A NEW ERA in IPF: - PowerPoint Presentation

Slide1

A NEW ERA in IPF:Trials and Treatments

Craig Thurm, MD

Director, Pulmonary Medicine

Director, Pulmonary Fellowship

Medical Director

,

Respiratory

Care

Jamaica Hospital Medical CenterSlide2

Disclosure of Relevant Financial RelationshipsIt is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all conflicts of interest prior to the release of this activity.Slide3

Faculty DisclosuresCraig Thurm, MD has received research and grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, and Forest Pharmaceuticals. He has served as a consultant for

Meda

Pharmaceuticals and

Sunovion

Pharmaceuticals, and is a shareholder with

Teva Pharmaceuticals. He has received honoraria from Boehringer Ingelheim, CSL Behring, Forest Pharmaceuticals, GlaxoSmithKlein, InterMune, Janssen Pharmaceuticals, and Merck.

Activity Staff Disclosures

The planners, reviewers, editors, staff, or other members at The France Foundation who control content have no relevant financial relationships to disclose.

Educational Support

Supported by educational grants from Boehringer Ingelheim and InterMune.Slide4

Accreditation / Designation StatementsThe France Foundation is accredited with commendation by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The France Foundation designates this activity for a maximum of 1.0

AMA PRA Category 1 Credit™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.Slide5

How to Receive CME CreditComplete the pretest (page one of your handout) and give this page to the coordinator when you leave

Keep page two of your handout and follow the instructions to go online to claim CME credit

Your CME certificate will be available to downloadSlide6

Educational Activity Learning ObjectiveUpon completion of this course, the participants should be able to:

Explain the considerations associated with clinical evaluation, imaging, and surgical

biopsy

in

differentially

diagnosing IPFIdentify opportunities for interdisciplinary collaboration and consultation and key aspects of guideline recommendations that can facilitate early and accurate IPF diagnosisSummarize the current understanding of the IPF disease process and strategies that can help measure disease progression and treatment

response Evaluate clinical trial data on available and emerging treatments for IPFIdentify opportunities for referral as part of multidisciplinary IPF management planSlide7

OutlineDiagnosisPathophysiology modelIPF drug trials PANTHER (NAC)

ASCEND (pirfenidone)

INPULSIS (nintedanib)

Recent drug approvals!

Referral of patients with IPFSlide8

Idiopathic Pulmonary Fibrosis

Peripheral lobular fibrosis of unknown cause

Clinical impact

Exertional dyspnea

Cough

Functional and exercise limitation

Impaired quality-of-life

Risk for acute respiratory failure and deathMedian survival time of 3-5 yearsTwo new drugs approved by the FDA in October 2014Nintedanib (Ofev)Pirfenidone (Esbriet)Slide9

Diffuse

Parenchymal Lung Disease (DPLD

)

DPLD of known cause, eg, drugs or association, eg, collagen vascular disease

Idiopathic interstitial pneumonias

Granulomatous DPLD, eg, sarcoidosis

Other forms of DPLD, eg, LAM, HX, etc

Idiopathic pulmonary fibrosis

IIP other than idiopathic pulmonary fibrosis

Desquamative interstitial pneumonia

Acute interstitial

pneumonia

Nonspecific interstitial pneumonia (provisional)

Respiratory bronchiolitis interstitial lung disease

Cryptogenic organizing pneumonia

Lymphocytic interstitial pneumonia

ATS/ERS Consensus Statement.

Am J Respir Crit Care Med.

2002;165:277-304.Slide10

Major Idiopathic Interstitial Pneumonias

Category

Clinical-Radiologic-Pathologic

Diagnosis

Associated

Radiographic and/or Pathologic pattern

Chronic fibrosingIPF

UIPIdiopathic nonspecific interstitial Pneumonia (iNSIP)NSIPSmoking-relatedRespiratory bronchiolitis-ILD (RB-ILD)Respiratory bronchiolitisDesquamative interstitial pneumonia (DIP)Desquamative interstitial pneumoniaAcute/ subacuteCryptogenic organizing pneumonia (COP)Organizing pneumoniaAcute interstitial pneumonia (AIP)Diffuse alveolar damage

Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.Slide11

Diagnostic Algorithm for IPF

Raghu

G, et

al

.

Am J Respir Crit Care

Med

. 2011;183:788-824.Suspected IPFIdentifiable causes for ILD?HRCT

Surgical Lung BiopsyMDD

IPF/Not IPF

IPF

Not IPF

No

Possible UIP

Inconsistent w/ UIP

UIP

Probable UIP

Non-classifiable fibrosisSlide12

Raghu

G, et

al

.

Am J Respir Crit Care

Med

. 2011;183:788-824.

