This document addresses the use of sarilumab (sanofi-aventis U.S., Bridgewater, NJ and Regeneron Pharmaceuticals, Inc., Tarrytown, NY) in adults with moderately to severely active rheumatoid arthritis and for other conditions.
Note: Please see the following related documents for additional information:
Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in DRUG.00101, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.
Sarilumab is considered medically necessary for the treatment of an individual with moderately to severely active rheumatoid arthritis when all of the following criteria are met:
Not Medically Necessary:
Sarilumab is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Sarilumab is considered investigational and not medically necessary when the criteria above are not met and for all other indications, including but not limited to the treatment of:
Sarilumab is a humanized monoclonal antibody directed against the interleukin-6 (IL-6) receptor intended for the treatment of adults with moderately to severely active rheumatoid arthritis. IL-6 is the most abundant cytokine in the serum and synovial fluid of individuals with rheumatoid arthritis and levels correlate with both disease activity and joint destruction. On May 22, 2017, the U.S. Food and Drug Administration (FDA) approved sarilumab for the treatment of moderate to severe rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Sarilumab may be used as monotherapy or in combination with methotrexate or other conventional DMARDs. Sarilumab is administered at the recommended dosage of 200 milligrams once every 2 weeks as a subcutaneous injection under the guidance of a healthcare professional. An individual may self-inject or a caregiver may administer sarilumab with proper training in the preparation and administration of the drug (Kevzara Product Information [PI] label, 2017).
The efficacy and safety of sarilumab was evaluated in two randomized, double-blind, placebo-controlled multicenter studies (Study 1, MOBILITY) (Genovese, 2015) (Study 2, TARGET) (Fleischmann, 2017) in adults ages 18 years and older with moderately to severely active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Eligible participants had at least eight tender and six swollen joints at baseline. Study 1 evaluated 1197 individuals with moderately to severely active rheumatoid arthritis who had an inadequate clinical response to methotrexate. Participants received subcutaneous sarilumab 200 mg, sarilumab 150 mg, or placebo every 2 weeks with concomitant methotrexate for 52 weeks. From week 16 in Study 1, participants (n=257) who did not achieve a ≥ 20% improvement from baseline in the swollen joint count or tender joint count at two consecutive assessments were offered rescue therapy with open-label sarilumab 200 mg every 2 weeks (Genovese, 2015).
Study 2 (Fleischmann, 2017) evaluated 546 individuals with moderately to severely active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more tumor necrosis factor antagonist drugs. Participants were randomly assigned to receive subcutaneous sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks for 24 weeks with concomitant conventional DMARDs (that is, methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine). From week 12, participants (n=114) who did not achieve a ≥ 20% improvement from baseline in the swollen joint count or tender joint count at two joint assessments ≥ 4 weeks apart were offered rescue therapy with open-label sarilumab 200 mg every 2 weeks.
In both studies, the co-primary efficacy endpoints were the proportion of participants who achieved an ACR20 improvement response at week 24, and change from baseline in Health Assessment Questionnaire Disability Index (HAD-QI) at week 16 in Study 1 and at week 12 in Study 2, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at week 52 in Study 1. In both studies, participants treated with either 150 mg or 200 mg of sarilumab every 2 weeks plus concomitant methotrexate/DMARD therapy had higher ACR20, ACR50, and ACR70 response rates compared with placebo plus methotrexate/DMARD-treated participants at week 24 (p<0.0001 each). Additionally, a greater proportion of participants treated with sarilumab 150 mg or sarilumab 200 mg every 2 weeks plus methotrexate/DMARD therapy achieved a low level of disease activity as measured by a Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) of < 2.6 compared with placebo plus methotrexate/DMARD at the end of the studies. In Study 1, the proportion of participants achieving DAS28-CRP < 2.6 who had at least three or more active joints at the end of week 24 was 37.8%, 33.1% and 20%, in the sarilumab 150 mg plus methotrexate/DMARD arm, sarilumab 200 mg plus methotrexate/DMARD arm, and placebo arm, respectively.
