Medical Policies - Prescription Drugs


Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases

Number:RX501.051

Effective Date:07-15-2018

Coverage:

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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

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:

Tumor Necrosis Factor (TNF) Alpha Inhibitors

Remicade® (Infliximab), Inflectra (Infliximab, Biosimilar), Renflexis (Infliximab, Biosimilar) Ixifi (infliximab-qbtx, Biosimilar)

1. For the reduction of the signs and symptoms, and inducing and maintaining clinical remission in adult and pediatric patients (6 to 17 years old) with moderately to severely active Crohn’s disease, who have had an inadequate response to conventional therapy.

2. Indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.

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. Indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.

5. Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

6. Reducing signs and symptoms, inducing and maintaining 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.

7. 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.

8. 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.

9. Treatment of adult patients (18 years of age or older) with severe refractory sarcoidosis.

10. Adult onset Still's disease.

11. Granulomatosis with polyangiitis, refractory, in combination with corticosteroids.

12. Hidradenitis suppurativa, severe, refractory.

13. Juvenile idiopathic arthritis (severe), refractory to other therapies.

14. Synovitis.

15. Takayasu's disease, refractory.

16. Uveitis, refractory; adjunct.

17. Severe immune-related colitis associated with anti-PD1 agents and ipilimumab that does not respond within 1 week to therapy with high-dose steroids (single dose).

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

Enbrel® (Etanercept)

This BRM is self-administered. Please refer to applicable pharmacy benefit plan.

Humira® (Adalimumab)

This BRM is self-administered. Please refer to applicable pharmacy benefit plan.

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/or 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:

o Inducing and maintaining clinical response,

o Improving endoscopic appearance of the mucosa during induction,

o Inducing clinical remission,

o Achieving and sustaining clinical remission in induction responders.

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

Simponi Aria® (golimumab):

Simponi Aria is indicated for treatment of adult patients with:

Moderately to severely active RA in combination with methotrexate (MTX),

Active psoriatic arthritis (PsA), or

Active ankylosing spondylitis (AS).

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

T-Cell Co-Stimulation Modulators

Orencia® (Abatacept):

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. Orencia may be used as monotherapy or concomitantly with disease-modifying anti-rheumatic drugs (DMARDs) other than TNF antagonists.

2. Indicated for reducing signs and symptoms in pediatric and adolescent patients aged 6 years and older with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA).

3. Adult Psoriatic Arthritis (PsA).

4. Rheumatoid arthritis, early disease, methotrexate naive with poor prognostic factors.

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

U. S. Food and Drug Administration (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)

This BRM may be self-administered. For self-administered, please refer to applicable pharmacy benefit plan.

Stelara® is indicated for the treatment of:

Patients 12 years or older with moderate to severe plaque psoriasis (Ps) who are candidates for phototherapy or systemic therapy.

Adult patients 18 years and older with active psoriatic arthritis (PsA), alone or in combination with methotrexate.

Adult patients 18 years and older with moderately to severely active Crohn’s disease (CD) who have failed or were intolerant to:

o Treatment with immunomodulators or corticosteroids, but never failed a tumor necrosis factor (TNF) blocker, or

o Treatment with one or more TNF blockers.

When meeting criteria noted above, adults with Crohn’s disease will receive the first dose of Stelara through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. Patients may then receive Stelara as an injection under the skin (subcutaneous injection) 8 weeks after the first dose.

Stelara is considered experimental, investigational, and/or unproven for all other indications.

Actemra® (tocilizumab)

Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis.

Indicated for treatment of patients 2 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 2 years of age and older with active polyarticular juvenile idiopathic arthritis (PJIA).

Indicated for adult patients with giant cell arteritis.

Indicated for adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.

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/or unproven for all other indications.

Benlysta® (belimumab)

Benlysta 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).

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/or unproven for all other indications.

Entyvio (vedolizumab)

Is indicated for adult patients (18 years of age or older) with moderate to severely active ulcerative colitis (UC) who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids. Treatment goals are:

o Inducing and maintaining clinical response;

o Inducing and maintaining clinical remission;

o Improving the endoscopic appearance of the mucosa; and

o Achieving corticosteroid-free remission.

Is indicated for adult patients (18 years of age or older) with moderate to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids. Treatment goals are:

o Achieving clinical response;

o Achieving clinical remission; and

o Achieving corticosteroid-free remission.

