TNF-α: The shape of small molecules to come?

In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira® generated US$165.8 billion in cumulative sales and snatched the crown for the industry's most successful drug from Lipitor (atorvastatin). TNF-α is a major component in beneficial and disease-related inflammation and TNF-α-inhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-α inhibitors, such as Alzheimer's disease (AD) or major depression. However, the nature of TNF-α-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.

Cost-Effectiveness Analysis of Biopharmaceuticals for Treating Rheumatoid Arthritis: Infliximab, Adalimumab, and Etanercept.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic progressive inflammatory disease that causes joint destruction. The condition imposes a significant economic burden on patients and societies. The present study is aimed at evaluating the cost-effectiveness of Infliximab, Adalimumab, and Etanercept in treating rheumatoid arthritis in Iran. METHODS: This is a cost-effectiveness study of economic evaluation in which the Markov model was used. The study was carried out on 154 patients with rheumatoid arthritis in Fars province taking Infliximab, Adalimumab, and Etanercept. The patients were selected through sampling. In this study, the cost data were collected from a community perspective, and the outcomes were the mean reductions in DAS-28 and QALY. The cost data collection form and the EQ-5D questionnaire were also used to collect the required data. The results were presented in the form of an incremental cost-effectiveness ratio, and the sensitivity analysis was used to measure the robustness of the study results. The TreeAge Pro and Excel softwares were used to analyze the collected data. RESULTS: The results showed that the mean costs and the QALY rates in the Infliximab, Adalimumab, and Etanercept arms were $ 79,518.33 and 12.34, $ 91,695.59 and 13.25, and $ 87,440.92 and 11.79, respectively. The one-way sensitivity analysis confirmed the robustness of the results. In addition, the results of the probabilistic sensitivity analysis (PSA) indicated that on the cost-effectiveness acceptability curve, Infliximab was in the acceptance area and below the threshold in 77% of simulations. The scatter plot was in the mentioned area in 81% and 91% of simulations compared with Adalimumab and Etanercept, respectively, implying lower costs and higher effectiveness than the other two alternatives. Therefore, the strategy was more cost-effective. CONCLUSION: According to the results of this study, Infliximab was more cost-effective than the other two medications. Therefore, it is recommended that physicians use this medication as the priority in treating rheumatoid arthritis. It is also suggested that health policymakers consider the present study results in preparing treatment guidelines for RA.

Uptake of Biosimilars and Its Economic Implication for the Treatment of Patients with Rheumatoid Arthritis in Korea.

BACKGROUND: We aimed to examine the uptake of infliximab and etanercept biosimilars in patients with rheumatoid arthritis (RA) and its economic implication for healthcare expenditure. METHODS: Using Korean Health Insurance Review and Assessment Service National Patient Samples, we extracted RA patients who used biologic disease modifying anti-rheumatic drugs (bDMARDs) between 2009 and 2018. Descriptive statistics were used to explain the basic features of the data. We calculated the proportion of users of each bDMARD among total patients with bDMARDs half-yearly. We assessed changes in the utilization proportions of bDMARDs including 4 tumor necrosis factor inhibitors (TNFis) and 2 non-TNFis, which have been approved for RA in Korea: etanercept, infliximab, adalimumab, golimumab, tocilizumab, and abatacept, and analyzed the changes in market share of biosimilars among the bDMARDs after their introduction. Overall trends of medical costs for each bDMARD were presented over the 10-year period. RESULTS: Since the introduction of the biosimilar TNFis in 2012, the proportion of their use among bDMARDs steadily increased to 15.8% in 2018. While there has been a gradual increase in the use of biosimilar TNFis, the use of the corresponding originators has been decreasing. The introduction of biosimilar TNFis has resulted in a decrease in the medical costs of patients using either originator or biosimilar TNFis. CONCLUSION: In Korea, the proportional use of biosimilar TNFis has gradually increased since their introduction. The availability of less expensive biosimilar TNFis seems to have brought about a decrease in the medical costs of users of the originators.

Uptake of biosimilars for TNF-α inhibitors adalimumab and etanercept following the best-value biological medicine initiative in Ireland.

