Biologics Becoming More Popular in Treating Chronic Diseases

St. Louis—At a satellite symposium at the AMCP meeting, a trio of speakers discussed the use of biologics in chronic diseases as well as the different pharmacy benefit designs, opportunities, challenges, trends, and costs associated with the drugs. The symposium was titled Evolving Role in the Treatment of Chronic Diseases: Value-Driven Benefit Design and Utilization Management Strategies. Kenneth Schaecher, MD, FACP, CPC, medical director of SelectHealth and attending physician of internal medicine at the Granger Medical Clinic in Salt Lake City, Utah, began the session by focusing on the following disease states treated with biologics: ulcerative colitis (UC), Crohn’s disease (CD), rheumatoid arthritis (RA), and psoriasis/psoriatic arthritis (PA). UC, which includes recurring episodes of inflammation limited to the mucosal layer of the colon, is 1 of 2 major causes of inflammatory bowel disease in North America and has an incidence rate of 2.2 to 14.3 cases per 100,000 person-years. Dr. Schaecher mentioned UC has a higher incidence rate in the Jewish population and a lower incidence rate in African Americans and Hispanics when compared with Caucasians. Because of the duration and extent of UC, the disease is associated with an increased risk of contracting colon cancer. The incidence of colon cancer increases relative to the general population 7 to 8 years after disease onset in patients with disease beyond the splenic flexure. Dr. Schaecher described the risk as increasing 0.5% per year. Patients with mild-to-moderate UC are typically treated with 5-aminosalicylate (5-ASA) and corticosteroids, while those with severe or recalcitrant disease receive cyclosporine. Ulcerative proctitis (UP) and left-sided colitis are usually treated with topical therapy, whereas extensive colitis and pancolitis are treated orally. In patients with UP, symptomatic improvement is typically seen within 3 to 4 weeks. Dr. Schaecher cited studies showing remission rates for UP were as high as 93%, while remission was maintained in 75% of the patients. In left-sided colitis, 5-ASA agents exert their maximum benefit within 3 to 6 weeks, whereas prednisone is effective within 10 to 14 days. Dr. Schaecher said prednisone should only be considered for patients with severe clinical presentation. CD is the other major cause of irritable bowel disease (IBD) in North America and affects the transmural inflammation of the gastrointestinal tract. Incidence rates in North America range from 3.1 to 14.6 cases per 100,000 person-years. Dr. Schaecher cited several studies that have demonstrated a negative correlation between smoking and UC, but a positive correlation between smoking and CD recurrence. In addition, genetic factors may be more important in contracting CD than UC. Standard therapy for CD and UC is similar. However, systemic antibiotics and probiotics are more commonly used to treat CD. Antibiotics are well established to treat septic complications of IBD such as abscesses and wound infections, but their benefit in treating primary disease processes of CD and UC has not been well established in clinical trials, according to Dr. Schaecher. Meanwhile, limited clinical trials have shown probiotic species (alone or in combination) can prevent recurrent intestinal inflammation and may treat active IBD. To treat IBD, researchers are exploring multiple biologically active agents, with 2 categories of agents gaining US Food and Drug Administration (FDA) approval: tumor necrosis factor (TNF)-alpha inhibitors and monoclonal antibodies against the cellular adhesion molecule alpha4-integrin. Infliximab is the only FDA-approved biologic for both UC and CD, while certolizumab, adalimumab, and natalizumab are FDA-approved to treat CD. In patients with moderate-to-severe CD, TNF-alpha inhibitors play a crucial role in the pathogenesis of mucosal inflammation. TNF-alpha inhibitors are also effective in patients with prominent symptoms such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, and anemia. Dr. Schaecher said studies evaluating the efficacy of infliximab, adalimumab, and certolizumab have shown similar results, although no study has compared the treatments. He also mentioned the decision to use one of the treatments is based on the convenience of subcutaneous administration in adalimumab and certolizumab compared with the larger data concerning infliximab’s safety and efficacy. Adalimumab and certolizumab require administration every 2 weeks, while infliximab is administered every 4 weeks. Infliximab and adalimumab are approved for reducing signs and symptoms of CD and inducing and maintaining clinical remission, while certolizumab does not have a maintenance indication. In addition, certolizumab’s labeling requires it to be reconstituted by a healthcare professional, although the drug’s