NAVIGATING the NEW ERA in IPF: Pathophysiology and Recent Clinical Trials
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NAVIGATING the NEW ERA in IPF:Pathophysiology and Recent Clinical Trials
FACULTYTitle
Affiliation
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PILOT Learning Objectives
• Summarize the current understanding of the IPF disease process and strategies that can help measure disease progression and treatment response
• Identify approaches to IPF management that are covered in current guidelines, taking into account the strength of relevant recommendations
• Evaluate clinical trial data on available and emerging treatments for IPF
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Outline
• Pathogenic model• Biomarkers• Review of clinical trials in IPF• 2011 ATS/ERS treatment guidelines• Clinical trial update• Recent drug approvals!• Clinical trial issues • Conclusions
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DrugsInfections-viruses
RadiationOther diseases
Steele MP, Schwartz DA. Annu Rev Med. 2013;64:265-276.
Exogenous and Endogenous stimuli
Microscopic lung injury:Separated spatially and temporally
Lung homeostasis Interstitial lung disease
Dust Fumes
Cigarette smokeAutoimmune conditions
Genetic predisposition
Wound healingIntact Aberrant
ILD Disease Progression
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Linking IPF Pathogenesis to Potential Therapies
Ahluwalia N, et al. Am J Respir Crit Care Med. 2014 Aug 4. [Epub ahead of print].
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Biomarkers for IPF
• Candidates– Serum CCL18– LOXL2– Telomerase– Surfactant proteins A & D– KL-6– Matrix Metallo-Proteases (MMP1/MMP7)– Circulating fibrocytes– Clinical parameters
• Pending validation• Not widely available
Rosas IO, et al. PLoS Med. 2008;5:e93.Prasse A, et al. Respirology. 2009;14:788-795.
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Elevated Baseline CCL18 Predicts Mortality
• Serum CC-Chemokine Ligand 18• Cut off of 150 ng/ml HR = 7.63 (P < 0.0001)
Prasse A, et al. Am J Respir Crit Care Med. 2009;179:717-723.
Time to Death (months)
Cum
ulati
ve S
urvi
val
CCL18 < 150 ng/ml
CCL18 > 150 ng/ml
P < 0.001
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LOXL2 Biomarker: Target for Therapy?
• Lysyl oxidase-like 2 (LOXL2) promotes cross-linking of collagen in pathological stroma
• Association between sLOXL2 levels and IPF disease progression in 2 cohorts
• Baseline sLOXL2 levels were not significantly correlated with FVC or DLCO
• Simtuzumab (humanized monoclonal, LOXL2 inhibitor) is in a phase 2 clinical trial
Chien JW, et al. Eur Respir J. 2014;43(5):1430-1438.
Cum
ulati
ve In
cide
nce
Prob
abili
ty
Time Months
Composite Disease Progression Endpoint(ARTEMIS Cohort)*
*Composite End-Point (time to first event)• Any cause mortality or• Respiratory hospitalization or • Decrease in lung function (FVC and DLCO criteria)
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Predictors of Disease Severity and Progression in IPFTESTS/ CLINICAL
FACTORS PREDICTIVE VALUE
FVC • Initial value and change over time correlate with mortality
DLCO • < 35% predicted lower survival
6MWT• O2 sat 88% increased mortality risk for IPF & NSIP• Walk distance correlates with mortality• Heart rate recovery correlates with mortality
Pulmonary hypertension • Associated with higher mortality
Dyspnea score • Correlates with survivalHospitalization • Predicts worse survival
Ley B, et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
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Predictors of Disease Severity and Progression in IPF
TESTS/ CLINICAL FACTORS Study Inclusion Criteria Study Endpoint
FVC DLCO 6MWT
Pulmonary hypertension Dyspnea score Hospitalization
Nathan SD, Meyer KC. Curr Opin Pulm Med. 2014;20(5):463-471.