In Study 1, both doses of sarilumab plus methotrexate significantly reduced radiographic progression of structural damage compared to the placebo plus methotrexate group in the change from baseline in mTSS over 52 weeks (mean change: 0.90, 0.25, and 2.78, respectively; p<0.0001). Both components of the mTSS score (that is, erosion score and joint space narrowing score) were reduced with each sarilumab dose compared with placebo at week 52 (55.6%, sarilumab 200 mg plus methotrexate arm; 47.8%, sarilumab 150 mg plus methotrexate arm; 38.7% placebo arm). Participants receiving sarilumab 150 mg or 200 mg plus methotrexate/DMARD every 2 weeks demonstrated significantly greater improvement from baseline in physical function and disability (as measured by the HAQ-DI) compared to placebo plus methotrexate/DMARD at week 16 and week 12 in Studies 1 and 2, respectively.
Strand and colleagues (2016) analyzed the effects of sarilumab plus methotrexate versus placebo on patient-reported outcomes (PROs) from the phase III MOBILITY trial (Genovese, 2015). PROs included patient global assessment of disease activity (PtGA), pain, HAQ-DI, Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). A mixed model for repeated measures was used to report changes from baseline at weeks 24 and 52. Post hoc analyses included percentages of participants reporting improvements ≥ minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24. The investigators reported both doses of sarilumab plus methotrexate versus placebo plus methotrexate resulted in clinically meaningful improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p<0.0001) that were maintained until week 52. In post hoc analyses, the percentages of participants with improvement ≥ the MCID across all PROs were greater with sarilumab than placebo (p<0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting ≥ normative scores.
Strand and colleagues (2017) evaluated the effects of sarilumab plus conventional synthetic DMARDS (csDMARDs) on PROs in the TARGET trial (Fleischmann, 2017) of participants with rheumatoid arthritis who had an inadequate response or intolerance to tumor necrosis factor antagonist drugs. A total of 546 participants were randomised to placebo, sarilumab 150 or 200 mg subcutaneously every 2 weeks plus csDMARDs. PROs included PtGA, pain, morning stiffness visual analogue scales, HAQ-DI, SF-36, FACIT-F, Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) and Rheumatoid Arthritis Impact of Disease (RAID). A mixed model for repeated measures was used to report changes from baseline at weeks 12 and 24. Post hoc analyses included percentages of participants reporting improvements ≥ MCID and scores ≥ normative values. The investigators reported sarilumab plus csDMARDs doses resulted in improvements from baseline at week 12 versus placebo plus csDMARDs in PtGA, pain, HAQ-DI, SF-36 and FACIT-F that were maintained at week 24. Use of sarilumab improved morning stiffness and reduced the impact of rheumatoid arthritis on work, family, social/leisure activities participation (WPS-RA) and on participants lives (RAID). The percentages of participants reporting improvements ≥ MCID and ≥ normative scores were greater with sarilumab than placebo.
As reported on the PI label (Kevzara PI label, 2017), the long-term safety of sarilumab in combination with conventional DMARDs was evaluated from data in seven studies which included two placebo-controlled trials (n=2887 participants). Of these, 2170 participants received sarilumab for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks. Most safety data are described for the pre-rescue participant population. The 52-week placebo-controlled population was used for reporting rarer adverse events. The most common serious adverse reactions were infections. The most frequent adverse reactions (occurring in at least 3% of participants treated with sarilumab in combination with DMARDs) in the clinical studies were neutropenia, increased alanine aminotransferase, injection site erythema, upper respiratory infections, and urinary tract infections. In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of participants treated with sarilumab 200 mg, sarilumab 150 mg, and placebo, respectively. The most common adverse reaction (> 1%) resulting in discontinuation of therapy with sarilumab was neutropenia. The use of sarilumab as monotherapy was assessed in 132 participants, of which 67 received sarilumab 200 mg and 65 participants received sarilumab 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the study population receiving concomitant DMARDs. In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection were reported.
