AFFIRM IN FOCUS AN INTERACTIVE OVERVIEW START HERE

Transcription

1 AFFIRM IN FOCUS AN INTERACTIVE OVERVIEW START HERE

2 INTENDED USE The information in this module is being provided to you to increase your knowledge and understanding of the AFFIRM a study. Although this study is referred to in the TYSABRI Prescribing Information (PI), not all of the data is included in the PI and not all of the data from AFFIRM is currently approved for promotion. It is important to remember that any discussions you have with your customers about the data from this study must be limited to the content included in PRC-approved materials and the TYSABRI PI. a Defined as NAtalizumab Safety and EFFIcacy in Relapsing-Remitting MS. 2

3 THE STORY BEHIND AFFIRM AFFIRM is the pivotal phase III clinical trial of TYSABRI as monotherapy in the treatment of MS. This is the same study that is referred to as MS1 in the Prescribing Information for TYSABRI. This interactive tool is intended to help you put AFFIRM and its results in perspective so that you can continue to effectively communicate the data to your customers and respond to their questions. A strong understanding of the study is essential because AFFIRM is the foundation for all clinical data presented in TYSABRI materials. Navigating This Document Throughout the document you will notice some hotlinks in running text. Click on these for a more in-depth definition or explanation of the concept or clinical measure being discussed. Where possible, there are also reference hotlinks that will open a PDF of the clinical reprint from which the data are taken. Select the indicated bookmark within the PDF to be taken to the page on which the data appear. You may use the and buttons to navigate though the document or click on one of the tabs above to go to a particular section. 3

4 Study Population Study Endpoints Study Procedures THE AFFIRM STUDY POPULATION Demographics AFFIRM enrollment was open to men and women with a diagnosis of relapsing MS Between the ages of 18 and 50 years With an EDSS score between 0 and 5.0 With an MRI showing lesions consistent with MS Who had 1 medically documented relapse in the 12 months prior to study enrollment Excluded from the study were patients with diagnoses other than relapsing MS and those who had been treated previously with certain medications. Among those excluded were patients Diagnosed with primary progressive, secondary progressive, or progressive relapsing MS Treated in the 6 months prior to study enrollment with interferon beta, glatiramer acetate, cyclosporine, azathioprine, methotrexate, or IV immune globulin ly treated with interferon beta and/or glatiramer acetate for longer than 6 months A relapse within 50 days before administration of study drug These data are presented in the Polman reprint. Please refer to that reprint for further details. 4

5 Study Population Study Endpoints Study Procedures THE AFFIRM STUDY POPULATION, cont d Baseline Disease Mean EDSS score at baseline was 2.3, with median disease duration of 5.0 years. All patients met the McDonald criteria for the diagnosis of MS. Patients also exhibited other signs of serious disease at baseline. 95% 95% of TYSABRI patients had 2 relapses and 1 lesion prior to study entry of TYSABRI patients had 9 T2 lesions at baseline 84% of TYSABRI patients had 2 relapses and 2 lesions prior to study entry These data are presented in the Polman reprint. Please refer to that reprint for further details. In addition, 49% of patients had 1 Gd+ lesion at baseline and 41% had at least 2 relapses in the year prior to study entry. 5

6 Study Population Study Endpoints Study Procedures THE AFFIRM STUDY POPULATION, cont d Randomization AFFIRM enrolled 942 patients who were randomized in a 2:1 ratio. 800 Number of patients (N=942) TYSABRI 300 mg These data are presented in the Polman reprint. Please refer to that reprint for further details. Patients received an IV infusion of assigned study medication every 4 weeks for up to 116 weeks. a a Patients had the option of taking concomitant rescue medication if they experienced disability progression that was sustained for at least 12 weeks. 6

