.    Simponi 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Study PsA.   Treatment with Simponi resulted in improvement in enthesitis and skin manifestations in patients with PsA.  However, the safety and efficacy of Simponi in the treatment of patients with plaque psoriasis has not been established.   ACR 20 responses were observed in 31% of patients in the Simponi 50 mg + MTX group at the first assessment (Week 4) after the initial Simponi administration.

In Study PsA, Simponi 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively).   In addition, the Simponi 50 mg group compared to the placebo group had a greater proportion of HAQ responders (≥ 0.3 change from baseline) at Week 24: 43% vs.  22%, respectively.

Ankylosing Spondylitis (AS)

The safety and efficacy of Simponi were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 356 adult patients with active AS according to modified New York criteria for at least 3 months (Study AS).   Patients had symptoms of active disease [defined as a Bath AS Disease Activity Index (BASDAI) ≥ 4 and VAS for total back pain of ≥ 4, on scales of 0 to 10 cm] despite current or previous NSAID therapy.   Patients were excluded if they were previously treated with a biologic TNF-blocker or if they had complete ankylosis of the spine.  Patients were randomly assigned to placebo (n = 78), Simponi 50 mg (n = 138), or Simponi 100 mg (n = 140) administered subcutaneously every 4 weeks.   Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a day), and/or NSAIDs during the trial.   The use of other DMARDs including cytotoxic agents or other biologics was prohibited.   The primary endpoint was the percentage of patients achieving an Assessment in Ankylosing Spondylitis (ASAS) 20 response at Week 14.  Placebo-controlled efficacy data were collected and analyzed through Week 24.

In Study AS, Simponi ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14.   There was no clear evidence of improved ASAS response with the higher Simponi dose group (100 mg) compared to the lower Simponi dose group (50 mg).

Cimzia for RA

The efficacy and safety of Cimzia were assessed in four randomized, placebo-controlled, double-blind studies (RA-I, RA-II, RA-III, and RA-IV ) in patients ≥ 18 years of age with moderately to severely active RA diagnosed according to the American College of Rheumatology (ACR) criteria.  Patients had ≥ nine swollen and tender joints and had active RA for at least six months prior to baseline.   Cimzia was administered subcutaneously in combination with MTX at stable doses of at least 10 mg weekly in Studies RA-I, RA-II, and RA-III.  Cimzia was administered as monotherapy in Study RA-IV.   Cimzia treated patients had higher ACR20, 50 and 70 response rates at 6 months compared to placebo-treated patients.   The results in study RA-II (619 patients) were similar to the results in RA-I at Week 24.   The results in study RA-III (247 patients) were similar to those seen in study RA-IV.   Over the one-year Study RA-I, 13% of Cimzia treated patients achieved a major clinical response, defined as achieving an ACR70 response over a continuous 6-month period, compared to 1% of placebo-treated patients.

In Study RA-I, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score, at Week 52, compared to baseline.   Cimzia inhibited the progression of structural damage compared to placebo plus MTX after twelve months of treatment.   In the placebo group, 52% of patients experienced no radiographic progression (mTSS ≤0.0) at Week 52 compared to 69% in the Cimzia 200 mg every other week treatment group.  Study RA-II showed similar results at Week 24.

In studies RA-I, RA-II, RA-III, and RA-IV, Cimzia-treated patients achieved greater improvements from baseline than placebo-treated patients in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI) at Week 24 (RA-II, RA-III and RA-IV) and at Week 52 (RA-I).   

Stelara

Stelara was studied in two multicenter, randomized, double-blind; placebo-controlled studies prior to FDA approval on September 25, 2009.  Study participants included a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score >12, and who were candidates for phototherapy or systemic therapy.

