1. Arthritis Advisory Committee March 5, 2003 Lee S. Simon, MD Division Director Analgesic, Anti-inflammatory, Ophthalmologic Drug Products HFD-550/CDER/FDA

2. Agenda Regulatory history of Arava in the context of therapy for Rheumatoid arthritis A discussion of outcome measures for disability and physical function Sponsor presentation of efficacy FDA statisticians’ assessment of impact of placebo withdrawals on 2 year landmark analyses –Representing data for discussion regarding change in guidance Discussion of questions regarding efficacy of Arava in the context of the indication for improvement in physical function Discussion of the RA guidance document of 1999 and the indication for improvement in disability which presently requires 2-5 years of data

3. Agenda continued FDA presentation regarding hepatotoxicity associated with Arava Sponsor presentation of overall safety of Arava and its benefit/risk ratio for use in the context of the universe of therapies for RA A presentation regarding risk communication Discussion regarding questions

4. Arava: Regulatory History in the Context of Treatments for RA Lee S. Simon, MD Division Director Analgesic, Anti-inflammatory, Ophthalmologic Drug Products HFD-550/CDER/FDA

5. Impact of Arthritis in the U.S. In 1994: - 40 million Americans were affected by arthritis By 2020: 59 million (1 in 6 persons) will be affected – a 57% increase from 1983, when 35 million persons had arthritis Arthritis costs the U.S. economy more than $54 billion/yr in lost wages and medical care

6. Impact of Arthritis in the U.S. Leading cause of disability in people over age 65 Limits activities of daily living (ADL) of 7 million people 6 million Americans report having arthritis but never seeing a doctor for help

7. Rheumatoid Arthritis Affects about 1% of the US population between the ages of 20-50 Heterogeneous disease Variable course Systemic inflammatory disease associated with an as yet poorly understood immune dysfunction Leads to the development of destructive erosive disease in a great majority Remission rare, cure not yet observed

8. Rheumatoid Arthritis Shortens life span in some patients Clinical outcomes most notable for state of debility –Questions regarding increase in cardiovascular events –Increased risk for non-Hodgkins lymphoma w/wo therapy Most patients suffer an unrelenting course characterized by recurrent flares over years leading to progressive loss of functional status and ultimately leading to significant disability; an unfortunate few have an accelerated mutilating course and a lucky few have either mild disease or enter into remission early

9. Rheumatoid Arthritis Chronic inflammatory autoimmune disease –Involves synovial membrane and extra-articular sites –Associated with rheumatoid factor (autoantibody) production Genetic predisposition –Familial incidence –Genetic factor: HLA-DR4-related antigens Unknown environmental trigger

11. Impact of RA on Health-Related Quality of Life Pain and suffering Decreased physical functioning Increased psychological distress Decreased social functioning Increased healthcare utilization Increased work disability

12. Treatment Goals for Arthritis Patients Halt progression of disease Maximize functional independence Optimize treatment of pain/inflammation Enhance quality of life (?Health related) Minimize potential for toxicity Provide easy access to care at reasonable cost

13. Arthritis Management, 1892 “….Many cases are greatly helped by prolonged residence in southern Europe or southern California. Rich patients should always be encouraged to winter in the south and in this way avoid cold, damp weather.” Osler, Principles and Practice of Medicine, 1892

14. Current Drug Therapy Options in Rheumatoid Arthritis ·Non-selective NSAIDs (R x, OTC)/ Selective COX-2 Inhibitors Disease Modifying Anti-rheumatic Drugs (DMARDs) Immunosuppressives Glucocorticoids Biologic agents Investigational agents

15. Drugs Used to Treat RA Prior to 1985 Antimalarials IM Gold Penicillamine Cyclosporins Azathioprine Cyclophosphamide Chlorambucil

16. Drug Therapy For many years it was considered standard of care to be cautious and not expose patients to potentially toxic therapy which had not clearly been shown to have a major impact on the disease Diagnosis was clinically driven, no biologic markers and many early patients suffered likely viral arthritis and not true RA; many early spontaneous remissions were likely due to a viral etiology Thus a treatment “pyramid” emphasized slow progression of therapy from least effective modalities but maybe “safer” to palliate pain and suffering to potentially more effective but also associated with more potential risk of adverse events

