Coverage Policy Manual
Policy #: 2021028
Category: Pharmacy
Initiated: September 2021
Last Review: June 2022
  Ustekinumab (e.g., Stelara)

Description:
Ustekinumab, a humanized monoclonal antibody, is an interleukin-12 (IL-12) and interkeukin-23 ((IL-23) antagonist. Ustekinumab binds to the p40 protein subunit, used by both IL-12 and IL-23 cytokines, and disrupts their interaction with receptors. This interaction inhibits the release of proinflammatory cytokines that have been implicated as important contributors to the chronic inflammation in both Crohn’s disease and ulcerative colitis.  
 
Regulatory Status
 
Ustekinumab (e.g., StelaraTM) is approved by the U.S. Food and Drug Administration (FDA) for treatment of the following:
    • Adult patients with moderate to severe plaque psoriasis (Ps) who are candidates for phototherapy or systemic therapy
    • Adult patients with active psoriatic arthritis (PsA), alone or in combination with methotrexate
    • Adult patients with moderately to severely active Crohn’s disease (CD)    
    • Adult patients with moderately to severely active ulcerative colitis (UC)
    • Pediatric patients 6 years and older with moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy.
 
Ustekinumab solution for intravenous infusion is indication for the single dose induction phase in CD and UC.
 
Ustekinumab subcutaneous injection is indicated for the Ps, PsA, and the maintenance phase of CD and UC.
 
Coding
 
The specific HCPCS code for Ustekinumab solution for intravenous infusion is J3358.
The specific HCPCS code for Ustekinumab subcutaneous injection is J3357.

Policy/
Coverage:
Effective September 1, 2021 Prior Approval is required for Ustekinumab.
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.  
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of Ustekinumab meets primary coverage criteria when dosed in accordance with FDA approved labeling AND when all the following criteria are met based on diagnosis:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Plaque psoriasis
Member is 6 years of age or older who have a diagnosis of moderate to severe Ps (3% BSA involvement) (Menter, 2018) OR involving sensitive areas or areas that significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia) (Menter, 2018) AND
        1. Member has previously met criteria for and received a FDA approved biologic indicated for the treatment of moderate to severe plaque psoriasis OR
        2. Member has had an inadequate response to either phototherapy or a pharmacologic treatment with methotrexate, cyclosporine, or acitretin or has an intolerance or contraindication to phototherapy or all non-biologic pharmacologic treatment (methotrexate, cyclosporine, or acitretin) (Menter, 2018)
 
Psoriatic arthritis
Member 18 years of age or older has a diagnosis of moderate to severe PsA AND
        1. Member has previously met criteria for and received a FDA approved biologic indicated for moderately to severely active psoriatic arthritis OR  
        2. Member has had an inadequate response to conventional therapy [nonbiologic DMARDs (such as methotrexate, sulfasalazine, or leflunomide)] or an intolerance or contraindication to conventional therapy (Singh, 2018)
 
Crohn’s disease
Member 18 years of age or older has a diagnosis of moderately to severely active CD AND
        1. Member has previously met criteria for and received a FDA approved biologic indicated for moderately to severely active Crohn’s disease OR  
        2. Member has had an inadequate response to at least one conventional therapy option (i.e. azathioprine, mercaptopurine, sulfasalazine, methotrexate, or corticosteroids) or member has an intolerance or contraindication conventional therapy options (Lichtenstein, 2018)
 
Ulcerative colitis
Member 18 years of age or older has a diagnosis of moderately to severely active UC AND
        1. Member has previously met criteria for and received a FDA approved biologic indicated for moderately to severely active ulcerative colitis OR  
        2. Member has had an inadequate response to at least one conventional therapy option (i.e. corticosteroids, azathioprine, or mercaptopurine) or member has an intolerance or contraindication conventional therapy options(Rubin 2019)
Continuation of therapy for 12 months:
 
        1. Member meets criteria for initial approval based on indication.
        2. Member has experienced a positive clinical response to ustekinumab.
        3. Dosed in accordance with FDA labeling.
 
