Clinical UM Guideline

 

Subject: Ustekinumab (Stelara®)
Guideline #: CG-DRUG-69 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017

Description

This document addresses the indications for ustekinumab, a biologic agent used for the treatment of active psoriatic arthritis, chronic moderate to severe plaque psoriasis, and moderately to severely active Crohn’s disease.

Note: Please see the following related documents for additional information:

Note: For additional information on review of clinically equivalent cost effective criteria for the product addressed in CG-DRUG-69, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Clinical Indications

Medically Necessary:

Ustekinumab is considered medically necessary when criteria are met for any of the following indications:

  1. Crohn’s disease when the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active Crohn’s disease; and
    2. Individual has failed to respond to, lost response to, is intolerant of, or has a medical contraindication to either of the following:
      1. A tumor necrosis factor antagonist drug; or
      2. Conventional drug therapy, such as aminosalicylate products (for example, mesalamine, sulfasalazine) or an immunomodulator drug (for example, azathioprine, 6-mercaptopurine, or methotrexate); or
    3. Individual has failed to respond to, is intolerant of, or has demonstrated dependence on systemic corticosteroids; and
    4. Ustekinumab is used for one of the following:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response or remission.
  2. Psoriatic arthritis when the following criteria are met:
    1. Individual is 18 years of age or older with active psoriatic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonbiologic disease-modifying antirheumatic drugs).
  3. Plaque psoriasis when the following criteria are met:
    1. Individual is 12 years of age or older with chronic moderate to severe plaque psoriasis with either of the following:
      1. Plaque psoriasis involving greater than 5% body surface area; or
      2. Plaque psoriasis involving less than or equal to 5% body surface area involving sensitive areas or areas that significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia); and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to phototherapy or other systemic therapy (such as acitretin, cyclosporine, or methotrexate).

Not Medically Necessary:

Ustekinumab is considered not medically necessary for an individual with any of the following:

  1. When used in combination with other immunosuppressive therapy or phototherapy for the treatment of plaque psoriasis; or
  2. History of reversible posterior leukoencephalopathy syndrome; or
  3. Tuberculosis, invasive fungal infection, other active serious infections, or a history of recurrent infections; or
  4. Individual has not had a tuberculin skin test or a Centers for Disease Control and Prevention-recommended equivalent test to evaluate for latent tuberculosis prior to initiating ustekinumab.

Ustekinumab is considered not medically necessary when criteria are not met and for the treatment of all other indications, including, but not limited to:

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J3357

Ustekinumab, for subcutaneous injection, 1 mg [Stelara subcutaneous]

J3358

Ustekinumab, for intravenous injection, 1 mg [Stelara IV for Crohn’s disease]

 

 

ICD-10 Diagnosis

 

K50.00-K50.919

Crohn's disease [regional enteritis]

L40.0

Psoriasis vulgaris

L40.1

Generalized pustular psoriasis

L40.2

Acrodermatitis continua

L40.3

Pustulosis palmaris et plantaris

L40.4

Guttate psoriasis

L40.50-L40.59

Arthropathic psoriasis

L40.8

Other psoriasis

L40.9

Psoriasis, unspecified

Discussion/General Information

Ustekinumab is a human IgG1қ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation (Stelara Product Information [PI] Label, 2017).

Ustekinumab for Crohn’s Disease

The cytokines IL-12 and IL-23 have been identified as contributors to the chronic inflammation that is a characteristic of Crohn’s disease. Two randomized, double-blind, placebo-controlled phase II trials evaluated the safety and effectiveness of ustekinumab to induce and maintain clinical remission in the treatment of individuals with moderately to severely active or refractory Crohn’s disease (Sandborn, 2008; Sandborn, 2012).

