Of the new generation of multiple sclerosis (MS) drugs, 4 oral agents-dalfampridine, laquinimod, cladribine, and fingolimod-could produce significant changes in the treatment landscape for MS. Current first-line treatments, which are administered via injection, are associated with poor treatment adherence, often due to lack of efficacy (perceived and real), adverse drug reactions, cost, and injection anxiety. Although concerns about safety and cost remain, preliminary results indicate that these oral agents are as effective as, or even more effective than, current injectable treatments. Oral MS agents are expected to cost patients less in out-of-pocket expenses, which will likely increase treatment adherence and lead to an overall reduction in medical costs. While many patients may prefer an oral MS drug, the ultimate choice of therapy will be a shared patient-physician decision based on a multitude of factors, including the efficacy of the current treatment regimen, patient compliance history, and the difference in out-of-pocket expenses.
(Am J Manag Care. 2010;16:S227-S233)
A new generation of multiple sclerosis (MS) therapies is currently emerging. Among them are 4 oral agents, dalfampridine, laquinimod, cladribine, and fingolimod, that have been or likely will be approved for managing patients with MS.1-11 Efficacy data for these new oral agents are impressive and demonstrate that they have the potential to eventually replace injectable treatment options currently used by most patients with MS. With any new treatment regimen, however, there are concerns relating to safety and cost. In addition, patients with MS have poor treatment adherence to the current available therapies12-18 and it is uncertain if the introduction of oral agents will increase patient adherence.
The purpose of this article is to discuss the possible ways that these new agents may affect patient adherence and how placement of these oral agents in managed care organization (MCO)s' formularies may also influence adherence and therefore outcomes.
Current MS Agents and Adherence
For over a decade, 3 disease-modifying drugs (DMDs) have dominated the treatment of MS: interferon beta-1a (IFNB-1a), interferon beta-1b (IFNB-1b), and glatiramer acetate (GA).19-22 These agents, as discussed in the earlier articles,23,24 have shown clinically significant efficacy in treating MS. One of the most notable limitations of the current first-line MS therapies is that they can only be delivered via injection. This is not simply a matter of inconvenience, but a factor that contributes to the poor patient adherence associated with MS treatment.
Patient adherence is a major concern for clinicians treating patients with MS. Rates of discontinuation are between 9% and 20% in the first 6 months of treatment.12-14 Although a recent review by Patti noted that patients are most likely to discontinue treatment within the first 6 months,12 a long-term, follow-up study (ie, 4.2 years) found that discontinuation rates were as high as 46%.15 Many factors influence adherence to MS therapy; the 4 main factors appear to be: (1) lack of efficacy (perceived and real); (2) adverse drug reactions; (3) cost to the patient; and (4) injection anxiety.
Lack of Efficacy: Perceived and Real
One major therapeutic goal for patients with relapsing-remitting MS is the reduction or prevention of further relapses. The natural history of MS leads to a reduction in relapses, as does effective therapy. In addition, many clinical trials with newly diagnosed patients have shown infrequent relapses at baseline. All of these factors often make it hard for patients to know if the therapy is working or not. This can lead to a perception that the medicine is not effective. Adding to that, these agents may not be entirely effective for some patients, and switching may be necessary. The lack of efficacy, whether it is real or not, is a substantial problem in MS therapy adherence. A study by Portaccio et al followed 225 patients with relapsing-remitting MS treated with IF NB and observed that 46% suspended therapy.15 Most of these patients (28%) suspended therapy because of a perceived lack of efficacy. The majority of these patients switched to another MS agent (62 of the 65 patients). The perceived critical importance of injections may be one reason why patients have an unrealistic expectation of efficacy with the current injectable MS agents.
Mohr et al also noted that many patients have unrealistic expectations of efficacy and that this can lead to poor adherence.14 In their interview study involving 99 patients with MS starting on IFNB-1b therapy, they observed that 57% of the patients had unrealistically optimistic expectations regarding reduction in attack rate. Education on the expected outcomes of therapy lowered that percentage to 33%. Among patients who discontinued therapy, 64% had overly optimistic expectations. In contrast, only 28% of the patients who were compliant with therapy expressed overly optimistic expectations.