Plaque psoriasis disease activity according to Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics:
 
Mild: <3% BSA
Moderate: 3% - 10% BSA
Severe: >10% BSA, serious emotional consequences, or when it occurs in select locations, including but not restricted to, the hands, feet, scalp, face, or genital area, or when it causes intractable pruritus.
 
Ulcerative Colitis activity index according to American College of Gastroenterology:
 
Remission: daily formed stools, no blood in stool, no urgency, normal hemoglobin, <30 erythrocyte sedimentation rate (ESR), normal C-reactive protein (CRP), <150-000 fecal calprotectin (FC), 0-1 Ulcerative Colitis Endoscopic Index of Severity (UCEIS)
Mild: <4 stools per day, intermittent bloody stools, occasional urgency, normal hemoglobin, <30 ESR, elevated     CRP, >150-200 RC, 2-4 UCEIS
Moderate - Severe: >6 stools per day, frequent blood in stools, urgency often, <75% of normal hemoglobin, >30 ESR, elevated CRP, >150-200 FC, 5-8 UCEIS
 
Dosage and Administration
 
The recommended dose of Ustekinumab is based on indication:
Plaque psoriasis adult subcutaneous injection:
    • Less than or equal to 100kg - 45mg administered subcutaneously initially and 4 weeks later, followed by 45mg administered subcutaneously every 12 weeks.
    • Greater than 100kg - 90mg administered subcutaneously initially and 4 weeks later, followed by 90mg administered subcutaneously every 12 weeks.
Plaque psoriasis pediatric subcutaneous injection:
    • Less than 60kg – 0.75mg/kg subcutaneously initially and 4 weeks later, then every 12 weeks thereafter.
    • 60kg to 100kg – 45mg subcutaneously initially and 4 weeks later, then every 12 weeks thereafter.
    • Greater than 100kg – 90mg subcutaneously initially and 4 weeks later, then every 12 weeks thereafter.  
Psoriatic Arthritis subcutaneous injection:  
    • 45mg administered subcutaneously initially and 4 weeks later, followed by 45mg administered subcutaneously every 12 weeks.
Crohn’s Disease and Ulcerative Colitis initial adult intravenous infusion:
    • Less than 55kg – 260mg
    • 55kg to 85kg – 390mg
    • Greater than 85kg – 520 mg
Crohn’s Disease and Ulcerative Colitis maintenance subcutaneous injection:
    • 90mg administered subcutaneously 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.  
 
Ustekinumab intravenous infusion (J3358) will only be available for a one-time initial infusion.
 
Ustekinumab intravenous infusion should be administered by a healthcare professional. In pediatric patients, Ustekinumab subcutaneous injection should be administered by a healthcare professional.
 
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Ustekinumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:
 
    1. Any other indications not included above: OR  
    2. In combination with TNF antagonists, JAK inhibitors, or other biologic drugs (such as, abatacept, anakinra, rituximab, or vedolizumab); OR  
    3. In combination with phototherapy OR
    4. If member has tuberculosis, other active serious infections, or a history of recurrent infections; OR
    5. Individual has not had a tuberculin skin test (TST) or a Centers for Disease Control (CDC-) and Prevention -recommended equivalent to evaluate for latent tuberculosis prior to initiating Ustekinumab.
For members with contracts without primary coverage criteria, Ustekinumab does not meet member benefit certificate primary coverage criteria for the following:
 
