Idiopathic Pulmonary Fibrosis Standards of Care

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Idiopathic Pulmonary FibrosisStandards of Care
Investigational Therapies

• Stephen K. Frankel, MD, FCCP
• Assistant Professor,
• Interstitial Lung Disease Program
• National Jewish Medical Research Center

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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

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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!!!
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What are the Standards of Care for IPF in 2005?

• Pharmacologic Therapy
• American Thoracic Society 2000 Consensus
  Statement
• Consideration for Lung Transplantation

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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. . .

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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

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Survival in Patients Treated with Azathioprine
Corticosteroids vs Corticosteroids Alone
Raghu, G. et al. Am Rev Respir Dis 1991 144
291-296.
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Survival in Patients Treated with
Cyclophosphamide Corticosteroids vs Untreated
Patients
Collard, H. R. et al. Chest 20041252169-2174
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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

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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)

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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.

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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

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Is an Investigational Trial for Me? Malefits

• Investigational agents may cause unforeseen harms
• You may be the placebo control
• Demands on time
• Opportunity costs

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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

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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

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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
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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.
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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

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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.)

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Imatinib (Gleevec)

• Definitive diagnosis of IPF
• Mild-moderate disease severity
• 100 patients, 2 years
• Enrollment status

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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.

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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

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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

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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

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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

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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.

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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

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Questions?