manufacturer is implementing a program that uses a home nursing service to dispatch a healthcare professional to the patient’s home. Natalizumab is only available through CD-Touch, a restricting prescribing program, and is used to induce and maintain clinical response and remission. The drug is intended for adult patients with moderately to severely active CD with evidence of inflammation who have had an inadequate response to or are unable to tolerate conventional CD therapies and TNF-alpha inhibitors. It is approved in the United States but not in Europe. Next, Dr. Schaecher spoke about RA, a chronic, systemic, inflammatory disorder primarily affecting joints that has an incidence of approximately 30 per 100,000 population. Women are affected 2 to 3 times more than men, and RA can occur at any age, although peak onset is 30 to 55 years of age. Contributing factors associated with RA include cigarette smoking as well as genetics. Researchers have identified 3 patterns of RA in patients: nearly 10% have prolonged clinical remissions, and the prognosis for good function is excellent; approximately 15% to 30% have intermittent disease characterized by partial to complete remissions without the need for continuous therapy, with remissions lasting ≤1 year and remissions often involving additional joints; and the remaining patients have progressive disease that can lead to joint destruction and disability. There are 5 main classes of drugs used to treat RA: analgesics, nonsteroidal anti-inflammatory drugs, glucocorticoids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs. The American College of Rheumatology (ACR) recommends using nonbiologic and biologic DMARDs based on disease duration, disease activity, and prognostic factors. ACR guidelines divide the use of biologic DMARDs into those for patients with RA for 6 months and those without RA for 6 months. They are also separated into low or moderate disease activity for 6 months and high disease activity for 3 months and for 3 to 6 months. Currently, there are 9 FDA-approved biologic agents used to treat RA: etanercept, infliximab, anakinra, adalimumab, abatacept, rituximab, golimumab, certolizumab pegol, and tocilizumab. Dr. Schaecher cautioned that there is a lack of data to determine the best agent to use and said the best results have been found when using biologic agents in combination with nonbiologic DMARDs, particularly methotrexate (MTX). He also said biologics should never be used together. Potential adverse events include opportunistic infections and possible increased risk of malignancies. Dr. Schaecher then discussed psoriasis, a chronic skin disorder typically characterized by erythematous papules and plaques with a silver scale. The estimated prevalence of psoriasis in the United States is 2.5% in Caucasians and 1.3% in African Americans. The disease affects men and women equally. Risk factors for psoriasis include infection, physical or psychological stress, medications, smoking, obesity, and alcohol consumption. Remissions are seen in approximately 25% of patients with psoriasis, and <33% of patients with psoriasis have PA. In approximately 15% of PA cases, arthritis precedes the skin disease. Patients with limited or mild-to-moderate psoriasis typically are treated with topical agents, while patients with moderate-to-severe disease may need systemic therapy. Moderate-to-severe psoriasis is typically defined as involving >5% to 10% of the body surface area or involving the face, palm, or sole, or disease that is otherwise disabling. Topical agents used to treat psoriasis include emollients, corticosteroids, topical vitamin D analogs, tar, tazarotene, and calcineurin inhibitors. Systemic therapies include nonbiologic agents, such as MTX, and biologics, such as alefacept, efalizumab, etanercept, infliximab, adalimumab, and ustekinumab. Biologics are usually reserved for severe or recalcitrant psoriasis. Dr. Schaecher mentioned that the only trial comparing the efficacy of biologic versus conventional systemic treatment for psoriasis indicated that adalimumab had significantly higher efficacy than MTX. Managed Care Pharmacy Implications Diana Brixner, RPh, PhD, professor and chair of the department of pharmacotherapy and executive director of the Outcomes Research Center at the University of Utah, spoke on Major Challenges and Opportunities for Managed Care Pharmacy. Dr. Brixner cited a May 2010 Kaiser Family Foundation report indicating that prescription drug spending in the United States is projected to increase from $234.1 billion in 2008 to $457.8 billion in 2019. Drug spending as a percent of overall national health spending is projected to increase from 10.0% in 2008 to 10.2% in 2019. To assess value for reimbursement decisions, Dr. Brixner mentioned 5 categories to consider: the scope and impact of the disease, the size of the market for treatment