Adverse Drug Reactions
MS agents are fairly well tolerated, but some adverse events are common and can lead to discontinuation. In the study by Portaccio et al, 15% of patients stopped therapy due to adverse events. Common adverse events included flulike syndrome, injection-site reactions, liver function abnormalities, and depression.15 Interestingly, patients suspending therapy due to adverse events tended to be those with higher relapse rates in the year prior to therapy. So, it is possible that some of these patients assigned a lower benefit-to-risk ratio to the drugs.
Patients who discontinue treatment due to adverse events generally do so in the first year of treatment. A retrospective chart analysis by O'Rourke and Hutchinson determined that flulike symptoms, depression, fatigue, and injection-site reactions were the most common adverse events leading to discontinuation in patients treated with IFNB.16 In patients given GA, common adverse events that led to discontinuation included injection-site reactions, dyspnea, urticaria, vasodilatation, and/or hypersensitivity.21
Since all current MS agents are administered by injection, some patients may not adhere to treatment due to their fear of needles. A recent study by Turner et al noted that injection anxiety was a strong predictor of nonadherence.17 Fortunately, few patients have injection anxiety severe enough to prompt poor adherence. Treadaway et al suggested that injection anxiety was not a major contributor to nonadherence.18 Instead, poor adherence was attributed to: "forgot to take" (>55%), "didn't feel like it" (>20%), and "tired of shots" (>15%). How many of these reasons are masking some anxiety toward injections is not known ().
Patient Responsibility and Cost
It is well-established that the out-of-pocket expenses accrued by a patient will affect adherence. Curkendall et al examined insurance claims of self-insured employer health plans (n = 2285) and calculated that the average out-of-pocket expenses accrued by patients with rheumatoid arthritis for anti-TNF agents were $7.84 ± $14.15 per week.25 This study also showed that adherence was inversely proportional to weekly out-of-pocket expenses. For every $5.50 increase in weekly out-of-pocket expenses, therapy was reduced by 1 week. A recent study by Gleason et al used a database of commercially insured individuals (>13 million persons) and found 2791 patients with MS beginning high-cost therapy.26 The researchers divided the members into 7 groups based on their annual out-of-pocket expenses ($0-$100, $101- $150, $151-$200, $201-$250, $251-$350, $351-$500, or >$500). As shown in Figure 2a and , adherence decreased as out-of-pocket expenses increased. There was a dramatic increase in nonadherence with the highest costs. The minimal increases at the lower cost differentials indicate that small increases in the cost of injectable medicines may have smaller effects on patient adherence. The same may not be true for oral medications. A recent study presented at the Academy of Managed Care Pharmacy's 2010 Annual Meeting and Showcase examined insurance records for patients taking new oral anticancer agents (n = 1909) and observed that costs may be more tightly linked to poor adherence, with abandonment rates rising with each copay step.27 Abandonment rates were 4.9% (77 of 1562) in the $0-$100 group, 6.5% (2 of 31) in the $101-$200 group, 16.1% (9 of 56) in the $201-$500 group, and 28.8% (75 of 260) in the >$500 group. Whether or not a similar pattern will be observed with newer oral MS agents remains to be seen; however, the authors cautioned that health insurers should consider the potential impact of member cost share on abandonment rates when designing pharmacy benefits. Similar results have been observed with oral antidiabetic agents.28 The authors of the diabetes study calculated that every $10 increase in copay rates resulted in a 26% relative increased risk of treatment discontinuation or switching. For patients with lower out-of-pocket expenses (<$10 or $10-$20), the time to discontinuing or switching therapy was longer (200.56 ± 137.98 days and 196.44 ± 136.29 days, respectively) compared with those who had higher out-of-pocket expenses ($20-$30 or >$30) (179.18 ± 131.63 days and 170.9 ± 131.10 days, respectively).
Oral Agents for MS
Of the new generation of oral agents for MS, there are 4 that show particular promise: dalfampridine, laquinimod, cladribine, and fingolimod ().1,2,5-7,10,11,29 These agents were discussed in detail in the previous article.24 A brief summary of our current knowledge on the efficacy and safety of these agents in MS is located below.
