Stacey Ruf, PhD

Multiple sclerosis (MS) is a chronic, unpredictable disease of the central nervous system. It is thought to be an autoimmune disease in which the body’s immune system attacks the myelin sheath (material that surrounds and protects nerve cells), causing brain signals to be interrupted.

 Symptoms commonly include numbness in the limbs, muscle weakness, paralysis, and/or vision distortion or impairment. The exact cause of MS is unknown, and symptoms vary greatly from one person to another and for any one person over time. Most people afflicted with MS have a normal or near-normal life expectancy, and the majority of people with the disease do not become severely disabled.

Although there is still no cure for MS, various strategies are available to modify the disease course, treat exacerbations (also known as relapses, attacks, or flare-ups), manage symptoms, and improve physical function and safety. In combination, these treatments are designed to enhance the quality of life for people living with MS. An individual’s treatment needs are best identified in an ongoing collaboration between a knowledgeable physician and other members of the treatment team.

Of the approximately 400,000 Americans who have MS

		Most are diagnosed between the ages of 20 and 50 years.

		Roughly 5% are diagnosed before age 21 years (early onset).

		Approximately 9.4% are diagnosed after age 50 years (late onset).

		An estimated 2 to 3 times as many women as men have MS.

Until recently, all MS-specific drug treatments were administered subcutaneously or intravenously. But in January 2010, Ampyra (dalfampridine) received US Food and Drug Administration (FDA) approval as the first orally administered MS drug indicated to improve patient ambulation.

 The trend toward less intrusive administration methods has prompted development of several oral drugs in this space.

MS drug utilization had a significant impact on trend in the last few years, as discussed in previously published articles including the generational trend research and the recent Alzheimer’s utilization trend research.

 However, future class costs are projected to outpace those of prior years because of the expected March 2010 launch of Ampyra and because of double-digit growth in utilization for existing market drugs. In this article we discuss the impact of MS therapy (MST) on trend and MST utilizers’ contributions to total annual drug expenditures compared with contributions of the overall commercial population.

This retrospective analysis was conducted using 241.9 million prescription claims from CVS Caremark’s computerized database. The population identified for the study consisted of 23.2 million members across funded benefit prescription plans administered by CVS Caremark. The plan sponsors included Medicaid, national and local employers, health plans, managed care organizations, insurance companies, unions, and government agencies located throughout the United States with prescription claims for all months between January 1, 2008, and December 31, 2009.

The members had claims in 2008 and 2009, categorized by generation: GI Generation (age ≥83 years), Silent Generation (age 63-82 years), Baby Boomers (age 44-62 years), Generation X (age 30-43 years), Generation Y (age 18-29 years), and Generation Z (age ≤17 years).4 In addition to categorizing utilizers by age band, we also separated metrics by sex (Table 1).

The utilization trend was based on average days supply and gross cost (which includes both plan sponsor and member contributions), reported on a per member per month basis. Medicare Part D plans were excluded. The plan sponsors had average eligibility changes limited to within ±15% period over period.

Patients on MST were identified by using the product indicator for approved MS treatments, which includes all strengths and dosage forms of the following: Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone (glatiramer acetate), Rebif (interferon beta-1a), Extavia (interferon beta-1b), and Tysabri (natalizumab). Novantrone (mitoxantrone) was not included in the analysis because of its approval and use as a cancer treatment.

Three primary types of injectable MS drugs are available: glatiramer acetate, interferon beta, and natalizumab (Table 2). Each type of drug commonly has a different effect on individual patients. As a result, some product switching may be necessary to find the drug with greatest efficacy.

Currently several disease-modifying medications are approved by the FDA for use in relapsing forms of MS (including secondary-progressive MS for those people who still are experiencing relapses). These drugs work to slow down the natural course of the disease and prevent recurring symptoms. More specifically, the medications reduce the number of days a person might be actively ill with an attack of symptoms; they reduce or even eliminate the accumulation of lesions, or damaged areas, within the central nervous system; and they appear to slow down the accumulation of disabilities. All class drugs have proven records of partial to substantial success. Unfortunately, none of the currently available disease-modifying drugs are approved for treating primary-progressive MS.

