Anna A. Theodorou, RPh, MBA

The use of specialty medications to treat an expanding number of conditions is growing at an impressive rate. As evidence of this, in 2010, only 3 specialty agents were in the list of top 10 drugs by revenue (representing 26%).

 By 2016, it is projected that 7 of the top 10 revenue drugs in the United States will be specialty agents (69% of revenue).

 This fact, along with the realization that hundreds of products are in the specialty pipeline awaiting approval, speaks to the need for more rigorous specialty management, especially for those drugs being utilized within the medical benefi t that are often unseen and unmanaged.1 Oral oncology is one example of a growing component of specialty that will shift drug use and fulfillment out of the medical benefit and place it into the pharmacy benefit. Insurers generally place oral oncology drugs under a patient’s pharmacy benefit; therefore, they are dispensed either within a retail setting or from a specialty pharmacy. It is to this end that these agents have become a focus of pharmacy benefit managers and pharmacy directors of various payers in the marketplace.

As we look back on 2011, we can see that the overall drug trend represented another year of slower gross trend. However, the specialty trend continued to have double digit increases, while nonspecialty had flat or negative movement due to the increase of generic utilization and minimal new molecular entities. Specialty pharmaceuticals continue to play a signifi cant role in drug spending growth. Factors promoting specialty growth include a wave of signifi cant launches and expansion of indications—both factors are increasing the impact to overall trend in drug spend. On a broad level, research and development efforts continue to focus on therapies to treat a wide range of cancers and will affect utilization trends. In addition, there is an increasing focus on oral cancer therapies to augment current injectable treatment options. This analysis will review the class cost, demographic profi le, and utilization trends of the oral antineoplastic enzyme tyrosine/multikinase inhibitor agents.

Cancer continues to be a major public health issue in the United States—1 in 4 deaths can be attributed to cancer.2,3 According to projections for 2012, it is estimated that there will be over 1.6 million new cancer cases and nearly 600,000 deaths from cancer (this figure does not include carcinoma in situ of any site except urinary bladder, nor does it include basal and squamous skin cancers).2 The most common cancers that cause death in men continue to be lung and bronchus, prostate, and colorectal; in women, the most common cancers that cause death are lung and bronchus, breast, and colorectal.

 Based on the experience of the general population, it is estimated that males (45%) have a greater lifetime probability of being diagnosed with an invasive cancer than females (38%).

Based on the most recent 5 years of mortality data (2004-2008), the overall cancer death rate decreased by 1.8% per year in males and 1.6% per year in females.

 Despite a decline in incidence for the major cancer sites, there are several cancers that are increasing—these include human papillomavirus (HPV)-related oropharyngeal cancer, esophageal adenocarcinoma, melanoma of the skin, and cancers of the pancreas, liver, and intrahepatic bile duct, thyroid, kidney, and renal pelvis.

The range of approved indications for currently marketed oral tyrosine/multikinase antineoplastic cancer drugs is shown in 

A retrospective claims analysis was conducted using CVS Caremark’s Book of Business (BOB) trend cohort for Employer and Health Plan clients using year to date (YTD) September 2011 versus YTD September 2010 claims data. The trend cohort clients represent CVS Caremark clients that have had a stable membership (variations not exceeding ± 20%) for at least 2 years. The Employer and Health Plan portion of the trend cohort represents 22 million lives. The cost per day and utilization trends were analyzed for selected oral antineoplastic enzyme inhibitor agents: imatinib (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey), sorafenib (Nexavar, Bayer Health-Care Pharmaceuticals Inc, Wayne, New Jersey), dasatinib (Sprycel, Bristol-Myers Squibb Company, Princeton, New Jersey), sunitinib malate (Sutent, Pfizer Inc, New York, New York), erlotinib (Tarceva, OSI Pharmaceuticals, LLC, Farmingdale, New York), and nilotinib (Tasigna, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey) (see Table 1 for a listing of selected US Food and Drug Administration—approved indications).

While many of the selected oral antineoplastic agents have seen a decrease in utilizers, dasatinib and nilotinib have seen a significant bump in utilizers when comparing YTD September 2010 with YTD September 2011 (

). All the oral antineoplastic tyrosine/multikinase inhibitors have seen an increase in the cost per claim during the same time period. 

 shows the demographic breakdown of utilizers for the selected agents.

While oral therapy oncology treatment adds convenience, it is not without serious concerns regarding patient monitoring and adherence. Although oral cancer drugs have been available in the marketplace for decades (eg, tamoxifen, methotrexate), there has been a rapid expansion in the last few years of new agents. This expansion raises serious concerns regarding adherence because their use shifts the site of drug administration from physician-monitored settings to the patient’s home. Due to the assumed perceived seriousness of a cancer diagnosis, some may believe that adherence would automatically be greater within this population and therefore not require intense monitoring, but that is not the case. In fact, adherence may even be lower than the 50% rate projected by the World Health Organization across all medication classes.

 One major reason for this is the reduced exposure to physicians and physician office staff oversight for patients administering oral drugs at home compared with patients taking their oncology medications intravenously. In general, there is a lack of infrastructure within physician offi ces to monitor proper administration of oral agents for patients at their home setting. This reduction in medical oversight involved in administration results in additional responsibility being placed on the patient to correctly adhere to and take his or her medication regimen. This problem was summed up well by Dr Ronald Walters of MD Anderson Cancer Center in Houston, Texas, when he stated that there is a “diffusion of responsibility that goes on in an oral chemotherapyprescription.”

Oral Oncology and Challenges to Adherence

According to a recent National Comprehensive Cancer Network task force report, one-fourth of all chemotherapeutic agents in development are expected to have an oral route of administration. Oral agents have transformed care for many patients, replacing long sessions in physicians’ offices for medication infusion services. Still, it is important that no distinction be set between oral and intravenous (IV) chemotherapy in terms of care, patient education, or monitoring.6 One important way to ensure this is to designate oral oncology drugs as specialty medications within the prescription benefit so that the same level of care coordination is provided to these agents as to their infused or injected counterparts. Oral oncology medications can be considered specialty because of several reasons, including the following: their use is associated with a chronic or complex disease state; they are generally high cost; they are part of a therapeutic class generally accepted as a specialty class; they carry the potential for highly prevalent and severe side effects; they often require advanced monitoring to avoid or identify serious adverse events; they require a considerable degree of administrative complexity for the patient; and regular dosing adjustments are possible in response to laboratory results, adverse events, and overall response to treatment.

While using oral oncology medications offers several advantages, not the least of which is convenience and the potential for less intense side effects compared with IV therapy, many issues can contribute to noncompliance within this population. Some important considerations when assessing a patient’s adherence to an oral oncology medication regimen include the patient’s education level regarding their regimen, diagnosis, and treatment; side effect management, especially now that the patient will have less exposure to healthcare professionals during the administration process; patient forgetfulness; challenges filling finding the medications (some pharmacies may not stock these agents due to their high acquisition costs); and patient out-of-pocket cost, especially for those patients who are subject to the Medicare Part D “donut hole” until catastrophic coverage is activated.