Entyvio (vedolizumab) is considered experimental, investigational and/or 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.

Indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) which is a subtype disease of Cryopyrin-Associated Periodic Syndromes (CAPS).

Chronic infantile neurological, cutaneous and articular syndrome, treatment-refractory.

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

Ilaris® (canakinumab)

Ilaris is indicated for the treatment of the following Periodic Fever Syndromes:

Cryopyrin-Associated Periodic syndromes (CAPs), in adults and children 4 years of age and older including:

o Familial Cold Autoinflammatory Syndrome (FCAS); OR

o Muckle-Wells Syndrome (MWS).

Tumor Necrosis Factor (TNF) receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients.

Hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.

Familial Mediterranean Fever (FMF) in adult and pediatric patients.

Gouty arthritis, acute

Ilaris is considered experimental, investigational, and/or unproven for all other indications.

Ilaris is 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 6 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/or 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/or unproven for all other indications.

Description:

Many biologic therapies are currently approved for the treatment of rheumatoid arthritis (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 biologic Kineret, blocks the action of another inflammatory cytokine called interleukin-1. Orencia 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 slow or prevent damage to joints. There have been serious side effects noted with biologic therapies, and risks and benefits should be discussed and its use monitored carefully by a physician. Biologic therapies may be given orally, injected under the skin (Enbrel, Humira, and Kineret) or infused through an intravenous infusion (IV) (Remicade, Orencia).

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 IV. 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.

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.

Simponi Aria (golimumab intravenous [IV])

In July 2013, the FDA approved Simponi Aria (golimumab intravenous [IV]), a TNF inhibitor, for the treatment of moderate-to-severe RA in combination with methotrexate. In October 2017, the FDA approved Simponi Aria for the treatment of adults with active psoriatic arthritis (PsA) or active ankylosing spondylitis (AS).

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

Actemra (tocilizumab)

Actemra (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody. It binds specifically to both soluble and membrane-bound IL-6 receptors, and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pro-inflammatory cytokine and has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.

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.

Stelara reduces the immune system’s 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.

Psoriatic Arthritis Recommended Adult Subcutaneous Dosage:

The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks.

For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks.

Crohn’s Disease Recommended Initial Adult Intravenous Dosage:

A single intravenous infusion using weight-based dosing.

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.

Entyvio (vedolizumab)

Entyvio is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressing cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).

The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn’s disease.

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 inadequate 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 patients 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.

Rationale:

Tumor Necrosis Factor (TNF) Alpha Inhibitors

Remicade

Methotrexate alone for patients with severe RA:

Approximately 50% of people who use 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 (Remicade) alone as an off-label use. This would be an acceptable benefit for those that do not develop the antibodies. (1, 2, 3 4, 6, 18)

Off-label use of Etanercept and Adalimumab

In the 2003 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation (TEC) “Off-Label Uses for Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis (AS), Ulcerative Colitis, and Psoriasis”, there is no evidence available to evaluate etanercept or adalimumab for the treatment of ulcerative colitis. In July 2003, the FDA approved etanercept for the treatment of ankylosing spondylitis. Therefore, ankylosing spondylitis is now an approved FDA indication for etanercept. 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 30, 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 psoriasis area severity index (PASI) calculator 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. (8)

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. (23) 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 4 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 American College of Radiology (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 methotrexate (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 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. (9)

Interleukin 1 Blocker

Kineret® (Anakinra)

Kineret® was FDA approved on April 23, 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. (21) 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, psoriatic arthritis (PsA), and AS. (25) 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 could 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 could 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 sulfasalazine (SSZ), hydroxychloroquine (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 a scale 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. (23) 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. (26) 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. (20) 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. (22) 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 (Actemra, Krystexxa, Amevive and Benlysta)

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. (20) 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. (16) 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. (15) 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 (30). 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. (6, 11, 12, 16, and 19).

Additional 2013 Update

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 biologics Cimzia, Simponi, Simponi Aria, and Stelara. (23, 24, 25 and 26)

2014 Update

Coverage position has been revised to address the recent FDA approved drug Entyvio (vedolizumab). Entyvio was FDA approved May 2014. The safety and effectiveness of Entyvio for ulcerative colitis were established in two clinical trials involving approximately 900 patients who had not responded adequately to corticosteroids, immunomodulators, or tumor necrosis factor blocker medications. Evaluations of patients included measures of stool frequency, rectal bleeding, endoscopic findings and a physician‘s overall assessment. Results showed that a greater percentage of participants treated with Entyvio compared to a placebo achieved and maintained clinical response, achieved and maintained clinical remission, achieved corticosteroid-free clinical remission, and as seen during endoscopy, had improved appearance of the colon.