options, the efficacy and safety of the therapy, the cost and cost-effectiveness versus current alternative therapies, and the cost per outcome as a measure of value. Citing a PharMetrics Patient-Centric Database from 2003 to 2004, Dr. Brixner mentioned the mean annual total cost for CD was $8256 per patient, while the mean annual total cost for UC was $5066 per patient. The costs included direct, outpatient, and pharmaceutical costs. The same database indicated infliximab was the most costly medication. Approximately 10% of patients with CD had ≥2 claims for infliximab infusions. In addition, Dr. Brixner cited a study analyzing the costs associated with CD and UC. In CD, 35.3% of costs were attributed to outpatient medications, 33.3% to outpatient services, 19.0% to medical hospitalizations, and 12.4% to surgical hospitalizations. In UC, 34.9% of costs were attributed to outpatient services, 27.5% to outpatient medications, 21.7% to medical hospitalizations, and 15.9% to surgical hospitalizations. Dr. Brixner also mentioned a 56-week study from a US payer perspective comparing the cost-utility of adalimumab and infliximab maintenance therapies for treating moderately to severely active CD. Hospital admissions were 34% to 40% lower for patients taking adalimumab than for those taking infliximab. Patients treated with adalimumab also had larger expected quality-adjusted life-years (0.014; 95% confidence interval [CI], 0.000-0.022) and lower costs (–$4852; 95% CI, –$6758 to $491) in the first year of therapy than those treated with infliximab. For RA costs, Dr. Brixner cited a National Data Bank database from 1999 to 2001 that estimated direct medical care costs at $9519 per year. Drug costs accounted for $6324 of the total direct medical costs, while hospitalization costs accounted for $1573. The same database found that annual direct costs for patients with biologics were $19,016, while the annual direct costs for patients without biologics was $6164. Approximately 25% of patients took biologics. Among the studies Dr. Brixner discussed was a 6-month decision-analysis model in which patients were treated with MTX, etanercept, leflunomide, sulfasalazine (SSZ), or no second-line agent. The trial used the ACR20 criteria, defined as ≥20% improvement in tender and swollen joint counts and ≥20% improvement in 3 of 5 other core set measures (patient global assessment, physician global assessment, physical disability score, acute reactant value, and patient assessment of pain). MTX and SSZ cost less and were more effective than no second-line agent, while leflunomide was more expensive and was less efficacious than SSZ. Etanercept was the most efficacious option and cost $41,900 per ACR20 and $40,800 per ACR70 when compared with MTX and SSZ. For psoriasis and PA costs, Dr. Brixner used a 2002 study that estimated total direct costs as $649.6 million: approximately $30.5 million for hospitalizations, $86.6 million for outpatient physician visits, $27.4 million for photochemotherapy, $147.9 million for dermatologic prescription drugs, and $357.2 million for over-the-counter drugs. The annual per patient cost was $452 in patients with clinically significant psoriasis and $718 in patients with active psoriasis. To illustrate the cost-effectiveness of biologic treatments for psoriasis, Dr. Brixner cited a review study from a third-party payer perspective that had a 12-week treatment period and studied the following drugs in various doses: etanercept, infliximab, adalimumab, efalizumab, and alefacept. Efficacy was measured by mean Dermatology Life Quality Index (DLQI) improvement as well as a 75% reduction in baseline psoriasis area and severity index score. The researchers found a minimally important difference in the cost per patient achieving DLQI. The most cost-effective agent was 25 mg of etanercept taken once per week. The next most cost-effective agents were infliximab (3 mg/kg for 3 infusions), adalimumab (40 mg every other week), and etanercept (25 mg twice weekly). Infliximab (3 mg/kg for 3 infusions) was the most cost-effective agent based on cost per patient achieving PASI-75 improvement. The next most cost-effective agents were infliximab (5 mg/kg for 3 infusions) and adalimumab (40 mg every other week). Dr. Brixner also discussed osteoarthritis (OA), which is caused by a loss of cartilage and is the most common form of arthritis. In the United States, nearly 27 million people (12.1% of adults) have OA. The joints of the hands, knees, and hips are the most commonly affected sites, with OA of the knee and hip most frequently associated with symptomatic, painful disease. Dr. Brixner cited a claims database of 5 million privately insured individuals from 2003 to 2004 to illustrate OA’s costs. The annual direct medical cost was $8601, including an annual direct drug cost of $2941 and annual indirect work-loss costs of $4603. She