 In addition to these concerns, oral therapy comes with the complex issue of drug-food interactions and the possibility of drug-drug interactions that may differ from the drug’s IV counterpart or alternative.

The importance of even brief interactions with healthcare professionals while on oral oncology therapy can be significant. This is because a patient’s inability to adhere to his or her medication for cancer can negatively affect the treatment outcome. This can result in disease progression and even death. It has been shown that patients who use only 1 pharmacy for their prescription fulfi llment are 5 times less likely to fall off therapy,1 so a simple recommendation to patients would be to consolidate their pharmacy use for improved adherence.

From a class-specific perspective, there are many common and predictable side effects that can be expected with the use of tyrosine/multikinase inhibitors reviewed within this article. Simple recommendations such as avoiding sun exposure and using moisturizers can help manage the majority of patients who will experience some dermatological effect from these agents. Education about other potential side effects such as diarrhea can be appropriately managed with the use of OTC remedies. More serious monitoring for cardiac issues, which is seen with drugs such as sorafenib and sunitinib malate, can also be discussed with patients during prescription fulfi llment by pharmacists.

Another important benefit available to patients is the use of a specialty pharmacy. In general, specialty pharmacies can help facilitate the process of making the patient a more adherent consumer of oral oncology products. This can be accomplished in a number of important ways, such as providing expert consultation through the use of a case manager and clinical staff; delivering medication to the location of the patient’s choosing, often at no additional cost; improving access to medications by facilitating the use of patient assistance programs; creating a personalized care plan with actionable steps the patient can take to help understand the regimen and avoid unnecessary adverse events

; collecting and monitoring relevant laboratory data and therapeutic response parameters; and screening for common, often underreported comorbid events such as depression.

The development of and expanded use for oral oncology agents has given pharmacists and specialty pharmacies a unique opportunity to work with the patient during a critical time of treatment. The pharmacist-patient intervention can involve several facets of care, including the management of side effects, education of the patient on the importance of adherence, and guidance to ensure there is no interruption in treatment.

 It is essential to treat oral oncology no differently from IV therapy in regard to safety and monitoring—this will improve the likelihood of improved health and positive outcomes.

The cost of treatment with oral oncology therapies continues to increase. The oncology pipeline is robust, with a trend in oncology toward additional personalized medicines, as well as a continuation of the trend toward more oral therapies. As more oncology treatment options move from those that are administered in a doctor’s office or clinic to oral agents, we will continue to see the cost shift from the medical benefi t to the pharmacy benefit. Additionally, as more and more patients use oral therapies to treat their cancer, we need to recognize that adherence is an issue that will need to be addressed.

Articles

An overview of the utilization and cost for selected oral antineoplastic agents, with discussion regarding oncology in general, as well as the topic of adherence.

Oral Oncology: Utilization of Selected Oral Antineoplastic Enzyme Inhibitor Agents

Due to warfarin’s (Coumadin and generics) narrow therapeutic index and the need for routine coagulation monitoring that leads to dosage adjustments, therapeutic alternatives to this longtime standard of care have been widely anticipated.

Recent entrants into the oral anticoagulant class have given patients and providers additional therapeutic options. The newest oral anticoagulants to come to market are Pradaxa (dabigatran) and Xarelto (rivaroxaban). Unlike warfarin, the most commonly prescribed oral anticoagulant, these newer oral anticoagulants do not require prothrombin time monitoring using international normalization ratio (INR) parameters to determine the clotting tendency of blood.

Keeping the INR in the therapeutic range can be a difficult and expensive process for some patients. If the INR is too high, risk of bleeding increases; if it is too low, there is an increased risk of stroke. British researchers with the Center for Evidence-Based Medicine at the University of Oxford have reported that patients taking warfarin who are able to monitor their own blood and adjust their dosage can reduce the risk of blood clots by half, but at a substantial cost that may offset much of the economic advantages from using the older, less expensive drug.

 Self-monitoring of warfarin involves use of a meter similar to those diabetics use for blood sugar testing. In this case, patients place a drop of blood from a finger prick on a test strip and insert the strip into the device, which reads the INR. The INR monitors cost $1500 to $2500, and strips can run from $7 to $18 per test, according to the National Blood Clot Alliance.

 Insurance coverage depends on the payer and the condition for which warfarin is being used.

While the Oxford-based researchers found that selfmonitoring reduced the risk of stroke or deep vein thrombosis by 49% compared with the standard care involving physician-conducted blood testing, it did not signifi cantly alter the odds of a major bleed or death.

 Of the 3 million Americans currently on warfarin, only about 1% conduct self-monitoring of their INR.

In October 2010, the US Food and Drug Administration (FDA) approved Pradaxa, a direct thrombin inhibitor, to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

 One of the benefits claimed for Pradaxa compared with warfarin is a short half-life in patients without renal dysfunction, which equates to both a quick onset and offset of action.

 The safety of Pradaxa, however, may be compromised in certain clinical situations, such as its use in patients with renal impairment, patients undergoing invasive procedures, and patients exposed to neuraxial anesthesia techniques.

 Additionally, Pradaxa, unlike warfarin, has no pharmacologic antidote to reverse/counter the effects of the drug—which may be problematic in situations where rapid reversal of anticoagulant therapy is required (eg, acute hemorrhagic complications or emergent invasive procedures).

Recent reports present growing evidence that Pradaxa may be associated with a signifi cant number of serious adverse events. According to the QuarterWatch report published by the non-profi t Institute for Safe Medicine Practices, there were 505 cases of Pradaxa-associated hemorrhage reported to the FDA in the fi rst quarter of 2011, more than for any other drug. By way of context, warfarin ranked second with 176 cases. These cases resulted in serious outcomes including death, disability, or hospitalization.

 In addition, a meta-analysis of 7 clinical trials published in the 

 online edition during January 2012 found Pradaxa was “significantly associated with a higher risk of heart attacks and acute coronary syndrome than that seen with agents used in control arms which included warfarin, enoxaparin, or placebo.”

 The growing evidence of a Pradaxa link to serious adverse events could provide a competitive advantage for rival drug Xarelto.

Approved in July 2011, Xarelto is a factor Xa inhibitor that carries the following indications: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (the atrial fibrillation indication was approved in November 2011), and for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.

Xarelto is dosed once daily, while Pradaxa is dosed twice daily— the more convenient dosing schedule would appear to be a commercial advantage for Xarelto.

 Xarelto has a boxed warning to highlight the risks of discontinuing treatment in patients with nonvalvular atrial fi brillation as well as the possibility of spinal/epidural hematoma.