Side effects are common when taking any of the disease-modifying drugs for the treatment of MS, although these vary in nature and severity. As a result, compliance rates can vary, and discontinuation of therapy is not uncommon.

Ampyra, approved in January 2010, is a (non—diseasemodifying) potassium channel blocker used to improve ambulation in MS patients and administered orally. It is awaiting market launch, expected in March 2010.

In 2009, 25,059 unique MST utilizers were identified based on prescription claim data, representing approximately 0.11% of the overall cohort population studied. More than 75% of utilizers were female and the majority were Baby Boomers, although Generation X represented 30% of the MST utilizers (Table 3).

The average age of the study commercial group was compared with 2005 US Census population estimates by age bands. According to the Census estimate, those aged 20 to 49 years comprised 42.8% of the population. The same population in the study cohort made up 41.3%.

Four disease-modifying injectable drugs dominate the MS treatment landscape: the complex nonbiologic Copaxone and 3 biologic derivative interferon-beta drugs (Avonex, Rebif, and Betaseron). The Figure indicates market share by days supply in 2009. Copaxone was the leader with a 37.5% market share. Avonex, the number 2 player, lost 2.2% share year-over-year, while Copaxone gained 2.3%. Despite a significant year-over-year increase in claims, Tysabri only gained 0.2% share due to low volumes.

Tysabri is commonly prescribed when other drugs fail to satisfy the patient’s needs, but the drug can lead to progressive multifocal leukoencephalopathy, a rare brain infection that usually causes death or severe disability. Therefore, Tysabri market penetration is likely to remain low.

The average cost per prescription for an MST drug was $3434.63. However, the average cost per day provides a better comparison, as the figure increased from $67.52 in 2008 to $81.15 (20.2%) in 2009. Table 4 provides the average gross cost per day for MST drugs.

Table 5 shows the top non-MST drugs by gross cost, the percentage of MST utilizers, and the ranking by gross cost, claims, and utilizers. Approximately 41.3% of MST utilizers also were on antidepressants (selective norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and miscellaneous), 31.7% were on a central muscle relaxant, and 27.4% were on an anticonvulsant. Although concomitant corticotropin utilization was very low (0.2%), this class was ranked number 2 in gross costs due to a gross cost per day of $2039.74.

According to the recent generational analysis, the gross cost for MST was ranked 5th for Generation X and 8th for Baby Boomers.

 The current study population had a 0.11% prevalence of members using MST compared with the reported 0.13% estimated in the US population. A recent study indicated that direct MST spending combined with concurrent drug utilization, on a per-patient basis, is estimated to be an average of $24,775 per year.

Recent, significant developments in the MS drug treatment market include:

		Another year of double-digit cost increases in 2009for all 4 of the major MS drugs.

		Regulatory filings with the FDA seeking marketing approval of the first oral MS drugs.

		Approval of the first drug indicated solely to improve mobility in MS patients.

All 4 of the leading MS drugs have had ongoing double-digit price increases well in excess of the inflation rate. In the CVS Caremark overall Book of Business data (a different cohort group than the underlying secular trend cohort), an analysis showed the overall average gross cost per day of therapy for MS drugs in December 2009 was $82.17. This increase followed a 21.28% price increase in December 2008 to $75.18 from $61.99 in December 2007.

 As the price hikes are greater than the number of new MS patients seeking treatment each year, they are the most significant source of sales growth for the class.

Teva, the Copaxone manufacturer, announced in August 2009 that the average copayment (at that time) for the drug was $26, and that more than half of the patients on the drug paid nothing at all.

 This phenomenon helps to promote therapy adherence despite very high drug costs.