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0 12 24 36 48 60 72 84 96 108 1200
20
40
60
80
100DLco=>50%
DLco35-49%
DLco<35%
Months
Pe
rce
nt
su
rviv
al
P=0.0001
Diffusing Capacity Predicts Survival in IPF
Nathan SD, et al. Chest. 2011;140:221-229.
0 12 24 36 48 60 72 84 96 108 1200
20
40
60
80
100DLco=>50%
DLco35-49%
DLco<35%
Months
Pe
rce
nt
su
rviv
al
DLco ≥ 50% DLco 35-49%Dlco < 35%
Months
Perc
ent S
urvi
val
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P=0.0053
FVC Predicts Survival in IPF
Nathan SD, et al. Chest. 2011;140:221-229.
0 12 24 36 48 60 72 84 96 108 1200
20
40
60
80
100FVC>or=70%
FVC 55-69%
FVC<55%
Months
Pe
rce
nt
su
rviv
al
FVC ≥ 70% FVC 55-69%FVC < 55%
Months
Perc
ent S
urvi
val
0 12 24 36 48 60 72 84 96 108 1200
20
40
60
80
100FVC>or=70%
FVC 55-69%
FVC<55%
Months
Pe
rce
nt
su
rviv
al
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6MWT Parameters Predict Survival in IPF
Days of Follow-Up
> 13bpm
D HR 1 minute after 6MWT
du Bois RM, et al. Eur Respir J. 2014;43(5):1421-1429.Swigris JJ, et al. Chest. 2009;136:841-848
6MWT distance at 24 weeks
Baseline 6MWT distance
Which 6MWT parameter best predicts survival in IPF?
D ≤ 13bpm
P = 0.0007
P < 0.001P = 0.01
Surv
ival
Pro
babi
lity
Surv
ival
Pro
babi
lity
Time Weeks Time Weeks
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Pharmacologic Agents for IPF
ATS Statement2011
Pre-ATS Statement 2011 2011-2013 2014
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Trial N Primary Endpoint ResultInterferon-beta (1999) 167 Progression-free survival time Negative
Interferon-gamma (GIPF-001) 330 Progression-free survival Negative
Interferon-gamma (Inspire) 826 Survival time Negative
Pirfenidone (CAPACITY 1) 344 Change in FVC Negative
Pirfenidone (CAPACITY 2) 435 Change in FVC Positive
Pirfenidone (Ogura) 275 Change in FVC Positive
Etanercept 100 Change in DLco, FVC Negative
Imatinib Mesylate 120 Progression-free survival Negative
Bosentan (BUILD 1 and 2) 132 Change in 6MW Negative
Bosentan (BUILD 3) 390 Progression-free survival time Negative
Anticoagulation 56 Survival Positive
N-acetylcysteine (NAC) (IFIGENIA) 184 Change in FVC, DLco Positive
Sildenafil (STEP) 29 Change in 6MWD, Borg dyspnea index Negative
Completed Trials for IPF: Prior to 2011 Consensus Statement
ATS 2011
2011-2013 2014Pre-2011
Subsequent trials showed that warfarin and NAC/azathioprine/prednisone
should not be used for IPF
Noth I, et al. Am J Respir Crit Care Med. 2012;186(1):88-95.