Atrial fibrillation (AF) affects more than 2 million Americans and is one of the most common types of abnormal heart rhythm. The prevalence of this condition is anticipated to increase signifi cantly over the next few decades as the US population ages.

In fact, it is estimated that as many as 12 million people will have AF by 2050. The cost of treating AF is significant. In 2005, the estimated cost of treating AF was $6.65 billion per year, including the costs of hospitalization, in- and outpatient physician care, and medications.

 The 2 most common complications of AF are stroke and heart failure, with AF responsible for 15% to 20% of ischemic strokes.

To determine the switch rate among the oral anticoagulants and to look at utilization of these agents by age band.

This retrospective analysis was conducted using the CVS Caremark Trend cohort, excluding Med-D for YTD September 2011. This retrospective analysis was conducted using prescription claims from the CVS Caremark computerized database. The following agents were included in our analysis: warfarin (generic and brand forms), Xar elto, and Pradaxa. The switch analysis was done by looking back from September 30, 2011, to fi nd the anticoagulant agent prior to the last therapy. If no agent was found in 2011, the patient was determined to be a “new utilizer” of anticoagulant therapy— otherwise, the last anticoagulant agent was determined to be the agent that the member had “switched” from.

A retrospective claims analysis was done using the CVS Caremark Trend cohort for employer and health plan clients, which represents 28 million lives. To be included in the trend cohort, clients must have had stable (not to exceed +/- 20%) membership for at least 2 years, with continuous claim activity over a period of at least 24 months. Looking at data for YTD September 2011, there were 80,373 Pradaxa utilizers, 391 Xarelto utilizers, and 756,727 warfarin utilizers. The cost per claim was much greater for Pradaxa comparatively (

, the majority of utilization across all 3 products falls within the 45 to 64 and 65+ age groups. Interestingly, only 33 percent of Xarelto users fall into the 65+ age band, while Pradaxa and warfarin users of that age represented 73.5 and 63.9 percent of total utilizers respectively.

Looking at the switch rate among the oral anticoagulants (

), we see that the majority of patients switching from a warfarin product to a newer oral agent are switching to Pradaxa. Additionally, the vast majority of patients new to any anticoagulant therapy that chose to use a newer oral anticoagulant are using Pradaxa over Xarelto. There are also many utilizers who switched from Pradaxa to a warfarin product—which could signal issues of tolerability or safety concerns.

The new oral anticoagulants offer improved patient convenience since regular coagulation monitoring is not needed. However, for some patients and clinicians, a monitored oral anticoagulant may be preferable.

There are a number of oral anticoagulant agents in the pipeline, and one product currently under FDA review receiving a lot of attention is Eliquis (apixaban).

 Additional oral anticoagulant agents in the pipeline include: semuloparin, a Factor Xa inhibitor/thrombin inhibitor which is anticipated to launch in the third quarter of 2012; edoxaban, a Factor Xa inhibitor that is anticipated to launch in 2013; and betrixaban, a Factor Xa inhibitor with an unspecifi ed projected launch date.

The availability of oral anticoagulants which do not require coagulation monitoring is a signifi cant advancement in patient care. However, the place of these agents in day-to-day clinical practice has yet to be solidifi ed. As additional oral anticoagulants enter the market, this class will continue to grow and will continue to play a larger part in drug trend since these newer agents are significantly more expensive than traditional warfarin therapy.

New and forthcoming oral anticoagulants, which do not require prothrombin time monitoring, will offer patients and providers additional therapeutic options.

Prescription Utilization of the Oral Anticoagulants

Hepatitis C is a viral disease that causes infl ammation and swelling of the liver, which can lead to diminished function or failure of the organ over time. Most people who are infected are unaware that they have the disease because it is frequently asymptomatic until liver damage occurs, often years after initial exposure to the virus. The disease is the leading cause of liver transplants in the United States.

 Hepatitis develops initially as an acute infection. Of those persons with acute infection, perhaps one-fourth will generate an immunologic response sufficient to clear the virus; the remaining three-fourths cannot do so, resulting in chronic hepatitis C virus (HCV) infection.

 According to the US Centers for Disease Control and Prevention, about 3.2 million Americans have chronic HCV.

Many chronic HCV patients are waiting for a new therapy option. This group includes those who are poor candidates for initiation of treatment with the existing standard of care for any one of several reasons, as well as those nonresponders who failed to achieve sustained virologic response (SVR) following their initial treatment.

In May 2011, the US Food and Drug Administration approved 2 new competing oral protease inhibitors, Vertex Pharmaceuticals’ Incivek (telaprevir) and Merck & Company’s Victrelis (boceprevir), to treat adults with chronic HCV infection who are either treatment naïve or who did not respond to drug therapy. Both Incivek and Victrelis are dosed 3 times daily, and are approved for adjunctive use with pegylated interferon and ribavirin.

Until recently (May 2011), the standard of care for most patients with chronic HCV was a combination of injectable pegylated interferon and oral ribavirin taken for 48 weeks, the goal of which is an SVR, or a suppression of the virus to undetectable levels for at least 24 weeks following the cessation of therapy.

 Achievement of SVR suggests that the virus has been eradicated. The purpose of treating the infection is to reduce the risk of developing long-term complications such as cirrhosis and hepatocellular carcinoma, and to reduce the mortality rate associated with the disease.

The treatment rate for chronic HCV is very low; it is estimated that fewer than one-fourth of chronically infected individuals have been treated. This low treatment rate is partly because many patients with HCV go undiagnosed, but it is also because of insuffi cient infl ammatory activity to merit therapy and the harshness of the interferon regimen.2 Of those patients who do receive the existing standard of care, fewer than 50% respond.

The stated benefit of these 2 new drugs is that they may increase the likelihood of treatment success for patients with genotype 1 hepatitis C infection.

 The 3-drug regimen (pegylated interferon plus ribavirin plus 

Victrelis or Incivek) signifi cantly increases the likelihood of an SVR for patients with genotype 1. The SVR rates with Incivek and Victrelis therapy cannot be directly compared because there have been no head-to-head trials of these agents. However, the SVR rates for the new protease inhibitors are very similar overall.

 Additionally, patients with a good response to the combination HCV regimen containing a protease inhibitor may have a potentially shorter duration of HCV therapy.

Our objectives were to determine what percentage of members receiving therapy for HCV are taking Incivek or Victrelis and to outline the demographic characteristics of these members.