In late 2009, new drug applications were filed with the FDA for the first oral MSTs. Neither of the 2 filings were for biologic drugs. Merck Serono’s candidate, cladribine, was submitted in September 2009, but the FDA refusedthe application 2 months later, which suggests that it was incomplete. Merck has said that it would meet with the agency in an effort to understand the deficiency and outline any next steps that might be necessary. The other oral drug, fingolimod, was submitted for approval by Novartis at the end of December 2009.

Oral therapies would be more convenient for the MS patient than the current regimen of injectables and would represent another treatment option for physicians. Still, it’s not clear that either cladribine or fingolimod will be approved, or if they are approved, that it will be on the first review cycle at the FDA. Furthermore, there are potential safety concerns, as there are with the injectable disease-modifying drugs. Oral therapies have been characterized as generally being more toxic and likely to have a more problematic side-effect profile than the injectables.

 Finally, given the many years of experience patients and physicians have with the existing drugs, it may be difficult initially for new oral therapies to gain widespread acceptance in the first-line treatment setting.

Using 2009 prescription data to determine MST utilization, 0.11% of commercial utilizers received an MS agent. The study results indicated that the average member on MST had an average annual prescription cost of $24,775. Of that amount, 87% ($21,635) was spent on MST.

According to the National Multiple Sclerosis Society, even a modest improvement in walking ability could mean that thousands of people might benefit from taking Ampyra.

 Ampyra’s manufacturer, Acorda, has set a price of $12,850 a year for the drug.

 Furthermore, the company added, the add-on therapy may be utilized by as many as 180,000 patients or approximately 40% of Americans with MS. If so, the class will experience a substantially higher trend in 2010.

Articles

Future costs of MS therapy are likely to increase due to new add-on therapy combined with double-digit growth in utilization for existing drugs.

Prescription Utilization by Multiple Sclerosis Patients in the United States

The proportion of Americans diagnosed with Alzheimer’s disease (AD) is projected to increase almost 2-fold over the next couple of decades due to size of the Baby Boom generation compared with the total US population. As a result, overall drug costs are likely to increase substantially over the same period. The impact on society and the nation’s healthcare system will be substantial. 

Alzheimer’s disease is characterized by progressive loss of memory, cognitive thinking, and motor skills. Noticeable symptoms commonly begin with signs of mild cognitive impairment progressing to severe dementia, usually leading to death within 8 to 10 years of diagnosis.1 The mental and physical effects of AD are devastating for patients as well as family members. Upon receiving the diagnosis, patients often suffer from depression and/or anxiety.2 As symptoms related to the disease become progressively more severe, patients not only have progressive cognitive dysfunction, but many also become highly combative. During this stage of the disease, managing patient behavior becomes increasingly difficult, often requiring several forms of treatment. As the patient progresses through the stages of the disease, simple life functions require caregiver assistance and can produce significant pressure and emotional stress on the provider. 

Care for patients receiving Alzheimer’s drug therapy (ADT) also can become financially burdensome because treatment, including medication, is very expensive. In addition to treatment of common conditions related to aging, such as high cholesterol and high blood pressure, patients receiving ADT may benefit from treatment of comorbid depression with antidepressants. Benzodiazepines occasionally have a role in treating patients with prominent anxiety, or they can be used on an as-needed basis for patients with infrequent episodes of agitation, although their effect is modest. Adverse effects from benzodiazepines include sedation, worsening cognition, delirium, increased risk of falls, and worsening of breathing disorders.2 Antipsychotic medications are prescribed by some physicians to treat aggression and agitation as well as severe or debilitating hallucinations and delusions. Neither typical nor atypical antipsychotics are approved by the US Food and Drug Administration (FDA) to treat psychosis in elderly demented patients. Both have a black box warning in their labeling that warns of an increased risk of death in this patient population. 