Background There is over 10 years of clinical experience and evidence to show that biosimilar medicines can be used as safely and effectively in approved therapeutic indications as their originator biological medicines. In Ireland, biosimilar medicine uptake has been very slow, and savings to the health service will only be realised through fostering a competitive biological medicine market. Objective The objective of this study was to investigate the utilisation of biosimilars following a 'best-value biological' medicine initiative for adalimumab and etanercept in the Irish healthcare setting. Methods Data was extracted from the National High Tech claims database and High Tech ordering and management hub for the following drugs; adalimumab (Humira®, Amgevita®, Hulio®, Idacio®, and Imraldi®) and etanercept (Enbrel® and Benepali®). Main outcome measure: uptake of the best-value biological medicines. Results In June 2019, just over 90 patients had been initiated on, or switched to a best-value biological for adalimumab or etanercept. Over the next 12 months this increased to over 8500 patients. With the best-value biologicals accounting for approximately 50 % of market share in June 2020, the combined estimated savings and avoided costs are €22.7 million to date. The gain-share prescribing incentive has raised over €3.6 million for the specialties to invest back into patient care. Conclusion Against the background of a finite healthcare budget, this study shows that increasing use of biosimilars can create the financial savings and space to invest in new innovative therapies for the benefit of many patients.

Cost-utility analysis of the anti-TNF therapy for rheumatoid arthritis in a real-world based model.

BACKGROUND: Spending on drugs provided by the Brazilian Public Health System (BPHS) for the treatment of rheumatoid arthritis (RA) increased substantially with the beginning of the supply of biological disease-modifying anti-rheumatic drugs (bDMARD). This study aims to perform a cost-utility analysis of the most used biological drugs for the treatment of RA in Brazil. METHODS: a Markov model was used to carry out the cost-utility analysis. The data were obtained from a prospective cohort of RA patients using adalimumab, etanercept, and golimumab in Brazil. The BPHS perspective was adopted and the time horizon was five years. Deterministic and probabilistic sensitivity analyses were performed to evaluate the uncertainty. RESULTS: golimumab was the most cost-effective drug. Etanercept was dominated by golimumab. Adalimumab presented an incremental cost-utility ratio (ICUR) of $95,095.37 compared to golimumab in five years of follow-up. These results were confirmed by sensitivity analyses. CONCLUSION: the utility among adalimumab, etanercept, and golimumab was similar and the cost was the component that most impacted the economic model. Therefore, depending on the agreed price with the drug manufacturers, the incremental cost-utility ratio may vary among them.

Potential Cost Implications of Mandatory Non-Medical Switching Policies for Biologics for Rheumatic Conditions and Inflammatory Bowel Disease in Canada.

In 2018, TNFα inhibitors were the highest cost drug class for Canadian public drug programs. In 2019, two Canadian provinces announced mandatory nonmedical switching policies in an attempt to reduce their costs by increasing biosimilar uptake. The national impact of similar policies across Canada is unknown. We conducted a cross-sectional analysis of monthly publicly funded prescription claims for infliximab, etanercept, and adalimumab between June 2015 and December 2019. We reported the market share of biosimilars for infliximab and etanercept in 2019 for each province and estimated the cost savings that public payers could have realized in 2019 if mandatory switching policies had been implemented across Canada, including a sensitivity analysis, which assumed that governments receive a 25% rebate on all biologics. Provincial drug programs spent CAD $991.84 million on infliximab, etanercept, and adalimumab in 2019, and, when biosimilars were available, they constituted only 15.5% of national utilization of these drugs. In British Columbia, the implementation of a mandatory switching policy for patients with rheumatic conditions increased the biosimilar market share of infliximab and etanercept by 299% (from 19.7% to 78.5%). If applied nationwide to all three biologics for all indications, we estimate such policies could lead to annual savings of between CAD $179.71 million and CAD $425.64 million nationally. The overall market share of biosimilars remains low in all provinces where mandatory switching policies have not been introduced. The cost implications of successfully increasing biosimilar uptake would be substantial, particularly as more biosimilars reach the Canadian market.