In a retrospective analysis of the CVS Caremark book of business, which represents approximately 41 million members, it was determined that as of September 2011, there were 3151 unique utilizers of HCV therapy. Of those unique utilizers, 46.14% had a regimen containing a protease inhibitor (ie, Incivek or Victrelis) for the treatment of HCV; 257 were taking Victrelis therapy and 1197 were taking Incivek (both agents were being taken in addition to a standard HCV regimen).

 outlines the demographics of members on Incivek or Victrelis therapy. Of the unique utilizers receiving therapy for HCV, 37.99% were on Incivek therapy and 8.16% were on Victrelis therapy. Of the 1454 members on a protease inhibitor for HCV, 17.68% were on Victrelis therapy and 82.32% were on Incivek therapy.

Following approval of Victrelis on May 13, 2011, Merck said that it would be launched to pharmacies within a week at a wholesale acquisition cost (WAC) of $1100 per week,

 dosed for 24 to 44 weeks, while Vertex said that Incivek would carry a WAC of $49,200 for a 12-week course of therapy.

 The WAC for Incivek will be only $800 higher for the course of therapy than the WAC for Victrelis patients who take that drug for 44 weeks. But for Victrelis patients who receive the drug for 24 weeks, the cost will be less than that for Incivek. The duration of treatment with Victrelis, however, is not determined until after starting treatment. Both agents produce a substantially greater SVR rate than that produced by the existing standard of care. Although Incivek and Victrelis have not been tested against each other in a head-to-head study, Incivek produced an SVR rate of 79% in treatment-naïve patients during a phase III trial, compared with 46% for the existing standard of care; and Victrelis produced SVR rates between 63% and 66% in treatment-naïve patients.

Merck also announced that Victrelis would be copromoted by Roche. Merck and Roche are the current market leaders in HCV treatments, with Merck selling PEG-Intron (pegylated interferon alfa 2b) and Rebetol (ribavirin), and Roche marketing Pegasys (pegylated interferon alfa 2A) and Copegus (ribavirin). In addition to the Merck and Roche branded versions, ribavirin also is available in generic form.

Incivek, however, was approved with labeling advantages that have enabled it to win a majority of the available market versus Victrelis.

 Incivek received a label that will enable an estimated 60% of patients (treatment-naïve and prior relapsers who achieved early rapid viral response) to receive the drug under a response-guided therapy regimen. A response-guided therapy regimen entails a 12- week course of Incivek plus the existing standard of care (pegylated interferon [which is self-injected once weekly during the treatment period] and ribavirin [an oral pill taken twice daily during the treatment period]),

 followed by another 12 weeks on standard of care. Patients who don’t qualify for that regimen will receive Incivek for 12 weeks with the standard of care, followed by another 36 weeks on standard of care alone.

Cost-Effectiveness Study Supports Limiting Incivek Use

A recent cost-effectiveness study conducted by Duke University researchers could support the limitation of first-line use of Incivek to those HCV patients who stand to benefi t the most, based on genetic testing.

 The study suggests that treatment-naïve genotype 1 patients who have the CC type IL28B polymorphism would do just as well on the existing standard-of-care treatment (pegylated interferon/ribavirin), which costs far less than either Incivek or Victrelis. Study results show that those with the CC type IL28B polymorphism respond well to standard of care, whereas those with the TT type tend to respond poorly and those with the CT type have a mixed response. About 65% of patients have either the TT or CT alleles. The existing standard-of-care treatment costs from $18,000 to $36,000, researchers noted; adding Incivek increases the cost to between $67,000 and $85,000, while adding Victrelis results in a total cost ranging from $47,000 to $71,000.

Leading up to the approval and launch of Victrelis and Incivek, some market analysts predicted that Incivek could outsell Victrelis on the basis of superior effi cacy and a shorter duration of therapy for many patients.

 The actual inequality in third-quarter sales of the 2 drugs has been surprising, however, as Incivek posted net sales of $420 million for the quarter while Victrelis recorded just $31 million in sales.

Vertex said that between 60% and 70% of Incivek prescriptions have been written for patients new to therapy, with the remainder going to patients who avoided the existing standard of care due to the length of therapy and severity of side effects.

 Merck noted that Victrelis is the only protease inhibitor for HCV listed on the Veterans Administration (VA) formulary, and that with 130,000 patients, the VA is the largest single healthcare provider for HCV patients in the country. The VA doctors also can prescribe Incivek for their patients, but under a more complicated, paperwork-intensive process.

Vertex hopes to offset the high price of Incivek by providing it at no cost to uninsured patients with household incomes up to $100,000, through copay assistance for patients with private insurance, and through indirect copay assistance for government-insured patients.

 Its copay assistance program will cover up to 20% of Incivek’s cost for patients with insurance plans that cover Incivek, regardless of income. To help patients covered through government programs or living in Massachusetts (where copay assistance limitations apply), Vertex will make donations to the nonprofit Patient Access Network Foundation, which has a fund to provide copay support for patients on HCV therapy.

 The company expects about 60% of patients to be covered by private insurance and 35% to have government coverage. Merck also offers a copay assistance program for Victrelis, offering patients a discount card that provides assistance of up to $200 off on up to 12 prescriptions of the drug.

The extent to which copay assistance may have an impact on product uptake and market share is diffi cult to gauge. Claims data indicate that a copay has been paid, but not who has paid it. Companies can only suspect coupon use when generic dispensing declines substantially or there is a spike in claims for certain brands.

There is a very active pipeline for HCV therapy. Selected drugs/indications in phase III trials include the following

• Incivek is in phase III trials for the treatment of genotype 1 chronic HCV in patients with the CC variation near the IL28B gene; approval for this supplemental indication may occur in 2014 if trial results are positive.

• PSI7977 is a DNA polymerase inhibitor in phase III trials for the treatment of HCV infection in combination with ribavirin. If approved, this agent is anticipated to launch in the second half of 2014.

• BI201335 is a protease inhibitor in phase III trials for the treatment of chronic HCV infection in combination with pegylated interferon-alfa 2a and ribavirin. If approved, this agent is anticipated to be available in 2015.

• Simeprevir is in phase III trials for the treatment of genotype 1 chronic HCV in combination with pegylated interferon and ribavirin. If approved, this agent is anticipated to become available in 2014.

Of the patients currently taking a regimen for the treatment of HCV, 46.14% were being treated with either Incivek or Victrelis. A larger percentage (82.32%) of members on HCV therapy containing a protease inhibitor were reasons for this are not entirely clear, Incivek’s more rapid uptake could have to do with a perception of superior efficacy coupled with its approval for use in a response-guided therapy regimen. The strong uptake of both agents in a short period of time is an indicator that this disease state is primed for new therapeutic options. The active pipeline for the treatment of HCV will have an impact on trend for a number of years to come.

Incivek and Victrelis, approved for Hepatitis C within weeks of each other in May 2011, look to change the way the disease is treated.

Initial Prescription Utilization of the New Hepatitis C Agents

Multiple sclerosis (MS) is a chronic, unpredictable, often disabling disease in which the immune system inappropriately attacks the central nervous system (CNS).