In September 2016, the U.S. Food and Drug Administration (FDA) approved ustekinumab for the treatment of adults with moderately to severely active Crohn’s disease who failed to respond to, or were intolerant of treatment with immunomodulator drugs or corticosteroids, but never failed treatment with a tumor necrosis factor (TNF) antagonist, or who failed to respond to, or were intolerant of treatment with one or more TNF antagonists. The FDA approval was based on data from three randomized, double-blind, placebo-controlled phase III studies: UNITI-1 induction study (CD-1; NCT01369329), UNITI-2 induction study (CD-2; NCT01369342) (Feagan, 2016), and IM-UNITI maintenance study (CD-3; NCT01369355). Study participants had moderately to severely active Crohn’s disease of at least 3 months duration with colitis, ileitis, or ileocolitis confirmed at some time in the past by radiography, histology, or endoscopy. Active Crohn’s disease was defined as a baseline Crohn’s Disease Activity Index (CDAI) score of 220 to 450. The two 8-week intravenous induction studies were followed by a 44-week subcutaneous randomized withdrawal maintenance study representing 52 weeks of therapy. In Studies CD-1 and CD-2, 1368 of the 1409 randomized participants (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. In both studies, participants were randomized to receive a single intravenous administration of ustekinumab at approximately 6 milligrams (mg)/kilogram (kg), placebo, or 130 mg (a lower dose than recommended).

In Study CD-1, participants had failed to respond to, lost response to continued therapy, or were intolerant of prior treatment with a TNF antagonist (that is, adalimumab, certolizumab pegol, or infliximab). At baseline and throughout the study, approximately 46% of the participants were receiving corticosteroids and 31% of the participants were receiving immunomodulator drugs (that is, 6-mercaptopurine [6-MP], azathioprine [AZA], methotrexate [MTX]). In Study CD-I, a greater proportion of ustekinumab-treated participants compared to placebo participants achieved clinical response at Week 6 (34% [84 of 249] vs. 21% [53 of 247] of participants, respectively) and clinical remission at Week 8 (21% [52 of 249] vs. 7% [18 of 247] of participants, respectively; treatment difference and 95% confidence interval [CI], 12% and 14%, respectively).

In Study CD-2, participants had failed to respond to, or were intolerant of prior treatment with corticosteroids (81% of participants), at least one immunomodulator drug (that is, 6-MP, AZA, MTX; 68% of participants), or both (49% of participants). Additionally, 69% of participants were never treated with a TNF antagonist and 31% previously received but had not failed a TNF antagonist. At baseline, and throughout the study, approximately 39% of the participants were receiving corticosteroids and 35% of the participants were receiving immunomodulator drugs (6-MP, AZA, MTX). In Study CD-2, a greater proportion of ustekinumab-treated participants compared to placebo participants achieved clinical response at Week 6 (56% [116 of 209] vs. 29% [60 of 209] of participants, respectively) and clinical remission at Week 8 (40% [84 of 209] vs. 20% [41 of 209] of participants, respectively; treatment difference and 95% CI, 27% and 21%, respectively). Clinical response and remission were significant as early as Week 3 in ustekinumab-treated participants and continued to improve through Week 8 (Feagan, 2016; Stelara PI, 2016).

The maintenance study (CD-3), evaluated 388 participants who achieved clinical response (≥ 100 point reduction in CDAI score) at Week 8 of induction with ustekinumab in Studies CD-1 or CD-2. Participants were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks. At Week 44, 47% of participants who received ustekinumab were corticosteroid-free and in clinical remission, compared to 30% of participants in the placebo group. At Week 0 of Study CD-3, 61% (34 of 56) of ustekinumab-treated participants who previously failed to respond to, or were intolerant of TNF antagonist therapies were in clinical remission and 41% (23 of 56) of these participants were in clinical remission at Week 44. In the placebo arm, 44% (27 of 61) of participants were in clinical remission at Week 0 while 26% (16 of 61) of these participants were in remission at Week 44. At Week 0 of Study CD-3, 64% (46 of 72) of ustekinumab-treated participants who had previously failed immunomodulator therapy or corticosteroids (but not TNF antagonists) were in clinical remission and 63% (45 of 72) of these participants were in clinical remission at Week 44. In the placebo arm, 71% (50 of 70) of these participants were in clinical remission at Week 0 while 44% (31 of 70) were in remission at Week 44. In the subset of these participants who were also naïve to TNF antagonist treatment, 65% (34 of 52) of ustekinumab-treated participants were in clinical remission at Week 44 as compared to 49% (25 of 51) in the placebo arm. Participants who were not in clinical response 8 weeks after ustekinumab induction were not included in the primary efficacy analyses for Study CD-3; however, these participants were eligible to receive a 90 mg subcutaneous injection of ustekinumab upon entry into Study CD-3. Of these participants, 47% (102 of 219) achieved clinical response 8 weeks later and were followed for the duration of the study (Stelara PI, 2016).