7 Study Population Study Endpoints Study Procedures AFFIRM ASSESSMENTS Numerous study objectives were identified in AFFIRM. Following are all the primary and secondary endpoints of AFFIRM that were prospectively defined in the study protocol. Also listed are prospectively defined tertiary endpoints and other analyses that have been used in promotion. Primary Endpoints Rate of clinical relapse 1 year a Probability of disability progression sustained for 12 weeks 2 years a Secondary Endpoints 1 year a Proportion of MRI activity relapse-free patients 2 years volume of T2 lesions number of new MRI activity T1 hypointense lesions number of new or enlarging T2 hyperintense lesions Rate of clinical relapsea number of Gd+ lesions Additional Endpoints Tertiary Endpoints Safety and tolerabilitya Quality-of-life assessmentb Other Analyses Probability of disability progression sustained for 24 weeks a a Reported in Polman et al. N Engl J Med b Reported in Rudick et al. Ann Neurol c Reported in Hutchinson et al. J Neurol Progression of disability as measured by the MS Functional Composite Retrospective analyses in the subgroup of patients with highly active MS c As defined in the study protocol Clinical relapse required new or recurrent neurologic symptoms that lasted 24 hours, as well as new neurologic signs observed by the examining neurologist Disability progression was an increase of 1.0 on the EDSS (from a baseline score of 1.0) or an increase of 1.5 (from a baseline score of 0) 7

8 Study Population Study Endpoints Study Procedures ASSESSMENT PROCEDURES Each study site had 2 primary neurologists (with a designated backup for each). Treating neurologists were responsible for patient care, which included treating relapse and addressing adverse events Examining neurologists performed objective assessments (EDSS and neurologic examination) at each study visit Schedule of Study Assessments Study Week Study drug administration Clinical evaluation MRI scans In AFFIRM, statistically significant results were indicated by a p value less than a a Statistical significance is a method of determining that an event is unlikely to have occurred merely by chance. As it applies to the AFFIRM study, for example, an efficacy result that is statistically significant for TYSABRI vs placebo means that the benefit seen is due to the effects of TYSABRI and does not just occur by happenstance. A threshold of p<0.05 is commonly used as the limit for statistical significance. 8

9 Efficacy Safety EFFICACY IN AFFIRM AFFIRM is the foundation for all efficacy data presented in TYSABRI materials. Primary Efficacy Endpoint: Rate of Clinical Relapse As reported by Polman et al, the relapse rate for patients treated with TYSABRI was 68% lower than for patients taking placebo at both the 1-year primary endpoint and at 2 years (a secondary endpoint of the study). Annualized rate of relapse p<0.001 The data at left show a different analysis than you are used to seeing in promotion (see the 67% relative reduction vs. 41% placebo data below), in which we only show the result at 2 years. The results at left were calculated using a statistical model that adjusts for baseline characteristics such as EDSS score, number of Gd+ lesions, age, and the number of relapses in the year prior to study entry. The data shown in promotion (and that are in the Prescribing Information for TYSABRI) are calculated as the mean relapse rate per patient (the actual number of relapses for each patient divided by the number of years of follow-up). However, the relative relapse rate remains nearly the same. 0.0 TYSABRI TYSABRI Year 1 Year 2 67 % These data are presented in the Polman reprint. Please refer to that reprint for further details. relative reduction in relapse rate vs placebo over 2 years Annualized relapse rate at 2 years (n=315) 0.22 TYSABRI (n=627) p<0.001 This information is included in the Prescribing Information These data are presented in the Polman reprint. Please refer to that reprint for further details. 9

10 Efficacy Safety EFFICACY IN AFFIRM, cont d Primary Efficacy Endpoint: Sustained Disability Progression Polman et al report that TYSABRI-treated patients had a 42% relative reduction in disability progression (sustained for 12 weeks) at the 2-year primary endpoint. Remember that when you discuss these data with physicians, you must specify that they demonstrate the effect of TYSABRI on sustained progression of physical disability. 42 % relative reduction vs placebo in the risk of increased physical disability sustained for 12 weeks, as assessed over 2 years Proportion with progression sustained for 12 weeks p< % TYSABRI 17% Hazard ratio= This information is included in the Prescribing Information Weeks These data are presented in the Polman reprint. Please refer to that reprint for further details. The data above are shown as a Kaplan-Meier curve, a commonly used statistical method for predicting the probability of an event happening. Dividing the TYSABRI value (17%) by the placebo value (29%) results in a hazard ratio (0.58), which indicates the difference in probability between the 2 groups. Subtracting 0.58 from 1.00 (which represents 100% probability) yields a relative risk reduction of 42%. 10

