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Idiopathic Pulmonary Fibrosis Standards of Care

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Assistant Professor, Interstitial Lung Disease Program ... Oxygen therapy. Physical & Occupational therapy. Pulmonary rehabilitation. Immunizations ... – PowerPoint PPT presentation

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Title: Idiopathic Pulmonary Fibrosis Standards of Care


1
Idiopathic Pulmonary FibrosisStandards of Care
Investigational Therapies
  • Stephen K. Frankel, MD, FCCP
  • Assistant Professor,
  • Interstitial Lung Disease Program
  • National Jewish Medical Research Center

2
What are the Standards of Care for IPF in 2005?
  • Non-Pharmacologic Therapy
  • Disease specific monitoring
  • Oxygen therapy
  • Physical Occupational therapy
  • Pulmonary rehabilitation
  • Immunizations
  • Patient education

3
What are the Standards of Care for IPF in 2005?
  • Non-Pharmacologic Therapy
  • Disease specific monitoring
  • Oxygen therapy
  • Physical Occupational therapy
  • Pulmonary rehabilitation
  • Immunizations
  • Patient education

Do not under-estimate the importance of
non-pharmacologic therapy!!!
4
What are the Standards of Care for IPF in 2005?
  • Pharmacologic Therapy
  • American Thoracic Society 2000 Consensus
    Statement
  • Consideration for Lung Transplantation

5
American Thoracic Society Consensus Statement
  • . . . Conventional Treatment Options
  • Treatment options include corticosteroids,
    immunosuppressive / cytotoxic agents (e.g.,
    azathioprine, cyclophosphamide), and antifibrotic
    agents (e.g., colchicine or D-penicillamine)
    alone or in combination. . .

6
Conventional Treatment Options
  • Older studies have suggested a 10-30 response
    rate for corticosteroids (Rudd et al. Am Rev
    Respir Dis 1241, 1981.)
  • Similarly modest improvements in outcome had been
    noted with azathioprine (Raghu et al. Am Rev
    Respir Dis 144291, 1991.)
  • Studies suggesting benefit are generally small
    and often not randomized, placebo-controlled or
    prospective
  • Treatment is similar to that used for ILD
    associated with connective tissue diseases or
    other IIPs
  • Significant potential for adverse side effects

7
Survival in Patients Treated with Azathioprine
Corticosteroids vs Corticosteroids Alone
Raghu, G. et al. Am Rev Respir Dis 1991 144
291-296.
8
Survival in Patients Treated with
Cyclophosphamide Corticosteroids vs Untreated
Patients
Collard, H. R. et al. Chest 20041252169-2174
9
The Quest for Novel Therapeutic Agents
Government-Sponsored
  • In 2005, the National Institutes of Health
    established the Idiopathic Pulmonary
    Fibrosis-Clinical Research Network to identify
    and test novel therapies for the treatment of
    IPF.
  • Familial Pulmonary Fibrosis Study

10
The Quest for Novel Therapeutic Agents
Industry-Sponsored
  • Gamma Interferon (Actimmune)
  • Imatinib (Gleevec)
  • Bosentan (Tracleer)
  • Etanercept (Enbrel)
  • N-acetylcysteine
  • Anti-Transforming Growth Factor-beta
  • Anti-Connective Tissue Growth Factor
  • Pirfenidone
  • Inhaled Iloprost (Ventavis)

11
Is an investigational trial for me?
  • Participation in research trials is a very
    personal and individual decision. Patients must
    be fully informed regarding the risks and
    benefits, pros and cons of participation.
  • Satisfied participants are often those who
    recognize that they are contributing to medical
    knowledge and potentially to treatment for the
    disease rather than those who expect a miracle
    cure.

12
Is an Investigational Trial for Me?Benefits
  • Empowerment
  • Contributing to developing knowledge and/or
    therapies for the disease
  • Access to physicians and centers expert in the
    disease
  • Disease and drug-specific monitoring
  • Latest information
  • Non-pharmacologic therapies
  • Physician and health allied professional
    comfort with your disease
  • Access to the latest medication

13
Is an Investigational Trial for Me? Malefits
  • Investigational agents may cause unforeseen harms
  • You may be the placebo control
  • Demands on time
  • Opportunity costs

14
Investigational TrialsWhat do you mean Im not
a candidate??!
  • A clinical diagnosis of IPF does not
    automatically mean that a person is a candidate
    for an investigational trial.
  • Confidence of diagnosis
  • Severity of disease
  • Age
  • Previous and concurrent therapies

15
Gamma-Interferon (IFN ?-1b)InterMune
  • 140 amino acid protein
  • Multiple biologic properties
  • Anti-fibrotic
  • Anti-infective
  • Immunomodulatory
  • Recently completed a phase III randomized,
    placebo controlled, prospectively trial
    evaluating the safety and efficacy of
    gamma-interferon for the treatment of pulmonary
    fibrosis