The safety and effectiveness of Entyvio for Crohn ‘s disease were established in three clinical trials involving approximately 1,500 patients who had not responded adequately to corticosteroids, immunomodulators, or tumor necrosis factor blocker medications. Results showed that a greater percentage of participants treated with Entyvio compared to a placebo achieved clinical response, achieved clinical remission, and achieved corticosteroid-free clinical remission. (27)

2015 Update

A search of the U. S. Food, Drug Administration (FDA) for all biologics addressed on this medical policy was conducted through September 10, 2015. This medical policy has been revised to reflect the FDA updated indications for the biologic Humira.

2017 Update

A search of the U. S. Food, Drug Administration (FDA) for all biologics addressed on this medical policy was conducted through February 2017. This medical policy has been revised to reflect the following FDA updated indications.

Ilaris - Treatment of Periodic Fever Syndromes: TRAPS, HIDS/MKD, and FMF

Treatment of TRAPS, HIDS/MKD, and FMF

A Phase III trial (TRAPS, HIDS/MKD, and FMF Study 1) investigated the safety of ILARIS in 3 cohorts (TRAPS, HIDS/MKD, and FMF) as follows: a 12-week screening period (Part 1), followed by a 16-week, randomized, double-blind, placebo-controlled parallel-arm treatment period (Part 2), followed by a 24-week randomized withdrawal period (Part 3), followed by a 72-week, open-label treatment period (Part 4). All patients randomized to treatment with ILARIS in Part 2 received 150 mg subcutaneously every 4 weeks if body weight was greater than 40 kg (or 2 mg/kg every 4 weeks if body weight was less than or equal to 40 kg).

In Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1, initially 90 patients were randomized to ILARIS treatment and 91 patients were randomized to placebo. Of patients randomized to ILARIS, 55.6% remained on the initial dose through week 16 with 6.7% receiving an additional ILARIS dose between Day 7 and Day 15. Of the patients randomized to placebo, 9.9% remained on placebo through Week 16 with 28.6% switching to active treatment with ILARIS by Day 15.

Overall, there were 43 TRAPS, 68 HIDS/MKD, and 58 FMF patients in the safety set with a cumulative canakinumab exposure of 47.61 patient-years. The cumulative exposure in the placebo group was 8.03 patient-years.

In Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1, a total of 22 TRAPS patients aged 3 to 76 years of age, 37 HIDS/MKD patients aged 2 to 43 years of age, and 31 FMF patients aged 2 to 60 years of age were initially randomized to treatment with ILARIS 150 mg every four weeks in the placebo-controlled period of the clinical trial. In addition, 4 non-randomized patients (2 FMF patients of age 20 and 29 years with non-exon 10 mutations and 2 HIDS/MKD patients both of 1 year of age) received open-label treatment in Part 2.

The most commonly reported adverse reactions (greater than or equal to 10%) associated with ILARIS treatment in TRAPS, HIDS/MKD, and FMF patients were injection-site reactions and nasopharyngitis. The reported adverse reactions (greater than or equal to 3%) associated with ILARIS treatment in TRAPS, HIDS/MKD, and FMF patients were injection-site reactions (10.1%), and infections including nasopharyngitis (10.7%), upper respiratory tract infection (7.1%), rhinitis (5.3%), gastroenteritis (3.0%), and pharyngitis (3.0%). Serious infections (e.g., conjunctivitis, pneumonia, pharyngitis, and pharyngotonsillitis) were observed in approximately 2.4% (0.03 per 100 patient-days) of patients receiving ILARIS in Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1. In the ILARIS treatment group, 1 TRAPS patient discontinued treatment due to adverse events, 2 HIDS/MKD patients discontinued treatment due to adverse events, and no FMF patients discontinued treatment due to an adverse event. In the TRAPS, HIDS/MKD, and FMF Study 1, subcutaneous injection-site reactions were observed in 10.1% of patients in Part 2 who had a mild or a moderate tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment.

Stelara - Intravenous (IV) induction dose for Crohn’s disease.