    1. Any other indications not included above: OR  
    2. In combination with TNF antagonists, JAK inhibitors, or other biologic drugs (such as, abatacept, anakinra, rituximab, or vedolizumab); OR  
    3. In combination with phototherapy OR
    4. If member has tuberculosis, other active serious infections, or a history of recurrent infections; OR
    5. Individual has not had a tuberculin skin test (TST) or a Centers for Disease Control (CDC-) and Prevention -recommended equivalent to evaluate for latent tuberculosis prior to initiating Ustekinumab.
For members with contracts without primary coverage criteria, the use of Ustekinumab for any condition other than listed above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
The use of Ustekinumab for plaque psoriasis was studied in two multicenter, randomized, double-blind, placebo-controlled trials. Patients 18 years of age and older with plaque psoriasis were enrolled in the study. Patients had a minimum body surface area involvement of 10%, Psoriasis Area and Severity Index (PASI) score 12 and were candidates for phototherapy or systemic therapy. Study 1 enrolled 766 patients and study 2 enrolled 1,230 patients. Patients were randomized to receive placebo, 45mg, or 90mg of Ustekinumab. Ustekinumab patients received their doses at Weeks 0, 4, and 16. Placebo patients received placebo doses at Weeks 0 and 4 and then crossed over to receive either dose of Ustekinumab at Weeks 12 and 16. Subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Across both studies about 66% of all patients had received prior phototherapy and 69% had received either prior conventional systemic or biologic therapy. 28% of patients had a history of psoriatic arthritis. In Study 1, 66% of patients who received 90mg of Ustekinumab and 67% of patients who received 45mg of Ustekinumab achieved a PASI 75 response compared to 3% of patients who received placebo. In Study 2, 76% of patients who received 90mg Ustekinumab and 67% of patients who received 45mg of Ustekinumab achieved a PASI 75 response compared to 4% of patients who received placebo. In patients who weighed greater than 100kg, higher response rates were seen with 90mg dosing compared with 45mg dosing.
 
The use of Ustekinumab for plaque psoriasis in adolescent patients 12 and older was evaluated in a multicenter, randomized, double blind, placebo-controlled study. This study enrolled 110 patients 12 – 17 years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy. Patients were randomized to receive 0.75mg/kg Ustekinumab (patients weighing less than 60kg), 45mg Ustekinumab (patients weighing 60kg to 100kg), 90mg Ustekinumab (patients weighing greater than 100kg), or placebo at Weeks 0 and 4 followed by every 12 weeks thereafter. At Week 12, 80.6% of patients who had received Ustekinumab achieved a PASI 75 response compared to 10.8% of patients who received placebo.
 
The use of Ustekinumab for psoriatic arthritis was studied in two randomized, double-blind, placebo-controlled trials. 927 patients who were 18 years of age and older with active PsA despite NSAID or DMARD therapy were enrolled in the studies. Active PsA was defined as 5 swollen joints and tender joints. Patients with each subtype of PsA were enrolled, including patients with polyarticular arthritis, spondylitis with peripheral arthritis, asymmetric peripheral arthritis, distal interphalangeal involvement, and arthritis mutilans. Patients were randomized to receive 45mg Ustekinumab, 90mg Ustekinumab, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks thereafter. About 50% of patients continued stable doses of methotrexate. Study 1 did not allow patients who had previously been treated with TNF inhibitors. 58% of patients in Study 2 had previously been on TNF inhibitor therapy and over 70% of them discontinued their TNF inhibitor therapy due to lack of efficacy or intolerance. In both studies, a greater proportion of patients achieved ACR 20, ACR 50, and PASI 75 response in the Ustekinumab 45mg and 90mg groups compared to placebo at Week 24. Response were similar in patients despite prior TNF inhibitor therapy.
 