 In MS, the immune system attacks myelin, a fatty substance that surrounds and protects the nerve fibers (axons) in the CNS, and the damaged myelin forms scar tissue (a process known as sclerosis).

 When damage occurs to the myelin sheath or nerve fiber, nerve impulses moving to and from the brain and spinal cord are altered or interrupted, producing a wide array of symptoms.

 Multiple sclerosis symptoms vary from person to person and can range from mild to severe. Symptoms are unpredictable and may include numbness in the limbs, paralysis, or loss/distortion of vision.

In the United States, approximately 400,000 people live with MS, and an estimated 2.1 million people worldwide are affected by this disease.

 Most patients (75%) are diagnosed between the ages of 20 and 50 years, with the onset of MS peaking in the early 30s.

 However, MS can appear in young children, teens, and even older adults. MS is 2 to 3 times more common in women than men.

There are 4 types of MS: relapsing-remitting, primaryprogressive, secondary-progressive, and progressiverelapsing. About 85% of patients have relapsing-remitting multiple sclerosis (RRMS) at the time of diagnosis. Some patients with relapsing-remitting disease develop secondary- progressive disease. Secondary-progressive multiple sclerosis starts out as RRMS, followed by continual disease worsening. Patients with secondary progressive MS may have flares, minor remissions, or plateaus.

As discussed in previous articles, MS therapies have had a significant impact on trend in recent years.

 The launch of Ampyra in early 2010 and the late 2010 launch of Gilenya were both expected to have a significant impact on trend within the class of medications used to treat MS.

Because MS is usually diagnosed in patients at a relatively young age, this disease has a greater economic impact than other debilitating diseases that may occur later in life (eg, Alzheimer’s disease).

 Appropriate management of this condition is essential.

Although there is still no cure for MS, various therapies are available to modify the course of the disease. The National Multiple Sclerosis Society recommends early use of disease-modifying therapies (DMTs).

 The first DMT approved specifically to treat the clinical progression of MS was Betaseron (interferon beta-1b) in 1993, followed by Avonex (interferon beta-1a) and Copaxone (glatiramer acetate) in 1996, Rebif (interferon beta-1a) in 1997, and Tysabri (natalizumab) in 2004.

 In 2009, an “authorized biogeneric” of Betaseron was launched as Extavia (interferon beta-1b).

In the years following their approval, the various formulations of beta interferon have become mainstays of MS drug therapy, although Copaxone is the single mostprescribed DMT. All of the beta interferon drugs, as well as Copaxone, are available as injectable formulations only.

 In 2010, the first oral agent, Gilenya (fingolimod), became available in the United States.

A recently published study in Neurology concluded that the use of injectable DMTs in treating MS offers modest health gains at a very high cost.

 The study found that adding a DMT to the treatment of MS patients roughly doubled the cost of care and that the cost of these agents far exceeded $800,000 per quality-adjusted life-year. A quality-adjusted life-year is a measure used in assessing the value of an intervention that looks at both the quantity and quality of life. In terms of their efficacy in preventing relapses, the study found that patients taking DMTs spent on average nearly 6 out of 10 years with no relapses, compared with 5 years with no relapses for those who did not take DMTs.

Oral Agents on the Market for Multiple Sclerosis

Until recently, all drug therapies specifically indicated for MS were administered subcutaneously or intravenously. However, the approval of recent oral therapies for MS has changed the landscape of therapies for this condition. The treatment of MS is becoming more complex as additional therapeutic options for MS enter the market.

 Ampyra (dalfampridine) was approved by the Food and Drug Administration (FDA) in January 2010 for the improvement of mobility in patients with MS as demonstrated by an increase in walking speed.

 Ampyra is not a DMT and is the first therapy specifically approved to treat a symptom of MS. Ampyra, formerly known as fampridine SR, is a sustained-release formulation of 4-aminopyridine, which blocks potassium channels on the surface of nerve fibers. This may improve the transmission of nerve signals in nerve fibers whose myelin coating has been damaged by MS. Ampyra may be taken with DMTs for MS. For many years, a compounded form of 4-aminopyridine has been used. However, the compounded product increased the risk of inconsistent dosing of 4-aminopyridine and the potential to cause seizures.

While Ampyra has the potential to significantly improve the quality of life for MS patients, it may also represent a substantial increase in the cost of treatment because it can be used as add-on therapy to a DMT. 

 Gilenya (fingolimod), the first oral DMT for MS, was approved by the FDA in September 2010 for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

 Gilenya is a sphingosine 1-phosphate receptor modulator (a new class of medication), which keeps lymphocytes (white blood cells) in the lymph nodes and thus prevents them from migrating to the CNS.

It is suspected that lymphocytes attack the myelin sheath.

 The exact mechanism of action of Gilenya in MS is unknown; however, it may involve the reduction of lymphocyte migration into the CNS.

Shortly following its approval, Gilenya manufacturer Novartis announced it would set a price of approximately $48,000 annually as the cost of therapy, making Gilenya more expensive than either the beta interferons (as a group) or Copaxone.

 Managed care organizations, employers who pay for benefits, and patients are all concerned about the potential impact Gilenya could have on cost. In fact, results from a survey of 100 top payers released in July 2011 found that a third of the respondents listed Gilenya among the top 5 specialty drugs representing the highest management priorities for their organization over the next 5 years.

The objectives of this study were to identify prescription utilization and cost trends for MS DMTs; to review Ampyra utilizers and their DMT utilization (if any) during the same time frame of January-June 2011; and to identify Gilenya utilizers, both those who were new to therapy and those who moved from other MS DMTs.

This retrospective analysis was conducted using the CVS Caremark Book of Business cohort, which only includes funded clients (cash/discount card claims are excluded). Additionally, cohort clients needed to have active membership and retail claims in all months from January 2011 to June 2011. This client cohort represents an average of 38 million members.

This retrospective analysis was conducted using prescription claims from the CVS Caremark computerized database. The following agents were included in our multiple sclerosis therapy (MST) analysis: Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone (glatiramer acetate), Rebif (interferon beta-1a), Extavia (interferon beta-1b), Tysabri (natalizumab), Gilenya (fingolimod), and Ampyra (dalfampridine). Novantrone (mitoxantrone) was not included in the analysis because of its approval and use as a cancer treatment.

The unique Ampyra and Gilenya utilizers were identified, and the review of other DMTs was conducted during the same period of January to June 2011. Concurrent prescription utilization was determined based on utilizers identified as having active Ampyra and DMT prescriptions as of June 30, 2011 (drug in hand).

The identification of Gilenya utilizers new to MS therapy was based on looking back 1 year from the first prescription for Gilenya and determining whether a different DMT prescription had been filled. If no other DMT agents had been prescribed in the 12 months before a Gilenya prescription was filled, the utilizer was considered a firsttime initiator; if a DMT agent had been prescribed during that time, that agent was identified as the most recent therapy used before Gilenya.