The studies demonstrate that the majority of patients with moderate to severe plaque psoriasis who received Stelara sustained, clinically significant improvement in their disease severity.  At week 12, the primary endpoint of both studies, 66 percent to 76 percent of patients who received just two doses of Stelara, 45 mg or 90 mg, respectively, at weeks 0 and 4, achieved PASI 75 (75 per cent improvement on the Psoriasis Activity and Severity Index) compared with three to four percent of patients receiving placebo.  Long-term results from these studies through 76 weeks appear strong.   Stelara is not recommended for use in children below age 18 due to a lack of data on safety and efficacy.

The question remains, how will patients manage over time, both in terms of effectiveness and whether any dangers emerge later that would not be seen early in a treatment?  The safety and efficacy of Stelara have not been evaluated beyond two years.    The FDA approval requires a risk evaluation and mitigation strategy (REMS) for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for consumers.   

2010 Update

Actemra

The effectiveness and safety of Actemra was determined in five randomized, double-blind, multicenter trials in adult patients with active rheumatoid arthritis. In all of the trials, patients treated with Actemra experienced greater improvement in their tender or swollen joints than patients treated with a placebo.  Patients had at least eight tender and six swollen joints at baseline.  Actemra was given intravenously every four weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).

Study I evaluated patients with moderate to severe active RA who had not been treated with MTX within 6 months prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response.  In this study, 67% of patients were MTX-naïve, and over 40% of patients had RA < 2 years.  Patients received Actemra 8 mg/kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly).  The primary endpoint was the proportion of Actemra patients who achieved an ACR20 response at Week 24.

Study II is an ongoing 2-year study with a planned interim analysis at week 24 that evaluated patients with moderate to severe active RA who had an inadequate clinical response to MTX.  Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly).  The primary endpoint at week 24 was the proportion of patients who achieved an ACR20 response.

Study III evaluated patients with moderate to severe active RA who had an inadequate clinical response to MTX.  Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly).  The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Study IV evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs.  Patients received Actemra 8 mg/kg or placebo every four weeks, in combination with the stable DMARDs.  The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Study V evaluated patients with moderate to severe active RA who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies.  The TNF antagonist therapy was discontinued prior to randomization.  Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly).  The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Clinical Response

In all studies, patients treated with 8 mg/kg Actemra had statistically significant ACR20, ACR50, and ACR70 response rates versus MTX- or placebo-treated patients at week 24.

Patients treated with Actemra at a dose of 4 mg/kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with Actemra  8 mg/kg.

Conclusion

The FDA is requiring the sponsor to conduct a post-marketing clinical trial to further evaluate the long-term safety of Actemra. Specifically, the FDA wants to evaluate the impact of elevated LDL cholesterol and blood pressure seen in some patients in shorter-term trials on the cardiovascular health of patients treated with Actemra.  In addition, a Risk Evaluation and Mitigation Strategy (REMS) will require the drug sponsor to implement a Communication Plan for physicians informing them how to appropriately monitor their patients for liver and/or gastrointestinal side effects. The REMS will include a Medication Guide to ensure that patients are informed of the benefits and risks of Actemra.

2010 UpdateIlaris® (canakinumab)

The efficacy and safety of canakinumab for the treatment of Cryopyrin-Associated Periodic Syndrome (CAPS) was established in a three-part study in patients (aged 9 to 74 years) with the Muckle-Wells Syndrome (MWS) phenotype of CAPS.  In the study, patients weighing more than 40 kilograms (kg) received 150 milligrams (mg) of canakinumab subcutaneously while patients weighing 15 to 40 kg received 2 mg/kg of canakinumab subcutaneously.  All patients received canakinumab during part one (an 8-week, open-label, single-dose period), and patients who attained a complete clinical response with no relapse were randomized into part two (a 24-week randomized, double-blind, placebo-controlled withdrawal period; n=31).  Patients who finished part two or had a disease flare went into part three (a 16-week, open-label, active treatment phase).  Patients with complete response had ratings of minimal or better for physician's assessment of disease activity (PHY) and assessment of skin disease (SKD) and serum levels of C-reactive protein (CRP) and Serum Amyloid A (SAA) of less than 10 mg/liter (L).  Patients with a disease flare had CRP and/or SAA serum levels greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD.  A complete response was achieved in 71% of patients one week following the start of treatment and in 97% of patients by week 8 during part 1 of the study.  In part two of the study, a total of 81% of patients in the placebo group experienced a flare compared with 0% of patients randomized to canakinumab (95% CI for treatment difference in proportion of flares, 53% to 96%).  All patients treated with canakinumab (n=15) had absent or minimal disease activity and skin disease at the end of part two.  Inflammatory markers (CRP and SAA) normalized in a majority of patients within 8 days and were sustained during treatment with canakinumab; withdrawal of canakinumab led to abnormal values which normalized during part three after reinitiation of canakinumab.  A second trial (open-label manner) in patients (4 to 74 years of age) with both MWS and Familial Cold Autoinflammatory Syndrome phenotypes of CAPS also established the efficacy of canakinumab. Canakinumab treatment led to clinically significant improvement in signs and symptoms and in normalization of high CRP and SAA within one week in the majority of patients.