11 Efficacy Safety EFFICACY IN AFFIRM, cont d Secondary Efficacy Endpoint: Proportion of Relapse-Free Patients The proportion of patients who were relapse-free was significantly higher in the TYSABRI population at both 1 year and 2 years. These data, which show a particularly strong placebo effect on this measure, were reported by Polman et al (2006) p< Relapse-free patients (%) TYSABRI TYSABRI Year 1 Year 2 These data are presented in the Polman reprint. Please refer to that reprint for further details. The 2-year data above are shown in promotion with the following graphic. NO Relapses 67% of TYSABRI patients were free of relapses vs 41% of placebo patients This information is included in the Prescribing Information 11

12 Efficacy Safety EFFICACY IN AFFIRM, cont d Secondary Efficacy Endpoint: MRI Activity Treatment with TYSABRI resulted in 92% relative reduction in the number of new or enlarging Gd+ lesions at both 1 year and 2 years. These results were reported by Polman et al (2006). Mean number of Gd+ lesions p< TYSABRI 0.1 TYSABRI Year 1 Year 2 These data are presented in the Polman reprint. Please refer to that reprint for further details. The same 2-year data shown above have been presented in promotion using the graphic below. 92 % reduction in the mean number of Gd+ lesions in TYSABRI patients at 2 years vs placebo Mean number of Gd+ lesions at 2 years p< (n=315) TYSABRI (n=627) 12

13 Efficacy Safety Efficacy in AFFIRM, cont d Secondary Efficacy Endpoint: MRI Activity, cont d In promotion, MRI activity has also been reported as the percentage of patients with no Gd+ lesions or with no new or enlarging T2 lesions. These measures, as evaluated at 1 year and at 2 years, were reported by Polman et al (2006). The 2-year data are included in the Prescribing Information. Patients with no new Gd+ lesions (%) TYSABRI 72 p< TYSABRI Patients with no new or enlarging T2 lesions (%) TYSABRI 15 p< TYSABRI Year 1 Year 2 Year 1 Year 2 These data are presented in the Polman reprint. Please refer to that reprint for further details. These data are presented in the Polman reprint. Please refer to that reprint for further details. The 2-year data above are shown in promotion using the graphic at right. This information is included in the Prescribing Information NO New or Enlarging MRI Lesions 57% of TYSABRI patients were free of new or enlarging T2 hyperintense lesions vs 15% of placebo patients 97% of TYSABRI patients were free of Gd-enhancing lesions vs 72% of placebo patients 13

14 Efficacy Safety EFFICACY IN AFFIRM, cont d Tertiary Efficacy Endpoint: Quality-of-Life Assessments Quality of life was measured in the AFFIRM study using the SF-36, a 36-question short-form health survey. Improvement in both the physical and mental component scores was observed with TYSABRI and compared with a worsening of quality of life in the placebo group. A retrospective analysis of these results, used in promotion, was reported by Rudick et al (2007). Mean change from baseline ±SE at 2 years Quality of life Physical 0.7 Quality of life Mental TYSABRI (n=536) (n=264) Improvement Worsening This data is no longer being used in the promotion of TYSABRI, and is included for background use only p=0.003 p=0.011 These data are presented in the Rudick reprint. Please refer to that reprint for further details. At the 2-year endpoint Significant improvement (vs placebo) was seen in the physical component subscales of physical functioning, role physical, and general health The analysis was not significant for the bodily pain subscale Significant improvement (vs placebo) was seen in the mental component subscales of vitality, social functioning, and role emotional The analysis was not significant for the mental health subscale 14