16
GIPF 001 ResultsPrimary Endpoint of Progression
Free Survival
1.0
IFN ?-1b
0.8
Placebo
P 0.53
0.6
Probability of Death or Progression
0.4
0.2
0.0
0
100
200
300
400
500
600
Day
Raghu G, et al. N Engl J Med. 2004350125-133
17
GIPF 001 ResultsITT Analysis-- Survival
1.0
0.8
P 0.08
Probability of Survival
0.6
IFN ?-1b
Placebo
0.4
0
100
200
300
400
500
600
Day
16 IFN ?-1b and 28 placebo deaths 41 relative
reduction
Raghu G, et al. N Engl J Med. 2004350125-133.
18
INSPIRE Trial
  • A randomized, placebo controlled, prospective
    study of the safety and efficacy of subcutaneous
    interferon gamma-1b (IFN ?-1b) in patients with
    idiopathic pulmonary fibrosis (IPF)
  • Definitive diagnosis of IPF
  • Mild-moderate disease severity
  • Primary endpoint-- survival time
  • 75 centers
  • 600 patient enrollment, 2 years
  • Enrollment remains open

19
Imatinib (Gleevec) Novartis
  • Currently approved for and highly effective for
    the treatment of chronic myeloid leukemia.
  • Mechanism of action believed to be the inhibition
    of fibroblast growth and survival factors PDGF
    and TGF-b.
  • Phase II clinical trial with centers in New
    Orleans (Tulane) and Rochester, Minnesota (Mayo
    Clinic.)

20
Imatinib (Gleevec)
  • Definitive diagnosis of IPF
  • Mild-moderate disease severity
  • 100 patients, 2 years
  • Enrollment status

21
Bosentan (Tracleer) BUILD-1 Actelion
  • Bosentan targets endothelin
  • Bosentan represents proven effective therapy for
    primary pulmonary hypertension
  • BUILD-1 (IPF) and BUILD-2 (Scleroderma) designed
    to study the safety and efficacy of bosentan for
    the treatment of fibrotic lung disease.
  • Phase 2, enrollment complete
  • Results anticipated in spring 2006.

22
Etanercept Trial Wyeth
  • Blocks tumor necrosis factor signaling
  • Approved and effective for the treatment of
    rheumatoid arthritis
  • Phase II study in 96 patients for the treatment
    of IPF. Enrollment closed.
  • Preliminary results expected in winter of 2005-06

23
GC-1008 Anti-Transforming Growth Factor-b (TGF-
b) monoclonal Genzyme
  • Phase I trial
  • Targets TGF-b, a signaling molecule that promotes
    fibroproliferation
  • 5 Centers (NJMRC, Univ of Michigan, Vanderbilt,
    Univ of Washington, and Mayo Clinic)
  • Mild-moderate disease severity
  • Enrollment in the process of opening

24
Anti-Connective Tissue Growth Factor (CTGF)
monoclonal antibody Fibrogen
  • Targets CTGF, a signaling molecule that promotes
    fibroproliferation
  • Results of a completed phase I trial are not
    released but appear to support continuing with
    the Phase II trial
  • Phase II trial to begin in late 2005 or early
    2006
  • Mild-moderate disease severity
  • Full list of centers not yet available

25
N-acetylcysteine (NAC) IFEGENIA Generic
  • Anti-oxidant
  • Approved for Tylenol overdose, Available OTC as a
    health supplement
  • A recent European study comparing azathioprine
    prednisone versus azathioprine prednisone NAC
    reportedly showed benefit to the NAC arm by
    physiologic testing
  • HOWEVER, this trial is not yet published and
    therefore has not been adequately reviewed
  • No clinical trials in the United States
  • No trials of NAC alone

26
Pirfenidone InterMune
  • Anti-fibrotic, anti-oxidant, anti-inflammatory
  • Recent study (Am J Respir Crit Care Med 171
    1040, 2005) found benefit to pirfenidone in IPF
    patients as assessed by lowest SpO2 achieved
    during a 6MWT in the subset of patients whos
    baseline nadir was gt80.
  • Statistically significant benefit also seen in
    number of disease exacerbations and vital
    capacity.
  • Pirfenidone is NOT yet in clinical trials in the
    United States.

27
Inhaled Iloprost (Ventavis) ACTIVE CoTherix
  • Vasodilator but also with effects on cell
    proliferation
  • Approved for primary pulmonary hypertension with
    NYHA class III or IV impairment
  • Phase II trial for pulmonary hypertension
    associated with mild-moderate pulmonary fibrosis
  • 50 patients, 15 sites
  • Will assess functional and hemodynamic endpoints

28
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