2011 Update (Rituxan, Actemra, Krystexxa, Amevive and Benlysta)

Rituxan for Wegener's Granulomatosis (WG) and Microscopic Polyangiitis (MPA)

A total of 197 patients with active, severe WG and MPA were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases - a six month remission induction phase and a twelve month remission maintenance phase.  All the patients had active disease.  Patients in both arms received 1000 mg of either Rituxan 375 mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for three to six months in the remission induction phase.  Following intravenous corticosteroid administration, all patients received oral prednisone (l mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission.  The Rituxan group did not receive additional therapy to maintain remission.  The main outcome measure for both WG and MPA patients was achievement of complete remission at 6 months defined as a BVAS/WG of 0, and off glucocorticoid therapy.  The pre-specified non-inferiority margin was a treatment difference of Rituxan to 20%.  The study demonstrated non-inferiority of cyclophosphamide for complete remission at six months. 

Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with WG and MPA. The safety and efficacy of retreatment with Rituxan have not been established.

Actemra for Systemic Juvenile Idiopathic Arthritis (SJIA):

The efficacy of Actemra for the treatment of active SJIA was assessed in a twelve-week randomized, double blind, placebo-controlled, parallel group, two-arm study.  Patients treated with or without methotrexate (MTX), were randomized to two treatment groups: 75 patients received Actemra infusions every two weeks and 37 were randomized to receive placebo infusions every two weeks.  Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response.  The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set.

Of patients with fever or rash at baseline, those treated with Actemra had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21 %) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to two out of the placebo-treated patients.  Responses were consistent in the open label extension (data available through 44 weeks).

Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), Actemra patients achieved a JIA ACR 70 response at week six or eight enabling corticosteroid dose reduction.  Seventeen (24%) Actemra patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR30 flare or occurrence of systemic symptoms to week twelve.  In the open label portion of the study, by week 44, there were 44 out of 103 (43%) of Actemra patients off oral corticosteroids.  Of these 44 patients 50% were off corticosteroids 18 weeks or more.

Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI).  Seventy-seven percent (58 out of 75) of patients in the Actemra treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of': 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.

Krystexxa

Krystexxa was evaluated in two replicate, multicenter, randomized, double-blind, placebo-controlled clinical trials.  Each study lasted six months.  Patients were randomized to receive Krystexxa every two or four weeks or placebo in a ratio of 2:2:1. For both trials, the primary end point was the proportion of patients in whom plasma uric acid was reduced to less than 6 mg/dL for at least 80% of the time during months three and six.  In both trials, more patients receiving Krystexxa every two weeks reached this end point than patients receiving placebo: 47% (P <.001) and 38% (P <.001), compared with 0% in the placebo arms. Two patients receiving Krystexxa every four weeks also achieved the primary end point; however, this regimen was associated with an increased frequency of infusion reactions and a decreased efficacy with the secondary end point. 