Dalfampridine is a potassium channel blocker approved by the US Food and Drug Administration (FDA) for treatment of MS in January 2010. Dalfampridine has a unique indication, specifically for improving walking in patients with MS. It is not indicated to reduce relapses or slow disease progression. Dalfampridine (above the recommended dosage of 10 mg twice daily) is associated with an elevated risk for seizures.30
The immunomodulator laquinimod is structurally similar to linomide, and it is currently being evaluated in 2 phase 3 trials. It has been granted fast-track review status by the FDA. In a phase 2b, double-blind, placebo-controlled study and 2 subsequent extension trials, laquinimod was more effective than placebo in reducing the cumulative number of gadoliniumenhancing lesions.4,6,7 The incidence of serious adverse events was 5.1% for laquinimod 0.3 mg/day, 2.8% for laquinimod 0.6 mg/day, and 4.9% for placebo.47
In the 24-month open-label extension trial, laquinimod was well tolerated and the most frequently reported adverse events were nasopharyngitis (25.8%), back pain (12.4%), and headache (8.1%).
The disease-modifying agent cladribine is a purine nucleoside analogue prodrug. Its active metabolite, 2-chlorodeoxyadenosine triphosphate, disrupts cellular metabolism and inhibits DNA synthesis and repair, and subsequently causes apoptosis.2 CLARI TY (CLAdRI bine Tablets in Treating MS OrallY) was a 96-week, phase 3 trial that showed cladribine to be superior to placebo in lowering relapse rates in patients with MS. However, CLARI TY also revealed significant safety concerns: 4 patients receiving cladribine were diagnosed with solid malignancies during the study. Cladribine was also associated with lymphopenia and neutropenia, and it is teratogenic.2,3,9 In November 2009, the FD A issued a refuse-to-file letter for the New Drug Application (NDA) for cladribine.10 The NDA was resubmitted in June 2010.29
Fingolimod is a sphingosine 1-phosphate-receptor modulator. In a 24-month, phase 3, double-blind, placebo-controlled study (FREDOMS [FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis] trial), fingolimod significantly reduced the relapse rate and risk of disability progression compared with placebo.11 In a 12-month, double-blind study that compared fingolimod with IFNB-1a, patients receiving fingolimod had greater reductions in relapse rates and improved MRI outcomes, although disability progression was similar between the 2 treatment groups.1 Two deaths and 4 cases of breast cancer occurred in patients receiving fingolimod compared with no deaths or cases of breast cancer in the IFNB-1a group. The incidence of localized skin cancer was also higher in those given fingolimod. It is uncertain whether treatment with fingolimod was related to these adverse events.1
Oral Agents and Adherence
In terms of adherence, oral drugs have a potential advantage over injected therapies. Generally, they are perceived to be better tolerated, physically and psychologically. Studies involving patients with diabetes31 or cancer32 have shown that patients prefer receiving medication in the form of inhaled or tablet preparations, rather than an injectable one. In patients with cancer, 63% preferred tablets compared with 24% who preferred an injection.32 Among the patients receiving an injectable medication, 38% were anxious about receiving injections, whereas 17% felt that their anxiety or dislike of needles might lead them to avoid injections. In contrast, most patients (94%) taking oral agents did not think it interfered with their daily lives, although 13% reported that they deliberately did not take their tablets on occasion.
Whether the same preference and behavior will hold true for oral MS agents has yet to be studied, but it is likely that oral agents will be the preferred formulation of most patients. One possible problem with oral medications is that they may be perceived as less effective than injections. This was recently seen by Halfdanarson and Jatoi,33 who commented that many of the patients' perceptions of oral chemotherapy agents, including their perceptions of their efficacy, are inaccurate and may lead to poor adherence.