Treatment Sequences After Discontinuing a Tumor Necrosis Factor Inhibitor in Patients With Rheumatoid Arthritis: A Comparison of Cycling Versus Swapping Strategies.

OBJECTIVE: To evaluate the sequences of tumor necrosis factor inhibitors (TNFi) and non-TNFi used by rheumatoid arthritis (RA) patients whose initial TNFi therapy has failed, and to evaluate effectiveness and costs. METHODS: Using the Truven Health MarketScan Research database, we analyzed claims of commercially insured adult patients with RA who switched to their second biologic or targeted disease-modifying antirheumatic drug between January 2008 and December 2015. Our primary outcome was the frequency of treatment sequences. Our secondary outcomes were the time to therapy discontinuation, drug adherence, and drug and other health care costs. RESULTS: Among 10,442 RA patients identified, 36.5% swapped to a non-TNFi drug, most commonly abatacept (54.2%). The remaining 63.5% cycled to a second TNFi, most commonly adalimumab (41.2%). For subsequent switches of therapy, non-TNFi were more common. Patients who swapped to a non-TNFi were significantly older and had more comorbidities than those who cycled to a TNFi (P < 0.001). Survival analysis showed a longer time to discontinuation for non-TNFi than for TNFi (median 605 days compared with 489 days; P < 0.001) when used after initial TNFi discontinuation, but no difference in subsequent switches of therapy. Although non-TNFi were less expensive for adherent patients, cycling to a TNFi was associated with lower costs overall. CONCLUSION: Even though patients are more likely to cycle to a second TNFi than swap to a non-TNFi, those who swap to a non-TNFi are more likely to persist with the therapy. However, cycling to a TNFi is the less costly strategy.

Cost-utility analysis of second-line therapy with rituximab compared to tumour necrosis factor inhibitors in rheumatoid arthritis.

OBJECTIVE: To compare direct costs and treatment utility associated with the second-line therapy with rituximab and tumour necrosis factor inhibitors (TNFis) (adalimumab, etanercept, and infliximab) in patients with Rheumatoid Arthritis (RA) using data from a prospective registry. METHODS: Health Assessment Questionnaire Disability Index (HAQ-DI) scores and RA-related healthcare resource utilization data (biologic agents and visits to rheumatologists) were extracted from a registry (Quebec, Canada) for patients with RA (n = 129) who had to discontinue a first-line TNFi and were treated with rituximab, adalimumab, etanercept, or infliximab as the second-line therapy between January 2007 and May 2016. A decision analytic model followed patients for 1 and 6 years. Treatment utility was measured as quality-adjusted life-years (QALYs) gained, which were calculated from HAQ-DI scores observed over the follow-up time. Quebec 2020 unit costs (Canadian Dollars, $) were used to value healthcare resource consumption. A probabilistic sensitivity analysis was performed with 10,000 Monte Carlo simulations to assess uncertainty around point-estimates of cost-utility. RESULTS: Over 1-year, rituximab and etanercept resulted in the effectiveness of 0.80 QALYs gained at the cost of $14,291and $18,880, respectively, and were dominant (i.e. associated with lower costs and more QALYs gained) compared to adalimumab (0.79 QALYs, $18,825) and infliximab (0.76 QALYs, $20,158). Over 6-years, rituximab (4.42 QALYs, $82,402) was dominant compared to adalimumab (4.30 QALYs, $101,420), etanercept (4.02 QALYs, $99,191), and infliximab (3.71 QALYs, $100,396). In the probabilistic analysis, rituximab was dominant over adalimumab, etanercept, and infliximab with the probability of 0.51, 0.62, and 0.65, respectively. CONCLUSION: Real-world data revealed differences between alternative biologic agents used as the second-line therapy in terms of both treatment costs for the healthcare system and utility of treatment for patients. Therefore, new guidelines on the order of selecting and switching biologic agents should be explored.

Cost-Effectiveness of Treatment Strategies with Biologics in Accordance with Treatment Guidelines for Ankylosing Spondylitis: A Patient-Level Model.

