Ganesh Raghu, MD, FCCP, FACP ofessor of Medicine and Laboratory Medicine (Adjunc University of Washington, Seattle, WA, USA Chief, Chest Clinic Director, Interstitial Lung Disease, Sarcoid and Pulmonary Fibrosis Program Medical Director, Lung Transplant Program University of Washington Medical Center Seattle, WA, USA
Ganesh Raghu, MD, FCCP, FACP. Professor of Medicine and Laboratory Medicine (Adjunct) University of Washington, Seattle, WA, USA Chief, Chest Clinic Director, Interstitial Lung Disease, Sarcoid and Pulmonary Fibrosis Program Medical Director, Lung Transplant Program - PowerPoint PPT Presentation
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Ganesh Raghu, MD, FCCP, FACP
Professor of Medicine and Laboratory Medicine (Adjunct)University of Washington, Seattle, WA, USA
Chief, Chest ClinicDirector, Interstitial Lung Disease, Sarcoid and
Pulmonary Fibrosis ProgramMedical Director, Lung Transplant ProgramUniversity of Washington Medical Center
Pirfenidone: Treatment for IPFDouble-Blind, Placebo Controlled Clinical Trial in Japan*
I. Primary Endpoint●Lowest SpO2 during 6MET higher in the
subset of pirfenidone group of patients completing the 6 minute walk at 6 months (p=0.0069), 9 months (p=0.0305)- a positive trend(p =0.07) was seen in
all the patients in the pirfenidone group(full analysis set)
Results
Azuma et al. AJRCCM (2005)
Pirfenidone treatment in IPF : Current Status(April 2007)
● Experimental anti fibrotic agent
● Only available for use in patients enrolled/participating in clinical studies and not for routine use in patients
● Phase III study began last Nov 2005 in Japan- results announced as a press release by Shionogi(Dec 21st 2006)
indicates a positive study(final results for scientific review awaited)
● Phase III study in North America and Europe just begun ● Until results of these studies are available for the scientific
community,unknown if effective for IPF
A Randomized Placebo-Controlled Trial Assessing the Efficacy and Safety of Etanercept in Patients with Idiopathic
Pulmonary Fibrosis
Data presented at CHEST : Nov,2005 and at ERS,Sep,2006
G Raghu*,1 JA Lasky,2 U Costabel*,3 KK Brown*,4 V Cottin,5 RM du Bois*,6 M Thomeer,7 J Utz*,8 L McDermott9
1University of Washington Medical Center, Seattle, WA 2Tulane University Medical Center , New Orleans, LA 3Ruhrlandklinik Essen-Heidhausen, Essen, Germany 4National Jewish Center, Denver, CO 5Center for Orphan Lung Diseases, Lyon, France 6Royal Brompton Hospital, London, UK, 7Universitaire Ziekenhuizen KULeuven, Leuven, Belgium 8Mayo Clinic, Rochester, MN 9Wyeth Research, Collegeville, PA Sponsor: Wyeth Research
*Consultants/Advisors
Proof of Concept Study : Etanercept in IPF(data presented Raghu et al CHEST NOV,05 and ERS Sept,06)
● 48 week, double-blind, placebo-controlled, randomized, parallel, multi-center international study – 88 IPF patients enrolled
– 85 in efficacy population, 87 in safety population– Primary comparison between groups: Baseline versus 48
weeks, LOCF
Placebo 2x/week S/C
Etanercept 25 mg 2x/week S/CScreen
48 weeks4 weeks
Proof of Concept Study : Etanercept in IPF(data presented at CHEST NOV,05 and ERS Sep.06)
Conclusions●Efficacy
– Primary and Secondary Endpoints not met– Trend in favor of etanercept for
– Post Hoc Analyses– Trend toward improved progression-free
survival– Highest treatment differences for tertile of
patients with entry FVC < 57%●Safety
– No significant difference in the overall incidence of adverse event, serious adverse events or infections between treatment groups
BUILD 1*
●A double-blind randomized placebo controlled multicenter study to assess the efficacy, tolerability, and safety of bosentan in patients with idiopathic pulmonary fibrosis (IPF)
* Sponsor : Actelion
BUILD 1 : Bosentan did not improve 6MWD up to 12 months (Primary Endpoint) (data presented at ATS* and
ERS meeting 5/06 and 9/06) : King*,Behr,Brown,Dubois** and Raghu)
All treated patients Placebon = 83
Bosentann = 71
Baseline (m) Mean (SD) Median
372 (74)387
375 (92)397
Month 12* (m) Mean (SD) Median
338 (162)369
323 (164)390
Change from baseline (m) Mean (SD) Median
-34 (127)-9
-52 (121)-23
Treatment effect Mean (SE) Median p-value (Mann-Whitney U-test)
-18 (20)-170.226
*Or earlier if premature discontinuation
BUILD 1 Predefined Population: In biopsy proven IPF, Bosentan delayed time to disease progression
or death (data presented at ATS*/ERS** meetings, 5 and 9/06:
King*,Behr,Brown,Dubois** and Raghu )
p=0.009
100908070
605040302010
00 3 6 9 12 15
Months treatment50 47 42 36 24 0
Placebo 49 47 42 41 22 0 Bosentan
Patients at risk
Placebo
Bosentan
Patients without event (%)
BUILD 1: Summary and Conclusions data presented at ATS* and ERS** meetings 5 and 9/06 :
(King*,Behr,Brown,Dubois** and Raghu )
– Bosentan did not improve the primary endpoint of 6MWD
– Bosentan showed a trend to delayed time to disease progression or death
– In the predefined population with biopsy proven IPF, treatment effect was more pronounced
– Bosentan was well tolerated, with no unexpected adverse events
– These promising results will be investigated in a larger study (BUILD 3)
BUILD 1 : Dyspnea & QoL Conclusions of Results(Raghu et al,ERS Sep.06)
● QoL in IPF patients is severely compromised at baseline● Treatment with bosentan resulted in significant QoL
improvements at month 6; favorable trend observed at month 12
● Bosentan improved the overall well-being of IPF patients, especially in the biopsy-proven IPF subpopulation
● These results concur with the observed delay in time to death or disease progression in the bosentan group1
● Results will be further investigated in the long-term morbidity/mortality BUILD 3 study
1du Bois RM, et al. Bosentan in IPF patients, BUILD 1 study [poster]. Presented at ERS; Munich, Germany; 4 September 2006.