The most common adverse reaction through Week 8 in Studies CD-1 and CD-2 (n=470) in ≥ 3% of ustekinumab-treated participants was vomiting (4%). Other less common adverse reactions reported in Study CD-1 and CD-2 included asthenia (1% vs. 0.4%), acne (1% vs. 0.4%) and pruritus (2% vs. 0.4%). Common adverse reactions through Week 44 in Study CD-3 occurring in ≥ 3% of ustekinumab-treated participants (n=131) that were higher than in the placebo group (n=133) included nasopharyngitis (11% vs. 8%), injection site erythema (5% vs. 0%), vulvovaginal candidiasis/mycotic infection (5% vs. 1%), bronchitis (5% vs. 3%), pruritus (4% vs. 2%), urinary tract infection (4% vs. 2%) and sinusitis (3% vs. 2%), respectively. Serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia; in addition, one case each of listeria meningitis and ophthalmic herpes were reported. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated participants (0.27 events per hundred patient-years) and in none of the placebo-treated participants. Two study participants were reported as experiencing hypersensitivity reactions following ustekinumab administration, with 1 participant experiencing signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration. In addition, 1 participant experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose. These participants were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. In the clinical studies, < 3% of participants treated with ustekinumab developed antibodies to ustekinumab. No apparent association was seen between the development of antibodies to ustekinumab and the development of injection site reactions (Stelara PI, 2016).

The FDA has postmarketing requirements in place for the manufacturer to conduct an observational study assessing the long-term safety of ustekinumab versus other therapies used in the treatment of adults with moderately to severely active Crohn’s disease. The study’s primary outcome is malignancy. Secondary outcomes include, but are not limited to, opportunistic infections (for example, tuberculosis). The scheduled date for study completion is August 2029. Other postmarketing requirements include conducting two studies in the pediatric population (2-17 years of age) with moderately to severely active Crohn’s disease: 1) a dose-ranging trial to determine the pharmacokinetics/pharmacodynamics, safety, and tolerability of ustekinumab induction dosing; and, 2) a multicenter, blinded, randomized controlled safety and efficacy trial. The scheduled dates for completion are February 2019 and February 2024, respectively.

Ustekinumab for Moderate to Severe Plaque Psoriasis

Ustekinumab selectively binds with high specificity and affinity to the cytokines IL-12 and IL-23, thereby suppressing IL-12 and IL-23-mediated inflammation associated with psoriasis. These cytokines are abundant in psoriasis skin and are thought to promote the accumulation of the psoriasis-causing T-cells.

The FDA approval of ustekinumab for use in the treatment of adults 18 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy was confirmed in two phase III, multicenter, randomized, double-blind, placebo-controlled trials, PHOENIX 1 and PHOENIX 2 (Leonardi, 2008; Papp, 2008). Of the 1996 subjects with moderate to severe plaque psoriasis, significantly more ustekinumab recipients (administered subcutaneous doses of 45 mgs or 90 mgs as two injections, 4 weeks apart) than placebo recipients achieved a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 weeks. Other measures, including the Physician’s Global Assessment (PGA) of clinical response at week 12, demonstrated efficacy of ustekinumab over placebo. Prolonged efficacy measured as psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks; however, intensification of dosing to once every 8 weeks with 90 mgs ustekinumab may be necessary to elicit a full response in individuals who only partially respond to the initial regimen (PHOENIX 2) (Papp, 2008). Adverse events were generally similar across treatment and control groups, including infections, injection-site reactions, psychological disorders, and development of anti-ustekinumab antibodies.

The long-term efficacy and safety of ustekinumab was evaluated in 68.7% (517 of 753) participants from the PHOENIX 1 trial who completed treatment through week 244 (5 years). Initial clinical responses were generally maintained through 5 years (PASI 75, 63.4% and 72.0%) for participants receiving 45 mg and 90 mg, respectively. There were 13 and 19 serious infections in the 45 mg and 90 mg groups, respectively. Non-melanoma skin cancers were reported in 14 individuals (n=10, 45 mg; n=4, 90 mg group). With 3104 patient-years of follow-up, rates of overall adverse events, serious adverse events, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses. Overall, there was no indication of cumulative toxicity with increased duration of exposure to ustekinumab (Kimball, 2013).