BACKGROUND: Ankylosing spondylitis (AS) is a form of rheumatic disease caused by chronic inflammation of the axial skeleton. Patients with AS experience significant functional limitations and reduced quality of life. Consequently, AS imposes a substantial economic burden on society due to productivity loss and work disability. Biologics, including tumor necrosis factor (TNF) inhibitors and human anti-interleukin-17A monoclonal antibody (IL-17A) agents, are effective treatment strategies in relieving symptoms and slowing down disease progression. Currently, 5 TNF inhibitors and 2 IL-17A antibody agents are approved by the FDA for the management of AS. Of these agents, there is no clear preferred agent in initial biologic therapy, although an IL-17A antibody agent or alternative TNF inhibitor agent is recommended after failure of the initial TNF inhibitor therapy. OBJECTIVE: To assess cost-effectiveness of treatment strategies with biologics, TNF inhibitor or IL-17A, in accordance with the treatment guidelines for patients with AS. METHODS: An economic patient-level simulation combining decision-tree and Markov models was constructed from the U.S. health care payer's perspective over a 10-year time horizon. The current model examined 5 treatment strategies: (1) conventional care treatment with nonsteroidal anti-inflammatory drugs, (2) 1 TNF inhibitor, (3) an IL-17A antibody agent, (4) sequential therapy with 2 TNF inhibitors, and (5) sequential therapy with a TNF inhibitor followed by an IL-17A antibody agent. Initially, treatment responses were determined after 12-week treatments. Patients who responded to treatment entered a "responders" Markov model. Patients entered a "nonresponders" Markov model if they inadequately responded to treatment. In sequential treatment strategies, patients who inadequately responded to treatment with the first TNF inhibitor received a second TNF inhibitor or an IL-17A antibody agent. Health utility was estimated based on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Functional Index (BASFI) scores. The models accounted for real-world adherence to TNF inhibitor treatment. Scenario and probabilistic sensitivity analyses were performed to test the robustness and uncertainty of the model results. RESULTS: Over a 10-year time horizon and 100,000 simulated patients for each treatment strategy, base-case results produced average total discounted per-patient costs of $19,765, $130,302, $159,934, $190,553, and $179,118 and quality-adjusted life-years (QALYs) of 4.675, 5.410, 5.499, 5.919, and 5.893 for conventional care, treatment strategies with 1 TNF inhibitor, an IL-17A, 2 TNF inhibitors, and a TNF inhibitor followed by an IL-17A, respectively. The optimal treatments at willingness-to-pay (WTP) thresholds ≤ $130,813 per QALY, between $130,813 per QALY and $442,728 per QALY, and > $442,728 per QALY were conventional care and sequential treatment strategies with 1 TNF inhibitor, followed by an IL-17A agent and 2 TNF inhibitors, respectively. CONCLUSIONS: Study findings suggested that all treatment strategies with biologics, TNF inhibitors or IL-17A antibody agents, in the treatment guidelines for AS were not cost-effective at the common WTP of $100,000 per QALY. However, the sequential treatment with 1 TNF inhibitor followed by an IL-17A antibody agent was considered cost-effective at a higher WTP of $150,000 per QALY. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Primary findings of this study were presented in part at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) in Baltimore, MD, May 2018.

Two-year cost effectiveness between two gradual tapering strategies in rheumatoid arthritis: cost-utility analysis of the TARA trial.