15 Efficacy Safety EFFICACY IN AFFIRM, cont d Other Efficacy Analysis: Sustained Disability Progression (for 24 Weeks) In addition to the primary endpoint of disability progression sustained for 12 weeks, a more stringent definition of disability progression sustained for 24 weeks was also evaluated and reported by Polman et al (2006). When detailing physicians on these data, be sure to specify that they demonstrate the effect of TYSABRI on sustained progression of physical disability. 54 % relative reduction vs placebo in the risk of increased disability sustained for 24 weeks, as assessed over 2 years Proportion with progression sustained for 24 weeks p< % TYSABRI 11% Hazard ratio= Weeks These data are presented in the Polman reprint. Please refer to that reprint for further details. Similar to the 2-year primary endpoint data (sustained disability progression for 12 weeks), the above data are presented as a Kaplan-Meier curve. Dividing the TYSABRI value (11%) by the placebo value (23%) results in a hazard ratio of Subtracting 0.46 from 1.00 yields a relative risk reduction of 54%. 15

16 Efficacy Safety Efficacy in AFFIRM, cont d Retrospective Efficacy Assessments: Patients With Highly Active MS Along with the many prospectively defined endpoints of AFFIRM, retrospective subgroup analyses were conducted in patients with highly active relapsing MS. The patients included in this subgroup had 2 relapses in the year prior to entering AFFIRM and 1 Gd+ lesion at study entry. The analyses in this subgroup included the 1-year primary endpoint of rate of clinical relapse as well as sustained disability progression (for 24 weeks rather than the 12 weeks required for the 2-year primary endpoint). These subgroup analyses, reported by Hutchinson et al (2009), showed an 81% relative reduction in relapse rate and a 64% relative reduction in the proportion of patients with sustained disability progression. 81 % reduction in annualized relapse rate vs placebo; p<0.001 Annualized relapse rate at 2 years (n=61) 0.28 TYSABRI (n=148) 64 % reduction in risk of disability progression vs placebo; p<0.008 Proportion of sustained progression % TYSABRI 10% Hazard ratio= Weeks These data are presented in the Hutchinson reprint. Please refer to that reprint for further details. These data are presented in the Hutchinson reprint. Please refer to that reprint for further details. 16

17 Efficacy Safety SAFETY IN AFFIRM Although the overall rate of adverse events was similar in both treatment groups (95% of TYSABRI-treated patients and 96% of placebo-treated patients), there are safety concerns that remain (for more information on adverse events, including post-marketing events, please see the TYSABRI PI). This section reviews the safety results of the AFFIRM study. Adverse Events The only adverse events to occur at a significantly higher frequency in patients who received TYSABRI than in those taking placebo were allergic reactions (9% vs 4%, respectively) and fatigue (27% vs 21%). There were no significant differences in the overall rate of serious adverse events and the rate of infections, which were generally mild to moderate. 100 p=ns Percentage of patients Infections TYSABRI Serious AEs TYSABRI These data are presented in the Polman reprint. Please refer to that reprint for further details. Six percent of TYSABRI-treated patients and 4% of placebo-treated patients discontinued study drug because of adverse events. Three percent and 2% of patients, respectively, withdrew from the study. 17

18 Efficacy Safety SAFETY IN AFFIRM, cont d Understanding Infusion Reactions and Hypersensitivity Reactions Because TYSABRI is administered as an infusion, patients may experience infusion reactions or hypersensitivity reactions. (Serious hypersensitivity reactions such as anaphylaxis have occurred in patients taking TYSABRI.) It is important to differentiate between these types of reactions because they require different action steps. Specific to the AFFIRM study Infusion reactions were defined as any event that occurred within 2 hours after infusion start Hypersensitivity reactions were defined as any event reported as hypersensitivity, allergic reaction, or anaphylactic/anaphylactoid by the investigator, and any report of urticaria, allergic dermatitis, or hives More generally, infusion and hypersensitivity reactions are defined and recognized as explained below. Definition Infusion Reactions Non immune-mediated reactions that occur during or shortly after infusion Immune-mediated reactions Hypersensitivity Reactions Onset During or shortly after the infusion procedure Can occur immediately or be delayed Causes Symptoms The drug, infusion solution, equipment, or infusion method (e.g., infusing too rapidly) Reactions include nonspecific symptoms, such as Headache Fatigue Dizziness Facial flushing Nausea Pruritus The drug, infusion solution, or the equipment used (e.g., latex tourniquets, packaging, rubber-stoppered vials, injection ports) Reactions can range from localized hives to a severe generalized immune response (e.g., anaphylaxis) that may lead to cardiopulmonary compromise. Reactions may include Urticaria/hives Angioedema Dyspnea Wheezing Upper-airway edema Dizziness Hypotension/shock Nausea/vomiting Abdominal cramps Flushing These data are presented in the O Leary reprint. Please refer to that reprint for further details. 18