● Large multicenter trial designed to determine if IFN- provides survival benefits in patients with mild-to-moderate IPF
●Tested signals of survival benefits from post hoc analysis in an earlier phase III trial that failed to show benefits on primary composite outcome of progression-free survival(Raghu et al. N Engl J Med. 2004;350:125-133.)
Raghu G. Eur Respir J. 2006;28:463-465.
INSPIRE
● Study Terminated on March 05 2007*
●No survival benefits associated with Interferon-gamma
* InterMune press Release.
Insights from Recent Clinical Trials
Raghu G. Eur Respir J. 2006;28:463-465.
Idiopathic Pulmonary Fibrosis
Clinical Course
* Martinez et al. AIM 2005; 142:963-7
New Insights on Disease Progression From Recent Clinical Trials
●Rapid decline of respiratory status precedes death in otherwise stable patients
●Remarkable stability without treatment in many patients
●Importance of acute exacerbations●Very low mortality during 1-yr follow-up in
patients with well-established IPF●Trials with true placebo-arm may be possible
based on observed stability without treatment
Raghu G. Eur Respir J. 2006;28:463-465.
● No differences in chosen primary endpoints between treatment groups– interferon (Raghu et al. data presented ATS 2000)– interferon (Raghu et al. NEJM 2004;InterMune press release March 2007)– Pirfenidone (Azuma et al. AJRCCM 2005)– Etanercept (Raghu et al. Chest Meeting Nov 05 and ERS meeting Sep 06)– Bosentan (King et al. ATS, May 23, 2006)
● N-acetylcysteine (NAC) added to prednisone and azathioprine preserved VC and DLCO better than prednisone + azathioprine (Demedts et al. NEJM 2005)
Percieved* time line of concurrent/new IPF multicenter clinical studies: yr 2007----
2007 2008 2009 20112010 2012
BUILD III
CAPACITY :PIPF 004
OTHERS ------ ? ----------------------??
CAPACITY :PIPF 006
NIH PANTHER (anticipated to begin 8/07-- )
(pred-Aza-NAC)
NIH STEP-IPF (anticipated to begin 6-7/07-- )
IPF TreatmentIn pursuit of evidence based decisions*
●Many ongoing or planned phase I, II, and III trials now underway may need to amend/modify protocols based on the significance of the results of phase III trials that will become available during the initial or mid stages of ongoing studies.
*Raghu G. Eur Respir J. 2006;28:463-465.
Idiopathic Pulmonary Fibrosis (IPF): TreatmentChallenges for New, multicenter, clinical trials: Yr 1999
Theoretic goals and realities (Yr 1999Theoretic goals and realities (Yr 1999))
Years
Specific new Rx
Functional impairment
Survival
• rate of progressionrate of progression• Improved functionImproved function• Better quality of lifeBetter quality of life• Prolong survivalProlong survival
Current Standard of Care?
●Prednisone + azathioprine has evolved as apparent “standard of care,” supplemented by other currently available prescription and over-the-counter medicines
●Subjective perceptions of patients and physicians based on signals from trials drive decisions, rather than grade A clinical trial evidence
Raghu G. Eur Respir J. 2006;28:463-465.
●Current standard of care: longstanding variability“Conventional” approaches
●Treatment deferred to worsening stages– Lone corticosteroids followed by adjunct
immunosuppression●“New guidelines” (Joint ATS/ERS Statement yr 2000)
– Prednisone plus azathioprine●Not based on scientific evidence
Idiopathic Pulmonary Fibrosis (Mild/Moderate)
Treatment
Standard of Care: Call to Action
●Clinical investigators must clarify current standard of care by providing new evidence
●Current chaotic and poor standard of care must be replaced
●Well-designed clinical trials will separate myth from facts and provide solid evidence to inform clinical decisions
Raghu G. Eur Respir J. 2006;28:463-465.
● clarify current standard of care
● improve standard of care
●Placebo control protocols for different stages of disease status(mild-moderate disease when diagnosed ; advanced stages)
●Revise existing international consensus statement for management of IPF
What Can We Do Now for Our Patients With IPF ?* - an evidence based approach
● No further harm/minimize iatrogenic problems● Interpret new data based on small nos. of patients with caution● Encourage patients to enroll in well-designed clinical trials● For those unwilling, unable, or ineligible to participate in trials,
provide option for conservative follow-up with “no specific medication” other than oxygen supplementation
● Provide the best supportive care possible based on clinical and physiological needs
● Monitor clinical course regularly; undertake appropriate diagnostic and therapeutic intervention for complications
● Consider lung transplantation in a timely manner for eligible patients