It is important to note that the prescription data do not include MS therapies that may have been administered in a physician office and reimbursed through the medical benefit rather than being adjudicated through the prescription benefit plan.

In the CVS Caremark Book of Business 2011 cohort, 42,596 unique MST utilizers were identified, with an average of 0.65 MST claims per month. Overall, the MS class saw a 14.88% increase in unique utilizers and a 28.58% increase in claim volume from January to June 2010 to January to June 2011. When comparing January to June 2010 with January to June 2011, the number of claims per utilizer increased by 11.90%. The most significant change was seen in the new oral agent Ampyra (

When looking at the MST users in the Book of Business cohort, we broke out the demographics by age and sex in order to better describe this population (

Among the unique MST utilizers, 23% were on Ampyra (9809 of the 42,596 unique MST utilizers). Of the 9809 patients who had an Ampyra prescription between January and June 2011, 7554 patients (77.01%) were using Ampyra without a DMT (these users had no prior fill of a DMT agent in the 6 months prior to the first fill of Ampyra); 902 (9.20%) were using Ampyra with Copaxone; 379 (3.86%) were using Ampyra with Avonex; 409 (4.17%) were using Ampyra and Rebif (includes Rebif titration pack); 289 (2.95%) were using Ampyra with Betaseron; 166 (1.69%) were using Ampyra with Gilenya; 6 (0.06%) were using Ampyra with Extavia; and 104 (1.06%) were using Ampyra with Tysabri (Figure). It should be noted that even when looking back 12 months from their first fill of Ampyra, 7437 patients were using the drug with no apparent history of MS DMT utilization. The data show that the top 3 classes used concurrently with Ampyra would also be very typical of those used by an MS patient, although it would be expected that a much higher percentage of MS patients would be utilizers of these classes than the fewer than 5% borne out by the data (

). Of the 9809 Ampyra users, 30.87% were male and 69.13% (n = 6781) were female.

In 2011, 3.5% of the unique MST utilizers were on Gilenya (1497 of the 42,596). Of the 1497 Gilenya utilizers, 49.70% had no MST prior to Gilenya (as of January 2011). The remaining Gilenya users switched from one of the other DMTs for MS to Gilenya (

As shown in Table 4A, 14.90% (n = 223) of Gilenya users had switched from Copaxone to Gilenya therapy; 13.23% (n = 198) had switched from Rebif to Gilenya (0.33% [n = 5] of Gilenya users who filled a prescription for a Rebif titration pack filled their next MST prescription for Gilenya); 10.42% (n = 156) had switched from Avonex; 9.29% (n = 139) had switched from Betaseron; 1.87% (n = 28) had switched from Tysabri; and 0.27% (n = 4) had switched from Extavia to Gilenya therapy.

Note that the average overall cost for MST per script ranged from $630 (Ampyra) to $4600 (Table 4B). Only Ampyra had a decline in cost per script (-4.55%). The majority of agents had a double-digit increase in cost per prescription over the last few years.

The data show that more than three-fourths (77%) of the Ampyra users identified were not concurrently using an MS DMT agent. The number of Ampyra users who take this agent without a concurrent DMT suggests a certain amount of off-label use. The top 3 classes of drugs used by Ampyra monotherapy users (muscle relaxers, urinary antispasmodics, serotonin antidepressants) would be very commonly utilized by MS patients, but in much higher percentages than those found in the data (<5%). 

One might reasonably expect a certain level of Ampyra use by itself in the MS population considering the relatively low early adoption and higher discontinuation rates of therapy with injectable DMTs. After all, the dalfampridine molecule has historically been compounded for off-label use in a number of indications, including acute spinal cord injury, disorder of neuromuscular transmission (eg, myasthenia gravis, Eaton-Lambert syndrome, congenital myasthenia), Alzheimer’s disease/ dementia, botulism (to aid in recovery from peripheral paralysis), reversal of neuromuscular blockade, and treatment of verapamil overdose.21 Even so, it was a surprising finding that 77% of Ampyra users were not concurrently using a DMT.

One limitation of this study is that we were unable to capture MST processed via the medical benefit; we can assume that a portion of the Ampyra monotherapy users had DMT that was/is being processed through the medical benefit. An additional possible explanation for the high percentage of Ampyra monotherapy users is that some of these patients may be on Ampyra monotherapy due to advanced progressive disease, for which DMT may not be as effective.

A large number of the Ampyra users in this analysis were found to be using Ampyra as monotherapy (no DMT). Many of the conditions for which fampridine has been used off-label, such as myasthenia gravis and other neuromuscular disorders, can be treated using similar agents. Thus, it is not possible to ascertain if there is a certain off-label condition for which Ampyra is being used based on the concurrent medication usage of Ampyra monotherapy utilizers. Listed in parentheses are the percentages of Ampyra monotherapy users in this analysis who were using the agents listed (where data were available). Myasthenia gravis can be treated by agents such as cholinesterase inhibitors (0.17%), corticosteroids (0.24%), immunosuppressants (0.20%), and intravenous immunoglobulin (0.01%). Acute spinal cord injury can be treated with methylprednisolone (glucocorticosteroids 0.24%). Eaton- Lambert syndrome can be treated with prednisone (glucocorticosteroids 0.24%), cholinesterase inhibitors (0.17%), or 3,4-diaminopyridine. Congenital myasthenia can be treated using pyridostigmine (0.17%), fluoxetine (selective serotonin reuptake inhibitors represented 1.15%), ephedrine, and 3,4-diaminopyridine. Alzheimer’s disease can be treated using Aricept (donepezil), Razadyne (galantamine), Namenda (memantine), Exelon (rivastigmine), and Cognex (tacrine); antidementia agents represented 0.17% of the concurrent therapy for Ampyra monotherapy users. Dementia can be treated using cholinesterase inhibitors (0.17%), anticonvulsants (0.98%), antidepressants (selective serotonin reuptake inhibitors represented 1.15%; serotonin-norepinephrine reuptake inhibitors represented 0.42%; miscellaneous antidepressants represented 0.26%), anxiolytics (0.08%), atypical antipsychotics, and Haldol. The patient analysis of Gilenya users shows that uptake has been respectable if not exceptionally strong. More revealing is that new users of the drug were divided rather evenly between those patients with no prescription record of a prior DMT and those with a prior DMT prescription record.

While both new oral agents are costly, Gilenya is particularly so. In fact, there has been significant discussion regarding the cost-effectiveness of MS DMTs. In a recent population-based study that examined the cost-effectiveness of MSTs, it was found that under current prescribing and pricing conditions, the DMTs help people with MS but that health and quality-of-life improvements appear to be modest compared with the high costs of these therapies, based on the study’s analytic model.