OBJECTIVE: The aim of the current study was to evaluate the 2-year cost-utility ratio between tapering conventional synthetic disease-modifying antirheumatic drugs (csDMARD) first followed by the tumour necrosis factor (TNF)-inhibitor, or vice versa, in patients with rheumatoid arthritis (RA). METHODS: Two-year data of the Tapering strategies in Rheumatoid Arthritis trial were used. Patients with RA, who used both a csDMARD and a TNF-inhibitor and had a well-controlled disease (disease activity score ≤2.4 and swollen joint count≤1) for at least 3 months, were randomised into gradual tapering the csDMARD first followed by the TNF-inhibitor, or vice versa. Quality-adjusted life years (QALYs) were derived from the European Quality of life questionnaire with 5 dimensions. Healthcare and productivity costs were calculated with data from patient records and questionnaires. The incremental cost-effectiveness ratio and the incremental net monetary benefit were used to assess cost effectiveness between both tapering strategies. RESULTS: 94 patients started tapering their TNF-inhibitor first, while the other 95 tapered their csDMARD first. QALYs (SD) were, respectively, 1.64 (0.22) and 1.65 (0.22). Medication costs were significantly lower in the patients who tapered the TNF-inhibitor first, while indirect cost were higher due to more productivity loss (p=0.10). Therefore, total costs (SD) were €38 833 (€39 616) for tapering csDMARDs first, and €39 442 (€47 271) for tapering the TNF-inhibitor (p=0.88). For willingness-to-pay (WTP) levels <€83 800 tapering, the csDMARD first has the highest probability of being cost effective, while for WTP levels >€83 800 tapering the TNF-inhibitor first has the highest probability. CONCLUSION: Our economic evaluation shows that costs are similar for both tapering strategies. Regardless of the WTP, tapering either the TNF-inhibitor or the csDMARD first is equally cost effective. TRIAL REGISTRATION NUMBER: NTR2754.

An Indian national survey of therapeutic drug monitoring with anti-tumor necrosis (TNF) medications in inflammatory bowel disease.

BACKGROUND: Evidence supports therapeutic drug monitoring (TDM) in improving efficacy and cost-effectiveness of anti-TNF therapy in inflammatory bowel disease (IBD). Data on perceptions and barriers to TDM use are limited and no data are available from India. Our objective was to assess clinicians' attitudes and barriers to TDM use in IBD. METHODS: A 16-question survey was distributed to members of the Indian Society of Gastroenterology. Information on clinician characteristics, demographics, use and barriers towards TDM with anti-TNFs was collected. Logistic regression was used to predict factors influencing TDM use. RESULTS: Two hundred and forty-two respondents participated (92.5% male); 83% were consultant gastroenterologists. Of 104 respondents meeting inclusion criteria (treating > 5 IBD patients and at least 1 with an anti-TNF per month), complete responses were available for 101 participants. TDM was utilized by 20% (n = 20) of respondents. Of them, 89.5% (n = 17) used TDM for secondary loss of response; 73.7% (n = 14) for primary non-response and 5.3% (n = 1) proactively. Barriers to TDM use were cost (71.2%), availability (67.8%), time lag in results (58.7%) and the perception that TDM is time-consuming (45.7%). Clinicians treating > 30 IBD patients were more likely to check TDM (OR = 4.9, p = 0.02). Of 81 respondents not using TDM, 97.5% (n = 79) would do so if all the barriers were removed. CONCLUSION: Significant barriers to TDM use were availability, cost and time lag for results. If these barriers were removed, almost all the clinicians would use TDM at least reactively and 25% would use proactively. There is an urgent need to address these barriers and optimize anti-TNF therapy for optimal outcomes.

TNF-α inhibitors biosimilars as first line systemic treatment for moderate-to-severe chronic plaque psoriasis.

INTRODUCTION: Biologics have revolutionized the therapy of moderate-to-severe plaque psoriasis. Despite their greater efficacy over conventional systemic therapies their high cost has represented a burden for health-care systems, which limited their use. The availability of biosimilars at low cost is changing the place in therapy of biologics for psoriasis. AREAS COVERED: The role of TNF- α inhibitors in the management of plaque psoriasis, their efficacy and safety profile are presented. Phase 3 clinical trials and real-life data from the use of TNF- α inhibitor biosimilars in the treatment of plaque psoriasis are also reviewed in detail. Furthermore, arguments in favor of the use of TNF- α inhibitor biosimilars as a first-line therapy in moderate-to-severe plaque psoriasis are discussed. EXPERT OPINION: An increasing amount of data show that biosimilars represent a safe and effective alternative to the originator biologics. In the face of ever-increasing health-care costs, switching to biosimilars and starting naïve patients on the best-value biologic can reduce expenditure for patients and payers while maintaining a high-quality care. Moreover, as the cost of biosimilars is approaching the cost of conventional systemic treatments, TNF-α inhibitors biosimilars may represent a first-line systemic treatment for psoriasis patients because they are effective and safe.

