Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice

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1 A Datamonitor report Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice Published: Dec-06 Product Code: Providing you with: An overview of epidemiology, presentation, referral and diagnostic assessment in multiple sclerosis A breakdown of first-line to fourth-line treatment regimens and treatment choice according to disease category Influences on treatment choice and perception of current drug therapies Use this report to... Evaluation of unmet needs and future outlook Target prescribers more effectively, through an understanding of prescribing behavior and its influences

2 Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice Introduction The disease-modifying drugs are considered by physicians to represent a significant advance for the management of MS. However, none is fully effective and there are problems with regards to side effects, dosing regimens and cost. Tysabri, a novel once-monthly drug is expected to be an improvement in terms of efficacy; however, there remains a concern over side effects and long-term safety. Multiple sclerosis is a chronic autoimmune disease characterized by demyelination of nerve fibres, leading to nerve damage and associated symptoms of fatigue, cognitive and visual impairments. Six disease modifying drugs are now available in one or more of the six major markets for the treatment of MS. This report examines how neurologists are utilizing established treatments and how new treatments such as Tysabri fit into the treatment algorithm. Key findings and highlights Multiple sclerosis affects less than 1 per cent of the population in the US and Europe. Despite the high level of general awareness of the disease, neurologists estimate less than half of individuals present at the time they suffer from first symptoms and it can take more than one year to receive an accurate diagnosis. Numerous strategies, including switching to an alternative interferon beta, are adopted as second-line therapy. Although not favored by opinion leaders or US neurologists, combining two disease-modifying drugs is popular in the 5EU markets. Given the willingness of neurologists to try this strategy, further trials are required. Tysabri is perceived by neurologists as offering a clear improvement in terms of diseasemodifying efficacy. However, a lack of long-term safety data will ensure for the moment it remains positioned as a last-line therapy for relapse-remitting patients who have failed firstand second-line treatment with interferon beta or glatiramer acetate. Reasons to buy Target prescribers more effectively, through an understanding of prescribing behavior and its influences Validate new product forecasting based on diagnosis and treatment rates, and the likely rate of uptake for new products Benchmark brand awareness and perceptions surrounding product positioning in order to formulate competitive lifecycle management strategies Contact us... From Europe: tel: fax: hcmarketing@datamonitor.com From the US: tel: fax: hcmarketing@datamonitor.com From Asia Pacific: tel: fax: apinfo@datamonitor.com

3 Sample pages from the report Introduction and Scope neurologists treatment choice at first, second, third and fourth line; neurologists treatment choice according to clinical type (severity) of disease; neurologists treatment choice for treatment of relapse; impact of drug attributes and side effects on patients discontinuing and/or switching therapies; current and future roles of Novantrone (mitoxantrone) and Tysabri (natalizumab) in the management of MS. Key prescribing influences Epidemiology and Patient Key factors influencing drug choice in the management Segmentation of MS; performance of disease-modifying drug therapies in terms of factors such as efficacy, onset of action, side effects, safety, dosing frequency, delivery method, cost and reimbursement. Well, people are all categorized, you know, differently. Those applications we attempt to use they re important as we put people in Unmet needs clinical trials. We try and match people and you know it s true that when we see people we give them sort of definitions at first. Then, over time Current major clinical unmet needs; they often move and change. Those are reasonable definitions that most people use, yes. recommendations for how to address unmet needs. US opinion leader Epidemiology of multiple sclerosis Young female adults are most at risk of developing multiple sclerosis Presentation and Diagnosis Interviewed neurologists were asked to estimate (on average) at what