In addition to medications, AD patients may benefit from nonpharmacologic and behavioral therapy. In some cases, patients also may require supervision in a managed care facility to control behaviors and ensure patient safety. Others may find it more beneficial to use a comprehensive disease management program. 

Currently, there is no cure for AD or treatment for the reversal of dementia, and scientists do not know exactly what causes the disease. Several drugs are available to treat symptoms; however, efficacy is commonly short-lived and varies from person to person. Although a cure is not expected in the near future, researchers believe substantial progress has been made in identifying potential causes and biomarkers as well as in diagnosing the disease. There also is significant research on the prevention of AD. 

CVS Caremark conducted an AD drug utilization study to identify prevalence, concomitant therapy, drug trend cost, and utilization patterns by demographic groups. 

The analysis is a retrospective study and was conducted using 571.3 million prescription claims from CVS Caremark’s computerized database. The population identified for the study consisted of 29.4 million members across funded benefit prescription plans administered by CVS Caremark. The plan sponsors included Medicaid, national and local employers, health plans, managed care organizations, insurance companies, unions, and government agencies located throughout the United States with prescription claims for all months between January 1, 2008, and December 31, 2008. Members were categorized by generation with the following age bands: 83 years and older (GI generation), 63 to 82 years (Silent generation), 44 to 62 years (Baby Boom), and 30 to 43 years (Generation X).4 Utilization figures were based on days supply, and gross cost figures (which includes both plan sponsor and member contributions) were reported on a per member per month basis.

Alzheimer’s disease, which is the accretion of amyloid plaques and neurofibrillary tangles in the brain, was the seventh leading cause of death in the United States for 2006.5,6 It is believed these buildups cause nerve cell death, resulting in progressive cognitive dysfunction. Symptoms usually first appear at age 60 years, but the rare early-onset form of the disease may appear as early as age 30.1 The disease usually causes dementia and is diagnosed using family history, brain scans, and neurologic and neuropsychologic tests, but can be confirmed only at autopsy. 

There are several nontreatable causes of dementia, primarily including AD, vascular disease, Lewy body disease, and Parkinson’s disease. Alzheimer’s disease is the most common form in individuals over the age of 65 years, accounting for approximately 60% of cases.7 Vascular disease accounts for up to 20% of dementia cases commonly associated with occurrence of a stroke.1 Multiple sclerosis also has been associated with dementia. Multiple sclerosis is a demyelination disease of the central nervous system (CNS) that commonly leads to inflammatory and atrophic brain pathology, often causing cognitive impairment.

Current prevalence estimates range from 2.4 million9 to as many as 5.3 million10 Americans suffering from AD. The variability in the range of estimates is likely partially due to the difference in tracking methodologies3,8 combined with the difficulty of providing an accurate diagnosis. Globally, prevalence is estimated at approximately 27 million people.11 More than 90% of those diagnosed with the disease are 64 years of age or older, and AD is more likely to affect women. 

All drugs in the AD therapeutic class work to slow the worsening of symptoms of the disease, but do not stop brain cell death3 (Table 1). 

It is believed that acetylcholinesterase inhibitors including Aricept (donepezil hydrochloride), Exelon (rivastigmine tartrate), and Razadyne (galantamine hydrobromide) work to prevent the breakdown of the acetylcholine chemical in the brain. Namenda (memantine hydrochloride), a N-methyl-d-aspartate receptor antagonist, works to control a different chemical named glutamate.12 Because Namenda has a different mechanism of action for treatment, the drug often is used in combination with 1 of the other 3 drugs. Drug efficacy is relatively short-lived, usually lasting for only a few months to a few years. 

Patient psychiatric management procedures and tasks are utilized to maximize patient functionality and enhance the safety and comfort of the patient and family. The American Psychiatric Association (APA) has outlined guidelines for the treatment of AD patients. Once a patient has been evaluated using a battery of tests and diagnosed, a treatment standard of practice may include the following elements for mildly, moderately, and severely impaired patients. 

