navigating the new era in ipf: pathophysiology and recent clinical trials

NAVIGATING the NEW ERA in IPF:Pathophysiology and Recent Clinical Trials

FACULTYTitle

Affiliation

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

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

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

Linking IPF Pathogenesis to Potential Therapies

Ahluwalia N, et al. Am J Respir Crit Care Med. 2014 Aug 4. [Epub ahead of print].

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.

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

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)

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.

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.

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

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

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

Pharmacologic Agents for IPF

ATS Statement2011

Pre-ATS Statement 2011 2011-2013 2014

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.

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

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

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

3 Clinical Trials Presented at ATS 2014

• PANTHER N-acetylcysteine (NAC)• ASCEND pirfenidone• INPULSIS nintedanib (BIBF1120)

ATS 2011

2011-2013Pre-2011 2014

PANTHERN-acetylcysteine (NAC)

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.

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

PANTHER 2012

Raghu G, et al. N Engl J Med. 2012;366:1968-1977.

ATS 2011

2011-2013 2014Pre-2011

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


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

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


Perc

enta

ge

ATS 2011

2011-2013 2014Pre-2011

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)


Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.

PANTHER 2014ATS

20112011-2013Pre-2011 2014

• 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


NAC Does Not Reduce FVC Decline



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

ASCENDPirfenidone

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)

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

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

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.

ASCEND 2014ATS

20112011-2013Pre-2011 2014

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

Primary ASCEND Endpoint Achieved


Patie

nts

with

≥ 1

0% F

VC

Dec

line

or D

eath

(%)

Week

Primary Endpoint

48% RelativeReduction

Pirfenidone Increased Progression-Free Survival*


*Progression is first occurrence of death, 10% ↓ FVC, or 50 m ↓ 6MWD

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

More Pirfenidone Patients Maintain Walk Distance or Survive


Prop

ortio

n of

Pati

ents

with

≥5

0 m

Dec

line

or D

eath

(%)

Week


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


Pirfenidone Associated with Less MortalityASCEND and CAPACITY data

From randomization to 28 days after last doseCox proportional hazard modelLog-rank test


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

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

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.


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.


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.

INPULSISNintedanib

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

Richeldi L, et al. N Engl J Med.2011:365;1079-1089.

Nintedanib Showed Promise for FVC Endpoint

ATS 2011

2011-2013 2014Pre-2011

INPULSIS 2014ATS

20112011-2013Pre-2011 2014

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


Primary INPULSIS Endpoint AchievedAnnual Rate of Change of FVC

INPULSIS-1 INPULSIS-2



Nintedanib Placebo

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

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


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

INPULSIS Mortality Rates


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


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


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

61

• 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)


62

• 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


63

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


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

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

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!

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

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

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.

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

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.

• 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

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

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

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

navigating the new era in ipf: pathophysiology and recent clinical trials

Documents

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