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2011 Guidelines on Management of IPF
Treatment Strong For
WeakFor
Weak Against
Strong Against
Corticosteroid XColchicine XCyclosporine A XInterferon γ 1b XBosentan XEtanercept XNAC/Azathioprine/Prednisone XNAC XAnticoagulation XPirfenidone XMechanical ventilation XPulmonary rehab XLong-term oxygen XLung transplantation X
ATS 2011
2011-2013 2014Pre-2011
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Trials for IPF Stopped Early
Trial N Primary Endpoint ResultPirfenidone (Azuma) 107 Exercise gas exchange Stopped +Ambrisentan (Artemis-IPF) 478 Progression-free survival Stopped -Ambrisentan (Artemis-PH) 50 6MWD Stopped -Warfarin (ACE study) 145/256 Death/hospitalization/∆10%FVC Stopped -Prednisone, Azathioprine, NAC
(PANTHER) 155* ∆FVC One arm stopped -
*number in placebo and triple therapy arms when latter arm halted
ATS 2011
2011-2013 2014Pre-2011
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Other Completed Trials for IPF (2011-2013)
Trial N Primary Endpoint ResultMacitentan FVC NegativeBIBF 1120
(nintedanib) 432 FVC Trend (P = 0.06)
Everolimus 89 Progression Negative
Co-trimoxazole 181 FVC Negative, but QOL↑Mortality 3/53 vs 14/65 (P = 0.02)
ATS 2011
2011-2013 2014Pre-2011
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3 Clinical Trials Presented at ATS 2014
• PANTHER N-acetylcysteine (NAC)• ASCEND pirfenidone• INPULSIS nintedanib (BIBF1120)
ATS 2011
2011-2013Pre-2011 2014
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PANTHERN-acetylcysteine (NAC)
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Possible NAC Mechanisms of Action
• Increase glutathione antioxidation • Downregulate lysyl oxidase (LOX) activity,
(essential for collagen deposition)
Li S, et al. Respiration. 2012;84(6):509-517.Rushworth GF, et al. Pharmacol Ther. 2014;141(2):150-159.
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Demedts M, et al. New Engl J Med. 2005;353:2229-2242.
+ azathioprine + steroids
+ azathioprine + steroids
Early Evidence for a NAC Cocktail
Acetylcysteine + azathioprine + steroids
Placebo + azathioprine + steroids
ATS 2011
2011-2013 2014Pre-2011
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PANTHER 2012
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
ATS 2011
2011-2013 2014Pre-2011
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PANTHER 2012 Interim Results
• Triple therapy has no benefit for FVC
• Increased risk of death
Primary Triple Therapy Placebo P-value
FVC (liters) -0.24 -0.23 0.85
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
Prob
abili
ty
Time to DeathKaplan–Meier Analysis
Weeks Since Randomization
HR 9.26 (95% CI 1.16-74.1)
P = 0.01
ATS 2011
2011-2013 2014Pre-2011
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PANTHER 2012 Adverse Events
Death
Respira
tory Dea
th
Hospita
lization
Acute
Exac
erbati
on
Serio
us Adve
rse Ev
ent
05
101520253035
Placebo Pred/Aza/NAC
• Triple therapy has higher incidence of adverse events than placebo
P-value for each comparison < 0.05
IPFNet writing committee. N Engl J Med 2012;366;1968-77.
P-values < 0.05
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
Perc
enta
ge
ATS 2011
2011-2013 2014Pre-2011
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PANTHER 2012 Conclusions
• “Increased risks of death and hospitalization were observed in patients with IPF who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo.”– Compelling evidence against the use of the triple
combination for patients with mild-to-moderate IPF
• Next steps– Combination arm terminated– Two arms of study continued (NAC vs placebo)
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
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Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
PANTHER 2014ATS
20112011-2013Pre-2011 2014
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• Subjects: 264 patients with IPF (2 arm continuation of PANTHER-IPF)
• Treatment: acetylcysteine (600 mg) or placebo 3 times daily
• Duration: 60 weeks• Primary end point: change in FVC • Secondary end points
– Time to the first acute exacerbation – Change from baseline in the total score on the St.
George’s Respiratory Questionnaire
PANTHER Study Design
Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
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NAC Does Not Reduce FVC Decline
Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
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Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
PANTHER Summary
Conclusion: NAC offered no significant benefit with respect to the preservation of FVC in patients with IPF with mild-to-moderate impairment in lung function
Endpoint NAC Placebo P-valueΔFVC (liters) −0.18 −0.19 0.77Rate of Death 4.9% 2.5% 0.30Acute Exacerbation 2.3% 2.3% >0.99
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ASCENDPirfenidone
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Possible Mechanisms of Pirfenidone Action
Hilberg O, et al. Clin Respir J. 2012;6:131-143.