also cited the Medical Expenditure Panel Survey taken from 1996 to 2005 that determined the annual medical care expenditures for OA were $185.5 billion. Insurer expenditures were $149.4 billion, while out-of-pocket expenditures were $36.1 billion. Dr. Brixner also spoke about an article in June on Pfizer halting a 10-trial, phase 3 program involving >7000 patients for tanezumab because a small number of patients experienced worsening OA, leading to joint replacement. One financial research analyst mentioned in the article said that some pain specialists speculate that tanezumab could lead to rapid joint deterioration because it masks moderate-to-severe OA. The use of biologics present several opportunities, according to Dr. Brixner, including improved efficacy, improved patient outcomes (activities of daily living and quality of life), and improved tolerability profiles. However, biologics also present challenges, among them: cost-effectiveness studies have indicated mixed results; the results must be validated in a health plan; the impact of rebates and benefit design is mostly unknown before implementation; and they have mostly quality-of-life end points, which may not be relevant to health plans. Management of Specialty Drugs Douglas Burgoyne, PharmD, RPh, chief pharmacy officer for Prodigy Health Group and Scrip World, was the final speaker. He discussed prescription trends, benefit design, and utilization management. In 2009, the market for prescription drugs in the United States exceeded $300 billion, an increase of 5.1% over 2008. Retail channels accounted for 71.7% of the market: chains had a 35.1% share, mail service had a 17.1% share, independents had a 12.4% share, and food stores had a 7.0% share. In addition, clinics accounted for 11.5%, and hospitals accounted for 10.6%. Third parties paid for 63.4% of prescriptions, Medicare Part D paid for 19.2%, Medicaid paid for 7.9%, and 9.5% were paid in cash. Dr. Burgoyne defined specialty drugs as injectable or noninjectable drugs that have ≥1 of the following characteristics: limited or exclusive product availability and/or distribution, specialized handling and/or administration requirements, cost exceeding $500 for a 30-day supply, frequent dosing changes and exacting patient training, and extensive clinical monitoring to decrease the potential for drug toxicity and increase the probability for beneficial clinical outcomes. In 2009, the generic drug market and the biotech drug market each increased 10.7%, while brands (excluding branded generics) grew by 3.5%. In addition, the member share of total drug costs decreased from 21.2% in 2008 to 20.5% in 2009, according to an Express Scripts 2009 Drug Trend Report that Dr. Burgoyne cited. Many employers include specialty drugs in their standard benefit design or cap the maximum copayment or coinsurance at $85 to $200 per month. Thus, specialty drugs have a low member share of cost (2.6% of the drug’s cost). Some employers have increased the member cost-share by including specialty drugs on a fourth tier with or without a cap on maximum copayment or coinsurance. Dr. Burgoyne warned that not having a cap risks member affordability and suggested health plans balance plan affordability with member affordability. Specialty drugs are also either a medical or pharmacy benefit, depending on the plan. “We’ve been debating this a lot,” Dr. Burgoyne said. “Is it best to put them in specialty pharmacy? Is it best to keep them in medical?” If specialty drugs are termed a medical benefit, they are either included in the office visit copayment, charged separately from the office copayment, or included in pharmacy through the medical benefit, which requires a specialty pharmacy to dispense and increases physician administration fee payment. If specialty drugs are in the pharmacy benefit, they can be available through retail, mail order, long-term care, or specialty pharmacies. Dr. Burgoyne finished his presentation by discussing utilization management (UM). He said the top medical categories for traditional UM were cancer, congestive heart failure, diabetes, asthma, hepatitis, blood disorders, and rare conditions. UM is also focused on the disease state and not medication therapy management. Dr. Burgoyne said UM should include specialty drug management, too. In general, UM focuses on adherence and persistence, which Dr. Burgoyne said could pose unique challenges for specialty drugs. Many people purchase specialty drugs but do not use them appropriately, leading to waste and poor outcomes. Dr. Burgoyne suggested sending one half of the prescribed quantity first and then evaluating the tolerability and effectiveness before sending the remaining half. To improve adherence, Dr. Burgoyne mentioned clinicians could call members at predetermined times in the fill cycle to set care expectations and explain the drug’s side effects.¬—Tim Casey