Stelara was evaluated in three randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction studies (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (CD-3) representing 52 weeks of therapy. The 1407 patients included in the clinical studies included 40 patients who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In Studies CD-1 and CD-2 there were 470 patients who received STELARA® 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo. Patients who were responders in either Study CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg Stelara every 8 weeks, or placebo for 44 weeks in Study CD-3. Patients in these 3 studies may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s Disease. The overall safety profile of Stelara was consistent with the safety profile seen in the psoriasis and psoriatic arthritis clinical studies.

2018 Update

A search of the U. S. Food, Drug Administration (FDA) and DrugDex for all biologics addressed on this medical policy was conducted through April 2018. This medical policy has been updated to reflect the most current FDA approved indications and DrugDex recommended off-label indications for the biologics addressed on this medical policy.

Contract:

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.

Coding:

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.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J0129, J0135, J0215, J0490, J0717, J1438, J1602, J1745, J2507, J3262, J3357, J3358, J3380, J3590, J0638, Q5102, Q5103, Q5104, Q9989, [Deleted 7/2017: C9487]

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov.

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. <http://www.fda.gov> (Last accessed March 2016).

6. FDA – Department of Health and Human Services – BL 103772/5145 - Remicade DC Maintenance <http://www.fda.gov> (Last accessed March 2016).

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Policy History:

Date Reason
7/15/2018 Document updated with literature review. The following added: 1) Specific to Remicade® (Infliximab) the following biosimilar wording added: Ixifi (infliximab-qbtx, Biosimilar). In addition, the following medically necessary indications added for Remicade: “Adult onset Still's disease; granulomatosis with polyangiitis, refractory, in combination with corticosteroids; hidradenitis suppurativa, severe, refractory; juvenile idiopathic arthritis (severe), refractory to other therapies; takayasu's disease, refractory; uveitis, refractory, adjunct; severe immune-related colitis associated with anti-PD1 agents and ipilimumab that does not respond within 1 week to therapy with high-dose steroids (single dose).” 2) Specific to Actemra for rheumatoid arthritis, the following wording was removed from the medically necessary coverage: “who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs)”; In addition, the following new indication added: “Indicated for adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome”. 3) Specific to Kineret the following indication was added: “Chronic infantile neurological, cutaneous and articular syndrome, treatment-refractory”. 4) Specific to Ilaris the following indication was added: “Gouty arthritis, acute”. 5) Specific to Orencia the following indications were added: “Rheumatoid arthritis, early disease, methotrexate naive with poor prognostic factors; and “adult Psoriatic Arthritis (PsA)”. 6) For Kystexxa the criteria for baseline uric acid level changed from “at least 8 mg/dL to “at least 6 mg/dL”.
2/15/2018 Partial update. Coverage criteria wording for Stelara® (ustekinumab) specific to severe plaque psoriasis (Ps) changed from “adults” to now state “12 years or older”. The other two indications for Stelara for adults had the following wording added: “18 years and older”. In addition, specific to Simponi Aria® (golimumab), the following two indications were added: active psoriatic arthritis (PsA) and active ankylosing spondylitis (AS).
8/15/2017 Partial update. The coverage statement “Is considered experimental, investigational and unproven for all other indications” was added to the coverage sections for Stelara and Ilaris.
7/15/2017 Partial update. The following new FDA approved indication was added to coverage for Actemra: “Indicated for adult patients with giant cell arteritis.
4/1/2017 Document updated with literature review. The following was added to the coverage section: 1) Stelara® is indicated for the treatment of adult patients with: Moderate to severe plaque psoriasis (Ps) who are candidates for phototherapy or systemic therapy, active psoriatic arthritis (PsA), alone or in combination with methotrexate, or moderately to severely active Crohn’s disease (CD) who have failed or were intolerant to: Treatment with immunomodulators or corticosteroids, but never failed a tumor necrosis factor (TNF) blocker, or failed or were intolerant to treatment with one or more TNF blockers. In addition, the following note was added specific to Stelara. “Note: When meeting criteria noted above adults with Crohn’s disease will receive the first dose of Stelara through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. Patients may then receive Stelara as an injection under the skin (subcutaneous injection) 8 weeks after the first dose.” 2) The following indications were added to the coverage indications for Ilaris for adult and pediatric patients: Tumor Necrosis Factor (TNF) receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF).
3/15/2016 Reviewed. No changes.
12/15/2015 Document updated with literature review. 1) The following was removed from the Remicade coverage specific to ankylosing spondylitis and psoriatic arthritis: “Patients with ankylosing spondylitis or psoriatic arthritis who are refractory to conventional therapies” and 2) The coverage statement for Remicade specific to ulcerative colitis modified to remove the word “achieving” and replaced with “inducing and maintaining”. The coverage reads: “Reducing signs and symptoms, inducing and maintaining 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”.
11/15/2015 Document updated with literature review. The following was changed: Specific coverage criteria for Humira, Enbrel, and Stelara was removed and replaced with the following statement: “This biologic response modifier (BRM) is self-administered. Please refer to applicable pharmacy benefit plan”.
10/1/2014 Document updated with literature review. The coverage section has been updated to reflect the U. S. Food, Drug Administration (FDA) approved drug Entyvio. Conditional coverage statement is based on FDA labeled indications for ulcerative colitis and Crohn’s disease (see coverage). CPT/HCPCS code(s) updated.
1/1/2014 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
8/15/2013 Document updated with literature review. This coverage section has been updated to reflect revised or additional approved FDA indications (since the time of the last medical policy update), for the following biologics: Remicade, Humira, Actemra, Kineret, and Ilaris (see coverage).
10/1/2011 Document updated with literature review. The following was added: Use of Amevive for specific FDA approved indications may be considered medically necessary when noted criteria are met.
7/1/2011 Document updated with literature review. The following was added: Use of Rituxan, Actemra, Krystexxa, and Benlysta for specific FDA approved indications may be considered medically necessary when noted criteria are met. All other indications are considered experimental, investigational, and unproven .
3/15/2010 Revised/updated entire document specific to the new FDA approved drug Actemra. Actemra is indicated for treatment of adult patients with moderately-to severely-active RA who have had an inadequate response to one or more TNF antagonist therapies. Actemra may be used as monotherapy or concomitantly with methotrexate or other DMARDs.
11/15/2009 Revised/updated entire document. Coverage position remains conditional with the addition of new RA indication for Cimzia and new coverage statement for drug Simponi and Stelara with coverage criteria based on FDA labeled indications.
10/1/2008 Revised/Updated Entire Document
8/15/2008 Revised/Updated Entire Document
6/15/2008 Revised/Updated Entire Document
3/15/2008 Revised/Updated Entire Document
5/1/2007 Revised/Updated Entire Document
12/1/2005 Revised/Updated Entire Document
2/1/2005 Revised/Updated Entire Document
7/30/2004 Revised/Updated Entire Document
12/1/2003 Revised/Updated Entire Document
5/1/2000 Revised/Updated Entire Document