TNF-αIL-6
Pirfenidone
TGF-βIL-6
MMPsCollagenases
ROIs
Collagen
• Antifibrotic• Molecular target
unclear• Active in several
animal models of fibrosis (lung, liver, kidney)
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Early Pirfenidone Results
FVC at 52 weeks
1800 mg -0.09
1200 mg -0.08
placebo -0.16
P = 0.04 vs placebo
Prog
ress
ion-
Free
Sur
viva
l
Time Days
Taniguchi H, et al. Eur Respir J. 2010;35:821-829.
Pirfenidone (2 Doses)
ATS 2011
2011-2013 2014Pre-2011
Placebo
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Noble P, et al. Lancet. 2011;377:1760-1769.
CAPACITY 2011
CAPACITY-2 CAPACITY-1
• One pirfenidone trial was positive, one was negative• CAPACITY-1 placebo group FVC declined more slowly than expected
ATS 2011
2011-2013 2014Pre-2011
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CAPACITY Endpoints
Endpoint CAPACITY-2 CAPACITY-1FVC X
Overall survival X X
Progression-free survival X
Six-minute walk distance X DLCO X X
Dyspnea X X
Exertional desaturation X X
Noble P, et al. Lancet. 2011;377:1760-1769.
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ASCEND 2014ATS
20112011-2013Pre-2011 2014
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Endpoints
10: Δ FVC or death
20: 6-MWDPFSDyspneaDeath
ASCEND Study Design
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Oral Pirfenidone 2403 mg Daily
Placebo
52 Weeks
PFS - Progression-free survival
Inclusion Criteria
• Age 40-80• Confirmed IPF• 50 - 90% FVC pred • 30 - 90% DLCO pred • FEV1/FVC ≥ 0.80 • 6-MWD ≥ 150 m
555 Patients
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Primary ASCEND Endpoint Achieved
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Patie
nts
with
≥ 1
0% F
VC
Dec
line
or D
eath
(%)
Week
Primary Endpoint
48% RelativeReduction
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Pirfenidone Increased Progression-Free Survival*
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
*Progression is first occurrence of death, 10% ↓ FVC, or 50 m ↓ 6MWD
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Pirfenidone Reduces Loss of FVC
<0.000001King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
235 ml
428 ml
Rank ANCOVA P-value < 0.00001 at each indicated time point
Mea
n Ch
ange
(ml)
Week
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More Pirfenidone Patients Maintain Walk Distance or Survive
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Prop
ortio
n of
Pati
ents
with
≥5
0 m
Dec
line
or D
eath
(%)
Week
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King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
ASCEND Adverse Events Adverse Event Pirfenidone (%)
(N = 278)Placebo (%)
(N = 277)Δ (%)
Nausea 36 13.4 22.6 Rash 28.1 8.7 19.4 Dyspepsia 17.6 6.1 11.5 Anorexia 15.8 6.5 9.3 GERD 11.9 6.5 5.4 Weight Loss 12.6 7.9 4.7 Insomnia 11.2 6.5 4.7 Dizziness 17.6 13 4.6 Vomiting 12.9 8.7 4.2
… … … …
Dyspnea 14.7 17.7 -3 Cough 25.2 29.6 -4.4 IPF 9.4 18.1 -8.7
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King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Pirfenidone Associated with Less MortalityASCEND and CAPACITY data
From randomization to 28 days after last doseCox proportional hazard modelLog-rank test
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King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
ASCEND Summary
• Treatment with pirfenidone for 52 weeks significantly reduced disease progression, as measured by – Changes in % predicted FVC (P < 0.001)
– Changes in 6-minute walk distance (P = 0.04)
– Progression-free survival (P < 0.001)
• Treatment with pirfenidone reduced all-cause mortality and treatment emergent IPF-related mortality in pooled analyses at week 52
• Pirfenidone was generally safe and well tolerated
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45
• Pirfenidone, as compared with placebo, reduced disease progression in patients with IPF
• Treatment was generally safe, had an acceptable side effect profile, and was associated with fewer deaths
ASCEND Conclusions
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46
• Approved October 15, 2014• Indicated for the treatment of IPF• Dosage and administration
– 801 mg (three 267 mg capsules) three times daily with food – Doses should be taken at the same time each day– Initiate with titration
• Days 1 through 7: 1 capsule 3x per day• Days 8 through 14: 2 capsules 3x per day• Days 15 onward: 3 capsules 3x per day
–Consider temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions.