19 Efficacy Safety SAFETY IN AFFIRM, cont d Infusion Reactions in AFFIRM Percentage of patients This information is included in the Prescribing Information 5 0 TYSABRI p=ns Among the 627 patients receiving TYSABRI, 148 (24%) experienced an infusion reaction. Of those patients, 25 (4%) had a hypersensitivity reaction. Of the reported hypersensitivity reactions in TYSABRI patients Five (an incidence of 0.8%) were classified as serious systemic (e.g., anaphylactic/anaphylactoid) reactions Eight (an incidence of 1.3%) were classified as serious hypersensitivity reactions Antibody Development A low rate of TYSABRI antibody development occurred in AFFIRM, with 9% of patients developing antibodies at some time during therapy. Persistent antibodies (detected on at least 2 occasions that were 42 days apart) developed in 6% of TYSABRI-treated patients. This resulted in decreased efficacy and an increase in infusion reactions. 19

20 AFFIRM STUDY CONCLUSIONS The AFFIRM study confirmed the benefits of TYSABRI in the treatment of relapsing forms of MS. As demonstrated in the efficacy analyses, treatment with TYSABRI resulted in a powerful response. Patients experienced a reduced risk of sustained physical disability progression, a reduction in annualized relapse rate, and significant efficacy benefits (vs placebo) on all secondary endpoints and analyses of primary endpoints. In addition, no other DMT has data that demonstrate a significant improvement in quality of life. There are no head-to-head studies of TYSABRI and our key competitors. Additionally, the clinical studies for our competitors do not necessarily use the same endpoints as the pivotal TYSABRI studies (as shown below). Betaseron Copaxone Rebif Gilenya Primary Endpoints Annual exacerbation rate Proportion of patients exacerbation-free Exacerbation frequency per patient Proportion of patients exacerbation-free at 2 years Relapse rate at 2 years Time to second exacerbation Number of clinical exacerbations at 2 years Proportion of patients exacerbation-free at 24 weeks Annualized relapse rate Other Endpoints Time to first on-study exacerbation Change in EDSS Percentage change in MRI lesion area Percentage of progression-free patients Change in EDSS T2 lesion volume Percentage change in T2 lesion area Number of active lesions per patient Percentage of patients without relapse Number of new or newly enlarging T2 lesions In all of your sales calls, stick to appropriately balanced approved TYSABRI messages and the results of the AFFIRM study. These data are compelling arguments for your customers to choose TYSABRI over the competition for appropriate patients. Results from separate clinical studies cannot be directly compared. 20

21 THE EXPANDED DISABILITY STATUS SCALE (EDSS) The EDSS is used to measure disability in MS and requires that the patient undergo a neurologic examination. The EDSS is one-half of a 2-part rating system. The other half consists of 8 subsets, called functional systems. The 8 functional systems are Pyramidal Bowel/bladder Cerebellar Visual Brainstem Cerebral/mental Sensory Other Each functional system has a subscale to rate disability, but the overall EDSS score is reported on a scale of 0 (normal) to 10 (death due to MS). The graphic below provides a description of the level of disability across the range of the EDSS. Note that the AFFIRM study only enrolled patients with EDSS scores of 0 to 5.0. ly Viewed Page Double-click to navigate back to the last page viewed. AFFIRM population: patients who were ambulatory (to varying degrees) without assistance 0 to 3.5: Fully ambulatory (with some signs of MS based on functional systems) 0.0 Normal function 1.0 No disability, minimal signs 2.0 Minimal disability 3.0 Moderate disability 4.0 Relatively severe disability 5.0 Disability affects daily routine 6.0 Assistance required to walk 7.0 Restricted to wheelchair 8.0 Restricted to bed or chair 9.0 Confined to bed 10 Death 21

