Mark W. Ward, BA

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.

Articles

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 2009, the treatment of diabetes was one of the top contributors to prescription drug trend. With the continued aging of the Baby Boomers and obesity in the United States, this trend will continue beyond 2011. The diabetes population in the United States will almost double over the next 25 years, and annual medical spending on the disease i

(up from $113 billion today), according to a recently

of Americans living with diabetes will rise from 23.7

million in 2009 to 44.1 million in 2034. For the Medicare

program, the projected increases over the next 25

years are even more dramatic: the number of Americans

living with diabetes and covered by Medicare will rise

from 6.5 million to 14.1 million, and Medicare spending

on diabetes will almost quadruple, skyrocketing from

$45 billion this year to $171 billion in 2034.

disproportionately affects minorities and low-income

 Greater numbers of patients with diabetes

will likely be covered under Medicaid and individual

exchange programs due to mandated changes of the

Diabetes is a disease characterized by abnormally high glucose levels in the blood, which are caused by the body’s inability to efficiently convert glucose into energy. The metabolic disorder develops because of either diminished production of the hormone insulin or insulin resistance. There are 3 major types of diabetes: type 1, type 2, and gestational. Type 1 is an autoimmune disease that causes insulin deficiency. Type 2 occurs when either the pancreas fails to produce enough insulin or the body becomes insensitive to insulin. Gestational diabetes occurs during pregnancy. Rarely, diabetes is due to genetic defects or pancreatic diseases, or is drug/chemical induced. Type 2 diabetes (T2DM) is the most common form, representing more than 90% of cases affecting both adults and children. In the United States, 23.6 million people (8.0% of the population, or 1 in every 13 Americans) have diabetes.

 The growing population of persons with prediabetes or impaired fasting glucose is a major concern. It was estimated that 57 million American adults 20 years or older had impaired fasting glucose in 2007.

Patients newly diagnosed with diabetes have several therapy options to control their blood sugar. Lifestyle (dietary and exercise) changes are essential for all diabetic patients, although the impact of these may not be sufficient to delay the initiation of pharmacotherapy. The spectrum includes multiple classes of oral and injectable drugs in addition to insulin treatment.

 Each of the drugs has several indications for glycemic control in patients, and many are used in conjunction with insulin. The noninsulin injectables Symlin and Byetta commonly are used as adjunctive therapy with oral antidiabetic drugs to improve glycemic control (

As a baseline objective of therapy, a recent (2009) consensus statement published by the American Association of Clinical Endocrinologists/American College of Endocrinology on glycemic control in diabetes mellitus gives as the stated goal the achievement of a glycosylated hemoglobin (A1C) level of 6.5% or less, with recognition of the need for individualization to minimize the risks of hypoglycemia (low blood sugar).

 The A1C targetof 6.5% may vary based on an individual’s age, useof other medications, number of comorbid conditions,duration of diabetes, history of hypoglycemia, and otherfactors. The organization has developed an algorithmfor a therapeutic approach to glycemic control basedon the A1C level, which can be broadly summarized asfollows:

• When the A1C level is 7.5% or lower, it may be possible to achieve a level of 6.5% with the use of monotherapy.

• If the A1C level falls to between 7.6% and 9.0%, treatment should begin with a dual therapy.

• Where the A1C level is in excess of 9.0%, triple therapy is appropriate.

• When triple drug therapy fails or is contraindicated, it is appropriate to initiate insulin treatment, either with or without additional orally administered agents.

• Other options within this framework include titrating medication dosages and changing regimens (adding or discontinuing medications); when combination therapy is prescribed, it is important to use drug classes that have complementary mechanisms of action.

Increasingly, there are multiple and complex regimen options for T2DM that consider postprandial hyperglycemia, insulin resistance, and weight changes. Updates to prescribing guidelines, research findings, and the spectrum of A1C levels of T2DM patients at diagnosis will drive increasing use of double and triple therapy as initial therapy.

In recent years, the thiazolidinediones (TZDs) Actos (pioglitazone) and Avandia (rosiglitazone), also referred to as insulin-sensitizing agents, were used as both monotherapy and adjunctively with other antidiabetic drugs. Utilization of TZDs peaked in 2007 when the class was ranked 12

 by gross cost in the overall CVS Caremark Book of Business. Their class ranking has fallen dramatically, to 17

 overall in August 2010, as a result of several published reports questioning their safety, beginning in May 2007.

On September 23, 2010, the Food and Drug Administration (FDA) said that it would significantly restrict the use of Avandia to patients with T2DM who are unable to control the disease with other drugs. The new restrictions are in response to data suggesting an elevated risk of cardiovascular events such as heart attack and stroke in patients treated with Avandia. The FDA also stated it will require a restricted access program for Avandia under which it will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (the only other currently marketed TZD). Current Avandia users benefiting from the drug will be able to continue using the medication if they so choose. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge that they understand the risks. The FDA anticipates that these requirements will significantly limit use of Avandia.

The antihyperglycemic therapeutic class will continue to be a major contributor to prescription drug trends in 2011 and beyond.