• Prior to treatment, conduct liver function tests.
FDA Approval of Pirfenidone (Esbriet)
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.
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http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.
Pirfenidone Warnings and PrecautionsTemporary dosage reductions or discontinuations may be required
• Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with pirfenidone. Monitor ALT, AST, and bilirubin before and during treatment.
• Photosensitivity and rash: Photosensitivity and rash have been noted with pirfenidone. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily.
• Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro-esophageal reflux disease, and abdominal pain have occurred with pirfenidone.
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http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.
Pirfenidone: Other Considerations• Post-marketing experience (reactions of unknown frequency)
– Agranulocytosis – Angioedema – Bilirubin increased in combination with increases of ALT and AST
• Drug interactions– Metabolized primarily via CYP1A2– Activators and inhibitors of CYP1A2 should be used with caution with
pirfenidone
• Use with caution with mild/moderate hepatic impairment, not recommended for patients with severe impairment
• Use with caution with mild/moderate/severe renal impairment, not recommended for patients with ESRD requiring dialysis
• Smoking causes decreased exposure to pirfenidone. Instruct patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.
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INPULSISNintedanib
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Possible Mechanisms of Nintedanib Action
• Triple kinase inhibitor• Phosphatase activator• Antiangiogenic,
antitumor activity VEGF
Nintedanib
PDGF FGF SHP-1
Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782.Tai WT, et al. J Hepatol. 2014;61(1):89-97.
Pleiotropic Effects
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Richeldi L, et al. N Engl J Med.2011:365;1079-1089.
Nintedanib Showed Promise for FVC Endpoint
ATS 2011
2011-2013 2014Pre-2011
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INPULSIS 2014ATS
20112011-2013Pre-2011 2014
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Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
INPULSIS-1 and INPULSIS-2 Study Design
Endpoints
10: ΔFVC
20: Time to first AE Δ SGRQ
Inclusion Criteria
• Age > 40• IPF ≤ 5y• ≥ 50% FVC pred • 30 - 79% DLCO pred • HRCT within 1y
Nintedanib 300 mg Daily
Placebo
52 Weeks
3
2
1066 Patients
AE – Acute ExacerbationSGRQ – St. George’s Respiratory Questionnaire
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Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
Primary INPULSIS Endpoint AchievedAnnual Rate of Change of FVC
INPULSIS-1 INPULSIS-2
45% RelativeReduction
52% RelativeReduction
Nintedanib Placebo
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Nintedanib Reduces Loss of FVC
INPULSIS-1
INPULSIS-2
Mea
n O
bser
ved
Chan
ge fr
om B
asel
ine
in F
VC (m
L)
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. Week
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Mixed Findings for Time to First Acute Exacerbation
Cum
ulati
ve In
cide
nce
of F
irst A
cute
Exa
cerb
ation
(%)
INPULSIS-1
INPULSIS-2
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. Days
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Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
Common Nintedanib Adverse Events
Event
INPULSIS-1 INPULSIS-2
Nintedanib (n = 309)
Placebo (n = 204)
Nintedanib (n = 329)
Placebo (n = 219)
Any (%) 96 89 94 90Diarrhea (%) 62 19 63 18
Nausea(%) 23 6 26 7
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INPULSIS Mortality Rates
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
DeathsNintedanib 150 mg bid
(n = 638)Placebo (n = 423) HR P-value
All-cause (%) 5.5 7.8 0.70 0.14
Respiratory (%) 3.8 5.0 0.74 0.34
On-treatment (%)* 3.8 6.1 0.68 0.16
* Deaths between randomization and 28 days after last dose
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Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
INPULSIS Summary
• Nintedanib had significant benefit in adjusted annual rate of change in FVC • INPULSIS-1 Δ = 125.3 ml P < 0.001• INPULSIS-2 Δ = 93.7 ml P < 0.001