Three FDA-approved (Table 1) acetylcholinesterase inhibitors are used for the treatment of cognitive impairment (ie, Aricept, Exelon, Razadyne). Additionally, psychologic evaluations commonly follow to determine potential suicidality, mood, and/or depression symptoms. Depression is relatively common, particularly after the initial diagnosis, and may require antidepressant/antianxiety drug therapy. 

Concomitant utilization of Namenda is currently recommended during this phase to delay the progression of symptoms. Patients in this phase may show significant signs of agitation and combativeness toward caregivers in addition to hallucinations, delusions, and/or depression requiring additional treatment, including antipsychotics.2,13 

The 2007 APA guidelines suggest that if psychosis and agitation symptoms do not cause any significant danger or distress to the patient or others, such symptoms are best treated with environmental measures including reassurance and redirection. Behavioral measures also may be helpful for agitation if environmental measures are unsuccessful. If the behaviors are particularly dangerous or distressing, then the symptoms may be treated judiciously with antipsychotics, with the families informed of the relative risks and benefits, particularly the risk of mortality. 

Patients in this stage are normally completely dependent on others to complete basic life functions, including eating, bathing, and using the restroom. Aricept is the only cholinesterase inhibitor indicated to treat severe AD, and this drug is commonly utilized with Namenda.2 

The AD pipeline is, at present, both extensive and diverse. Drug development for AD has become substantially more focused as researchers continue to gain a better understanding of the disease. In 2000, acetylcholinesterase inhibitors, cholinergic agonists, neurotrophic factors, and anti-inflammatory agents formed the bulk of the late-stage pipeline. In 2009, a number of molecules were focused on beta-amyloid deposition and several others targeted tau protein formation. Additionally, several prospective agents are intended to protect neurons from degeneration. 14 Clinical trials have had mixed results. For example, a recent late-stage trial of a gamma-secretase modulator showed it did not prevent AD progression.15 

Despite the need for disease-modifying therapies, it is unlikely that a treatment will be developed in the next 10 years that completely halts or reverses progression of the disease. As a result, there will be continued demand for drugs that offer better symptomatic relief. Several of these also are in the nearterm pipeline, including transdermal and sustained-release reformulations. 

According to a recent report, more than a half-dozen investigational drug candidates are in late-stage development for the treatment of AD.14 Their launch is either projected for or may be reasonably expected to occur in the next few years. Recently approved, Aricept ODT (orally disintegrating tablet) is anticipated to have a generic alternative available in late 2010, and an Exelon (oral) generic is expected in 2012. 

There is a direct correlation between age and increased risk of AD. According to metrics from this study, once a person becomes age 84 years or older, the likelihood of being on AD drug therapy almost quadruples (Table 2). 

In 2008, approximately 1 in every 1000 baby boomers, 3% of those in the Silent generation, and more than 11% of those in the GI generation were utilizing an AD drug therapy. 

Results indicate 63.9% of overall utilizers were female and 36.1% male. The delta was much smaller for the Baby Boom generation (53.0% female) but widened dramatically as patients got older. Among utilizers age 84 years and older, 71.0% were female. Women have a longer average life span, which contributes to a higher relative risk of developing dementia and/or AD. However, AD is slightly more common in women16 (Figure 1). 

The Alzheimer’s Association estimates approximately 1 in 100 women at age 65 will develop dementia in their lifetime. By age 75, this figure increases to approximately 7 in 100 women. By the age of 85 the figure increases to more than 20 in every 100 women.8 

Aricept dominated the AD market with 53.6% of claims, followed by Namenda at 33.3%, and Exelon at 7.9%. Little change is expected over the next 10 to 12 months until the anticipated launch of Aricept ODT generic, expected in late 2010, which will likely have a significant impact on the class market shares and costs (Figure 2). 