The use of Ustekinumab for Crohn’s Disease was evaluated in three randomized, double-blind, placebo-controlled clinical studies. Patients enrolled had moderately to severely active Crohn’s disease. Patients in Study 1 had failed or were intolerant to treatment with one or more TNF inhibitor. Patients in Study 2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF inhibitor. Study 1 and Study 2 were two 8-week intravenous induction studies followed by a 44-week subcutaneous randomized withdrawal maintenance study (Study 3). In Study 1, 741 patients were included in the final efficacy analysis. In Study 2, 627 patients were included in the final efficacy analysis. In both studies, patients were randomized to receive a single intravenous infusion of Ustekinumab at either approximately 6mg/kg, placebo, or 130mg (a lower dose than recommended). In the two induction studies, a greater portion of patients treated with Ustekinumab, at the recommended dose of 6mg/kg dose, achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo. In Study 3, 388 patients were enrolled who achieved a clinical response at Week 8 with either induction dose of Ustekinumab in Studies 1 or 2. Patients were randomized to receive either a subcutaneous maintenance dose of 90mg Ustekinumab or placebo every 8 weeks for 44 weeks. At Week 44, 47% of patients who received Ustekinumab were corticosteroid-free and in clinical remission, compared to 30% of patients in the placebo group. For the patients who previously failed or were intolerant to TNF inhibitors, 61% of the Ustekinumab treated patients were in remission at Week 0 of Study 3 and 41% were in clinical remission at Week 44. In the placebo patients, 44% were in clinical remission at Week 0 and 26% of these patients were in clinical remission at Week 44. For the patients who had previously failed immunomodulator therapy or corticosteroids (but not TNF inhibitors), 64% of the Ustekinumab treated patients were in clinical remission at Week 0 of Study 3 and 63% were in remission at Week 44.  In the placebo patients, 71%% were in clinical remission at Week 0 and 44% were in clinical remission at Week 44.
 
The use of Ustekinumab for ulcerative colitis was evaluated in two randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic, corticosteroids, and/or mercaptopurine or azathioprine therapy. Study 1 was an 8-week intravenous induction study of Ustekinumab. Study 2 followed and was a 44-week subcutaneous randomized withdrawal maintenance study. Patients could continue other concomitant therapies such as aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids. In Study 1, 961 patients were randomized to receive a single intravenous infusion of Ustekinumab 6mg/kg, 130mg (a lower dose than recommended), or placebo. The primary endpoint was clinical remission at Week 8. A significantly greater proportion of patients treated with 6mg/kg of Ustekinumab were in clinical remission and response and achieved endoscopic improvement and histologic-endoscopic mucosal improvement compared to placebo. In Study 2, 523 patients were evaluated who had achieved clinical response after the 8-week intravenous infusion. Patients were randomized to receive either a subcutaneous maintenance dose of 90mg Ustekinumab every 8 weeks, 90mg every 12 weeks, or placebo for 44 weeks. The primary endpoint was the proportion of patients in clinical remission at Week 44. 74% of patients who had received the recommended dose of 90mg Ustekinumab every 8 weeks were in clinical remission at Week 44 compared to 48% of patients who received placebo.
 
2022 Update
The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease.
 
Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively.
 
Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE.
 
Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355. (Sandborn WJ, Rebuck R, Wang Y, et.al., 2021).

CPT/HCPCS:
J3357Ustekinumab, for subcutaneous injection, 1 mg
J3358Ustekinumab, for intravenous injection, 1 mg

References: Lichtenstein GR, Loftus EV, Isaacs KL et al.(2018) 2018 American College of Gastroenterology Guideline for the management of Crohn’s disease in adults. Am J Gastroenterol 2018; 113:481–517.

Menter A, Strober BE, Kaplan DH et al.(2018) Joint AAD-NPF Guidelines of Care for the Management and Treatment of Psoriasis with Biologics. Am Academy of Dermatology 2018; 80:1029-72.

Rubin DT, Ananthakrishnan AN, Siegel CA et al.(2019) American College of Gastroenterology Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol 2019; 114:384-413.

Sandborn WJ, Gasink C, Gao LL et al.(2012) Ustekinumab Induction and Maintenance Therapy in Refractory Crohn's Disease. N Engl J Med. 2012 Oct 18;367(16):1519-28.

Sandborn WJ, Rebuck R, Wang Y, Zou B, Adedokun OJ, Gasink C, Sands BE, Hanauer SB, Targan S, Ghosh S, de Villiers WJS, Colombel JF, Feagan BG, Lynch JP(2022) Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022 Mar;20(3):578-590.e4. doi: 10.1016/j.cgh.2021.02.025. Epub 2021 Feb 19. PMID: 33618023; PMCID: PMC8374005.

Singh, Jasvinder A, et al.(2018) 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis. Arthritis & Rheumatology, 71(1), 2018, pp. 5–32.

Stelara [package insert], Horsham, PA. Janssen Biotech, Inc;


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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