PATIENT JOURNEYS IN THE TREATMENT OF RA Speaker Notes Hello. I’m Dr. Jim O’Dell from the University of Nebraska Medical Center and I’m going to spend the next 20 minutes discussing results from a claims analysis that explored how patients with rheumatoid arthritis — RA — are treated in the US as well as some of the implications of these treatment patterns. MP-RA-0392

Data Source and Extraction This study used Symphony Health Solutions Integrated Dataverse which contains medical, hospital, and prescription healthcare claims data Patient information was de-identified for Health Insurance Portability and Accountability Act (HIPAA) compliance and encrypted with unique identifiers for longitudinal tracking The database covers approximately 274 million patients in the United States Patients diagnosed with RA defined as ICD-9 codes 714.0 and 714.30 in 2008 or 2009 were identified as candidates for this study: Patients were required to have an RA claim in each year included in the study: 2009 thru 2014 Patients were also required to be naïve to MTX as defined by a 1-year look-back period Patients were followed through to end of year 2014 tracking all medical, hospital, and prescription claims, thus creating a stable patient panel Speaker Notes This study used Symphony Health Solutions Integrated Dataverse which contains medical, hospital, and prescription healthcare claims data. The database covers approximately 274 million patients in the US. Patients diagnosed with RA, defined as ICD-9 codes 714.0 and 714.30 in 2008 or 2009, were identified as candidates for this study. Patients were required to have an RA claim in each year included in the study, from 2009 through 2014. They were also required to be naïve to methotrexate as defined by a 1-year look-back period. Patients were followed through to the end of 2014, with tracking all medical, hospital, and prescription claims. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

Claims Analyzed National Drug Codes and the Healthcare Common Procedure Coding System were used to identify the products in the claims database for MTX and biologics Biologics included: Abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. All patients’ medical, hospital, and prescription claims were extracted for the study: Comorbidities and prescription treatments of interest were identified using ICD-9 codes, Healthcare Common Procedure Coding System, and National Drug Codes Patients’ comorbidities were defined based on the presence of an ICD-9 code submitted any time during the study period Prescription medications of interest included nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, hydroxychloroquine, sulfasalazine, leflunomide and other conventional DMARDs. These medications were included in the patient demographics if the drug was ever prescribed for the patient during the study period. Speaker Notes All patients’ medical, hospital, and prescription claims were extracted for the study. Comorbidities and prescription treatments of interest were identified using ICD-9 codes, Healthcare Common Procedure Coding System, and National Drug Codes. Comorbidities were defined based on the presence of an ICD-9 code submitted any time during the study period. Prescription medications of interest included nonsteroidal anti-inflammatory drugs, glucocorticoids, methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and other conventional DMARDs. Biologics agents used to treat RA included abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

Characteristics of Treaters Patients were managed predominantly by rheumatologists (~75% for each group at all stages of treatment) Not Found 3% Other 7% Family Medicine 9% Internal Medicine 12% Rheumatology 73% Speaker Notes We also collected information on the specialties of the physicians who managed these patients. Not surprisingly, the great majority were under the care of a rheumatologist. Reference O’Dell JR, Cohen S, Thorne C, Mikuls TR, et al. Presented at EULAR, 2016. Abst: FRI0181. O’Dell JR, et al. Presented at EULAR, 2016. Abst: FRI0181

Patient Journeys 2014 End Period 2009 13,270 Patients 27% Remained on Initial Biologic n=9039 68% 13,270 Patients 27% No Switch ≥1 Switch in Biologic Treatment n=4231 Mean: 774 days Median: 657 days New to Biologic 32% Oral MTX n=15,599 44% 35,640 Patients 73% No Switch Mean: 478 days Median: 169 days Biologic n=17,528 from MTX New to Oral MTX 49% Mean: 727 days Median: 530 days Speaker Notes This slide summarizes the treatment pathways for 13,270 patients with RA initially exposed to a biologic and 35,640 initially exposed to methotrexate in 2009, who were followed for 5 years. It’s important to remember that these patients could have received a conventional disease- modifying anti-rheumatic drug — DMARD — other than methotrexate, prior to their initial treatment with a biologic or methotrexate in this analysis. So, not all of the patients were newly diagnosed or treatment-naïve at the beginning of the study period. As you can see, patients followed several different treatment pathways and we will consider each of these in detail in the following slides. References Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. O’Dell JR, Cohen S, Thorne C, Mikuls TR, et al. Presented at EULAR, 2016. Abst: FRI0181. SC MTX (n=2513) Mean: 457 days Median: 289 days Biologic n=711 2% Remained on SC MTX for rest of follow-up (n=1802) 5% Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18. O’Dell JR, et al. Presented at EULAR, 2016. Abst: FRI0181.