 The study also found that starting treatment with a DMT earlier was associated with a more favorable cost-effectiveness ratio compared with initiating treatment at any phase of MS.

Following the trend toward less-intrusive administration methods, we see there are some oral agents for MS in the pipeline.

Laquinimod is an oral, once-daily capsule in phase III trials for the treatment of RRMS.

Laquinimod is an immunomodulator/ neurotrophic factor modulator.

 If approved for the treatment of MS, laquinimod is anticipated to launch sometime in 2012.

Panaclar (dimethyl fumarate) is an oral capsule in phase III trials for the treatment of RRMS.

 If approved, this product is anticipated in 2012.

 This product appears to have an immunosuppressive/anti-inflammatory and cytoprotective mechanism of action.

Aubagio (teriflunomide) is an oral, once-daily immunomodulator in phase III trials for the treatment of RRMS.

Teriflunomide is the active metabolite of leflunomide and is a dihydroorotate dehydrogenase inhibitor. This immunomodulatory agent has a pharmacologic profile similar to that of injectable interferons for MS relapse and progression, but with improved safety. Clinical development of teriflunomide (as monotherapy and adjunctive therapy) is under way in several countries, including the United States.

 If approved, Aubagio is anticipated to launch in 2012.

 Additionally, an intravenous infusion product is in the pipeline for MS.

Lemtrada (alemtuzumab) is an intravenous infusion product in phase III trials for the treatment of previously untreated patients with RRMS.

 Alemtuzumab is an antilymphocyte monoclonal antibody currently approved to treat chronic lymphocytic leukemia. The therapy is marketed as Campath or MabCampath for oncology indications and will be sold as Lemtrada for multiple sclerosis.

If approved for the MS indication, Lemtrada is anticipated to launch sometime in 2012. Lemtrada is an infusion that will be given annually, beginning with an initial 5-day infusion and followed by 3 infusions 12 months later.

Multiple sclerosis therapies as a class will continue to be a significant driver of drug trend. Given that the MS treatment market offers limited growth through new patient diagnoses, sales growth has come primarily via a series of aggressive manufacturer price increases. For example, in recent patent litigation relating to Copaxone, it was noted that Teva twice raised the price of the drug in 2010, each time by approximately 9.9%, followed by a 14.9% increase in January 2011; that was despite a nominal inflation rate of 1.5% in 2010.

 In addition, the pipeline for new MSTs is robust, with some promising oral agents for MS anticipated in the next few years. Uptake of the new oral agents Gilenya and Ampyra may be expected to increase more rapidly in the months and years to come, if perhaps for largely different reasons.

The uptake of Gilenya and other oral MS DMTs will be driven by patient perceptions of superior efficacy and safety, as well as by the substantially more convenient route of administration compared with injectable drugs. A recent study found that many consumers mistakenly believe that new prescription drugs are always safer than older drugs and that only very efficacious drugs without major side effects are approved by the FDA.

Prescribing of oral MS DMT agents may also be driven by the recognition on the part of neurologists that patients are more likely to use an oral agent earlier in the course of their disease and to remain compliant, thereby improving treatment outcomes. Injectable DMTs, on the other hand, face several barriers to early adoption and ongoing adherence.

Early use of DMT is both recommended and shown to be important in slowing the progression of MS and reducing impairment.

However, complacency on the part of some MS patients poses a barrier to early adoption of therapy. Frequently, MS patients will not experience another relapse or significant signs or symptoms for some time following their initial diagnosis, which may make it difficult for them to accept the need for daily self-administered injections. Once they have accepted the need for this treatment regimen, MS patients must then remain compliant with their prescribed therapy. Evaluations of treatment with traditional injectable DMTs suggest that MS patients frequently become noncompliant with these treatments, particularly within the first 6 months of therapy, and that approximately 60% to 76% of patients with MS remain adherent to therapy for 2 to 5 years.

Injectable therapies are associated with several unique challenges to adherence, including problems with injecting, a perceived lack of efficacy, and adverse events. Patients often feel an aversion to self-administered injections. In addition, patients may feel as though treatment is ineffective if their symptoms persist or they experience new issues. Studies show that perceived lack of efficacy accounts for 30% to 52% of discontinuations. Side effects of treatment are also cited as a common cause of nonadherence to DMT, with studies reporting that 14% to 51% of patients discontinue therapy because of adverse events. In the case of the beta interferons (Betaseron, Rebif), side effects can include flu-like symptoms, depression, fatigue, and injection site reactions. Copaxone’s most commonly encountered side effects include injection site reactions, vasodilation, tachycardia, tremor, and depression.

Uptake of the new oral agents gilenya and Ampyra may be expected to increase rapidly in the future, if for largely different reasons.

Early View of Ampyra and Gilenya Use by MS Patients

In the wake of what was the Food and Drug Administration’s (FDA’s) lowest new drug approval total in several years, the pharmaceutical industry is once again showing signs of life. The FDA’s Center for Drug Evaluation and Research approved a total of 21 new drugs in 2010; of these, 15 were new molecular entities (NMEs) and 6 were novel therapeutic Biologic License Applications (BLAs). As of July 20, 2011, the agency has approved 19 new drugs: 16 NMEs and 3 BLAs. Furthermore, of the 19 new drugs approved by the FDA this year, several have blockbuster sales potential, defined as a product that generates at least $1 billion in annual revenue for the manufacturer that produces it. These include new treatments for hepatitis C, lupus, and melanoma.

The new approvals of potential blockbusters represent a significant new source of revenue for pharmaceutical manufacturers, who will also experience a significant loss of income from blockbuster products expected to see generic competition for the fi rst time in 2011. The year has thus far seen the introduction of generic versions of Concerta and Levaquin. Before the year is out, generic versions of Lipitor and Zyprexa are expected.

New drug approvals are but 1 element—albeit a significant one&mdash;among many factors that impact drug spending via increased utilization. Other factors include new approved indications, reformulations, off-label drug use, changing demographics (eg, our aging population), pharmacy benefit designs, pharmaceutical promotional spending, new treatment guidelines, and the economy.

A full list of new drug approvals through July 20, 2011, can be found in the 

, including all NMEs and therapeutic BLAs approved by the Center for Drug Evaluation and Research. The most significant of these identified as having a strong potential impact on utilization, cost, and overall trend include the following:

Human Genome Sciences’ biologic Benlysta (belimumab), approved in March, is the fi rst new drug for lupus in more than 50 years.

 The company said Benlysta would cost (at launch) $443 for a 120-mg vial and $1477 for a 400-mg vial. The FDA puts the systemic lupus population at around 300,000 minimum.