In October 2017, the FDA expanded approval of ustekinumab for use in the treatment of adolescents 12 years of age or older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Landells and colleagues (2015) evaluated the efficacy and safety of ustekinumab in the adolescent population age 12 to 17 years in the randomized, phase III (CADMUS) study. Participants (n=110) were randomly assigned to ustekinumab standard dosing (SD, 0.75 mg/kg [≤ 60 kg], 45 mg [> 60 to ≤ 100 kg], and 90 mg [> 100 kg]) or half-standard dosing (HSD; 0.375 mg/kg [≤ 60 kg], 22.5 mg [> 60 to ≤ 100 kg], and 45 mg [> 100 kg]) at weeks 0 and 4 and every 12 weeks, or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical outcome measures included the proportion of participants achieving a PGA 0/1, at least 75% improvement in PASI 75, and at least 90% in PASI (PASI 90). Adverse events were assessed through week 60. At week 12, 67.6% and 69.4% of participants receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 compared to 5.4% for placebo (p<0.001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (p<0.001). Through week 12, 56.8% of placebo participants, 51.4% of HSD participants, and 44.4% of SD participants reported at least one adverse event; additional adverse events were reported through week 60 in 81.8% of participants. According the label (Stelara PI Label, 2017), the dosage regimen for adolescents (12-17 years old) is based on body weight, administered subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.

Other Considerations

A head-to-head industry-sponsored, randomized active-control trial of 903 individuals evaluated the efficacy of ustekinumab compared to high-dose etanercept (Enbrel®, Immunex Corporation, Thousand Oaks, CA) in the treatment of moderate to severe plaque psoriasis (Griffiths, 2010). The ACCEPT study evaluated either 45 mgs or 90 mgs of ustekinumab subcutaneous every 12 weeks compared to etanercept 50 mgs subcutaneous twice weekly. The primary endpoint was the proportion of individuals with at least 75% improvement in the PASI at week 12, reported as significantly higher with 45 mgs and 90 mgs of ustekinumab compared to individuals who received etanercept (68% and 74% to 57%; p=0.012 and p<0.001, respectively). Similarly, individuals who received 45 mgs or 90 mgs of ustekinumab compared to individuals who received etanercept (65% and 71% to 49%; p<0.001, both comparisons) had cleared or minimal disease according to the PGA. In the crossover portion of the trial, 48% of individuals who did not respond to etanercept had at least 75% improvement in the PASI in response to ustekinumab within 12 weeks. One or more adverse events occurred through week 12 in 66% and 69% of individuals who received 45 mgs or 90 mgs of ustekinumab, respectively compared to 70% who received etanercept. Safety patterns were similar before and after crossover from etanercept to ustekinumab.

Meng and colleagues (2015) performed a systematic review and meta-analysis of the peer-reviewed published literature of ustekinumab for moderate to severe plaque psoriasis. A total of nine randomized controlled trials involving 11,381 participants performed over > a 13-year time period reported the following results: (1) at the end of 12 weeks, participants in the ustekinumab-treated group demonstrated improvement in PASI (50, 75, 90) and Dermatology Life Quality Improvement (DLQI) index of 0 to 1; (2) there was no significant difference in efficacy between 45 mg and 90 mg ustekinumab at the end of 12 weeks; and (3) the incidence of serious adverse events at the end of 12 weeks of treatment was reported in six studies with no significant difference between the ustekinumab 45 mg group and the placebo group in the incidence of infections and serious infections. There was also no significant difference between the ustekinumab 90 mg group and the placebo group or between the two doses of ustekinumab for the incidence of infections, serious infections and nonmelanoma skin cancer. These results were reported as consistent with the short-term reports of ustekinumab safety.

Ustekinumab is approved for administration by a healthcare provider as a 45 mgs or 90 mgs subcutaneous injection at week 0 and week 4 then every 12 weeks. The higher dose is recommended for individuals weighing over 100 kgs and the lower dose for those under 100 kgs. In clinical trials, the 45 mgs dose was found to be efficacious in subjects over 100 kgs; however, the 90 mgs dose improved efficacy.