22 THE McDONALD CRITERIA New diagnostic criteria for MS were presented by the International Panel on the Diagnosis of Multiple Sclerosis in 2001 and have come to be known as the McDonald criteria. These criteria (since revised in 2005) were put forward as a convenient and accurate diagnostic tool for the practicing neurologist, with the intent of allowing early diagnosis and avoiding false positives. The core clinical presentation criteria include 2 attacks a and 2 lesions 2 attacks and 1 lesion 1 attack and 2 lesions 1 attack and 1 lesion Insidious progression suggestive of MS ly Viewed Page Double-click to navigate back to the last page viewed. In the AFFIRM study, all patients met 1 of the first 4 criteria. Patients were required to have had 1 relapse in the 12 months prior to study enrollment. a An attack is defined as a neurological disturbance with lesions that are likely to be inflammatory and demyelinating. The event must last 24 hours. 22

23 MRI ACTIVITY The secondary endpoints of the AFFIRM study included the following measures of MRI activity. T2 hyperintense ly Viewed Page T2 hyperintense lesions show the footprint of prior inflammatory events and represent the cumulative burden of disease. Double-click to navigate back to the last page viewed. Gadolinium-enhancing (Gd+) Gadolinium-enhancing (Gd+) lesions show areas of blood-brain barrier disruption and indicate active inflammation. T1-weighted Gd+ T1 lesions are indicative of demyelination or axonal loss and correlate with disability and its progression. 23

24 THE MULTIPLE SCLEROSIS FUNCTIONAL COMPOSITE (MSFC) The MSFC was originally developed to create an MS rating scale that would fulfill the following criteria: 1. Be multidimensional to reflect the varied clinical expression of MS across patients and over time 2. Have dimensions that change relatively independently over time 3. Evaluate important clinical dimensions, such as cognitive function, that were not emphasized in existing rating scales ly Viewed Page Double-click to navigate back to the last page viewed. The MSFC scale is used to measure the progression of disability. The scale consists of 3 easily administered quantitative tests of neurological function. Note that the MSFC allows for a choice of the tests administered to evaluate each of the neurological functions listed in the table below. The 3 tests included below were those chosen for the AFFIRM study. Test Function Description Timed 25-foot walk Ambulation Patients are timed on how long it takes them to walk 25 feet. 9HPT (9-hole peg test) Upper limb dexterity Patients are timed on inserting and removing 9 pegs in a pegboard. The final score is the mean of the right- and left-arm scores. PASAT-3 (3-second paced auditory serial addition test) Cognition Patients must do mental addition of the numbers they are given orally, 3 seconds apart. The test lasts 3 minutes and the score is given as the number of correct calculations. This data is no longer being used in the promotion of TYSABRI, and is included for background use only. Visit the National MS Society website ( for more information about MSFC and to download the MSFC Administration and Scoring Manual. 24

25 THE SF-36 The SF-36 is a short-form health survey that measures functional health and well-being. The questionnaire consists of 36 questions across 8 subscales to create physical and mental health summary scores. One item (self-reported health transition) is not included in any of the 8 subscales. Summary Measure Measure Item Physical health Physical functioning Vigorous activities Climb one flight Walk one block Moderate activities Bend, kneel Bathe, dress Lift, carry groceries Walk one mile Climb several flights Walk several blocks ly Viewed Page Double-click to navigate back to the last page viewed. Role physical Cut down time Limited in kind Accomplished less Had difficulty Bodily pain Pain magnitude Pain interfere General health EVGFP a rating As healthy Health excellent Sick easier Health to get worse Mental health Vitality Pep/life Worn out Energy Tired Social functioning Social extent Social time Role emotional Cut down time Accomplished less Not careful Mental health Nervous Peaceful Happy Down in dumps Blue/sad a Excellent, very good, fair, poor. 25