Another biologic, Bristol-Myers Squibb’s injectable drug Yervoy (ipilimumab), was approved in March for late-stage or metastatic melanoma, and is the first drug shown to prolong the lives of patients with this form of advanced skin cancer. It will be priced at $30,000 per injection, for a total price of $120,000. Melanoma is the deadliest type of skin cancer, but the FDA has only approved 2 other drugs for advanced melanoma. The newer of those drugs was cleared more than 13 years ago. Neither drug has been shown to significantly extend patient lives.

The FDA approved 2 new hepatitis C treatments in May: Merck’s Victrelis (boceprevir) and Vertex Pharmaceuticals’ Incivek (teleprevir). Merck said the wholesale acquisition cost (WAC) for Victrelis will be $1100 per week,

 dosed for 24 to 44 weeks, whereas Vertex said Incivek would carry a price of $49,200 for a 12-week course of therapy. The WAC for Incivek will be only $800 higher for the course of therapy than the WAC for Victrelis when patients take that drug for 44 weeks. But for Victrelis patients who receive the drug for 24 weeks, the cost will be significantly lower than that for Incivek. The duration of treatment with Victrelis, however, is not determined until after starting treatment. Both agents produced a substantially greater sustained virological response rate compared with the existing standard of care.

On July 1, the FDA approved Johnson & Johnson/Bayer’s Xarelto (rivaroxaban) to prevent certain blood clots, known as venous thromboembolisms, in people undergoing knee- and hip-replacement surgery. Johnson & Johnson said Xarelto is the first new oral anticoagulant approved to prevent venous thromboembolisms in joint-replacement surgeries. An older drug used for this purpose, Lovenox (enoxaparin), is injected. A bigger market for Xarelto lies in its use to prevent strokes in people with atrial fibrillation. The companies have filed for approval to market Xarelto for this use, and a decision could come later this year from the FDA. Xarelto was launched shortly after approval with a WAC of $6.75 per unit.

Also in July, the FDA approved AstraZeneca’s Brilinta (ticagrelor) to reduce thrombotic events in patients with acute coronary syndrome, including unstable angina, and in patients with myocardial infarction who are candidates for stenting. Acute coronary syndrome includes a group of symptoms for any condition, such as unstable angina or heart attack, that could result from reduced blood flow to the heart. The FDA said Brilinta’s label will include a “boxed warning to healthcare professionals and patients warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication.” A widely touted benefit of Brilinta is that its effect can be quickly switched off because it has a much shorter half life than either of the 2 approved antiplatelets, Plavix (clopidogrel) and Effient (prasugrel). A limitation of Brilinta’s pivotal trial program is that most of the patients came from Europe, the Middle East, or Africa. Only 11% of the patients were recruited in North America. In that cohort, Brilinta-treated patients were 27% more likely to suffer one of the end point events, although the difference fell short of statistical significance.

As new drugs become available, prescribing guidelines are updated and may impact utilization trends. An example of this is the updated protocol for treatment of atrial fibrillation published by the American College of Cardiology (ACC) and the American Heart Association (AHA). Pradaxa (dabigatran) capsules were approved by the FDA in October 2010 for prevention of stroke and systemic embolism in patients with atrial fibrillation, making it the first oral anticoagulant to enter the market since warfarin (Coumadin and generics) was approved in the 1950s. While Pradaxa is exponentially more expensive than generic warfarin, its competitive advantage and market positioning relate to superior efficacy; in a pivotal study used to support approval, Pradaxa patients had 34% fewer strokes and systemic embolisms than warfarin patients.

 While the approval of Pradaxa in October came too late for inclusion in the new ACC/AHA guidelines published in December,

 an additional update was published by the groups in February 2011 that said that Pradaxa can be used as an alternative to warfarin to prevent blood clots and stroke in certain atrial fibrillation patients.

Arguably, the most significant approvals for the year have already been made, based on the list of products that have a 2011 review goal date at the FDA. However, a number of other novel products are expected to receive a review at the agency before the end of the year, including:

Firazyr (icatibant), Shire’s hereditary angioedema (HAE) drug, won support from an FDA advisory committee for a claim to allow patients to self-inject the product, which would distinguish it from established treatments that must be delivered by a physician or infused in a clinical setting. Additionally, because HAE attacks are unpredictable, the ability to self-inject and receive the medication quickly is very important to patients. The HAE treatment population is small (an estimated 7000 Americans suffer from HAE), so Firazyr is likely to be costly if approved.

 (NOTE: Firazyr was approved by the FDA on August 25, 2011.)

Ruxolitinib, Incyte’s myelofibrosis (a disorder of the bone marrow) candidate, demonstrated superiority compared with the best available therapy with respect to reducing splenomegaly and alleviating symptoms in patients with myelofibrosis. Also, ruxolitinib treated patients saw a reduction in a variety of disease-related symptoms; patients receiving the existing standard of care did not.

Significant new drug approvals that could occur in 2012 include the following:

Apixaban, by Bristol-Myers Squibb/Pfizer, is from the same class of blood thinners as Xarelto. Although it will be the third new oral anticoagulant to reach the market (following Pradaxa and Xarelto), in certain clinical settings it has demonstrated superiority to warfarin on safety and efficacy, which could help it gain market share against established products. Xarelto was shown to be noninferior, not superior, to warfarin on efficacy and bleeding in a pivotal study. Pradaxa demonstrated superior efficacy compared with warfarin, but it had a comparable risk of bleeding. The projected 2012 market entry is based on the intent by Bristol-Myers Squibb/Pfizer to file for FDA approval in the third or fourth quarter,

Bydureon (exenatide) is Eli Lilly/Alkermes’ once-weekly subcutaneous injectable glucagon-like peptide-1 analog for type 2 diabetes. The companies recently said that they plan to resubmit Bydureon to the FDA in the third or fourth quarter after announcing that the drug met the primary end point of an FDA-mandated cardiovascular risk study. In a 3-year study, patients treated with Bydureon showed sustained decreases in blood sugar, weight loss, and improvements in blood pressure and cholesterol levels.

In 2012, the number and significance of the brand-name drugs losing marketing exclusivity via the so-called “patent cliff” will experience a maximum value in terms of sales dollars at risk, with first-generic entries projected for Actos, Diovan, Geodon, Lexapro, Plavix, Provigil, Seroquel, and Tricor. Before the year is out, generic versions of Lipitor and Zyprexa are expected.

 Approximately $25 billion in domestic brand sales are expected to be lost to generic drugs in 2011, according to IMS Health, which noted that the amount of brand sales lost to generic drugs in 2010, by comparison, was half that amount. The company has characterized the first-generic approvals in 2011 and 2012 as the largest generic opportunities ever, in terms of the protected brand sales that will be exposed to generic competition.18

Approvals of potential blockbuster drugs represent a new source of revenue for pharmaceutical manufacturers, who will experience significant income loss from generic competition in 2011-2012.