The 2015 ACR updated treatment recommendations for RA (Singh, 2015) include guidance on DMARDS, biologic agents, tofacitinib, and glucocorticoids in established and early rheumatoid arthritis. Recommendations were issued on using a "treat-to-target approach," discontinuing and tapering medications, and the use of DMARDS and biologic agents for individuals with high-risk comorbidities such as serious infections, hepatitis, congestive heart failure, and malignancy. The ACR stated that their "treatment recommendations apply to common clinical situations, since the panel considered issues common to most patients, not exceptions." Concerning the potential use of a non-tumor necrosis factor biologic for early disease (defined as < 6 months, disease activity moderate or high despite monotherapy with a DMARD), the ACR recommends use of combination DMARDs or use of a tumor necrosis factor inhibitor (antagonist) or a non-tumor necrosis factor biologic (all options are with or without methotrexate and given in no preference order) rather than continuing monotherapy with a DMARD (Recommendation: strong; Level of evidence: low). For established disease (defined as > 6 months), if the disease activity remains moderate or high despite monotherapy with a DMARD, the recommendation is to use combination traditional DMARDs or add a tumor necrosis factor inhibitor or a non-tumor necrosis factor inhibitor biologic (all options are with or without methotrexate and given in no preference order) rather than continuing monotherapy with a DMARD (Recommendation: strong; Level of evidence: moderate to very low). For individuals with high-risk comorbid conditions with established rheumatoid arthritis with moderate or high disease activity and a history of a previously treated lymphoproliferative disorder, the ACR conditionally recommends using combination biologic DMARD therapy, rather than a tumor necrosis factor inhibitor.
Other Proposed Uses of Sarilumab
Sarilumab has been studied for the treatment of other conditions, including ankylosing spondylitis (Sieper, 2015). In the ALIGN study (NCT01061723), no statistically significant difference in Axial Spondyloarthritis International Society response rate was reported in any sarilumab dose group when compared to placebo (ASA20, 24%) in the treatment of active ankylosing spondylitis.
A search of the ClinicalTrials.gov database has identified clinical trials in various phases evaluating the efficacy and safety of sarilumab in the treatment of other conditions. A phase II study (NCT01900431) of sarilumab in adults (18 years and older) with non-infectious, intermediate, posterior or pan-uveitis was last updated in April 2016. A phase II study (NCT02776735) of sarilumab in children and adolescents (aged 2 to 17 years) with polyarticular-course juvenile idiopathic arthritis is currently recruiting participants with a primary completion date of September 2017. Another phase II study (NCT02991469) of sarilumab in children and adolescents (aged 1 year to 17 years) with systemic juvenile idiopathic arthritis is currently recruiting participants with a primary completion date of August 2018. To date, the FDA has not approved the use of sarilumab for the treatment of any of these conditions.
Rheumatoid arthritis is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints. If left untreated it may lead to joint destruction and progressive disability. The disease affects approximately 2.1 million Americans usually affecting people between the ages of 20 and 60, and people in their mid to late fifties are especially vulnerable. Rheumatoid arthritis is three times more common in women than in men.
The PI label for sarilumab (Kevzara PI label, 2017) includes the following black box warning, general considerations for administration, contraindications, and warnings and precautions for use:
Black Box Warning: Risk of Serious Infections
Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death (See Warnings and Precautions section below. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Avoid use of KEVZARA in patients with an active infection.
Reported infections include:
Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled.
Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection.
General Considerations for Administration
KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.
Warnings and Precautions
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-Ra, IL-1ß, IL-6, IL-12, IL-17A, and/or IL-23, or by directly suppressing lymphocytes. Drugs in this class include the interleukin-1 receptor antagonists (IL-1Ra), interleukin-1 beta (IL-1ß) antagonists, interleukin-6 (IL-6) receptor antagonists, interleukin (IL)-12 and IL-23 antagonists, selective co-stimulation modulators, and the tumor necrosis factor antagonists.
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).
Interleukin-6 (IL-6) receptor antagonist: A class of biologic DMARDs shown to be involved in diverse physiological processes and produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as RA. A drug in this class includes tocilizumab.
Nonbiologic 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. Drugs in this class include 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.
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:
|J3490||Unclassified drugs [when specified as sarilumab (KEVZARA)]|
|J3590||Unclassified biologics [when specified as sarilumab (KEVZARA)]|
|M05.00-M05.9||Rheumatoid arthritis with rheumatoid factor|
|M06.00-M06.09||Rheumatoid arthritis without rheumatoid factor|
|M06.80-M06.89||Other specified rheumatoid arthritis|
|M06.9||Rheumatoid arthritis, unspecified|
When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above for the situations indicated in the Position Statement as not medically necessary.
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses, 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.
|09/27/2017||Added Note to Description section regarding CG-ADMIN-02.|
|New||06/13/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development.|
|Preliminary Discussion||11/03/2016||MPTAC review. Pre-FDA approval review.|