LCD L39467: MolDX: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis

This is a limited coverage policy for molecular biomarker tests to guide targeted therapy selection in Rheumatoid Arthritis (RA).

Coverage criteria:

• The patient is an adult with a confirmed diagnosis of moderately to severely active RA.

• The patient has a history of failure, contraindication, or intolerance to at least one first-line therapy for the treatment of RA (i.e., conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs)) despite adequate dosing.

• The patient has not initiated a biologic or targeted synthetic therapy (b/tDMARD) for RA (i.e., Tumor Necrosis Factor-alpha inhibitor [TNFi], Janus Kinase [JAK] inhibitor, etc.) OR has initiated b/tDMARD therapy and is being considered for an alternate class of targeted therapies as a result of failure, contraindication, or intolerance to the initial targeted therapy despite adequate dosing.

• The test predicts response and/or non-response to at least one class of targeted or biologic therapies for RA according to multiple validated response/remission criteria (a) with an accuracy that exceeds that which can be obtained from the combination of existing clinical and other data AND (b) with demonstrated reproducibility across clinical study cohorts.

• Testing using molecular biomarkers has not been previously performed for predictive therapy selection in RA.

• Testing is performed according to the intended use of the test in the intended patient population for which the test was developed and validated.

• The test demonstrates analytical validity (AV), clinical validity (CV) and clinical utility (CU), establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management in a clearly defined population.

• Clinical validity of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed published literature for the intended use of the test in the intended population.

• If the test relies on an algorithm, the algorithm must be validated in a cohort that is not a development cohort for the algorithm.

• The lab providing the test is responsible for clearly indicating to treating physicians the population and indication(s) for test use.

• The test successfully completes a Molecular Diagnostic Services Program (MolDX ® ) Technical Assessment that ensures that AV, CV, and CU criteria set in this policy are met to establish the test as Reasonable and Necessary.

• If applicable, performance characteristics are equivalent or superior to the average performance of other similar tests (for the same intended use) evaluated by this contractor upon successful completion of a technical assessment.

Since the clinical utility of predictive testing is largely dependent upon consensus-based management recommendations, this coverage decision is subject to change pending changes in the literature and in consensus guidelines.

Finally, new tests that become available with significantly improved performance may render older tests no longer compliant with this policy.

Rheumatoid arthritis (RA) is complex and heterogeneous inflammatory autoimmune disease, with a multifactorial etiology. 1-3 An estimated 1.3 million adults in the United States live with RA and though the disease affects both sexes, the incidence is higher in women than in men (53/100,000 vs 29/100,000 population). 4 Left improperly treated, it can progress and become a debilitating disease with significant morbidity as well as increased mortality. 2,5,6

RA treatment response is defined in terms of disease activity or remission scores. Commonly used are the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) response criteria. 7-10 EULAR response criteria are based on changes in the Disease Activity Score (DAS), while the ACR improvement scores of ACR20, ACR50, and ACR70, represent the percent improvement in a standard set of indices, including clinical factors as well as laboratory markers (i.e. acute-phase reactants). 11,12 A 50% response (ACR50) is needed for most patients to reach low disease activity. 3 The ACR and EULAR criteria have been reported to have comparable validity. 13 However, given that their components and requirements are different, and that there is known variability in patient disease assessments (PDAs) and patient-reported outcome measures (PROMs) as well as in the composite of clinical metrics used that are included in the response criteria, some patients who are classified as responders by one criterion may not be classified as responders by another criterion. 9,14-16 For example, differences are seen among the various EULAR response criteria, depending on which of the composite measures is used (i.e. disease activity score using 28 joint counts (DAS28)/Erythrocyte Sedimentation Rate (ESR) vs DAS28/C-reactive protein (CRP)). 17,18 Other scores, namely the clinical disease activity index (CDAI), and the simplified disease activity index (SDAI), are also commonly used in clinical care and correlate with outcomes such as progression and functional impairment. 19

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate are considered first-line therapy for many patients with RA. 20 However, up to 60% of patients fail to achieve treatment targets on csDMADRs. 21 For them, biologic and targeted synthetic DMARDs (b/t DMARDs), are often recommended. 20,22 These include tumor necrosis factor-alpha inhibitors (anti-TNFs, or TNFis), Janus Kinase tyrosine kinases (JAKs), Interleukin-6 (Il-6) inhibitors, T- and B-cell therapies. The various b/tDMARDs have, on the whole, shown similar efficacy and safety profiles; as such, many guidelines have not preferred or prioritized among them. 20,23,24 Despite the fact that there are multiple classes of targeted therapies available, TNFis remain the predominant first-line b/tDMARDs in the majority of patients with RA for a variety of reasons, including long-term established efficacy and safety profiles, the comfort level of ordering physicians, and insurance policy requirements. 25-29 However, up to two-thirds of patients will fail to achieve ACR50 within 6 months of therapy with their first TNFi, and more than 60% will require a third DMARD. 19,30,31 After patients fail their first TNFi therapy, they are approximately 12-30% more likely to inadequately respond to their second targeted medication. 32-35 Over time, up to 75% of patients may eventually reach treatment targets with multiple trial-and-error sequential approaches to treatment. 19

When TNFi therapy is ineffective or results in adverse effects, patients may ‘cycle’ to another TNFi or to ‘switch’ to a drug with a different mechanism of action (MOA). The ACR conditionally recommends ‘switching’ over ‘cycling,’ based on evidence supporting greater improvement in disease activity when patients switch drug classes, rather than cycle between them. 20,32,36-38 However, a claims analysis-based study found that most (~64%) patients still often cycle to a second TNFi before switching to a non-TNFi, and that patients who switch to a non-TNFi are significantly older with more comorbidities. 39 These trial-and-error attempts using various drugs and drug classes, often with inadequate disease response and with drug-induced side-effects, can result in continued disease progression, as effective therapy (which is important early in RA to delay or prevent debilitating disease outcomes) is delayed. 5,20