Arthritis Advisory Committee March 5, 2003

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Arthritis Advisory CommitteeMarch 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

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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

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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

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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

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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

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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

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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

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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

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Current Drug Therapy Options in Rheumatoid
Arthritis

• Non-selective NSAIDs (Rx, OTC)/ Selective COX-2
  Inhibitors
• Disease Modifying Anti-rheumatic Drugs (DMARDs)
• Immunosuppressives
• Glucocorticoids
• Biologic agents
• Investigational agents

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Drugs Used to Treat RA Prior to 1985

• Antimalarials
• IM Gold
• Penicillamine
• Cyclosporins
• Azathioprine
• Cyclophosphamide
• Chlorambucil

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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

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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

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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

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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

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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

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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

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Drug Therapy After 1985
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Drug Therapy

• Methotrexate
• First studied at low dose in the 1960s
  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

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Estimated Continuation of Initial Second-line
Therapy Over 60 Months
Pincus et al. J Rheumatol 191885, 1992.
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Disease Modifying Anti-Rheumatic Therapies
(DMARTs)

• Sulfasalazine
• Methotrexate
• Leflunomide
• Biologic response modifiers
• TNF alpha inhibitors
• Etanercept
• Infliximab
• Adalimumab
• IL-1ra

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Advantages of DMARTs

• Slow disease progression
• Improve functional disability
• Decrease pain
• Interfere with inflammatory processes
• Retard development of joint erosions

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

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Summary of ACR Response Rates for Leflunomide,
Sulfasalzine, Methotrexate
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The ACR 20, 50 70 Responses with Etanercept
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PERCENTAGE OF PATIENTS WHO ACHIEVED AN ACR
RESPONSE AT WEEKS 30 AND 54 with infliximab
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ACR Responses in Placebo-Controlled Trials of
Humira (adalimumab) (Percent of Patients)
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Percent of Patients with ACR Responses of
IL1-ra
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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

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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

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Arava Regulatory History
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Arava Regulatory History

• 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

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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

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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

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Regulatory History
At that time, FDA requirements for a prevention
of disability claim as per the RA guidance were

• At least 2 year study duration
• Validated measure of physical function (HAQ or
  AIMS)
• Validated generic health-related quality oflife
  measure (SF-36) as supportive and should not
  worsen
• Requirement to demonstrate improvement in signs
  and symptoms

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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

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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

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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