age do their MS patients report experiencing their first episode of MS. Figure 7 shows that the most frequent average age in the US and 5EU for MS patients to experience their first Datamonitor believes there are two key reasons that may explain why less than half episode is between 20 and 39 years of age. of patients present to a physician at the time they suffer from first symptoms of MS. Firstly, the initial symptoms may not be sufficient to cause alarm to the patient and Figure 7: Age that MS patients experience their first episode of MS, therefore deemed to be of a serious nature by the patient. Secondly, the initial symptoms may resolve almost spontaneously; with many patients not experiencing a 40 relapse of symptoms for several months (or even years). 35 Stakeholder Insight: Multiple Sclerosis 30 it all depends upon what the symptom is [if a patient presents with the Datamonitor (Published 12/) 25 Page 15 first symptoms of MS]. If somebody presents with optic neuritis (with This report is a licensed product and is not to be photocopied 20 blindness in one eye) they re not going to ignore it; they re going to go to 15 the doctor and be seen. If they present with a paralysis of an arm or a leg 10 they re going to go to the doctor right away. But if they present with some 5 numbness or tingling they may not go and be seen. So it s going to vary 0 depending upon what the first symptom / what the first presentation Under is and overhow bad the initial presentation is. Age at which patients in US and 5EU markets experience their first episode of MS US opinion leader It is not surprising then that common presenting symptoms in MS include optic Source: Datamonitor, Stakeholder Insight: Multiple Sclerosis survey (Q1.8) neuritis, D A T A Mparesthesias, O N I T O R weakness, and impaired coordination. Frequently accompanying signs and symptoms include bladder urgency or retention, constipation, sexual dysfunction, fatigue, depression, diplopia, gait and limb ataxia, Figure 8 provides a more detailed breakdown of the data displayed and Lhermitte s in Figure sign 7 (electrical sensation down the spine on neck flexion) (Calabresi, breaking it down by the proportion of patients within each country 2004). that fall into each % of MS patient population Stakeholder Insight: Multiple Sclerosis So, unless a patient is equipped to recognize the initial symptoms of MS, the Datamonitor (Published 12/) Page 25 condition may be overlooked and the patient may go several months before This report is a licensed product and is not to be photocopied presenting to a physician (and ultimately being diagnosed and prescribed treatment). This hypothesis, that patients can take several months to present to a physician, is supported by the responses gathered from interviewed neurologists. Figure 13 shows that respondents estimated the average time from onset of first symptoms of MS to initial presentation to a physician is between five and nine months. Stakeholder Insight: Multiple Sclerosis Datamonitor (Published 12/) Page 38 This report is a licensed product and is not to be photocopied...i think [the role of mitoxantrone] could change in two ways. If we can develop secure drugs to protect the heart against heart damage we might be able to extend its use. That would be one way; and the other way is if newer other agents come along that are safer, then I think Novantrone will be used less and less... Key opinion leader, Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice

4 Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice Table of contents ABOUT DATAMONITOR HEALTHCARE About the CNS pharmaceutical analysis team EXECUTIVE SUMMARY Scope of the analysis Datamonitor insight into the multiple sclerosis market INTRODUCTION AND SCOPE Coverage of the Stakeholder Insight Survey - Disease definition & epidemiology - Presentation and diagnosis - Treatment - Key prescribing influences - Unmet needs COUNTRY TREATMENT TREES US France Germany Italy Spain UK EPIDEMIOLOGY AND PATIENT SEGMENTATION Disease definition - There is no universal course for multiple sclerosis - Researchers have attempted to classify multiple sclerosis according to the clinical course of the disease Epidemiology of multiple sclerosis - Young female adults are most at risk of developing multiple sclerosis - Other genetic and environmental factors appear to play a role in onset of MS - Prevalence of multiple sclerosis - The majority of patients suffer from relapse remitting multiple sclerosis PRESENTATION AND DIAGNOSIS Presentation - Symptoms typically first emerge in relapsingremitting course of multiple sclerosis - Fatigue and depression are most common symptoms - Less than half of new patients present to a physician at the time they suffer from first symptoms of MS - The majority of patients present to a primary care physician Diagnosis - Diagnostic criteria - Only half of patients with multiple sclerosis symptoms receive an accurate diagnosis on initial presentation to a physician TREATMENT OPTIONS AND GUIDELINES Treatment options - Symptomatic treatment - Disease-modifying drug treatments - Acute relapse treatment Treatment guidelines - There are no official international guidelines for the chronic treatment of multiple sclerosis and use of disease-modifying therapies - Several treatment guidelines are in place for the management of acute relapses of multiple sclerosis PRESCRIBING TRENDS IN MULTIPLE SCLEROSIS Treatment of multiple sclerosis with diseasemodifying drug treatments - Across all stages of MS, 53 per cent of total diagnosed patients receive disease modifying therapies - First-line therapy - Second-line therapy - Third-line therapy - Fourth-line therapy - Summary of treatment lines according to country - Novantrone (mitoxantrone) - Tysabri (natalizumab) Treatment for acute relapse of multiple sclerosis - Steroids have historically been the mainstay of treatment - Interviewed neurologists consider intravenous methylprednisolone the number one treatment for acute relapses - Interviewed neurologists use numerous other therapies Contact us... From Europe: tel: fax: hcmarketing@datamonitor.com From the US: tel: fax: hcmarketing@datamonitor.com From Asia Pacific: tel: fax: apinfo@datamonitor.com

5 INFLUENCING FACTORS ON PRESCRIBING TRENDS IN MULTIPLE SCLEROSIS Current market overview - The disease-modifying drugs have continued to perform well in terms of revenues Factors driving prescribing choice - Disease-modifying efficacy is the number one influential factor - Side effects are accepted as an inherent outcome of taking any disease-modifying drug but the nature and severity of the side effects are key influencers - Speed of onset of action is desirable - Ability to combine a drug with other therapies is heavily influenced by prescribing practices and trends - Drugs are used over a long period of time and must be considered safe for extended use - Dosing frequency and delivery methods may compromise patient compliance - In Europe cost typically has a greater influence on prescribing choice than formulary / reimbursement status - In the US formulary / reimbursement status is considered a greater influence on prescribing choice than cost IMPROVING TREATMENT OUTCOMES Performance of prescribed drugs against attributes - Neurologists in the US and UK are most satisfied with current therapies - Avonex is perceived to perform slightly better across all attributes than the other diseasemodifying therapies - Tysabri is perceived to perform best on disease modification efficacy - Higher dosed interferons are perceived to have a faster onset of action - None of the drugs are perceived to have a very good side-effect profile - Ability to combine with other therapies - A higher dosing frequency is perceived to more efficacious - Intravenous delivery methods are perceived less favorable - Interferons and Copaxone are considered safe for extended use - There is room to improve patient treatment compliance - Formulary / reimbursement status - Drugs with increased disease-modifying efficacy are considered to perform better on cost Reasons for discontinuing therapy/switching to alternative drug therapy - Lack of efficacy and intolerable side effects are the key reasons for discontinuing or switching treatment - Occurrence of any side effect if poorly managed can lead to treatment discontinuation Unmet needs APPENDIX TABLES Table 1: Prevalence of MS in the US and 5EU markets, Table 2: Most common signs and symptoms of RRMS, Table 3: Poser criteria for the diagnosis of clinically definite MS and laboratory supported MS Table 4: Key facts for marketed disease-modifying drug for MS Table 5: Key recommendations for treatment of multiple sclerosis relapses: EFNS task force: Table 6: Percentage of patients diagnosed with each stage of MS who receive disease-modifying drug therapy, Table 7: Percentage of all interviewed neurologists who prescribe each disease-modifying drug/ combination for first-line treatment of MS, Table 8: Percentage of all interviewed neurologist's patients who are prescribed disease modifying drugs / combinations for first-line treatment of MS, Table 9: Proportion of patients prescribed disease modifying treatments as monotherapy versus combination therapy