Dose reduction and withdrawal strategy for TNF-inhibitors in psoriatic arthritis and axial spondyloarthritis: design of a pragmatic open-label, randomised, non-inferiority trial.

BACKGROUND: Tumour necrosis factor inhibitors (TNFi) are effective in the treatment of patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). However, these drugs come with some disadvantages such as adverse events, practical burden for patients and high costs. Dose optimisation of TNFi after patients have reached low disease activity (LDA) has been shown feasible and safe in rheumatoid arthritis (RA). However, data on TNFi dose optimisation in PsA and axSpA are scarce, especially pragmatic, randomised strategy studies. METHODS: We developed an investigator-driven, pragmatic, open-label, randomised, controlled, non-inferiority trial (DRESS-PS) to compare the effects of a disease activity-guided treat-to-target strategy with or without a tapering attempt in patients with SpA (PsA and axSpA combined), ≥ 16 years of age, who are being treated with TNFi, and have had at least 6 months of low disease activity. The primary outcome is the percentage of patients in LDA after 12 months of follow up. Patients are assessed at baseline, 3, 6, 9, and 12 months of follow up. Bayesian power analyses with a weakened prior based on a similar study performed in RA resulted in a sample size of 95 patients in total. DISCUSSION: More knowledge on disease activity-guided treatment algorithms would contribute to better treatment choices and cost savings and potentially decrease the risk of side effects. In this article we elucidate some of our design choices on TNFi dose optimisation and its clinical and methodological consequences. TRIAL REGISTRATION: Dutch Trial Register, NL6771. Registered on 27 November 2018 (CMO NL66181.091.18, 23 October 2018).

The value of persistence in treatment with subcutaneous TNF-alpha inhibitors for ankylosing spondylitis.

OBJECTIVE: To estimate the impact of persistence on cost-effectiveness of subcutaneous tumor necrosis factor-α inhibitors (SC-TNFis) from healthcare and societal perspectives in a United Kingdom ankylosing spondylitis (AS) population using a recently published Markov cohort model. METHODS: A recently published cost-effectiveness model developed for a National Institute for health and Care Excellence appraisal was extended to fit the current study; in brief, it is a Markov cohort model where treatment responders continue from the trial period with maintenance SC-TNFi treatment, while non-responders transition to conventional care. Costs and effects were modeled for a hypothetical SC-TNFi with average efficacy and price. Model outcomes included quality-adjusted life-years (QALYs), total direct and indirect lifetime costs, and incremental cost-effectiveness ratios (ICERs). The cost-effectiveness of SC-TNFi persistence was estimated by decreasing the annual discontinuation probability in five percentage point increments from 25 to 5% per annum. RESULTS: From a health care perspective, the ICERs for the modeled discontinuation rates compared to the baseline annual discontinuation rate (25%) ranged between GBP 17,277 and GBP 18,161. From a societal perspective, increased discontinuation rates resulted in decreased total costs and higher QALYs; hence, lower discontinuation rates dominated higher discontinuation rates from a societal perspective. CONCLUSION: In conclusion, this study shows that, all else equal, higher SC-TNFi treatment persistence in AS is cost effective from a health care perspective and dominant from a societal perspective. Hence, all else equal, prescribing the SC-TNFi with the highest persistence may be considered a cost-effective strategy.

Anti-TNF biosimilars in psoriasis: from scientific evidence to real-world experience.

Tumor necrosis factor (TNF) inhibitors account for a large proportion of drugs used to treat psoriasis and are indicated first-line options in certain settings. Several biosimilar drugs based on the anti-TNF agents adalimumab, infliximab, and etanercept are now available for use in patients with psoriasis. The favorable cost differential of biosimilars is expected to improve access to biologic therapy for biologic-naive psoriasis patients, who are often undertreated. Also, substantial cost savings can be made if patients are switched to biosimilars. To date, most clinical testing of anti-TNF biosimilars approved for use in psoriasis has been performed in patients with rheumatoid arthritis, and the results extrapolated to psoriasis. Although this may initially raise concerns for clinicians looking to start their psoriasis patients on biologic treatment with a biosimilar or switch from an original biologic to a biosimilar, the process of extrapolation is tightly regulated and scientifically justified. Furthermore, available real-world evidence of the safety and efficacy of anti-TNF agents in patients with psoriasis complements clinical trial data in patients with rheumatoid arthritis. When equipped with the appropriate knowledge, clinicians should have confidence to use biosimilars for the treatment of psoriasis.