The American Academy of Dermatology published clinical guidelines in 2008 that include recommendations for use of biologic agents in the management of psoriasis and psoriatic arthritis; however, these recommendations preclude the FDA approval of ustekinumab for these conditions. In general, the guideline emphasizes the treatment options must be individualized to the needs of each individual, taking into account treatment efficacy, side effects, availability, ease of administration, comorbid conditions, and family history. For those individuals with more extensive or moderate to severe disease, defined as body surface area (BSA) involvement “affecting more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals” or plaque psoriasis involving sensitive areas or areas that would significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia), less than or equal to 5% of BSA involvement is considered as moderate to severe disease. Treatment planning for use of an FDA-approved biologic agent for moderate to severe plaque psoriasis considers this definition of BSA involvement with plaque psoriasis. The guideline recommends the following treatments (along with adjunctive topical agents): 1) first-line therapy (if available) with targeted ultraviolet B light therapy (UVB), with or without methotrexate/acetretin or topical psoralen plus ultraviolet light (PUVA); or 2) first line therapy with methotrexate, cyclosporine, acitretin, or TNF antagonists, with or without methotrexate.

Ustekinumab for Active Psoriatic Arthritis

The FDA approval of ustekinumab as a single agent or in combination with MTX was based on the results of two double-blind randomized controlled trials (PSUMMIT 1 [n=615] and PSUMMIT 2 [n=312]) in 927 participants with active psoriatic arthritis despite prior nonsteroidal anti-inflammatory or disease-modifying antirheumatic drug therapy. In the phase III, multicenter PSUMMIT I trial (McInnes, 2013), adults with active psoriatic arthritis (defined as ≥ 5 tender joints and 5 swollen joints, and a C-reactive protein ≥ 3.0 mg/L) were randomly assigned (1:1:1) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. Approximately 50% of participants continued on stable doses of MTX (≤ 25 mg/week). At week 16, participants with < 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining participants in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. The primary endpoint was 20% or greater improvement in American College of Rheumatology 20% (ACR20) criteria at week 24. More ustekinumab-treated (87 of 205 [42%] in the 45 mg group and 101 of 204 [50%] in the 90 mg group) than placebo-treated (47 of 206 [23%]) participants achieved ACR20 at week 24 (p<0.0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of participants with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [42%] vs. 86 of 205 [42%]).

In the phase III PSUMMIT 2 trial, 44% of the participants in both dose groups, including those previously treated with a biologic anti-tumor necrosis factor alpha (anti-TNF-α) agent (of whom 70% had discontinued treatment for lack of efficacy or intolerance at any time) achieved ACR20 at week 24. Improvements in soft tissue components (enthesitis and dactylitis) as measured by the PASI 75 were also associated with use of ustekinumab compared with placebo (Ritchlin, 2014; Stelara PI Label, 2017).

Off-Label Uses of Ustekinumab

Segal and colleagues (2008) conducted a phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial that assessed the efficacy and safety of ustekinumab for individuals (n=249) with advanced relapsing remitting multiple sclerosis (RRMS). Ustekinumab was generally well tolerated but no clinical or radiologic improvement (such as, a reduction in the cumulative number of gadolinium-enhancing T1-weighted lesions) was found in any treatment group compared with placebo controls. At week 37, AEs occurred in 38 (78%) placebo-treated individuals and 170 (85%) ustekinumab-treated individuals. Serious AEs occurred in 6 (3%) ustekinumab-treated individuals. The advanced disease of the study participants may have partially contributed to the reported lack of efficacy. To date, the FDA has not approved ustekinumab for use in the treatment of RRMS.

Judson and colleagues (2014) performed a phase II randomized, multicenter, comparative study evaluating the clinical efficacy and safety of ustekinumab and golimumab for the treatment of pulmonary sarcoidosis. Participants with chronic pulmonary sarcoidosis (lung group) and/or skin sarcoidosis (skin group) received either 180 mg ustekinumab at week 0 followed by 90 mg every 8 weeks. Corticosteroid use was tapered between weeks 16 and 28. The primary endpoint at week 16 was a change in percentage predicted forced vital capacity (ΔFVC % pred) in the lung group. Secondary endpoints included week 28 for ΔFVC % pred, 6-minute walking distance, St George's Respiratory Questionnaire (lung group), and Skin PGA response (skin group). At week 16, no significant differences were observed in ΔFVC % pred with ustekinumab (-0.15; p=0.13) compared with placebo (2.02). There were no significant improvements in the major secondary endpoints at week 28. Although treatment was well tolerated, use of ustekinumab failed to demonstrate efficacy in the treatment of pulmonary sarcoidosis.

Use of ustekinumab has been studied in combination therapy for the prevention of acute graft-versus-host disease and as a single agent for ankylosing spondylitis (Poddubnyy, 2014), hidradenitis suppurativa, primary biliary cirrhosis, psoriasis vulgaris, rheumatoid arthritis, and severe palmar plantar psoriasis. To date, the FDA has not approved ustekinumab for use in the treatment of any of these conditions.

