Idiopathic Pulmonary Fibrosis Standards of Care & Investigational Therapies Stephen K. Frankel, MD,...
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Idiopathic Pulmonary Fibrosis Standards of Care & Investigational Therapies Stephen K. Frankel, MD, FCCP Assistant Professor, Interstitial Lung Disease Program National Jewish Medical & Research Center
Idiopathic Pulmonary Fibrosis Standards of Care & Investigational Therapies Stephen K. Frankel, MD, FCCP Assistant Professor, Interstitial Lung Disease
Idiopathic Pulmonary Fibrosis Standards of Care &
Investigational Therapies Stephen K. Frankel, MD, FCCP Assistant
Professor, Interstitial Lung Disease Program National Jewish
Medical & Research Center
Slide 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
Slide 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!!!
Slide 4
What are the Standards of Care for IPF in 2005? Pharmacologic
Therapy American Thoracic Society 2000 Consensus Statement
Consideration for Lung Transplantation
Slide 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...
Slide 6
Conventional Treatment Options Older studies have suggested a
10-30% response rate for corticosteroids (Rudd et al. Am Rev Respir
Dis 124:1, 1981.) Similarly modest improvements in outcome had been
noted with azathioprine (Raghu et al. Am Rev Respir Dis 144:291,
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
Slide 7
Survival in Patients Treated with Azathioprine +
Corticosteroids vs Corticosteroids Alone Raghu, G. et al. Am Rev
Respir Dis 1991; 144: 291-296.
Slide 8
Survival in Patients Treated with Cyclophosphamide +
Corticosteroids vs Untreated Patients Collard, H. R. et al. Chest
2004;125:2169-2174
Slide 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
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.
Slide 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
Slide 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
Slide 14
Investigational Trials: What 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
Slide 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
Slide 16
GIPF 001: Results Primary Endpoint of Progression Free Survival
Probability of Death or Progression IFN -1b Placebo 0.0 0.2 0.4 0.6
0.8 1.0 0100200300400500600 Day P = 0.53 Raghu G, et al. N Engl J
Med. 2004;350:125-133
Slide 17
GIPF 001: Results ITT Analysis-- Survival 16 IFN -1b and 28
placebo deaths: 41% relative reduction Probability ofSurvival
Probability of Survival 0.4 0.6 0.8 1.0 0100200300400500600 Day IFN
-1b Placebo P = 0.08 Raghu G, et al. N Engl J Med.
2004;350:125-133.
Slide 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
Slide 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- . Phase II clinical trial with
centers in New Orleans (Tulane) and Rochester, Minnesota (Mayo
Clinic.)
Slide 20
Imatinib (Gleevec) Definitive diagnosis of IPF Mild-moderate
disease severity 100 patients, 2+ years Enrollment status
Slide 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.
Slide 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
Slide 23
GC-1008: Anti-Transforming Growth Factor- (TGF- ) monoclonal
Genzyme Phase I trial Targets TGF- 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
Slide 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
Slide 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
Slide 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 >80%. Statistically significant
benefit also seen in number of disease exacerbations and vital
capacity. Pirfenidone is NOT yet in clinical trials in the United
States.
Slide 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