Archived Document(s):

Title:Effective Date:End Date:
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases02-15-201807-14-2018
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases08-15-201702-14-2018
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases07-15-201708-14-2017
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases04-01-201707-14-2017
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases03-15-201603-31-2017
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases12-15-201503-14-2016
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases11-15-201512-14-2015
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases10-01-201411-14-2015
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases01-01-201409-30-2014
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases08-15-201312-31-2013
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases10-01-201108-14-2013
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases07-01-201109-30-2011
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases01-01-201106-30-2011
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases03-15-201012-31-2010
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases11-15-200903-14-2010
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases10-01-200811-14-2009
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases08-15-200809-30-2008
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases06-15-200808-14-2008
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases03-15-200806-14-2008
Biologic Response Modifiers (BRMs) for the Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases05-01-200703-14-2008
Tumor Necrosis Factor (TNF) Alpha Inhibitors for Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases03-01-200704-30-2007
Tumor Necrosis Factor (TNF) Alpha Inhibitors for Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases02-08-200702-28-2007
Tumor Necrosis Factor (TNF) Alpha Inhibitors for Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases12-01-200502-07-2007
Tumor Necrosis Factor (TNF) Alpha Inhibitors for Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases02-01-200511-30-2005
Tumor Necrosis Factor (TNF) Alpha Inhibitors for Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases07-30-200401-31-2005
Tumor Necrosis Factor (TNF) Alpha Inhibitors for Treatment of Rheumatoid Arthritis (RA) and Other Chronic Inflammatory Diseases12-01-200307-29-2004
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