2011 ATS/ERS

Diagnostic Criteria for IPF

*also

known as diffuse parenchymal lung disease,

DPLD

Exclusion of

known

causes of ILD*

UIP pattern on HRCT without surgical biopsy

OR

Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable

UIP

ANDSlide13

Idiopathic Pulmonary Fibrosis

Normal Lungs

Usual Interstitial PneumoniaSlide14

Idiopathic Pulmonary Fibrosis

Normal Lung

Usual Interstitial PneumoniaSlide15

Idiopathic Pulmonary Fibrosis

Normal Lung

Fibroblastic Focus in

Usual

Interstitial PneumoniaSlide16

Clinical-Radiologic-Pathologic Approach to ILDSlide17

DrugsInfections-virusesRadiationOther diseases

Steele MP, Schwartz

DA.

Annu

Rev Med. 2013;64:265-276.

Exogenous and Endogenous stimuli

Microscopic lung injury:Separated spatially and temporallyLung homeostasisInterstitial lung disease

Dust FumesCigarette smokeAutoimmune conditionsGenetic

predisposition

Wound healing

Intact

Aberrant

ILD Disease ProgressionSlide18

Eras of Care for IPF

ATS Statement

2011

Pre-ATS

Statement 2011

2011-2013

2014Slide19

Trial

N

Primary Endpoint

Result

Interferon-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

DL

co

, FVC

Negative

Imatinib Mesylate

120

Progression-free survival

Negative

Bosentan (BUILD 1 and 2)

132

Change in 6MW

Negative

Bosentan (BUILD 3)

390Progression-free survival time

Negative

Anticoagulation

56

Survival

Positive

N-acetylcysteine (NAC) (IFIGENIA)

184

Change in FVC, DL

co

Positive

Sildenafil (STEP)

29

Change in 6MWD, Borg dyspnea index

Negative

Completed Trials for IPF:

Prior to 2011 Consensus Statement

Noth I, et al.

Am J

Respir

Crit

Care Med

. 2012 Jul 1;186(1):88-95.\

Subsequent trials showed that warfarin and NAC/azathioprine/prednisone

should not

be used for IPFSlide20

2011 Guidelines on Management of IPF

Treatment

Strong

For

Weak

ForWeak Against

Strong AgainstCorticosteroidXColchicineXCyclosporine A X

Interferon γ 1b

X

Bosentan

X

Etanercept

X

NAC/Azathioprine/Prednisone

X

NAC

X

Anticoagulation

X

Pirfenidone

X

Mechanical ventilation

X

Pulmonary rehab

X

Long-term oxygen

XLung transplantation

XSlide21

Three Recent IPF Clinical Trials American Thoracic Society 2014

PANTHER N-

acetylcysteine

(NAC)

ASCEND pirfenidone

INPULSIS nintedanib (BIBF1120)Slide22

PANTHERN-acetylcysteine (NAC)Slide23

NAC Does Not Reduce FVC Decline

Martinez FJ, et al.

N

Engl

J Med.

2014;370(22):2093-2101.

Conclusion

: NAC offered no significant benefit with respect to the preservation of FVC in patients with IPF with mild-to-moderate impairment in lung functionSlide24

ASCENDPirfenidoneSlide25

Possible Mechanisms of Pirfenidone Action

Hilberg O,

et al.

Clin Respir

J.

2012;6:131-143.

TNF-αIL-6

PirfenidoneTGF-βIL-6MMPsCollagenasesROIs

Collagen

Antifibrotic

Molecular target unclear

Active in several animal models of fibrosis (lung,

liver, kidney)Slide26

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

2014

Pre-2011Slide27

CAPACITY Endpoints

Endpoint

CAPACITY-2

CAPACITY-1

FVC



X

Overall survivalXXProgression-free survivalXSix-minute walk distance

X

DL

CO

X

X

Dyspnea

X

X

Exertional

d

esaturation

X

X

Noble P, et al.

Lancet.

2011;377:1760-1769.Slide28

ASCEND 2014

ATS 2011

2011-2013

Pre-2011

2014Slide29

Endpoints10

:

Δ

FVC

or

death20: 6-MWD PFS

Dyspnea Death

ASCEND Study DesignKing TE, et al. N Engl J Med. 2014;370(22):2083-2092.Oral Pirfenidone 2403 mg DailyPlacebo52 Weeks

PFS -

Progression-free

survival

Inclusion Criteria

Age 40-80

Confirmed IPF

50 -

90%

FVC

pred

30 -

90%

DL

CO

pred

FEV1/FVC ≥ 0.80 6-MWD ≥ 150 m 555 PatientsSlide30

Primary ASCEND Endpoint Achieved

King TE, et al.

N

Engl

J Med.

2014;370(22):2083-2092.