Initiation and Persistence with a Biologic Agent 2014 End Period Remained on Initial Biologic n=9039 2009 68% No Switch 13,270 Patients 27% New to Biologic Speaker Notes We will consider the patients who initiated treatment with a biologic agent first. Overall, 68% of the patients who initiated treatment with a biologic in 2009 remained on this agent until the end of follow-up in 2014. Reference O’Dell JR, Cohen S, Thorne C, Mikuls TR, et al. Presented at EULAR, 2016. Abst: FRI0181. O’Dell JR, et al. Presented at EULAR, 2016. Abst: FRI0181.

Persistence with First TNF Inhibitor: The RADIUS Cohort All Discontinuations Retrospective analysis of results from RADIUS 1, a 5-year observational registry of patients with RA (N=2418) 1.0 0.9 0.8 0.7 0.6 Proportion of Patients Continuing on the Same Agent 0.5 0.4 Treatment Group Adalimumab Etanercept Infliximab 0.3 0.2 0.1 0.0 5 10 15 20 25 30 35 40 45 50 55 Discontinuations Due to Inadequate Efficacy 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 55 50 45 40 35 30 25 20 15 10 5 Proportion of Patients Continuing on the Same Agent Time on Drug (months) Treatment Group Adalimumab Etanercept Infliximab Time on Drug (months) Discontinuations Due to Toxicity 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 55 50 45 40 35 30 25 20 15 10 5 Proportion of Patients Continuing on the Same Agent Time on Drug (months) Treatment Group Adalimumab Etanercept Infliximab Speaker Notes The results from the patients we followed were comparable to those from RADIUS 1, a 5-year observational registry of patients with RA. This analysis included 2,418 patients. Mean persistence rates were similar among treatments, etanercept, adalimumab, and infliximab; and about 50% of patients remained on their initial biologic for 55 months of follow-up. The risk for discontinuation due to inadequate efficacy was similar to that for discontinuation due to adverse events. Reference Markenson JA, Gibofsky A, Palmer WR, et al. Persistence with anti-tumor necrosis factor therapies in patients with rheumatoid arthritis: observations from the RADIUS registry. J Rheumatol. 2011;38:1273-1281. Markenson JA, et al. J Rheumatol. 2011;38:1273-1281.

Initiation then Switching Biologic Agents 2009 2014 End Period 13,270 Patients 27% ≥1 Switch in Biologic Treatment n=4231 Mean: 774 days Median: 657 days New to Biologic 32% Speaker Notes The next subgroup of patients we’ll consider are those that started treatment with a biologic and then changed to a second biologic during the follow-up period. This occurred for 32% of the patients who started biologic therapy without prior methotrexate treatment, and the median time to switching was a bit less than 2 years. Reference O’Dell JR, Cohen S, Thorne C, Mikuls TR, et al. Presented at EULAR, 2016. Abst: FRI0181. O’Dell JR, et al. Presented at EULAR, 2016. Abst: FRI0181.

Kaplan-Meier Survival Estimates, by order of treatment Persistence with First, Second, and Third TNF Inhibitor: The BIOBADASER Cohort Kaplan-Meier Survival Estimates, by order of treatment 1.00 0.75 0.50 0.25 0.00 2 1.5 1 .5 Analysis Time (years) 4707 495 49 3967 376 26 3150 228 7 2487 119 1925 69 First TNF-antagonist Second one Third one First Third Second Survival Probability Speaker Notes The trend toward shorter persistence with a second- versus first-line biologic agent in patients with RA is supported by results from the BIOBADASER registry, which showed further that persistence with third-line biologic treatment was even shorter than that for second-line therapy. Reference Gomez-Reino JJ, Carmona L; BIOBADASER Group. Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period. Arthritis Res Ther. 2006;8:R29. Gomez-Reino JJ, Carmona L; BIOBADASER Group. Arthritis Res Ther. 2006;8:R29.

Percentage of Patients The Probability of a Clinical Response Declines with Each TNF Inhibitor Switch: ACR Responses 1 2 2+ 3 4 Number of Biologics 20 40 60 80 Percentage of Patients ACR20 ACR50 ACR70 Speaker Notes Treatment efficacy also declines with succeeding lines of biologic therapy in patients with RA. A systematic review that included results from 41 publications indicated that the likelihood of responding to a given TNF inhibitor decreased as the number of previous treatments with TNF inhibitors increased. Reference Rendas-Baum R, Wallenstein GV, Koncz T, et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res Ther. 2011;13:R25. Rendas-Baum R, et al. Arthritis Res Ther. 2011;13:R25.

Switching Biologics Is Associated with Increased Healthcare Costs P=0.007 Annual Per-patient Cost Speaker Notes As you might expect, the cost of treatment increases when RA patients switch biologic therapies. Results from the drug utilization analysis shown in this slide indicated that the mean cost of treatment for a patient switching from initial treatment during the first year of follow-up were higher than for patients who did not change treatment. Reference Esposti DL, Favalli EG, Sangiorgi D, et al. Persistence, switch rates, drug consumption and costs of biological treatment of rheumatoid arthritis: an observational study in Italy. Clinicoecon Outcomes Res. 2017;9:9-17. Esposti DL, et al. Clinicoecon Outcomes Res. 2017;9:9-17.

Initiation and Persistence with Oral MTX 2014 End Period 2009 Oral MTX n=15,599 44% 35,640 Patients 73% No Switch New to Oral MTX Speaker Notes This slide summarizes the simple journey for patients who remained on their initial treatment with oral methotrexate for the duration of our study. Of the 35,640 patients who initiated treatment with oral methotrexate in 2009, 44% remained on their initial agent through the end of the follow-up period. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

About One-Fourth of Patients with RA Can Be Effectively Managed with Oral MTX TEAR Initial treatment with MTX with the option to step-up to treatment with either MTX plus etanercept or MTX plus SSZ plus HCQ if the DAS28 at week 24 is ≥3.21 SWEFOT Initial treatment with MTX with the option to step-up to treatment with either MTX plus etanercept or MTX plus SSZ plus HCQ or infliximab if the DAS28 at 3-4 months is ≥3.22,3 30 28 Speaker Notes A very large number of clinical trials have evaluated the efficacy of methotrexate monotherapy in patients with RA and results from two of them, TEAR and SWEFOT, are shown in this slide. Both of these studies assessed achievement of low disease activity with methotrexate monotherapy as one of several treatment arms, and results indicated that 28-30% of patients reached this goal on oral methotrexate alone. References Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64:2824-2835. van Vollenhoven RF, Ernestam S, Geborek P, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009; 374:459-466. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.Lancet. 2012; 379:1712-1720 Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2835. van Vollenhoven RF, et al. Lancet. 2009; 374:459-466. van Vollenhoven RF, et al. Lancet. 2012; 379:1712-1720.

Percentage of Patients Oral MTX Monotherapy Has Long-Term Clinical Benefit in Initial Responders: TEAR In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early poor-prognosis RA were randomized to receive: MTX monotherapy Combination therapy (MTX + etanercept or MTX + sulfasalazine + hydroxychloroquine) Participants randomized to receive MTX monotherapy were stepped up to combination therapy at 24 weeks if the DAS28-ESR was ≥3.2 Percentage of Patients Speaker Notes It should be noted that patients who have a good initial response to oral methotrexate are likely to achieve sustained control over their disease with this treatment. This slide shows results at 2 years from the TEAR trial; and results for ACR20/50/70 improvement demonstrated that the subset of patients with a good response to methotrexate at 24 weeks also had good clinical efficacy after 2 years of this treatment. Reference O'Dell JR, Curtis, JR, Mikuls TR, et al. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum. 2013;65:1985-1994. O'Dell JR, et al. Arthritis Rheum. 2013;65:1985-1994.

Long-Term Oral MTX Efficacy: Radiologic Outcomes in TEAR 80 IC SU MM 70 60 50 40 Change in TSS (Year 2 – Baseline) 30 20 100 Speaker Notes This slide illustrates very well-known results from the TEAR study. The cumulative probability plot of in this slide demonstrates that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Reference O’Dell JR, Curtis, JR, Mikuls T, et al. Validation of the Methotrexate-First Strategy in Patients With Early, Poor-Prognosis Rheumatoid Arthritis. Arthritis Rheum. 2013;65:1985-1994 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 -10 -20 Cumulative Probability of Change IC, immediate combination; MM, methotrexate monotherapy; SU, step-up to combination therapy O’Dell JR, et al. Arthritis Rheum. 2013;65:1985-1994.

Staying on Oral MTX: Per-patient Costs 5-year per Patient Cost $250,000 $200,000 $150,000 $100,000 $50,000 $0 Continued oral MTX Emergency department costs Hospitalization costs Office visit costs Pharmaceutical costs Speaker Notes As you might expect, patients who stayed on their initial treatment with oral methotrexate had a low 5-year total treatment cost of $47,464. Reference Lee J, Pelkey R, Gubitosa J, et al. Comparing Healthcare Costs Associated with Oral and Subcutaneous Methotrexate or Biologic Therapy for Rheumatoid Arthritis in the United States. Am Health Drug Benefits. 2017;10:42-49. Lee J, et al. Am Health Drug Benefits. 2017;10:42-49.

Initiation with Oral MTX then Switch to/Add Biologic 2009 2014 End Period 35,640 Patients 73% Biologic n=17,528 from MTX New to Oral MTX Mean: 478 days Median: 169 days 49% Speaker Notes This slide summarizes the journey for another subgroup of patients. Of the 35,640 patients who initiated treatment with a oral MTX in 2009, 49% switched to or had a biologic agent added to their treatment by the end of the follow-up period. This change in treatment occurred a median 169 days after the initiation of oral methotrexate treatment. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

Percentage of Total Group Switching Switching to a Biologic Occurs Most Often in the First Month of Oral MTX Treatment 51% of patients switched from oral MTX to a biologic in the first 6 months N=17,528 Percentage of Total Group Switching Speaker Notes Switching to or adding a biologic occurred during the first 6 months of treatment for most patients who had this change in therapy. Remarkably, 25% of patients in this group switched treatment during the first month. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Month Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

Percentage of Patients Oral MTX dose (mg/week) About One-third of Patients Received Oral MTX Doses >15 mg/week Prior Switching to a Biologic Oral MTX dose at time of switch to biologic (n=17,528, mean dose = 15.3 ± 4.7 mg/week) Percentage of Patients Speaker Notes Patients who switched from oral methotrexate to a biologic or had one of these agents added to their regimen generally did not achieve a very high dose of methotrexate by the time their treatment was changed. The mean methotrexate dose at the time of switching to or adding a biologic was 15.3 mg/week and only 28% of patients received methotrexate doses ≥20 mg/week prior to adding or switching to a biologic. References Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Medac Pharma, data on file. Oral MTX dose (mg/week) Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18. Medac Pharma, data on file.

Switching from Oral MTX to a Biologic: Per-patient Costs $250,000 $200,000 $150,000 $100,000 $50,000 $0 Continued oral MTX Switched to a biologic 5-year per Patient Cost Speaker Notes The mean 5-year treatment costs for a patient who switched from oral methotrexate to a biologic or had one of these agents added to their regimen were $212,595. As you would expect, most of this cost was for acquisition of the biologic agent. The costs for these patients are much higher than those for a patient who remained on oral methotrexate. Reference Lee J, Pelkey R, Gubitosa J, et al. Comparing Healthcare Costs Associated with Oral and Subcutaneous Methotrexate or Biologic Therapy for Rheumatoid Arthritis in the United States. Am Health Drug Benefits. 2017;10:42-49. Emergency Department Costs Hospitalization Costs Office Visit Costs Pharmaceutical Costs Lee J, et al. Am Health Drug Benefits. 2017;10:42-49.

Initiation Oral MTX, Switch to SC MTX, and Persist with SC MTX 2009 35,640 Patients 73% 2014 End Period New to Oral MTX Mean: 727 days Median: 530 days SC MTX (n=2513) Remained on SC MTX for rest of follow-up (n=1802) Speaker Notes This slide summarizes results for patients who switched from oral to SC methotrexate and remained on this treatment until the end of follow-up. Of the 35,640 patients who initiated treatment with oral methotrexate in 2009, 5% switched to SC drug and remained on this treatment to the end of the follow-up period. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. 5% Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

Subject Characteristics   Initiated and Remained on Oral MTX (n=15,599) Switched from Oral MTX to a Biologic (n=17,528) Switched from Oral to SC MTX and Remained on this Treatment (n=1802) Switched from Oral to SC MTX then to a Biologic (n=711) Age, years (mean) 66 59 60 54 Sex, % Male Female 24 76 22 78 18 82 Race/Ethnicity, % African American Caucasian Hispanic Missing/uncoded 8 6 27 10 57 25 58 7 Comorbidities, % Ischemic CVD Heart failure Malignancy Malignancy history Psychiatric disease 19 9 17 11 28 14 13 32 15 16 35 12 38 Treatment with non-MTX DMARD, % Sulfasalazine Hydroxychloroquine Leflunomide Other conventional DMARD 33 30 47 21 45 29 Speaker Notes This slide shows the characteristics of the patient groups included in this analysis. References Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Lee J, Pelkey R, Gubitosa J, Henrick MF, Ganz ML. Comparing healthcare costs associated with oral and subcutaneous methotrexate or biologic therapy for rheumatoid arthritis in the United States. Am Health Drug Benefits. 2017;10:42-49. Medac Pharma, data on file. Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18. Lee J, et al. Am Health Drug Benefits. 2017;10:42-49. Medac Pharma, data on file.

Significantly Better Disease Control with SC vs Oral MTX ACR Responses† EULAR Remission† Speaker Notes It is well known that SC delivery of methotrexate results in higher bioavailability versus oral administration; and the improved pharmacokinetic profile for SC versus oral methotrexate translates into improved efficacy. Results from a head-to-head comparison of SC versus oral methotrexate in patients with RA has shown that SC administration results in significantly higher percentages of patients achieving ACR20 and ACR70 improvement in their clinical condition versus oral drug. Subcutaneous delivery of methotrexate also resulted in a significantly higher percentage of patients achieving European League Against Rheumatism criteria for remission. References Braun J, Kastner P, Flaxenberg P, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58:73-81. Braun J. Optimal administration and dosage of methotrexate. Clin Exp Rheumatol. 2010;28(suppl 61):S46-S51. †Week 16 results were carried forward for patients who were switched from oral to SC MTX or had their SC MTX dosage increased from 15 to 20 mg/wk. 1. Braun J, et al. Arthritis Rheum. 2008;58:73-81. 2. Braun J. Clin Exp Rheumatol. 2010;28(suppl 61):S46-S51.

Clinical Efficacy of SC vs Oral MTX: Meta-Analysis Equality P=0.04 P=0.02 Speaker Notes Results from clinical trials and registry studies have shown that about one-fourth of patients with RA can achieve and maintain disease control with oral methotrexate. For those who do not achieve and maintain treatment goals on oral drug, switching to SC methotrexate increases bioavailability of the drug and may improve the clinical response. This is supported by a recent meta-analysis that combined results from some of the studies shown and others and demonstrated that SC methotrexate improves achievement of ACR20 and ACR70, compared to oral drug. Reference Li D, Yand Z, Kang P, Xie X. Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate: A systematic review and meta-analysis. Semin Arthritis Rheum. 2016;45:656-662. Odds Ratio (SC vs oral)* *Higher odds ratio indicates increased probability of outcome Li D, et al. Semin Arthritis Rheum. 2016;45:656-662.

SC vs Oral MTX: Prospective Results Adverse Event SC MTX (n=46) % Oral MTX (n=46) Nausea 37 63 Vomiting 11 30 Dyspepsia 29 48 Dizziness 41 52 Alopecia 72 85 Speaker Notes Several studies have shown that SC methotrexate has lower risk for gastrointestinal adverse events vs oral drug. This slide illustrates results from a prospective study which indicated that nausea, vomiting, and dyspepsia also occurred less frequently with SC methotrexate versus oral drug. Reference Islam MS, Haq SA, Islam MN, et al. Comparative efficacy of subcutaneous versus oral methotrexate in active rheumatoid arthritis. Mymensingh Med J. 2013;22:483-488. Islam MS, et al. Mymensingh Med J. 2013;22:483-488.

Significant Improvement in Disease Control Following Switch from Oral to SC MTX Retrospective analysis of 103 RA patients switched from oral to SC MTX: 40 switched due to inadequate efficacy of oral MTX 63 patients switched due to gastrointestinal side effects of oral MTX P=0.006 P=0.0001 Speaker Notes This slide shows clinical results demonstrating significant improvement in DAS28 scores for patients who were switched from oral to subcutaneous administration of methotrexate and were followed for 3 months. Improvements in DAS28 scores were observed for patients who switched treatment due to inadequate efficacy or intolerable side effects. Reference Hameed B, Jones H. Subcutaneous methotrexate is well tolerated and superior to oral methotrexate in the treatment of rheumatoid arthritis. Int J Rheum Dis. 2010;13:e83-e84. Hameed B, Jones H. Int J Rheum Dis. 2010;13:e83-e84.

Last Visit on Oral MTX (N=80) Significant Improvements in Multiple Disease Parameters after Switching from Oral to SC MTX Retrospective analysis of 80 patients with RA who were switched from oral to SC MTX due to GI intolerability Oral MTX dose = 15.1 mg/week; SC MTX dose = 16.5 mg/week Measure  Last Visit on Oral MTX (N=80) 1-month Visit on SC MTX (N=80) 3-month Visit on SC MTX P-value DAS28 Score 4.0 ± 0.9 3.6 ± 0.8 3.4 ± 0.8 <0.01 ESR (mm/h) 42.5±21 33.8 ± 17.4 29.7 ± 15 <0.05 CRP (mg/dL) 2.3 ± 2.8 1.4 ± 1.4 0.8 ± 0.9 Pain by VAS 66.9 ± 18.9 53.9 ± 14.2 51.6 ± 14.4 Speaker Notes Switching patients from oral to SC methotrexate may result in improvement in many disease parameters. A study that included 80 patients with RA showed that this change in treatment resulted in significant improvements in DAS28 scores, erythrocyte sedimentation rate, C-reactive protein levels, and pain. Reference Borman P, Demir G, Kaygisiz F, Okumus M. Subcutaneous (SC) Methotrexate (MTX) is Better and Well-Tolerable than Oral MTX in Rheumatoid Arthritis Patients, Switched from Oral to SC Administration Due to Gastrointestinal Side Effects. Open Rheumatol J. 2014;8:18-19. Borman P, et al. Open Rheumatol J. 2014;8:18-19.

Better Persistence Is Achieved With SC vs Oral MTX: CATCH Cohort Time (months) 0.2 0.0 0.4 0.6 0.8 1.0 3 6 9 12 SC MTX (n=249) Oral MTX (n=417) Proportion of Initial Treatment 49% 77% Failed Initial Treatment Log-rank P<0.001 417 249 233 184 130 136 104 117 66 88 PO SC Speaker Notes The better efficacy and tolerability of SC methotrexate over oral drug contribute to longer persistence with this approach to delivery. This slide shows results from 666 patients in the CATCH cohort who initiated RA treatment with oral or SC MTX. At the end of 1 year of follow-up, 51% of patients who started on SC methotrexate remain on this treatment vs only 23% who started on oral drug. Reference Hazlewood GS, Thorne JC, Pope Je, et al. The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis. 2016;75:1003-1008. PO, oral Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008, with permission from BMJ Publishing Group Ltd.

Switching to SC MTX and Staying on this Therapy: Per-patient Cost $250,000 $200,000 $150,000 $100,000 $50,000 $0 Continued oral MTX Switched to a biologic SC MTX and remained 5-year per Patient Cost Speaker Notes Switching from oral to SC methotrexate was much less costly than moving directly to a biologic. The mean 5-year total treatment costs for a patient in this pathway were $59,058. This cost is slightly higher than that for patients who remained on oral drug, but much less than that for patients who switched to a biologic. Reference Lee J, Pelkey R, Gubitosa J, et al. Comparing Healthcare Costs Associated with Oral and Subcutaneous Methotrexate or Biologic Therapy for Rheumatoid Arthritis in the United States. Am Health Drug Benefits. 2017;10:42-49. Emergency Department Costs Hospitalization Costs Office Visit Costs Pharmaceutical Costs Lee J, et al. Am Health Drug Benefits. 2017;10:42-49.

Initiation Oral MTX, Switch to SC MTX, and then to a Biologic 73% 2% 2009 35,640 Patients New to Oral MTX Biologic n=711 2014 End Period Mean: 727 days Median: 530 days Mean: 457 days Median: 289 days SC MTX (n=2513) Speaker Notes The last few slides summarize results for patients who switched from oral to SC methotrexate and then to a biologic agent. Of the 2,518 patients who switched from oral to SC methotrexate, 711 (2% of the total that started on oral methotrexate) switched to a biologic or had one added to therapy by the end of the follow- up period. These patients remained on SC methotrexate for more than 9 months prior to switching to a biologic agent. Reference Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O'Dell JR. The Underuse of Methotrexate in the treatment of RA: A National Analysis of Prescribing Practices in the U.S. Arthritis Care Res (Hoboken). 2016 Nov 18. Rohr MK, et al Arthritis Care Res (Hoboken). 2016 Nov 18.

Percentage of Total Group Switching Switching from SC MTX to a Biologic in the First Year after Switching to SC MTX N=711 Percentage of Total Group Switching Speaker Notes Most of the patients on SC methotrexate who switched to or added a biologic did so during the first year of SC treatment. Reference Medac Pharma, data on file. Month Medac Pharma, data on file.

SC MTX Therapy: An Alternative to Initiating a Biologic 301 Patients Failing Oral MTX 68 Patients on SC MTX 1-year of follow-up 20 (29%) Discontinued SC MTX 33 (49%) Stabilized on SC MTX 15 (22%) Advanced to MTX + Biologic Speaker Notes The results shown in this slide demonstrate how inclusion of SC methotrexate may delay progression to biology therapy. This was a retrospective analysis of records of 301 patients with RA who failed treatment with oral methotrexate. Of these patients, 68 switched to SC methotrexate and the rest moved on to a biologic agent. Of the 68 patients who tried SC methotrexate, 29% subsequently discontinued this treatment, mostly as a result of adverse effects. Of the remaining patients still on SC methotrexate, 22% were also on anti-TNF therapy, while 49% were established with stable disease taking SC methotrexate alone. Reference Hassanzadeh R, Mangan C, France J, Bawa S. Subcutaneous methotrexate to cut costs? J Rheumatol. 2012;39:1764-1765. One-half of patients started on SC MTX had a biologic delayed for at least 1 year Hassanzadeh R, et al. J Rheumatol. 2012;39:1764-1765.

Switching from Oral to SC MTX then to a Biologic: Per-patient Costs $250,000 $200,000 $150,000 $100,000 $50,000 $0 Continued oral MTX Switched to a biologic SC MTX and remained SC MTX then to a biologic Emergency Department Costs Hospitalization Costs Office Visit Costs Pharmaceutical Costs 5-year per Patient Cost Speaker Notes Patients who switched from oral methotrexate to SC methotrexate and then switched to a biologic added to therapy had mean 5-year total treatment costs of $175,391. This was substantially less than that for switching directly from oral methotrexate to a biologic agent. Reference Lee J, Pelkey R, Gubitosa J, et al. Comparing Healthcare Costs Associated with Oral and Subcutaneous Methotrexate or Biologic Therapy for Rheumatoid Arthritis in the United States. Am Health Drug Benefits. 2017;10:42-49. Lee J, et al. Am Health Drug Benefits. 2017;10:42-49.

Summary The results of our claims analysis indicate that there are many different ” patient journeys” for patients receiving DMARDs for RA. They also show that: Many patients initiate biologic therapy prior to an adequate trial of oral MTX Inclusion of SC MTX in treatment sequencing has the potential to prevent or significantly delay progression to a biologic Optimizing both oral and SC MTX has the potential to substantially decrease the cost of care for patients with RA Speaker Notes The results of our claims analysis indicate that there are many different ”journeys” for patients receiving DMARDs for RA. They also show that many patients initiate biologic therapy prior to an adequate trial of oral methotrexate, with respect to both dosing and treatment duration. Inclusion of SC methotrexate in treatment sequencing has the potential to prevent or significantly delay progression to a biologic agent. The pharmacoeconomic analysis demonstrated that optimizing both oral and SC MTX has the potential to substantially decrease the cost of care for patients with RA