Role of Managed Care Organizations in Appropriate Utilization and Access to New MS Agents
The key factors for placement of these new agents in formularies are 3-fold: (1) Are they safer than current agents? (2) Are they more effective than current agents? (3) Are they less expensive than current agents? At present, we do not entirely know the answers to these questions. However, some data are available. Cohen et al recently published data from the TRANSFORMS study.1 This 12-month, double-blind, double-dummy study compared the efficacy and safety of oral fingolimod (0.5 mg or 1.25 mg daily) with IF NB-1a (30 μg intramuscularly once weekly) in patients with relapsingremitting MS (n = 1153). Both doses of fingolimod were associated with significantly lower relapse rates versus IFNB- 1a (P <.001 for both doses), but disability progression was not significantly different among groups. Both treatments were well tolerated.1
It is likely that the oral medications will cost patients less out of pocket compared with the injectable medications because of the current tier system, in which most MCOs place injectable medications in specialty tiers. However, a recent trend is to place expensive oral cancer therapies in the highest tiers as well. If oral MS agents are placed in the more traditional third and fourth tiers, it is very likely that a positive impact on adherence will be seen in patients with MS26 based on comparable data in oncology and diabetes.27,28,31,32 Furthermore, if patient adherence improves, total medical costs will likely decrease. A study by Birnbaum et al compared workers with MS receiving DMDs (n = 258) with those not receiving DMDs (n = 322).34 Treatment with DMD s led to reduced medical and indirect costs ().
In the United States, the average annual cost for the direct care of MS is $12,879 (2004 dollars).35 Cost is largely dependent on the overall health of the patient, and among those patients reporting conditions such as abnormality of gait, ataxia, convulsions, malaise or fatigue, optic neuritis, or spasms, total costs were significantly higher. The extent to which these conditions can be avoided by better adherence with oral medications remains to be seen.
The introduction of oral agents for MS has the potential to greatly impact patients, clinicians, and MCOs. Several factors will likely determine the extent to which third-party payers make these therapies available to patients. At present, it is expected that oral medications will require less out-of-pocket expenses for members compared with current injectable medications. This, in turn, will likely lead to improved adherence and ultimately reduce overall medical costs.
Preliminary results indicate that oral medications are as effective as, or possibly more effective than, current injectable formulations. It is hoped that improved outcomes will translate into higher real and perceived efficacy rates and contribute to improved adherence. Patients newly diagnosed with MS may prefer oral agents when they become available. It is difficult to predict their uptake at this time. In patients currently receiving therapy, clinicians may be more reluctant to alter successful therapy. The decision to switch established patients from injectable to oral medications will likely be a personal matter that takes into account the efficacy and tolerability of the patient's existing therapy, their compliance history, and differences in out-of-pocket expenses.
Author Affiliations: University of Arizona, College of Pharmacy, Tucson, AZ
Funding Source: Financial support for this work was provided by Teva Neurosciences, Inc.
Author Disclosure: Dr Lipsy reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and supervision.
Address correspondence to: Robert J. Lipsy, PharmD, FASHP, BCPS, University of Arizona, College of Pharmacy, 8530 E Green Acres Dr, Tucson, AZ 85715. E-mail: firstname.lastname@example.org.
1. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415.
2. Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-426.
3. Cook S, Vermersch P, Comi G, et al. Safety of cladribine tablets in relapsing-remitting multiple sclerosis (RRMS): results from the CLARITY study, a 96-week, phase III, double-blind, placebocontrolled trial. Meeting Abstract. European Neurological Society (ENS), Milan, Italy, June 20-24, 2009. J Neurol. Abstract 256:S128.
4. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371:2085-2092.
5. Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics, Inc; 2010.
6. Comi G, Abramsky O, Arbizu T, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 9-month double-blind active extension of the multicenter, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler. 2008;14:S37.
7. Comi G, Abramsky O, Arbizu T, et al. Long-term open extension of oral laquinimod in patients with relapsing multiple sclerosis shows favourable safety and sustained low relapse rate and MRI activity. Presented at European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting; September 9-12, 2009; Düsseldorf, Germany.
8. Spurgeon S, Yu M, Phillips JD, Epner EM. Cladribine: not just another purine analogue? Expert Opin Investig Drugs. 2009;18(8): 1169-1181.
9. Leustatin (cladribine injection) [package insert]. Bedford, Ohio: Bedford Laboratories; June 2005.
10. Merck KGaA. Merck KGaA receives refuse to file letter from FDA on cladribine tablets new drug application. November 30, 2010. http://www.merck.de/en/media/extNewsDetail.html?newsId=4E1C821B42D7479CC25767E003BD45B&newsType=1. Accessed May 2, 2010.
11. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.
12. Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010;4:1-9.
13. Tremlett HL, Oger J. Interrupted therapy: stopping and switching of the beta-interferons prescribed for MS. Neurology. 2003;61:551-554.
14. Mohr DC, Goodkin DE, Likosky W, et al. Therapeutic expectations of patients with multiple sclerosis upon initiating interferon beta-1b: relationship to adherence to treatment. Mult Scler. 1996;2(5):222-226.
15. Portaccio E, Zipoli V, Siracusa G, Sorbi S, Amato MP. Long-term adherence to interferon beta therapy in relapsing-remitting multiple sclerosis. Eur Neurol. 2008;59:131-135.
16. O'Rourke KE, Hutchinson M. Stopping beta-interferon therapy in multiple sclerosis: an analysis of stopping patterns. Mult Scler. 2005;11(1):46-50.
17. Turner AP, Williams RM, Sloan AP, Haselkorn JK. Injection anxiety remains a long-term barrier to medication adherence in multiple sclerosis. Rehabil Psychol. 2009;54(1):116-121.
18. Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol. 2009;256(4):568-576.
19. Avonex [package insert]. Cambridge, Mass: Biogen Idec, Inc; 2008.
20. Betaseron [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals, Inc; 2008.
21. Copaxone [package insert]. Kansas City, Mo: Teva Neuroscience Inc; 2009.
22. Rebif [package insert]. Rockland, Mass: EMD Serono, Inc; 2009.
23. Markowitz CE. The current landscape and unmet needs in multiple sclerosis. Am J Manag Care. 2010;16(suppl):S211-S218.
24. Fox EJ. Emerging oral agents for multiple sclerosis. Am J Manag Care. 2010;16(suppl):S219-S226.
25. Curkendall S, Patel V, Gleeson M, Campbell RS, Zagari M, Dubois R. Compliance with biologic therapies for rheumatoid arthritis: do patient out-of-pocket payments matter? Arthritis Rheum. 2008;59(10):1519-1526.
26. Gleason PP, Starner CI, Gunderson BW, Schafer JA, Sarran HS. Association of prescription abandonment with cost share for high-cost specialty pharmacy medications. J Manag Care Pharm. 2009;15(8):648-658.
27. Starner CI, Gleason PP, Gunderson BW. Oral Oncology Prescription Abandonment Association with High Out-of-Pocket Member Expense Oral Agents for MS. Poster presented at: Academy of Managed Care Pharmacy's 22nd Annual Meeting & Showcase; April 7-10, 2010; San Diego, Calif.
28. Barron J, Wahl P, Fisher M, Plauschinat C. Effect of prescription copayments on adherence and treatment failure with oral antidiabetic medications. P T. 2008;33(9):532-553.
29. Reuters. Merck KGaA again seeks U.S. nod for MS pill. Reuters Web page. http://www.reuters.com/article/idUSLDE62O0CG20100608. Accessed July 17, 2010.
30. US Food and Drug Administration. NDA Approval Letter. January 22, 2010. AMPYRA, NDA no. 022250. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022250s000REMS.pdf. Accessed August 4, 2010.
31. Bellary S, Barnett AH. Inhaled insulin (Exubera): Combining efficacy and convenience. Diab Vasc Dis Res. 2006;3(3):179-185.
32. Fallowfield L, Atkins L, Catt S, et al. Patients' preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol. 2006;17:205-210.
33. Halfdanarson TR, Jatoi A. Oral cancer chemotherapy: the critical interplay between patient education and patient safety. Curr Oncol Rep. 2010;12(4):247-252.
34. Birnbaum HG, Ivanova JI, Samuels S, et al. Economic impact of multiple sclerosis disease-modifying drugs in an employed population: direct and indirect costs. Curr Med Res Opin. 2009;25(4):869-877.
35. Prescott JD, Factor S, Pill MW, Levi GW. Descriptive analysis of the direct medical costs of multiple sclerosis in 2004 using administrative claims in a large nationwide database. J Manag Care Pharm. 2007;13(1):44-52.