17. Drug Therapy Antimalarials –Fortuitously discovered when given for either antimalarial prophylaxis or treatment in World War II to people concomitantly with RA –Reasonably well tolerated –Some patients were improved but no change in x- ray progression evidenced –Long list of potential toxicity including dose related loss of vision due to drug deposition in retina

18. Drug Therapy IM gold previously used to treat some infections 1966 Empire Rheumatism Council studied IM gold therapy demonstrating in some patients significant improvement and an occasional case of “remission” with significant risk in over 40% of patients: –Heavy metal induced kidney damage –Bone marrow suppresion –Liver effects, skin, vasculitis

19. Drug Therapy Cyclophosphamide –Significant benefit with decreasing disease activity –Evident benefit of decreasing x-ray progression –Chemotherapeutic agent altering or killing cells of many types –Appropriate doses were hard to define –Chronic oral therapy associated with increased risk of urogenital cancer, leukemia, clinically important immunosuppression, bone marrow failure, nausea vomiting, hair loss

20. Drug Therapy Antimalarials –Fortuitously discovered when given for either antimalarial prophylaxis or treatment in World War II to people with RA IM gold –previously used to treat some infections –1966 Empire Rheumatism Council studied IM gold therapy demonstrating significant improvement and an occasional case of “remission” with significant risk in over 40% of patients: Heavy metal induced kidney damage Bone marrow suppresion Liver effects, skin, vasculitis Cyclophosphamide –Significant benefit with decreasing disease activity and x-ray benefit –Chronic oral therapy increased risk of urogenital cancer, leukemia, immunosuppression, bone marrow failure, nausea vomiting, hair loss

21. Drug Therapy Known “truths” –NSAIDs were/are palliative: do not alter fundamental disease –DMARDs Important for those patients with progressive disease: likely would take 6 months to know benefit Potentially toxic, were associated with significant risk Required weekly surveillance with initiation of therapy and if tolerated would still require monthly visits Many patients did not have an adequate response/adverse events Standard of care was still associated with damage evident by x-ray and progressive loss of functional status

22. Drug Therapy After 1985

23. Drug Therapy Methotrexate –First studied at “low dose” in the 1960’s: concerns surrounded use of chemotherapy agent in chronic “non-fatal” disease –1985 new description of use at 7.5 mgs weekly showing benefit Subsequently more common dose is 15-17.5 mgs weekly –Better tolerated than previous DMARDS –Some evidence of true disease modification –Potential adverse effects included progressive liver damage even with consistent monitoring, lung fibrosis, acute pulmonary disease, bone marrow suppression, immunosuppression

24. Pincus et al. J Rheumatol 19:1885, 1992. Estimated Continuation of Initial Second- line Therapy Over 60 Months

25. Disease Modifying Anti-Rheumatic Therapies (DMARTs) Sulfasalazine Methotrexate Leflunomide Biologic response modifiers –TNF alpha inhibitors Etanercept Infliximab Adalimumab –IL-1ra

26. Advantages of DMARTs Slow disease progression Improve functional disability Decrease pain Interfere with inflammatory processes Retard development of joint erosions

27. Some US FDA-Approved RA Therapies (year of approval)

28. Drug Therapy The following 5 slides show the ACR 20, 50, 70 for each of the products considered to be “disease modifying therapies” The data is extracted from the labels In general, it is difficult to compare these data across clinical trials without “head to head” trials due to differences in trial design, patients recruited (e.g.activity of disease, prior therapies, length of time with disease, etc) However, with these caveats, all of these therapies have similar benefit as expressed by the ACR 20 measure and often require combination therapy with MTX to achieve similar effects

29. Summary of ACR Response Rates* for Leflunomide, Sulfasalzine, Methotrexate

30. The ACR 20, 50 70 Responses with Etanercept

31. PERCENTAGE OF PATIENTS WHO ACHIEVED AN ACR RESPONSE AT WEEKS 30 AND 54 with infliximab

32. ACR Responses in Placebo-Controlled Trials of Humira (adalimumab) (Percent of Patients)

33. Percent of Patients with ACR Responses of IL1-ra

34. Drug Therapy Paradigm shift –Inversion of conservative standard of care DMARTs clearly improve patient outcomes by improving signs and symptoms decreasing pain and inflammation DMARTs have been shown to retard x-ray progression –Thus the standard of care is to start aggressive therapy as soon as a certain diagnosis of progressive disease has been made