The secondary end point was the effect of Krystexxa on tophi, which are deposits of monosodium urate crystals in patients who have sustained long-term high levels of serum uric acid.  Seventy-one percent of patients had baseline tophi. At six months, the combined data from both trials showed that 45% (P <.02) of patients receiving Krystexxa every two weeks had a complete response, which was considered 100% resolution of at least one target tophus, no new tophus developing, and no single tophus showing progression. In comparison, 8% of patients in the combined placebo arms achieved a complete response.

Amevive

Amevive was evaluated in two randomized controlled clinical studies.  Included in the studies were 1060 patients who had chronic (i.e., duration of one year or longer) plaque psoriasis with involvement of at least 10% of the body surface area and who were candidates for or had previously received systemic therapy or phototherapy.  In these studies, 14 or 21% of patients receiving Amevive 7.5 mg intravenous (IV) or 15 mg intramuscular (IM) once weekly, respectively, achieved a response (i.e., reduction in PASI score of at least 75% compared with baseline) at two weeks following a 12-week course of therapy, compared with 4–5% of patients receiving placebo.  An additional 7–11% of patients receiving Amevive achieved a response (i.e., reduction in PASI score of at least 75% compared with baseline) beyond two weeks post-treatment. Response rate at two weeks following a second 12-week course of IV or IM Amevive therapy was 262, or 30%, respectively.  In both clinical studies, onset of response (reduction in PASI score of at least 50% compared with baseline) reportedly was observed 60 days after initiation of Amevive therapy.

The median duration of response (maintenance of 75% or greater reduction in PASI score) after a 12-week course of therapy with Amevive 7.5 mg IV or 15 mg IM once weekly was 3.5 or two months, respectively.  However, patients who achieved at least a 75% reduction in baseline PASI score during or after a single 12-week course of IV Amevive therapy maintained a 50% or greater reduction in PASI score for a median of seven months.  The median reduction in PASI score was greater in patients who received a second course of Amevive treatment compared to patients who received placebo.

Benlysta

Two clinical studies involving 1,684 patients with lupus demonstrated the safety and effectiveness of Benlysta. The studies diagnosed patients with active lupus and randomized them to receive Benlysta plus standard therapy, or an inactive infused solution (placebo) plus standard therapy.  The studies excluded patients who had received prior B-cell targeted therapy or intravenous cyclophosphamide, and those who had active lupus involving the kidneys or central nervous system.

Patients treated with Benlysta and standard therapies experienced less disease activity than those who received a placebo and standard of care medicines. Forty three percent of patients receiving Benlysta experienced a reduction in symptoms after one year compared with 33.8 percent of those on a placebo. Results suggested that some patients had a decreased probability of severe flares, and some patients reduced their steroid doses.

2013 Update ( Remicade, Humira, Actemra, Kineret, and Ilaris)

A search of the U. S. Food, Drug Administration (FDA) for the existing biologics addressed on this medical policy was conducted through June 2013. This medical policy has been revised to reflect approved FDA indications for the following biologics Remicade, Humira, Actemra, Kineret, and Ilaris. 

December 2013 Update (Cimzia, Simponi, Simponi Aria, and Stelara)

 A search of the U. S. Food, Drug Administration (FDA) for biologics addressed on this medical policy was conducted through June 2013. This medical policy has been revised to reflect approved FDA indications for the following biologics. (27, 28, 29, 30)