• Nintedanib had significant benefit in time to the first acute exacerbation in INPULSIS-2• INPULSIS-1 HR = 1.15 P = 0.67• INPULSIS-2 HR = 0.38 P = 0.005
• Significant difference in favor of nintedanib for the change from baseline in the total SGRQ score in INPULSIS-2 but not INPULSIS-1
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Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
INPULSIS Conclusions
• Nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression
• Nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients
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• Approved October 15, 2014• Indicated for the treatment of IPF• Dosage and administration
–150 mg twice daily approximately 12 hours apart taken with food
–Consider temporary dose reduction to 100 mg, temporary interruption, or discontinuation for management of adverse reactions.
–Prior to treatment, conduct liver function tests.
FDA Approval of Nintedanib (Ofev)
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.
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• Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with nintedanib. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required.
• GI disorders: Diarrhea, nausea, and vomiting have occurred with nintedanib. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue nintedanib if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment.
• Embryofetal toxicity: Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
• Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known CAD.
• Bleeding events have been reported. Use nintedanib in patients with known bleeding risk only if anticipated benefit outweighs the potential risk.
• GI perforation has been reported. Use nintedanib with caution when treating patients with recent abdominal surgery. Discontinue nintedanib in patients who develop GI perforation. Only use nintedanib in patients with known risk of GI perforation if the anticipated benefit outweighs the potential risk.
Nintedanib Warnings and Precautions
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.
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Nintedanib: Other Considerations
• Drug interactions– Nintedanib is a substrate of P-glycoprotein (P-gp) and CYP3A4– Concomitant use of P-gp and CYP3A4 inducers with nintedanib should be
avoided– Patients treated with P-gp and CYP3A4 inhibitors and nintedanib should
be monitored closely for adverse reactions
• Nintedanib is a VEGFR inhibitor, and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
• Nintedanib not recommended for patients with moderate or severe hepatic impairment
• < 1% excreted via the kidney; no data on patients with severe renal impairment and ESRD
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.
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Current Phase 2 Trials for IPFNext Generation Therapy?
Trial Target N Primary Endpoint
Co-trimoxazole (Ph 3) Pneumocystis jiroveci 56 Change in FVC or respir. Hospital’n
FG-3019 Anti-CTGF 90 Change in FVC from baseline
Rituximab CD-20 58 Titers of anti-HEp-2 autoantibodies
Simtuzumab Anti-LOXL2 500 PFS
GC-1008 TGF- 25 Safety, tolerability, PK
QAX576 Anti-IL-13 40 Safety, tolerability, FVC
Tralokinumab Anti-IL-13 302 Change in FVC from baseline
STX-100 αvβ6 32 Adverse events
BMS-986020 LPA Receptor 300 Rate of change in FVC
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Clinical Trial Conclusions
• 2014 is a watershed year in IPF– NAC did not show efficacy (PANTHER)– Pirfenidone (ASCEND) and nintedanib (INPULSIS) showed
efficacy in mild/moderate IPF– Pirfenidone and nintedanib approved 10/15/14 for the
treatment of IPF– Still need data on advanced disease, combination therapy,
long-term safety, adherence
• Implications of having approved drug(s)– Need early and accurate diagnosis– Role of IPF and ILD Centers of Excellence is evolving
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IPF: Role of Clinical Trials
• Prior to 2000, only 1 multicenter RCT in IPF• 2000–2013: ~ > 25 multicenter RCTs in IPF• Trials in IPF are difficult to recruit and populate
– Need effort, collaboration, and partnership of multiple health care providers
– ILD centers are important for patients, providers, and clinical studies
• IPF patients of tomorrow need our help today!