at first-line, Table 10: Percentage of all interviewed neurologists who prescribe each disease-modifying drug/ combination for second-line treatment of MS, Table 11: Percentage of all interviewed neurologist's patients who are prescribed disease modifying drugs /combinations for second-line treatment of MS, Table 12: Proportion of patients prescribed diseasemodifying treatments as monotherapy versus combination therapy at second-line, Table 13: Percentage of all interviewed neurologists who prescribe each disease-modifying drug / combination for third-line treatment of MS, Table 14: Percentage of all interviewed neurologist's patients who are prescribed disease modifying...many [neurologists] are concerned about it [the potential risk of PML with Tysabri]. Some are not that concerned about it and, unfortunately, we don't have much data to go on. We've only had three cases and essentially we need more time and more data... Key Opinion Leader, Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice

6 Stakeholder Insight: Multiple Sclerosis Disease-modifying Efficacy and Side Effects Guide Treatment Choice drugs /combinations for third-line treatment of MS, Table 15: Proportion of patients prescribed disease modifying treatments as monotherapy versus combination therapy at third-line, Table 16: Percentage of all interviewed neurologists who prescribe each disease-modifying drug / combination for fourth-line treatment of MS, Table 17: Percentage of all interviewed neurologist's patients who are prescribed disease modifying drugs /combinations for fourth-line treatment of MS, Table 18: Proportion of patients prescribed disease modifying treatments as monotherapy versus combination therapy at fourth-line, Table 19: Percentage of total mitoxantrone prescriptions that fall under each treatment strategy, Table 20: Percentage of total mitoxantrone prescriptions that interviewed neurologists in the US and 5EU markets would ideally like to see fall under each treatment strategy in the future treatment of MS, Table 21: Percentage of neurologists in each country who provided each rating, Table 22: Percentage of neurologists in each country who provided each rating, Table 23: Likely use of how Tysabri will be prescribed where 1= strongly disagree and 5= strongly agree, Table 24: Total of mean scores for likely use of how Tysabri will be prescribed- before, with or after other disease modifying therapies, Table 25: Percentage of treated patients receiving therapy specifically for the treatment of a relapse of MS, Table 26: Sales of disease-modifying drugs across the seven major markets, 2005 Table 27: Factors which influence drug choice for the management of multiple sclerosis, Table 28: Overall performance of each disease-modifying drug against 10 attributes according to interviewed neurologists in the US and 5EU markets, Table 29: Performance of disease-modifying drugs on disease modification efficacy (where 1= very poor performance; 10 = very good performance), Table 30: Performance of disease-modifying drugs on onset of action (where 1= very poor Table 31: Performance of disease-modifying drugs on side-effect profile (where 1= very poor Table 32: Performance of disease-modifying drugs on ability to combine with other therapies (where 1= very poor performance; 10 = very good performance), Table 33: Dosing frequency of disease modifying drugs Table 34: Performance of disease-modifying drugs on dosing frequency (where 1= very poor Table 35: Performance of disease-modifying drugs on delivery method (where 1= very poor Table 36: Performance of disease-modifying drugs on safe for extended use (where 1= very poor Table 37: Performance of disease-modifying drugs on patient compliance (where 1= very poor Table 38: Performance of disease-modifying drugs on formulary / reimbursement status (where 1= very poor performance; 10 = very good performance), Table 39: Cost analysis of disease-modifying therapies (based on patient receiving treatment for one year) Table 40: Performance of disease-modifying drugs on cost (where 1= very poor performance; 10 = very good performance), Table 41: Reasons for patients discontinuing a therapy / switching to an alternative drug therapy on a scale of 1 to 10, where 1 = factor of low influence and 10 = factor of high influence, Table 42: Influence of side effects on discontinuing a therapy / switching to an alternative drug therapy, where 1 = factor of low influence and 10= factor of high influence, Table 43: Priority assigned by interviewed neurologists to unmet needs or improvements which need to be made in the diagnosis, pharmacological treatment, management or awareness of MS, by country, Table 44: US physician sample breakdown, Table 45: France physician sample breakdown, Table 46: Germany physician sample breakdown, Table 47: Italy physician sample breakdown, Table 48: Spain physician sample breakdown, Table 49: UK physician sample breakdown, Contact us... From Europe: tel: fax: hcmarketing@datamonitor.com From the US: tel: fax: hcmarketing@datamonitor.com From Asia Pacific: tel: fax: apinfo@datamonitor.com