Patients with ≥ 10% FVC Decline or Death (%)

WeekPrimary Endpoint48% RelativeReductionSlide31

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 ↓ 6MWDSlide32

Pirfenidone Reduces Loss of FVC

<0.000001

King TE, et al.

N

Engl

J Med.

2014;370(22):2083-2092.

235 ml428 ml Rank ANCOVA P-value < 0.00001 at each indicated time pointMean Change (ml)WeekSlide33

More Pirfenidone Patients Maintain Walk Distance or

Survive

King TE, et al.

N

Engl

J Med. 2014;370(22):2083-2092.

Proportion

of Patients with ≥50 m Decline or Death (%)WeekSlide34

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 (%) Nausea3613.422.6

Rash28.1

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

12.67.94.7 Insomnia11.2

6.54.7

Dizziness17.613

4.6 Vomiting12.9

8.74.2

………… Dyspnea14.7

17.7-3

Cough25.2

29.6-4.4 IPF

9.418.1

-8.7Slide35

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 model

Log-rank testSlide36

King TE, et al.

N

Engl

J Med.

2014;370(22):

2083-2092.

ASCEND SummaryTreatment 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 52Pirfenidone was generally safe and well toleratedSlide37

37Pirfenidone, 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

ConclusionsSlide38

38Approved 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 dayInitiate with titration Days 1 through 7: 1 capsule 3x per day

Days 8 through 14: 2 capsules 3x per dayDays 15 onward: 3 capsules 3x per dayConsider 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.Slide39

http

://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/.

Accessed October 2014.

Pirfenidone Warnings

and Precautions

Temporary dosage reductions or discontinuations may be

requiredElevated 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. Slide40

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

ASTDrug interactionsMetabolized primarily via CYP1A2Activators and inhibitors of CYP1A2 should be used with caution with pirfenidoneUse with caution with mild/moderate hepatic impairment, not recommended for patients with severe impairmentUse with caution with mild/moderate/severe renal impairment, not recommended for patients with ESRD requiring dialysisSmoking causes decreased exposure to pirfenidone. Instruct patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.Slide41

INPULSISNintedanibSlide42

Possible Mechanisms of Nintedanib ActionTriple kinase inhibitor

Phosphatase activator

Antiangiogenic

, antitumor activity

VEGF

Nintedanib

PDGF

FGFSHP-1

Hilberg

F, et al.

Cancer Res

. 2008;68(12

):

4774-4782.

Tai

WT, et

al.

J

Hepatol

. 2014;61(1

):

89-97.

Pleiotropic EffectsSlide43

Richeldi L, et al.

N

Engl J

Med.

2011:365;1079-1089.

Nintedanib Showed Promise

for FVC Endpoint

ATS 20112011-2013

2014Pre-2011Slide44

INPULSIS 2014

ATS 2011

2011-2013

Pre-2011

2014Slide45

Richeldi L, et al. N Engl J Med. 2014;370(22):

2071-2082.

INPULSIS-1 and

INPULSIS-2 Study Design

Endpoints

1

0

: ΔFVC 20: Time to first AE Δ SGRQInclusion CriteriaAge > 40IPF ≤ 5y≥ 50% FVC pred 30 - 79% DLCO pred HRCT within 1yNintedanib

300 mg Daily

Placebo

52 Weeks

3

2

1066

Patients

AE – Acute Exacerbation

SGRQ – St. George’s Respiratory QuestionnaireSlide46

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Primary

INPULSIS Endpoint

Achieved

Annual Rate of Change of FVC

INPULSIS-1

INPULSIS-2

45% RelativeReduction

52% RelativeReduction

Nintedanib PlaceboSlide47

Nintedanib Reduces Loss of FVC

INPULSIS-1

INPULSIS-2

Mean Observed Change from Baseline in FVC (mL)

Richeldi

L, et al.

N

Engl J Med. 2014;370(22):2071-2082.WeekSlide48

Mixed Findings for Time to First Acute Exacerbation

Cumulative Incidence of First Acute Exacerbation (%)

INPULSIS-1

INPULSIS-2

Richeldi

L, et al.

N

Engl J Med. 2014;370(22):2071-2082.DaysSlide49

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 (%)96899490Diarrhea (%)62196318

Nausea(%)236

26

7Slide50

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 < 0.001INPULSIS-2 Δ = 93.7 ml P < 0.001Nintedanib had significant benefit in time to the first acute exacerbation in INPULSIS-2INPULSIS-1 HR = 1.15 P = 0.67INPULSIS-2 HR = 0.38 P = 0.005Significant difference in favor of nintedanib for the change from baseline in the total SGRQ score in INPULSIS-2 but not INPULSIS-1Slide51

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

progressionNintedanib was frequently associated

with diarrhea, which led to discontinuation of the study medication in less than 5% of patientsSlide52