35. Drug Therapy Even so –There is still no cure, real remissions are very rare –Ideally would prefer robust ACR 50 and 70 responses: not yet seen with monotherapy –The data from clinical trials really only approximate what may happen in the “real world”: is a 1 or 2 year data set reasonable to predict long term results over 20-30 years –Most patients need access to many possible therapies since there is no way to predict who might respond to any one therapy: thus it is important to have available as many potential therapies as possible with an acceptable benefit/risk ratio

36. Arava Regulatory History

37. Original NDA clinical program beginning 1989 –Leflunomide clinical program consisted of three randomized, controlled trials (RCTs); The US trial was designed as a 2 year study with the primary analysis for efficacy at 1 year while the two other pivotal trials were one year with a second extension year requiring new consent: Unique design addressing short placebo exposure of 4 months with subsequent conversion to active therapy in all patients who were non-responders Original NDA submitted Feb 1998 –Included proposed claim of improvement in signs and symptoms of RA and retarding x-ray progression –Included proposed claim of improved functional ability, reduced disability, and improved health-related QOL –Priority review granted

38. Arava Regulatory History Arthritis Advisory Committee (August 1998) –Concurrence with FDA that studies demonstrated benefit for signs and symptoms as well as x-ray benefit –Question: “Should leflunomide be approved for the prevention of disability?” Updated draft FDA guidance (March 1998) newly defined the claim to “Improvement in physical function/disability” and now required “2- to 5-year” data –Exact type of study not defined eg blinded, controlled, randomized, etc –Committee Response: Preliminary consensus: reasonable data set New guidance which was in draft format but soon to be approved required 2-5 year data thus, no action taken until 2 year data collected

39. Regulatory History Leflunomide NDA approved September 1998 –For the treatment of active RA to reduce signs and symptoms and retard structural damage The second years of the 3 original NDA studies begun as extension trials, providing blinded 24- month data to support prevention of disability indication FDA guidance for rheumatoid arthritis products finalized in February, 1999

40. At least 2 year study duration Validated measure of physical function (HAQ or AIMS) Validated generic health-related quality of life measure (SF-36) as supportive and should not worsen Requirement to demonstrate improvement in signs and symptoms Regulatory History At that time, FDA requirements for a prevention of disability claim as per the RA guidance were:

41. Arava Regulatory History Supplemental NDA submitted describing improvement in physical function in December 2002 after discussions with the Division associated with the approval of one biologic “DMARD” based on 1 year blinded data with a second year of follow-up demonstrating durability of that response in those patients who were responders

42. DMARTs Sulfasalazine, leflunomide, methotrexate, etanercept, infliximab, and adalimumab –Improvement in signs and symptoms expressed in terms of an ACR 20 responder index: all therapies have similar effects with effect sizes ranging in ACR 20 responses of about 26-45% (in context of different trials, patients: early vs late disease, how many other drugs patients failed, other concomitant therapies such as folic acid, combination therapies, etc) –Delay in x-ray damage progression by about the same degree when measured –Potential adverse effects although of different types are not uncommon with any of these therapies and all convey the potential for risk with appropriate use

43. Agenda Regulatory history of Arava in the context of therapy for Rheumatoid arthritis A discussion of outcome measures for disability and physical function Sponsor presentation of efficacy FDA statisticians’ assessment of impact of placebo withdrawals on 2 year landmark analyses –Representing data for discussion regarding change in guidance Discussion of questions regarding efficacy of Arava in the context of the indication for improvement in physical function Discussion of the RA guidance document of 1999 and the indication for improvement in disability which presently requires 2-5 years of data

44. Agenda continued FDA presentation regarding hepatotoxicity associated with Arava Sponsor presentation of overall safety of Arava and its benefit/risk ratio for use in the context of the universe of therapies for RA A presentation regarding risk communication Discussion regarding questions