The Danish model for the quick and safe implementation of infliximab and etanercept biosimilars.

PURPOSE: A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, but most countries have extensive possibilities of untapped cost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNF inhibitor biosimilars (infliximab and etanercept). METHODS: We shed light on the considerations and experiences made during the implementation, and present key figures from the implementation. RESULTS: The infliximab biosimilar constituted 90.6% of the total amount of infliximab four months following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds. CONCLUSION: We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars.

The Cost-effectiveness of Initial Immunomodulators or Infliximab Using Modern Optimization Strategies for Crohn's Disease in the Biosimilar Era.

BACKGROUND: Treatment cost, efficacy, and safety are integral considerations when optimizing management of Crohn's disease (CD). This study assessed the cost-effectiveness of initial immunomodulator and anti-tumor necrosis factor (anti-TNF) agents for the treatment of CD from a US third-party perspective, incorporating current treatment algorithms, optimization strategies, and reduced costs availed by biosimilars. METHOD: A 1-year Markov model was developed to simulate the cost and quality-adjusted life-years (QALYs) of initial azathioprine, infliximab, and combination therapy for moderate to severe CD. Treatment was changed based on tolerability and clinical disease activity at 3-monthly intervals. Efficacy data were based on published literature. RESULTS: Initial azathioprine had the lowest cost and utility ($35,337 and 0.63 QALYs), whereas combination therapy was the costliest yet conferred the highest health benefits ($57,638 and 0.67 QALYs). The incremental cost-effectiveness of infliximab and combination therapy compared with azathioprine were both in excess of $500,000 per QALY gained. Initial azathioprine remained the most cost-effective treatment on sensitivity analysis compared with infliximab and combination therapy, with 90% reductions in anti-TNF therapy costs and a 5-year time horizon, although combination therapy had an acceptable cost-effectiveness when costs were reduced in the extended model. Initial infliximab, ustekinumab, and vedolizumab were dominated by combination therapy. CONCLUSIONS: In the biosimilar era, initial azathioprine with escalation to infliximab appeared more cost-effective in the short term compared with infliximab or combination therapy, although initial combination therapy yields acceptable ICERs in the long term with continued reductions in anti-TNF therapy costs and will likely be the preferred treatment strategy in the future.

Cost-Effectiveness of Combination Disease-Modifying Antirheumatic Drugs Versus Tumor Necrosis Factor Inhibitors in Active Rheumatoid Arthritis: A Pragmatic, Randomized, Multicenter Trial.

OBJECTIVE: To determine whether intensive combinations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) achieve similar clinical benefits more cheaply than high-cost biologics such as tumor necrosis factor inhibitors (TNFi) in patients with active rheumatoid arthritis (RA) whose illness has failed to respond to methotrexate and another DMARD. METHODS: We used within-trial cost-effectiveness and cost-utility analyses from health and social care and 2 societal perspectives. Participants were recruited into an open-label, 12-month, pragmatic, randomized, multicenter, 2-arm, noninferiority trial in 24 rheumatology clinics in England and Wales. Costs were linked with the Health Assessment Questionnaire (HAQ; primary outcome) and quality-adjusted life years derived from 2 measures (Short-Form 36 health survey and EuroQol 5-domain 3-level instrument). RESULTS: In total, 205 participants were recruited, 104 in the csDMARD arm and 101 in the TNFi arm. Participants in the csDMARD arm with poor response at 6 months were offered TNFi; 46 participants (44%) switched. Relevant cost and outcome data were available for 93% of participants at 6-month follow-up and for 91-92% of participants at 12-month follow-up. The csDMARD arm had significantly lower total costs from all perspectives (6-month health and social care adjusted mean difference -£3,615 [95% confidence interval (95% CI) -4,104, -3,182]; 12-month health and social care adjusted mean difference -£1,930 [95% CI -2,599, -1,301]). The HAQ score showed benefit to the csDMARD arm at 12 months (-0.16 [95% CI -0.32, -0.01]); other outcomes/follow-ups showed no differences. CONCLUSION: Starting treatment with csDMARDs, rather than TNFi, achieves similar outcomes at significantly lower costs. Patients with active RA and who meet the National Institute for Health and Care Excellence criteria for expensive biologics can be treated with combinations of intensive csDMARDs in a cost-effective manner.