7 FIGURES Figure 1: US MS patient population split by physician estimated diagnoses by subtype, diseasemodifying therapy treated population and firstand second-line disease-modifying drug usage, Figure 2: France MS patient population split by physician estimated diagnoses by subtype, diseasemodifying therapy treated population and firstand second-line disease-modifying drug usage, Figure 3: Germany MS patient population split by physician estimated diagnoses by subtype, disease-modifying therapy treated population and first- and second-line disease-modifying drug usage, Figure 4: Italy MS patient population split by physician estimated diagnoses by subtype, diseasemodifying therapy treated population and firstand second-line disease-modifying drug usage, Figure 5: Spain MS patient population split by physician estimated diagnoses by subtype, diseasemodifying therapy treated population and firstand second-line disease-modifying drug usage, Figure 6: UK MS patient population split by physician estimated diagnoses by subtype, diseasemodifying therapy treated population and firstand second-line disease-modifying drug usage, Figure 7: Age that MS patients experience their first episode of MS, Figure 8: Percentage of patients who experience their first episode of MS within each specific age range, Figure 9: Prevalence rate of multiple sclerosis in the general population in each of the US and 5EU markets, Figure 10: Percentage of diagnosed MS patients who suffer from each type of MS, Figure 11: Emergence of symptoms with disease progression Figure 12: Percentage of new patients who suffer from their first symptoms of multiple sclerosis that present to a physician, Figure 13: Average time from the onset of symptoms of multiple sclerosis to initial presentation to a physician, Figure 14: Stages in the diagnosis of MS leading to a confirmed diagnosis Figure 15: Percentage of patients presenting to a physician with multiple sclerosis symptoms that receive an accurate diagnosis, Figure 16: The average time from presentation to a physician to receiving an accurate diagnosis of multiple sclerosis, Figure 17: Timeline: launch dates of disease modifying therapies for treatment of MS, Figure 18: Percentage of patients diagnosed with each stage of MS who receive disease-modifying drug therapy, Figure 19: Percentage of patients receiving first-line disease-modifying therapy that move to second-line therapy, Figure 20: Average number of months patient continues on first-line therapy before moving to secondline therapy, Figure 21: Percentage of patients receiving second-line disease-modifying therapy that move to thirdline therapy, Figure 22: Average number of months patient continues on second-line therapy before moving to thirdline therapy, Figure 23: Percentage of patients receiving third-line disease-modifying therapy that move to fourthline therapy, Figure 24: Average number of months patient continues on third-line therapy before moving to fourthline therapy, Figure 25: Interviewed neurologists who prescribe mitoxantrone to their MS patients, Figure 26: Physicians who would consider prescribing Tysabri for the treatment of multiple sclerosis when it is launched / relaunched, Figure 27: Mean score indicating the extent to which Tysabri administered as an infusion would be a barrier to use, Figure 28: Mean score indicating the extent to which PML with Tysabri would be a barrier to use, where 1= a significant barrier and 5 = no barrier at all, Figure 29: Patient group that interviewed neurologists are likely to prescribe Tysabri for, Figure 30: Percentage of treated patients in the US and 5EU markets receiving therapy specifically for the treatment of a relapse of MS, Figure 31: Overview brand map of attributes versus brand perception, Figure 32: Priority of clinical unmet needs in MS according to interviewed neurologists, where 1 = unmet need of low priority and 10 = high priority, Contact us... From Europe: tel: fax: hcmarketing@datamonitor.com From the US: tel: fax: hcmarketing@datamonitor.com From Asia Pacific: tel: fax: apinfo@datamonitor.com

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