FDA Product Information (PI) for Ustekinumab (Stelara PI Label, 2017)

Warnings and Precautions:

Additional drug interactions, contraindications for use, and use in specific populations are available on the current PI label for ustekinumab.

Definitions

Biologic disease-modifying antirheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing IL-1ß, IL-6, IL-12 and/or IL-23, IL-17A, IL-1Ra, or by directly suppressing lymphocytes.

Conventional therapy: Treatments that are widely accepted and practiced by the medical community.

Disease-modifying antirheumatic drugs (DMARDs): A variety of drugs that work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.

Immunomodulator drugs: A class of drugs that modifies or influences the immune system.

Immunosuppressant drugs: A class of immunomodulator drugs that includes, but is not limited to 6-mercaptopurine (6-MP), azathioprine, cyclophosphamide, cyclosporine, MTX, and tacrolimus. Drugs that reduce inflammation by affecting the immune system.

Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).

Monoclonal antibody: A laboratory-produced substance that can locate and bind to specific cells wherever they are in the body. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to their target cell.

Nonbiologic disease modifying antirheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown; includes azathioprine, hydroxychloroquine, leflunomide, MTX, minocycline, organic gold compounds, penicillamine, and sulfasalazine.

Tumor necrosis factor (TNF) antagonist: A class of biologic DMARDs designed to neutralize inflammatory cytokines that target specific pathways of the immune system and either enhance or inhibit immune response.

References

Peer Reviewed Publications:

  1. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2016; 375(20):1946-1960.
  2. Gelfand JM, Wan J, Callis Duffin K, et al. Comparative effectiveness of commonly used systemic treatments or phototherapy for moderate to severe plaque psoriasis in the clinical practice setting. Arch Dermatol. 2012; 148(4):487-494.
  3. Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010; 362(2):118-128.
  4. Judson MA, Baughman RP, Costabel U, et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014; 44(5):1296-1307.
  5. Kavanaugh A, Puig L, Gottlieb AB, et al. Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2). Ann Rheum Dis. 2016; 75(11):1984-1988.
  6. Kavanaugh A, Ritchlin C, Rahman P, et al. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014; 73(6):1000-1006.
  7. Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol. 2013; 27(12):1535-1545.
  8. Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015; 73(4):594-603.
  9. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008; 371(9625):1665-1674.
  10. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013; 382(9894):780-789.
  11. Meng Y, Dongmei L, Yanbin P, et al. Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis. Clin Exp Dermatol. 2014; 39(6):696-707.
  12. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008; 371(9625):1675-1684.
  13. Poddubnyy D, Hermann KG, Callhoff J, et al. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis. 2014; 73(5):817-823.
  14. Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety  of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014; 73(6):990-999.
  15. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008; 135(4):1130-1141.
  16. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012; 367(16):1519-1528.
  17. Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008; 7(9):796-804.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Dermatology (AAD). American Academy of Dermatology Association (AADA). Guidelines of care for management of psoriasis and psoriatic arthritis. May 2008. Available at: http://www.aad.org/education-and-quality-care/clinical-guidelines. Accessed on October 16, 2017.
  2. Centers for Disease Control (CDC) and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010; 59(No. RR 5):1-28. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. Accessed on October 16, 2017.
  3. Khanna R, Preiss JC, MacDonald JK, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2015;(5):CD007572.
  4. Stelara [Product Information], Horsham, PA. Janssen Biotech, Inc.; October 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125261s138lbl.pdf. Accessed on October 16, 2017.
  5. Ustekinumab. In: DrugPoints® System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated October 6, 2017. Available at: http://www.micromedexsolutions.com. Accessed on October 16, 2017.
Websites for Additional Information
  1. U.S. National Library of Medicine. Health Topics. Available at: http://www.nlm.nih.gov/medlineplus/healthtopics.html. Accessed on October 16, 2017.
Index

IgG1қ Monoclonal Antibody

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development. Moved content of DRUG.00042 Ustekinumab (Stelara®) to new clinical utilization management guideline document with the same title. Expanded MN statement for use of ustekinumab to include adolescents 12 years of age or older with chronic moderate to severe plaque psoriasis when criteria are met. Updated Coding section with 01/01/2018 HCPCS changes; removed Q9989 deleted 12/31/2017.