52Approved October 15, 2014

Indicated

for the treatment of

IPF

Dosage and administration

150 mg twice daily approximately 12 hours apart taken with foodConsider 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.Slide53

53Elevated 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 Precautionshttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.Slide54

Nintedanib: Other ConsiderationsDrug interactions

Nintedanib is a substrate of

P-glycoprotein (P-

gp

) and CYP3A4

Concomitant use of P-gp and CYP3A4 inducers with nintedanib should be avoidedPatients 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 ESRD54http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.Slide55

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 Receptor300Rate of change in FVCSlide56

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 IPFPirfenidone and nintedanib approved

10/15/14 for the treatment of IPFStill need data on advanced disease, combination therapy, long-term safety, adherenceImplications of having approved drug(s)

Need early and accurate diagnosisRole of IPF and ILD Centers of Excellence is evolvingSlide57

EARLY REFERRAL for SPECIALTY CARESlide58

Why refer early to an ILD Center?Diagnostic expertise

Standardized assessment

Confirmation of diagnosis

Management expertise

Choice of an appropriate therapy

Oxygen prescription

Pulmonary rehabilitationAttention to obesity and sarcopenia/frailtyPotential enrollment in a clinical trial

Transplant evaluationFlaherty et al. Am J Respir Crit Care Med 2004;170:904-10.Flaherty et al. Am J Respir Crit Care Med 2007;175:1054-60.Lamas et al. Am J Respir Crit Care Med 2011;184:842-7.Slide59

ILD ChecklistTherapeutic

options x

Supplemental oxygen

Age-appropriate vaccinations

Risk factor reduction x

Pulmonary rehabilitation x

Clinical trials xLung transplant evaluation x Patient education Advocacy group involvement xMental health needs x

ReferralOpportunity?Slide60

Delayed Care Associated with Higher Mortality

Lamas et al.

Am J

Respir

Crit

Care Med. 2011

;184:842-847.P for trend = 0.04Slide61

Lung Transplantation is Increasing

http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry.

Accessed August 2014.

IPF

CF

COPDSlide62

Lung Transplantation for IPF:

2014 Referral Guidelines

Histopathologic or radiographic evidence of usual interstitial pneumonitis (UIP)

Abnormal lung function: FVC < 80% predicted or DL

CO

< 40% predicted

Any dyspnea or functional limitation attributable to lung disease

Any oxygen requirement, even if only during exertion Weill D, et al. J Heart Lung Transplant.2014 Jun 26. [Epub ahead of print].Slide63

ConclusionsPirfenidone and nintedanib

are FDA approved for treatment of IPF

Diagnosis of IPF requires a patient history, physical exam, lab tests, HRCT, and sometimes a biopsy

Patients should be referred early

Pulmonary rehabilitation

ILD centerLung transplantation evaluationSlide64

To Receive Credit for this Activity:Please Complete the Evaluation and Posttest at www.pilotforipf.org/credit/##Slide65

Supplemental SlidesSlide66

Possible NAC Mechanisms of ActionIncrease glutathione

 a

ntioxidation

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. Slide67

Demedts

M, et al.

New Engl J

Med

.

2005;353:2229-2242

.

+ azathioprine + steroids+ azathioprine + steroidsEarly Evidence for a NAC CocktailAcetylcysteine + azathioprine + steroids

Placebo + azathioprine + steroids

ATS 2011

2011-2013

2014

Pre-2011Slide68

PANTHER 2012

Raghu G, et al.

N

Engl J

Med.

2012;366:1968-1977.

ATS 2011

2011-20132014Pre-2011Slide69

PANTHER 2012 Interim ResultsTriple therapy has no benefit for FVCIncreased risk of death

Primary

Triple Therapy

Placebo

P-value

FVC

(liters)-0.24-0.230.85

Raghu G, et al.

N

Engl J

Med.

2012;366:1968-1977.

Probability

Time to Death

Kaplan–Meier Analysis

Weeks Since

Randomization

HR 9.26

(

95% CI 1.16-74.1)

P

=

0.01

ATS 2011

2011-20132014Pre-2011Slide70

PANTHER 2012 Adverse Events

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.

Percentage

ATS 2011

2011-2013

2014

Pre-2011Slide71

PANTHER 2012 ConclusionsCompelling evidence against

the use of the

triple combination for patients

with

mild-to-moderate IPF

Next stepsCombination arm terminatedTwo arms of study continued (NAC vs placebo)

Raghu G, et al.

N Engl J Med. 2012;366:1968-1977.Slide72

Martinez FJ, et al.

N

Engl

J Med.

2014;370(22

):2093-2101.

PANTHER 2014

ATS 20112011-2013Pre-20112014Slide73

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 DesignMartinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.Slide74

To Receive Credit for this Activity, Please Complete the Evaluation and Posttest:

PILOTforIPF.org/credit/13