Assessing the Association of Formulary Copayment Changes with Real-World Treatment Patterns in Patients with Rheumatoid Arthritis on Etanercept.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic disease that requires long-term treatment to improve or maintain stable disease activity. Tumor necrosis factor inhibitors (TNFi), a class of biologic disease-modifying antirheumatic drugs (bDMARD), are effective at treating symptoms and inhibiting joint progression. Although treatment changes are not recommended in patients with stable disease, health plans have recently enacted formulary changes with higher copayments that could disrupt patient access to TNFis. OBJECTIVE: To assess the association of formulary copayment changes with real-world treatment patterns, treatment effectiveness, and health care costs among bDMARD-naive patients with RA receiving the TNFi etanercept. METHODS: This retrospective observational cohort analysis used the IBM Watson Health MarketScan Commercial Claims and Encounters Database. Adult patients with RA with 6 months of stable etanercept use (no refill gap ≥ 45 days) from January 1, 2013, through December 31, 2015, were selected and the index date was set to the first fill date after the stable-use period. Average etanercept copayment was calculated at the drug-plan level. Copayment change was defined as a monthly increase of at least $40 to account for copayment changes attributable to etanercept wholesale acquisition costs between 2014 and 2015. This amount also corresponded to the 90th percentile of average plan-level changes in etanercept copayments in the database, representing an average change in copayment by a payer. Patients were followed ≥ 12 months before and after the index date to track etanercept treatment changes and ≥ 12 months after a treatment change to track costs after etanercept copayment changes. Etanercept persistence, bDMARD switching, refill gaps, and treatment effectiveness (using a validated effectiveness algorithm) were described for patients with or without copayment change during the 12 months post-index or postchange. We also assessed the mean total of all-cause and RA-related expenditure during the 12-month post-index (or postchange) period. RESULTS: 1,970 stable patients met study inclusion criteria (mean [standard deviation] age: 50.3 [9.5] years; 77.8% female) and were evaluated. Of these, 133 (6.8%) patients had a copayment change ≥$40 during follow-up. Overall, most patients (60.3%) persisted on etanercept for the 12-month follow-up period, while 13.0% switched from etanercept, and 8.1% discontinued (refill gap of ≥ 45 days). Nearly half (48.0%) of all patients were considered effectively treated according to a validated algorithm. Compared with patients without a copayment change, those with a copayment change were more likely to switch biologics (19.5% vs. 12.6%; P = 0.021). Although statistical significance was not reached, patients with a copayment change were less likely to be persistent (54.1% vs. 60.7%; P = 0.135), and less likely to be effectively treated (42.1% vs. 48.4%; P = 0.161) than patients without a copayment change. All-cause and RA-related expenditures at baseline and post-copayment change were similar between patients with and without a copayment change. CONCLUSIONS: Changing formulary copayment of etanercept was associated with higher switching without difference in costs or health care utilization between copayment and no copayment change groups. DISCLOSURES: This study was sponsored by Amgen. Bonafede, Manjelievskaia, and Lopez-Gonzalez are employees of IBM Watson Health, which received funding from Amgen to conduct this study. Oko-osi, Collier, and Stolshek are employees and shareholders of Amgen. Gharaibeh was an employee of Amgen at the time of study execution and manuscript drafting. The authors have no other relationships that present a potential conflict of interest. Data pertaining to this study were presented in a poster at the 2018 ACR/ARHP Annual Meeting; October 19-24, 2018; Chicago, IL.