As previously mentioned, Namenda is commonly utilized as both monotherapy and in conjunction with another AD drug. To provide another perspective on individual drug utilization, we determined how many AD patients utilized each drug by name. Results were as follows: 71.7% of patients used Aricept, 43.3% used Namenda, and 12.5% used Exelon. 

ADT patients’ overall annualized total drug cost was greater than that of non-ADT patients. The average annual total drug cost for a Silent generation member without AD was $2381 compared with $5268 for a Silent generation member with AD. A significant portion of the additional cost was due to concomitant drug therapy associated with the condition (Figure 3). 

Patients with AD often are subject to bronchial, cardiovascular, and other conditions associated with aging. In most cases, these conditions require additional drug treatment. Fortunately, many of the drugs used to treat these conditions are dispensed as generics, helping to moderate costs. As previously discussed, some AD drug utilizers have not been diagnosed with AD. Instead, many have other diseases, including multiple sclerosis, Parkinson’s disease, and Lewy body disease. The specialty drugs used to treat those conditions are very expensive. 

Of the top 10 drugs (by gross cost) used concomitantly with AD medications, 4 were atypical antipsychotics and 1 was a selective serotonin reuptake inhibitor (Table 3). The proton pump inhibitors Nexium and Prevacid were ranked 6th and 7th and at the time of the study were available as branded drugs. 

The symptoms/effects of AD require substantial caregiver responsibility. Additionally, the rapid progression of the disease and its symptoms increases the level of difficulty in providing care. Metrics obtained from the CVS Caremark study helped demonstrate the depth of the effect AD has on patients. Foremost, these patients have a large degree of concomitant drug utilization. Not only do they require common disease-related medications, but many also take antidepressants, antianxiety agents, or antipsychotic medication in addition to AD drugs. In addition to the clinical aspects of treatment and difficulty in providing care, AD patients’ overall drug costs are staggering. 

The FDA has not approved the use of antipsychotic drugs (typical or atypical) for treatment of elderly patients with dementia-related psychosis. In 2008, the FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementiarelated psychosis. Although the current guidelines issued by the APA do not indicate removing antipsychotics as therapy, they recommend that these medications be used with caution and at the lowest effective dosage after considering the risks of not treating the psychiatric symptoms. 

The likelihood of developing AD increases with age. As people get older, they become more likely to be in the latter stages of the disease, often requiring more behavior management. 

In addition to drugs used to treat diseases commonly seen in the elderly, AD patients’ drug regimens also may include multiple CNS-related medications to help manage symptoms that are distressing to both the patient and the caregiver. Compounded by year-over-year increased utilization and price inflation, the high degree of concomitant drug use contributes to increasing yearover- year drug spending. Availability of a generic version of Aricept ODT in 2010 and Exelon in 2012 could moderate future costs. 

Existing pharmacologic therapies provide a degree of symptomatic relief for some patients; however, responses vary widely, with efficacy often diminishing over time. No way has yet been shown to slow or reverse the clinical progression of the disease. Although AD drug efficacy is less than optimal, any degree of patient relief is highly desirable. The AD drug pipeline appears relatively rich in prospects, many of which have targeted the root cause of the disease as it is currently understood. However, none of these drugs have yet proven their safety and efficacy. 

What is currently known about AD is that it is an exceptionally debilitating, costly illness without a cure that results in substantial caregiver burden. Experts believe the number of persons diagnosed with AD may almost double within 20 years. The Centers for Disease Control and Prevention notes: 

The United States is on the brink of a longevity revolution. By 2030, the proportion of the US population aged 65 and older will double to approximately 71 million older adults, or 1 in every 5 Americans. The farreaching implications of the increasing number of older Americans and their growing diversity will include unprecedented demands on public health, aging services, and the nation’s healthcare system.

The proportion of Americans diagnosed with Alzheimer's disease (AD) is projected to increase almost 2-fold over the next couple of decades due to size of the Baby Boom generation compared with the total US population.