|Policy #:||DRUG.00042||Current Effective Date:||01/05/2016|
|Status:||Revised||Last Review Date:||11/05/2015|
This document addresses the indications for ustekinumab, a biologic agent used for the treatment of chronic moderate to severe plaque psoriasis (Ps) and active psoriatic arthritis (PsA) in individuals 18 years of age or older and for other conditions.
Note: Please see the following document for information concerning other biologic disease-modifying antirheumatic drugs (DMARDs) that may be used for the treatment of chronic moderate to severe Ps and active PsA:
Ustekinumab is considered medically necessary when the following criteria are met for either indication:
Not Medically Necessary:
Ustekinumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Ustekinumab is considered investigational and not medically necessary when criteria are not met and for the treatment of all other indications, including, but not limited to:
Ustekinumab for Moderate to Severe Plaque Ps
Ustekinumab is a fully human monoclonal antibody that 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. In September 2009, the FDA approved ustekinumab for use in the treatment of individuals 18 years of age and older with moderate to severe plaque Ps who are candidates for phototherapy or systemic therapy.
The safety and efficacy of ustekinumab for adult moderate to severe plaque Ps 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 Ps, significantly more ustekinumab recipients (administered subcutaneous doses of 45 milligrams [mgs] or 90 mgs as 2 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 (AE) 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 AEs, serious AEs, 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).
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 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 end point 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 AEs 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 9 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 6 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 2 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. Limitations of this meta-analysis include lack of allocation concealment in all 9 studies, the potential risk of selective reporting bias (all 9 trials supported by the pharmaceutical vendor), and the lack of long-term high quality studies beyond 5 years.
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 kilograms (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 (AAD) published a set of evidence-based guidelines, Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis (AAD, 2008), intended to assist physicians in managing the complexities of the treatment of individuals with Ps and PsA. The first guideline, Section 1: Overview of Psoriasis and Guidelines of Care for the Treatment of Psoriasis with Biologics (AAD, 2008) provides an overview of psoriasis classification, co-morbidities, assessment tools, and the use of biologics to treat psoriasis. The work group states that approximately 80% of individuals affected with psoriasis have mild to moderate disease, with 20% having moderate to severe psoriasis, defining the extent of BSA involvement as:
…affecting more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals…The areas of involvement and types of psoriasis should be considered in evaluating severity of disease because the impact of these types of psoriasis may be quite substantial.
Treatment planning for use of an FDA-approved biologic agent for moderate to severe plaque Ps considers this definition of BSA involvement with plaque Ps. In addition, for individuals with plaque Ps involving sensitive areas or areas that would significantly impact daily function (for example, palms, soles of feet, head/neck, or genitalia), ≤ 5% BSA involvement is considered as moderate to severe disease.
An Agency for Healthcare Research and Quality (AHRQ) (Lee, 2012) review examined the comparative effectiveness of biologic systemic agents, nonbiologic systemic agents and phototherapy, for treatment of chronic plaque Ps regarding the effectiveness, safety and any individual characteristics that could modify outcomes of interest. With regard to ustekinumab, a single observational study was found comparing the efficacy of ustekinumab to methotrexate. Based on this study (Gelfand, 2012), achievement of a PGA of "clear" or "minimal" was increased in individuals treated with ustekinumab compared with methotrexate (strength of evidence: low), however, there was insufficient evidence to grade health-related quality of life, BSA and PASI, and no other intermediate health outcomes were reported.
Ustekinumab for Active PsA
The FDA approval of ustekinumab as a single agent or in combination with methotrexate was based on the results of 2 double-blind randomized controlled trials (PSUMMIT 1 [n=615] and PSUMMIT 2 [n=312]) in 927 participants with active PsA despite prior nonsteroidal anti-inflammatory (NSAID) or DMARD therapy. In the phase III, multicenter PSUMMIT I trial (McInnes, 2013), adults with active PsA (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 methotrexate (≤ 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 end point 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 AEs 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 Product Information [PI] Label, 2014).
Several randomized, double-blind trials have 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 (Mannon, 2004; Sandborn, 2008). In a phase II trial, Sanborn and colleagues (2012) evaluated the efficacy of ustekinumab to induce response and maintain clinical remission in 145 individuals with refractory Crohn's disease. The primary end point was a clinical response at 6 weeks. The proportions of participants who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mgs of ustekinumab per kg, respectively, compared with 23.5% for placebo (p=0.005 for the comparison with the 6 mgs group). At 6 weeks, the rate of clinical remission with the 6 mgs dose did not differ significantly from the rate of clinical remission with placebo. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%; p=0.03) and response (69.4% vs. 42.5%; p<0.001) at 22 weeks. Serious infections occurred in 7 participants (6 receiving ustekinumab) during induction and 11 participants (4 receiving ustekinumab) during maintenance. Participants with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. However, participants who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab therapy in the maintenance phase. The investigators suggested the inability to identify significant differences in the induction of remission may be explained by the study participants having relatively high baseline Crohn's Disease Activity Index (CDAI) scores, a long disease duration, and a history of failed therapies. Limitations of this study include the relatively small sample size and short duration of the maintenance phase. Additional efficacy data are needed to assess the clinical utility of ustekinumab as maintenance therapy for individuals with Crohn's disease. To date, the FDA has not approved ustekinumab for use in individuals in the treatment of moderate to severely active Crohn's disease.