Coding

Disclaimer for coding information on Medical Policies

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

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

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

ICD-9 Codes
274.00, 274.01, 274.02, 274.03, 555.0, 555.1, 555.2, 555.9, 556.5, 556.8, 696.0, 696.1, 714.1, 719.30, 720.0
Procedural Codes: J0129, J0135, J0215, J0490, J0717, J0718, J1438, J1745, J2507, J3262, J3357, J3590. J0638
References
  1. Antoni, C.E, Kavanaugh, A., et al.   Sustained benefits of infliximab for dermatologic and articular manifestations of psoriatic arthritis results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT).   Arthritis Rheumatology (2005) 52(4):1227-36.
  2. Gottlieb, A.B., Evans, R., et al.  Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial.   Journal of American Academy of Dermatology (2004) 51(4):534-42.
  3. Rutgeerts, P.  Feagan, B.G., et al.   A randomized placebo controlled trial of infliximab therapy for active ulcerative colitis: Act 1 trial.   Gastroenterology (2005) 128(4 suppl 2):A-105 (abstract).
  4. Sandborn, W.J., Rachmilewitz, D.R., et al.   Infliximab induction and maintenance therapy for ulcerative colitis: the Act 2 trial.   Gastroenterology (2005) 128(4 suppl 2): A-104 (abstract).
  5. FDA – Department of Health and Human Services – U.S.  BL 103705 Supplement Amendment: Rituxan RA - Genentech, Inc.  (2006 February 3).
  6. FDA – Department of Health and Human Services – BL 103772/5145 - Remicade DC Maintenance (2006 October 11).
  7. FDA – Department of Health and Human Services – Anakinra BL 10395015039 (2004 April 23).
  8. FDA – Department of Health and Human Services – Enbrel – Label supplement (2006 June 14)
  9. FDA – Department of Health and Human Services – Orencia – Approval Labeling (2005 December 12).
  10. Pariser, D.M., Bagel, J. et al.  National Psoriasis Foundation, Clinical Consensus on Disease Severity. Archived of Dermatology (Feb 2007) 143: 239-242.
  11. FDA – Department of Health and Human Services – Cimzia – Approval Labeling (18 April 2008).
  12. FDA – Department of Health and Human Services – Simponi – Approval Labeling (May 2009).
  13. FDA – Department of Health and Human Services – Cimzia – Approval Labeling (13 May 2009).
  14. FDA – Department of Health and Human Services – Stellar – Approval Labeling ( 25 September, 2009).
  15. FDA – Department of Health and Human Services – Stellar – Approval Labeling (8 January, 2010)
  16. Ilaris [product information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010.
  17. Micromedex Healthcare Series Web site. Available at:  http://www.thomsonhc.com . Accessed November, 16, 2010.
  18. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360;23:2416-25.
  19. FDA – Department of Health and Human Services – Amevive – Approval Labeling (January 2003). Last accessed April 2011.
  20. FDA – Department of Health and Human Services – Krystexxa– Approval Labeling (September 2010). Accessed April 2011.
  21. FDA – Department of Health and Human Services –Rituxan– Approval Labeling (April 2011). Accessed April 2011.
  22. FDA – Department of Health and Human Services – Remicade- Approval Labeling (Revised March 2013). Last accessed June 2013.
  23. FDA – Department of Health and Human Services – Humira- Approval Labeling (Revised September 2012). Last accessed June 2013.
  24. FDA – Department of Health and Human Services – Actemra- Approval Labeling (Revised April 2013). Last accessed June 2013.
  25. FDA – Department of Health and Human Services –Kineret - Approval Labeling (Revised December 2012). Last accessed June 2013.
  26. FDA – Department of Health and Human Services –Ilaris- Approval Labeling (Revised October 2012). Last accessed June 2013.
  27. FDA – Department of Health and Human Services –Cimzia- Approval Labeling (Revised October 2013). Last accessed December 2013.
  28. FDA – Department of Health and Human Services –Simponi- Approval Labeling (Revised November 2013). Last accessed December 2013.
  29. FDA - Department of Health and Human Services –Simponi Aria - Approval Labeling (Revised July 2013). Last accessed December 2013.
  30. FDA – Department of Health and Human Services –Stelara- Approval Labeling (Revised January 2013). Last accessed December 2013.
History
October 2013 New 2013 BCBSMT medical policy.
February 2014 Document updated with literature review.  The coverage section has been updated to reflect revised or addition approved FDA indications for the following biologics: Cimzia, Simponi, Simponi Aria, and Stelara.   CPT/HCPCS code(s) updated.
BCBSMT Home
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases