Specialty drugs are a significant cost trend driver for

2009 Drug Utilization and Cost Trends: Tumor Necrosis Factor Inhibitors Drug Trends Anna A. Theodorou, RPh, MBA; Kelly M. Johnson, MBA; and John A. Szychowski, AAS, BS Specialty drugs are a significant cost trend driver for the majority of plan sponsors. According to IMS Health, specialty drug utilization increased 7.5% in 2009 and comprised 21.0% of US market value, which included figures obtained through retail, mail, and longterm care channels. 1 For the last 3 years, rheumatoid arthritis (RA) drugs were the top specialty class by gross cost, driven by tumor necrosis factor (TNF) inhibitors. Multiple sclerosis agents ranked second, and oncology drugs, including antineoplastic enzyme inhibitors, ranked third. 2,3 Combined, the 3 classes comprised more than 54% of total specialty spend (Table 1). Tumor necrosis factor inhibitors are primarily used to treat painful and debilitating inflammatory diseases such as RA, Crohn s disease, and plaque psoriasis all associated with high levels of TNF in the body. The drugs are considered slow acting, disease-modifying anti-rheumatic drugs (DMARDs). Tumor necrosis factor inhibitors are believed to attack the source of the problem, reducing the amount of TNF in the body and subsequently slowing the progression of the disease, especially important to patients with profound rheumatic symptoms. 4 High class costs are associated with double-digit utilization trend combined with year-over-year (YOY) price inflation. Preliminary metrics indicate a similar trend for 2010, driving overall class costs upward. Currently, an estimated 1.3 million adult Americans have been diagnosed with RA, of whom 75% are women. An estimated 500,000 Americans have Crohn s disease, and approximately 6 million suffer from plaque psoriasis. 4-6 METHODS The analysis was a retrospective study of 23.2 million CVS Caremark members who used more than 240 million prescription claims. The CVS Caremark de-identified database was used to study utilization from January 1, 2008, through December 31, 2009. The population identified for the study was a representative sample of members across a variety of plan sponsors including health plans, managed care organizations, Medicaid, unions, national and local employers, and government agencies located throughout the United States. Only clients with stable membership (±15% change in eligibility in 24 months) and prescription claims in the entire 24-month study period were included. Currently, an estimated 1.3 million adult Americans have been diagnosed with rheumatoid arthritis, of whom 75% are women. An estimated 500,000 Americans have Crohn s disease, and approximately 6 million suffer from plaque psoriasis. Gross cost includes discounts, member contributions, and plan sponsor contributions. The manufacturer rebates were excluded. Gross cost per day was determined by the total gross cost divided by the total days supply for the time frame. The gross per member per month (PMPM) cost was determined by the total gross spending divided by the total member months of eligible plan participants (members). Utilization was based on days supply and number of unadjusted prescriptions PMPM. OVERVIEW Rheumatic diseases are characterized by inflammation (signs include redness or heat, swelling, and symptoms such as pain) and loss of function of 1 or more connecting or supporting structures of the body. These diseases especially affect joints, tendons, ligaments, bones, and muscles. Common signs and symptoms are pain, swelling, and stiffness. There are more than 100 rheumatic diseases. www.ajpblive.com Vol. 2, No. 6 The American Journal of Pharmacy Benefi ts 387

n Theodorou Johnson Szychowski Table 1. Top 3 Gross Cost Specialty Classes Specialty Therapeutic Category and Top Drugs Rheumatoid arthritis Enbrel Humira Remicade Multiple sclerosis Copaxone Avonex Rebif Oncology (cancer) Gleevec Revlimid Tarceva CY 2008 Rank CY 2009 YTD June 2010 YTD June 2010 % of Total Spending YTD June 2010 % of Total Specialty Spending YTD June 2010 % of Total Specialty Days Supply 1 1 1 3.2% 23.2% 18.1% 2 2 2 2.4% 17.6% 9.6% 3 3 3 1.9% 14.0% 6.3% CY indicates current year; YTD, year to date. Source: CVS Caremark Book of Business Trend Cohort Excluding Medicare Part D (CY 2008, CY 2009, and YTD June 2010). This review focused on 5 specialty drugs: Enbrel, Humira, Simponi, Remicade, and Cimzia. Although these drugs are primarily used to treat RA, many have indications that span different disease states; therefore, we did not analyze the actual number of prescriptions directly associated with any specific disease state. Remicade is the only infused drug in the class; the other 4 drugs are administered by patient or provider injection. The drugs are commonly used as monotherapy or with an adjunctive therapy such as methotrexate. Each is protein-based and reduces the effectiveness of the body s immune system, significantly increasing a patient s risk of developing serious infections. Rheumatoid arthritis is an inflammatory disease of the immune system that first targets the synovium (lining of the joint), resulting in pain, stiffness, swelling, joint damage, and loss of function of the joints. This inflammation most often affects joints of the hands and feet, and tends to be symmetrical (occurring equally on both sides of the body). This symmetry helps distinguish RA from other forms of the disease. 7 The disease can affect individuals of all ages, as opposed to osteoarthritis, which is more commonly associated with joint wear and tear through aging. Additionally, osteoarthritis is much more common, affecting more than 27 million Americans 25 years and older, and is treated with less costly, nonspecialty prescriptions and over-the-counter medications. 8 INDICATIONS Table 2 shows US Food and Drug Administration (FDA) indications for the 5 drugs. Humira and Remicade have the greatest number of indications, and Cimzia has the fewest. PIPELINE In August 2009, the FDA announced it would require stronger warnings in the prescribing information for all TNF blockers. The warnings, which include an updated boxed warning, highlight the increased risk of cancer in children and adolescents. Additional required updates to the prescribing information include incorporation of reports of new-onset psoriasis associated with the use of TNF blockers. 9 Cimzia received initial marketing approval for Crohn s disease in April 2008 and FDA approval for RA in May 2009. 10,11 Humira is in phase III trials for ulcerative colitis and pediatric Crohn s disease with regulatory filings with the FDA anticipated in 2010. 12 FINDINGS Utilization Change in Days Supply. In 2009, the combined class had a 10.0% PMPM utilization trend by days supply, driven primarily by a 19.8% increase in days supply PMPM for Humira and marginal increases for the other 4 drugs in the class. Although the Remicade days supply growth rate was high (20.6% PMPM), volumes were comparatively very low, resulting in minimal impact on the combined class overall trend. Additionally, many Remicade claims are adjudicated through the medical benefit rather than the drug benefit; thus, they were not included in these figures. An analysis of Simponi prescriptions was not conducted due to recent product launch (May 2009) and subsequent lack of meaningful comparison data. However, Simponi claims and days supply climbed monthly and volumes remain relatively low compared with other drugs in the class (Table 3). 388 The American Journal of Pharmacy Benefits November 2010 www.ajpblive.com

2009 Drug Utilization and Cost Trends: Tumor Necrosis Factor Inhibitors Table 2. Selected FDA Indications FDA Indications a Enbrel Humira Simponi Remicade Cimzia Reduce symptoms of moderate to severe rheumatoid arthritis in adults b b c b Reduce symptoms of psoriatic arthritis b b Reduce symptoms of moderate to severe polyarticular juvenile idiopathic arthritis d e Reduce symptoms of ankylosing spondylitis b b Reduce symptoms of moderate to severe Crohn s disease b Reduce symptoms of moderate to severe plaque psoriasis b b b Reduce symptoms of moderate to severe ulcerative colitis b FDA indicates US Food and Drug Administration. a Not a complete description of indications. See prescribing information for details. b Indicated for adults. c When used in conjunction with methotrexate. d For patients 2 years and older. e For patients 4 years and older. Source: Reference 24. Change in Claims. Overall claims PMPM increased 10.9% YOY, led by Humira, which had a 22.4% increase in claims PMPM. Market leader Enbrel had a decrease of 0.6%. Remicade prescription claims increased 8.2%, and both Cimzia and Simponi had increasing claim volumes month-over-month. Cost. The 16.2% gross trend in 2009 was primarily attributable to the substantial increase in utilization of Humira, which also had an increase of $2.36 in the average gross cost per day, to $62.55 (Figure 1). Remicade (-6.8%) and Cimzia (-8.8%) had a decrease in gross cost per day trend in 2009, which acted to moderate gross costs. Market Share In the combined class, Enbrel currently controls the market with a 53.9% market share, followed by Humira at 41.6%. In 2009, however, Enbrel lost 5.7% of the market share and Humira gained 3.4%. Despite a decline in the Enbrel prescription market share, days supply increased. The change was attributable to increasing volumes for Humira, which outpaced those of Enbrel. As of the fourth quarter 2009, Humira market penetration continued to increase on a quarterly basis. The remaining players Remicade, Cimzia, and Simponi hold a combined 4.5% market share, collectively gaining 2.2% share YOY (Figure 2). ANALYSIS AND DISCUSSION The combined class had a 16.2% gross trend for 2009, driven primarily by a 10.0% utilization trend. Both utilization and the 5.7% increase in gross cost per day trend were attributable to increased prescription claims and days supply for Humira. Additionally, Humira had a higher gross cost per day than Enbrel, and it had a YOY increase of 3.9%. More specifically, Humira days supply PMPM increased 19.8% and claims PMPM increased 22.4% in 2009. Enbrel contributed to rising gross costs because its gross cost per day increased 7.2%, while experiencing a marginal decrease in days supply PMPM of -0.5%. The remaining drugs in the class had low volumes and a combined 4.5% market share, but all had a significant percent increase YOY. Remicade and Cimzia had declines in gross cost per day YOY of 6.8% and 8.9%, respectively. These had little effect on the overall gross trend. According to the American College of Rheumatology, patients with an established diagnosis of RA should begin treatment with DMARDs such as methotrexate or Arava (leflunomide). For patients with more significant disease, medications referred to as biologic response modifiers can specifically target parts of the immune system that lead to inflammation and joint and tissue damage. These include the TNF-inhibiting drugs, which also are DMARDs, because they slow the progression of the disease. 13 Table 3. Percent Change in Utilization by Drug % Change YOY by Drug a (PMPM) Rank (Gross) Drug Name Claims, % Days, % 1 Enbrel 0.6 0.5 2 Humira 22.4 19.8 3 Remicade 8.2 20.6 4 Cimzia b b 5 Simponi c c Class total 10.9 10.0 PMPM indicates per member per month; YOY, year over year. a Twelve-month comparison (January-December 2008 vs January-December 2009). b Denotes misleading (high) growth rate due to low prior-year volumes. c Cannot calculate growth due to lack of prior-year prescription claims. Source: CVS Caremark BOB Metrics 2009 Trend Cohort Excluding Medicare Part D (January-December 2008 vs January-December 2009). www.ajpblive.com Vol. 2, No. 6 The American Journal of Pharmacy Benefits 389

n Theodorou Johnson Szychowski Figure 1. Gross Cost per Day by Drug $ $57.13 $61.26 $60.19 $62.55 $98.21 $91.57 Enbrel Humira Remicade Cimzia Period ending December 2008 Period ending December 2009 $77.10 $70.28 Source: CVS Caremark BOB Metrics 2009 Trend Cohort Excluding Medicare Part D (January-December 2008 vs January-December 2009). Study results presented at the annual European Congress of Rheumatology in June 2010 showed that TNF inhibitors significantly reduced joint damage progression by 61% in RA patients after 2 years compared with conventional DMARD treatment. 14 In another study, researchers presented findings that TNF inhibitors appear to constrain the radiographic progression of damage to large, weight-bearing joints in RA patients who have lowgrade damage scores. The findings are important, because although TNF-blocking therapy has been shown to inhibit disease progression in smaller joints of the hands and feet, its effects on large, weight-bearing joints have been unclear until now. The findings of this study also suggest that at least in certain patients with lower-grade damage and lower disease activity TNF inhibitors may be effective for halting and even reversing joint damage. 15 Contributing to growth in TNF inhibitor utilization is a Figure 2. Market Share by Drug (Days Supply), Period Ending December 2009 Simponi 1.0% Cimzia 1.2% Enbrel 53.9% Remicade 2.3% Humira 41.6% Source: CVS Caremark BOB Metrics 2009 Trend Cohort Excluding Medicare Part D (January-December 2008 vs January-December 2009). growing trend toward earlier utilization. Rheumatologists and clinicians are taking an aggressive approach to possibly reduce damage and create permanent change via remission of the disease. 16 In other recent study results, patients with moderate to severe Crohn s disease who received a combination of Remicade (infliximab) plus azathioprine or Remicade alone were more likely to have a corticosteroid-free clinical remission than those treated with azathioprine alone, according to researchers at the Mayo Clinic, who said the new finding promises to change current treatment of Crohn s disease. After 26 weeks, 56.8% of those getting combination therapy had complete remission of symptoms, compared with 44.4% of those getting only infliximab and 30% of those getting only azathioprine. Currently, the first-line therapy for Crohn s disease is steroids, followed by azathioprine if the steroids do not provide relief. If that treatment fails, newer biologics such as Remicade are tried. Researchers said the trial showed that azathioprine monotherapy should be skipped altogether in favor of a regimen containing a biologic and that combination therapy with both azathioprine and Remicade appears to be the treatment of choice if steroids are not effective. 17 According to a recent report published by Decision Resources, 63% of surveyed gastroenterologists prescribe Humira (adalimumab) off-label for the treatment of ulcerative colitis. The surveyed gastroenterologists added that they most often prescribe Humira for patients who have experienced loss of response, intolerance, or no response to Remicade (infliximab), the mainstay treatment for the disease. Analysis of patient-level claims data revealed that Humira also is being prescribed in a minority of instances as first- or second-line ulcerative colitis therapy. Estimates by the surveyed gastroenterologists of their use of the top-selling anti-inflammatory by line of therapy support the early-line use of Humira that was observed in these patient-level claims, as the clinicians estimated that more than one-third of their Humira prescriptions in ulcerative colitis were for first- or second-line therapy. 18 In January 2009, Abbott Laboratories reported 2008 global sales of $1.3 billion for Humira. 11 During an investor call to present quarterly financial data in July 2009, the company announced that Humira had captured 45% of the market for Crohn s disease and 35% for dermatology indications, a 20% gain since psoriasis was added to the label in January 2008. Abbott s growth strategy for Humira involves adding both ulcerative colitis and pediatric Crohn s disease to the label. 19 Humira s approved indication for the treatment of moderate to severe Crohn s disease may be 390 The American Journal of Pharmacy Benefits November 2010 www.ajpblive.com

2009 Drug Utilization and Cost Trends: Tumor Necrosis Factor Inhibitors a potential contributor to the drug s growth in volume in 2009 versus that of Enbrel. Further, given Abbott s pursuit of supplemental indications for Humira, potential FDA approval may induce greater market share penetration as well as influencing higher overall class gross costs. In July 2010, Abbott reported that total sales of Humira rose 2.15% in the second quarter of 2010 to reach $1.59 billion. A recent study by EvaluatePharma forecast that by 2016 Humira will be the world s top-selling drug, with sales growing 9% a year to total $10.1 billion in that year. 20 For Medicare patients, Humira and Enbrel usually fall under the Part D benefit for prescription drugs, while Remicade (infused drug) is covered under Part B, which helps cover doctor visits and outpatient care. Because of the administration method, Remicade is costlier, but patients on Medicare can be attracted to it in order to avoid falling into the Part D donut hole. 21 Biogeneric Availability A May 2009 report from the Generic Pharmaceutical Association found that spending on biologics is expected to increase by 18% to 21% annually, and will exceed $100 billion by 2011. By 2012, according to the Generic Pharmaceutical Association report, nearly half of all newly approved prescription drug products are expected to be biologics. 22 Additionally, biosimilars are expected to be priced initially at least 25%-30% below the reference branded biologic drug. 23 Hospira is set to begin the early phase of a clinical study on a biosimilar version of Amgen s Epogen (epoetin alfa) in anemic patients with renal dysfunction. The biogeneric, marketed as Retacrit in Europe, will be tested at 20 hemodialysis centers nationwide. Biotechnology drugs in biosimilar forms are unavailable domestically because they were not part of the 1984 landmark Hatch-Waxman law that provided a pathway for approval of generic drugs. This law generally applies to products derived only from chemicals. These drugs are more complex to make, and the new health reform law requires lengthy clinical trials before they are approved in less expensive biosimilar form. Despite the challenges, the new law does clear a path for the FDA to approve biosimilar versions of brand-name biotechnology drugs. To date, the FDA has not established guidance to drug makers on how the approval process will work, given that the law was enacted only in March 2010. But the agency is allowing Hospira to begin clinical trials. 24 CONCLUSION Tumor necrosis factor inhibitors are projected to comprise the largest portion of specialty drug spending in 2010 and 2011 because of broad efficacy and the scope of their approved indications, combined with changing prescribing patterns that include earlier and off-label use, which effectively increases utilization. Additionally, no near-term biosimilars are anticipated, and historic doubledigit manufacturer price inflation is likely to contribute to a high gross trend in 2010 and 2011. Author Affiliations: From the Division of Analytics & Outcomes (AAT, KMJ, JAS), CVS Caremark, Scottsdale, AZ. Funding Source: None reported. Author Disclosure: The authors (AAT, KMJ, JAS) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of CVS Caremark. Address correspondence to: Anna A. Theodorou, RPh, MBA, Director, Industry Analytics & Outcomes, CVS Caremark, 9501 East Shea Blvd, Mail Code #034, Scottsdale, AZ 85260. E-mail: anna.theodorou@ caremark.com. REFERENCES 1. Gatyas G. IMS Health reports U.S. prescription sales grew 5.1 percent in 2009 to $300.3 billion. April 1, 2010. http://www.imshealth.com/portal/site/imshealth/ menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=d690a27e9d5b 7210VgnVCM100000ed152ca2RCRD&vgnextfmt=default. Accessed August 23, 2010. 2. Theodorou AA, Johnson KM, Ruf S, Szychowski JA. Prescription utilization by multiple sclerosis patients in the United States. Am J Pharm Benefits. 2010;2(2): 147-151. 3. Theodorou AA, Johnson KM, Wade T. Antineoplastic enzyme inhibitor drug trend utilization in the United States. Am J Pharm Benefits. 2010;2(3):231-234. 4. 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n Theodorou Johnson Szychowski 16. Commercial Insight: Disease Modification in Rheumatoid Arthritis. DMHC 2448. New York: Datamonitor; January 2009:32. 17. Edelson E. Better treatment found for Crohn s disease. http://news.health. com/2010/04/14/better-treatment-found-crohns-disease/. Accessed September 8, 2010. 18. Taylor L. Gastroenterologists prescribing Humira off-label for ulcerative colitis. PharmaTimes. August 9, 2010. 19. Haas J. With strong Humira sales growth, Abbott is bullish on its second quarter results. The Pink Sheet. July 15, 2009. 20. Diller W. Market snapshot: anti-tnfs grow despite tough market. The Pink Sheet. December 8, 2008;70(049):18. 21. Generic Pharmaceutical Association. Economic analysis of generic pharmaceuticals 1999-2008: $734 billion in health care savings. May 2009:10-11. 22. Generic Pharmaceutical Association. Economic analysis of generic pharmaceuticals 1999-2008: $734 billion in health care savings. May 2009:11. 23. Japsen B. Hospira to test generic anemia drug. Chicago Tribune. July 28, 2010. 24. US National Library of Medicine. About DailyMed. http://dailymed.nlm.nih.gov/ dailymed/about.cfm. Accessed August 24, 2010. 392 The American Journal of Pharmacy Benefits November 2010 www.ajpblive.com