Other Proposed 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 individuals 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 end point at week 16 was a change in percentage predicted forced vital capacity (ΔFVC % pred) in the lung group. Secondary end points 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.
A search of the ClinicalTrials.gov database identified several phase I-III trials evaluating the use of ustekinumab in combination therapy for the prevention of acute graft-versus-host disease (GVHD) and as a single agent for AS (Poddubnyy, 2014), hidradenitis suppurativa, primary biliary cirrhosis, psoriasis vulgaris, RA, and severe palmar plantar psoriasis. To date, the FDA has not approved ustekinumab for use in the treatment of any of these conditions.
Plaque Psoriasis (Ps) and Psoriatic Arthritis (PsA)
According to the American Academy of Dermatology (AAD, 2008) plaque Ps is a multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. The major manifestation of plaque Ps is chronic inflammation of the skin, characterized by "disfiguring, scaling, and erythematous plaques that may be painful or often severely pruritic and may cause significant quality of life issues." Treatments available to help manage the symptoms of plaque Ps include topical therapy, phototherapy, systemic therapy, and biologic DMARDs.
PsA is a condition associated with plaque Ps. PsA is characterized by stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments and tendons. Symptoms of PsA can range from mild to very severe. Approximately 15% of people with plaque Ps develop PsA (National Psoriasis Foundation [NPF], 2015).
Precautions and Warnings with Use of Ustekinumab (Stelara PI Label, 2014)
Biologic disease modifying anti-rheumatic 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-12 and/or IL-23, or by directly suppressing lymphocytes.
Disease modifying anti-rheumatic 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 RA, AS, and PsA.
Immunosuppressant drugs: A class of immunomodulatory drugs including 6-mercaptopurine (6-MP), azathioprine, cyclophosphamide, cyclosporine, methotrexate, and tacrolimus 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, methotrexate, minocycline, organic gold compounds, penicillamine, and sulfasalazine.
The following codes for treatments and procedures applicable to this document 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.
When services may be Medically Necessary when criteria are met:
|J3357||Injection, ustekinumab, 1 mg [Stelara]|
|L40.1||Generalized pustular psoriasis|
|L40.3||Pustulosis palmaris et plantaris|
When services are Not Medically Necessary:
For situations described in the Position Statement section as not medically necessary.
When services are Investigational and Not Medically Necessary:
When criteria are not met for the diagnoses indicated above or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
T-SPOT.TB test (T-Spot)
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.
|Revised||11/05/2015||Medical Policy & Technology Assessment Committee (MPTAC) review. Clarified medically necessary statement for use of ustekinumab in adult PsA and chronic Ps for consistency with clinical trial data and structured criteria in related biologic DMARD documents. Clarified not medically necessary criterion 4, adding "and Prevention" to CDC. Added sarcoidosis to investigational and not medically necessary indications. Updated Rationale, References, and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.|
|Revised||11/13/2014||MPTAC review. Format changes to Position Statements and throughout document. Clarified Position Statement, that ustekinumab is considered not medically necessary unless the individual is evaluated for latent TB prior to initiating ustekinumab therapy. Updated Description, Rationale, Background, Definitions, and References sections.|
|Revised||11/14/2013||MPTAC review. Revised medically necessary statement, adding criteria for new FDA approved indication for adult active psoriatic arthritis. Format change to plaque psoriasis statement without a change to criteria. Revised and clarified investigational and not medically necessary statement. Updated Rationale, Background, Definitions, Coding, References, and Websites for Additional Information sections.|
|Reviewed||02/14/2013||MPTAC review. Updated Rationale, Background, Definitions, References, and Index.|
|Revised||02/16/2012||MPTAC review. Clarified not medically necessary criteria. Updated Rationale, Coding, References and Websites for Additional Information.|
|Revised||02/17/2011||MPTAC review. Revised not medically necessary Position Statement, deleting: Genetically deficient in IL-12/IL-23. Revised Medical Management Information with updated FDA label warnings and precautions. Added Definition for interferon gamma (IFN- γ) release assay (IGRA). Updated Rationale, Discussion, References and Index.|
|01/01/2011||Updated Coding section with 01/01/2011 HCPCS changes; removed C9261 deleted 12/31/2010.|
|New||02/25/2010||MPTAC review. Initial document development.|