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Issues in Clinical Trials of IPF
• Which patients should be studied?
IPF
IPF/COPD
IPF rapidaccelerators
IPF/PH
IPF slowprogressors
IPF acute
exacerbators
Clinical Phenotypes
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Is There a Role for Genomics in Defining the Patient Cohort(s) to Study?
• Will characterization of the patients genomic profile define responders versus non-responders?
• Examples:–Familial (autosomal dominant, up to 20%-25% of
cases)–Telomerase mutations in ~10% –Surfactant C mutations–Muc 5B variants
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Genomics Applied to IPF
• Gene Expression Profiling
CTHRC1MMP7
FHL2 PCSK1
CTSEGAL
C6 NELL1
GREM1LCN2
PLA2G2A SLC2A5
IPF Susceptibility
TOLLIP
SPPL2C
Mortality
TOLLIP rs5743890
• Genome-Wide Association
Bauer Y, et al. Am J Respir Cell Mol Biol. 2014 Jul 16. [Epub ahead of print].Noth I, et al. Lancet Respir Med. 2013;1:309-317.
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Issues in Clinical Trials of IPF
• Fixed duration or event-driven?• How will drug approvals affect trial design?• What is the best endpoint?
– Lung function– FVC, DLco
– Functional status (6MWT)– QOL measures– Hospitalization– Mortality– Composite endpoint
– Increasingly used in clinical trials
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Composite Endpoints:Potential Advantages
• Increases statistical power & improved trial efficiency
• Estimates net clinical benefit by capturing different disease domains–Accounts for several equally important endpoints
• Improves understanding of effect of intervention
Adapted from Ferreira-González I et al. J Clin Epidemiol. 2007;60:651-657.
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• Interpretation problematic when – Components are dissimilar in clinical importance– Event rates vary appreciably across components– Components vary in sensitivity to treatment
• May be influenced by clinician subjectivity– Some components can be difficult to adjudicate
• Potential masking of a harmful effect
Ferreira-González I et al. J Clin Epidemiol. 2007;60:651-657. Nathan SD, du Bois RM. Eur Respir J. 2011;38:1002-1004.
Composite Endpoints:Potential Advantages
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Candidate Components of Composite EndpointsΔFVC
Mean change or categorical?Slope of change?Frequency of measurement
Δ6MWT HospitalizationMean change or categorical?Δ Distance or desaturation?Δ Pulse rate recovery?Δ Borg?
Respiratory or all-cause?Different thresholdsRemote hospitalizations?Patient complianceNeed vs. actual?
ΔNYHA FC
“Blunt” instrumentSubjectiveAssessor dependentRemote monitoring?
ΔPRO Death
Which instrument?Patient-centeredRequires further validation
Respiratory or all-cause?
ΔBiomarker
Which?Require validationRole in patient selection?
ΔHRCT Score Acute Exacerbations
Refinement neededRequires validationMonitoring intervals
Rare?Difficult to differentiate Colinear with hospitalization?
Exploratory
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Conclusions I
• Many candidates have failed in clinical trials– Pathogenesis models have had limited use – Endpoints– Inclusion criteria/disease stage
• 2014 is a pivotal year in IPF– NAC did not show efficacy (PANTHER)– Pirfenidone and nintedanib are FDA approved for
treatment of IPF– Still need data on advanced disease, combination
therapy, long-term safety, adherence
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Conclusions II
• Implications of having an approved drug–Therapeutic option for patients–Need to make an accurate diagnosis
• Treat appropriately• Avoid treating inappropriately
–Earlier diagnosis becomes essential– Increased awareness
• The role of Pulmonary Fibrosis Centers of Excellence is developing