Transcript Idiopathic Pulmonary Fibrosis Standards of Care

Idiopathic Pulmonary Fibrosis
Standards of Care
&
Investigational Therapies
Stephen K. Frankel, MD, FCCP
Assistant Professor,
Interstitial Lung Disease Program
National Jewish Medical & Research Center
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
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!!!
What are the “Standards of Care” for
IPF in 2005?
• Pharmacologic Therapy
– American Thoracic Society 2000 Consensus
Statement
– Consideration for Lung Transplantation
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. . .”
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
Survival in Patients Treated with
Azathioprine + Corticosteroids vs
Corticosteroids Alone
Raghu, G. et al. Am Rev Respir Dis 1991; 144: 291-296.
Survival in Patients Treated with
Cyclophosphamide + Corticosteroids vs
“Untreated” Patients
Collard, H. R. et al. Chest 2004;125:2169-2174
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
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)
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.”
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
Is an Investigational Trial for Me?
Malefits
• Investigational agents may cause unforeseen
harms
• You may be the placebo control
• Demands on time
• “Opportunity costs”
Investigational Trials:
What do you mean I’m 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
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 gammainterferon for the treatment of pulmonary
fibrosis
Probability of Death or Progression
GIPF 001: Results
Primary Endpoint of Progression Free
Survival
1.0
IFN -1b
0.8
Placebo
P = 0.53
0.6
0.4
0.2
0.0
0
100
200
300
Day
Raghu G, et al. N Engl J Med. 2004;350:125-133
400
500
600
GIPF 001: Results
ITT Analysis-- Survival
Probability of Survival
1.0
0.8
P = 0.08
0.6
IFN -1b
Placebo
0.4
0
100
200
300
400
500
Day
16 IFN -1b and 28 placebo deaths: 41% relative reduction
Raghu G, et al. N Engl J Med. 2004;350:125-133.
600
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
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.)
Imatinib (Gleevec)
•
•
•
•
Definitive diagnosis of IPF
Mild-moderate disease severity
100 patients, 2+ years
Enrollment status
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.
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 200506
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
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
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
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 who’s
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.
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
Questions?