Direttore UOSD DH Pneumologico e Interstiziopatie Polmonari

Azienda Ospedaliera S. Camillo-Forlanini,Roma

Cosa abbiamo imparato e come

migliorare la gestione dell’IPF in futuro.

Alfredo Sebastiani

Disclosure

• Dr Alfredo Sebastiani has served as investigator in clinical trials, speaker, or scientific advisory board member for

– Boehringer Ingelheim

– Roche

• BACKGROUND (EVOLUTION OF IPF THERAPY) • «NEW» ANTIFIBROTIC DRUGS (PIRFENIDONE, NINTEDANIB) :

WHAT WE KNOW - EFFECTS ON THE COURSE OF IPF

- WHEN TO START THERAPY- WHEN TO STOP THERAPY- ADVERSE EFFECTS- EFFECTS IN REAL LIFE

• WHAT WE WANT TO KNOW IN THE FUTURE- WHICH DRUG FOR WHICH PATIENT ?

- WHICH THERAPY FOR EXACERBATIONS ?- NEW DRUGS ? - SAME DRUGS IN NON-IPF ILDS?

• THE REAL LIFE : THE UNMET NEED OF PATIENTS AND OLISTIC APPROACH TO THEIR CARE

AGENDA

King TE Jr, et al. Lancet. 2011;378(9807):1949-1961.

(5-10% of patients per year)

IPF BEHAVIOUR IS HIGHLY VARIABLE AND SUBSTANTIALLY UNPREDICTABLE

HOW LONG ??

Progression even if not predicatable is a real problem

since ALL patient are going to loose on average 200ml

FVC/year

Data from placebo arms in phase III

trials

Clinical Trials Presented at ATS 2014

• ASCEND pirfenidone

• INPULSIS nintedanib (BIBF1120)

ATS 2011

2011-2013Pre-2011 2014

Supportive Analysis of Primary Endpoint: Mean Change in FVC Volume (mL)*ASCEND: mean change in FVC volume (mL)

Supportive analyses of the primary endpoint were consistent with a significant treatment effect of pirfenidone on the rate of FVC decline.

WeekAbsolute

difference mL

Relative difference

%

Rank ANCOVAP-value

13 59.6 62.5 < 0.0001

26 111.0 54.9 < 0.0001

39 116.7 43.9 < 0.0001

52 192.8 45.1 < 0.0001

-500

-400

-200

-100

0

0 13 26 39 52

Me

anch

ange

inFV

C(m

L)

Placebo (n = 277)

Pirfenidone (n = 278)

Week

Absolute difference = 193 mL Relative difference = 45.1%

-300

All-cause Mortality: ASCEND and CAPACITY Pooled (1 Year)

HR = Hazard Ratio; 95% CI=95% confidence interval

* Cox proportional hazards model

† Log-rank test

0 3 6 9 12

Month

0

4

6

Cu

mu

lati

ve

Ris

k o

f D

ea

th (

%)

Placebo (N=624)

Pirfenidone (N=623)

8

HR 0.52 (95% CI 0.31, 0.87)*

P=0.0107†

2

Pirfenidone 623 618 609 596 509

Placebo 624 619 603 586 490

Patients at Risk:

*Adjusted mean difference versus placebo at Week 52 based on MMRM.

bid, twice daily; CI, confidence interval; FVC, forced vital capacity.

Placebo

Nintedanib 150 mg bid

Me

an

(S

E)

ob

se

rve

d c

ha

ng

e f

rom

ba

se

lin

e in

FV

C (

mL

)

*110.6 mL

(95% CI: 83.2, 137.9)

p<0.0001

2 4 6 1

2

2

4

3

65

2Week

0

No. of patientsNintedanib 626 616 613 604 587 569 519Placebo 417 408 407 403 395 383 345

CHANGE FROM BASELINE IN FVC OVER TIME:

POOLED DATA

Placebo

Nintedanib 150 mg bid

HR 0.70

(95% CI; 0.43, 1.12)

p=0.1399

The INPULSIS™ trials were not powered to show a difference in mortality.

bid, twice daily; CI, confidence interval; HR, hazard ratio.

ALL-CAUSE MORTALITY OVER 52 WEEKS

(PRESPECIFIED ANALYSIS OF POOLED DATA)

IPF THERAPY WITH NEW ANTIFIBROTIC DRUGS : WHAT WE KNOW

• IS THE EFFICACY OF THERAPY CLEAR IN ALL SUBGROUPS OF PATIENTS?

• PIRFENIDONE AND NINTEDANIB REDUCE FVC DECLINE IN ALL SUBGROUPS OF PATIENTS

ANNUAL RATE OF DECLINE IN FVC BY HRCT CRITERIA

-108.7 -122.0

-225.7 -221.0

-300

-250

-200

-150

-100

-50

0

Honeycombing on HRCT and/or confirmation of UIP by

biopsyn=425 n=298 n=213 n=125

NO honeycombing on HRCTand NO biopsy

Raghu G et al. AJRCCM 2016 Jun 22 [Epub ahead of print]

Ad

just

ed a

nn

ual

rat

e (S

E) o

f d

eclin

e in

FV

C (

mL/

year

)

Nintedanib 150 mg bid Placebo

WHEN TO START ANTIFIBROTIC THERAPY?

• AS SOON AS THE DIAGNOSIS IS MADE!

FVC100-80%

EVIDENZE DI EFFICACIA DEGLI ANTIFIBROTICI

Ad

just

ed a

nn

ual

rat

e (S

E) o

f d

eclin

e in

FV

C (

mL/

year

)

Nintedanib Placebo

Treatment-by-time-by-subgroup interaction

p=0.5300

∆102.1 mL (95% CI: 61.9, 142.3)

FVC ≤90% predicted

∆133.1 mL(95% CI: 68.0, 198.2)

n=472 n=315 n=166 n=108

FVC >90% predicted

Kolb M, et al. Thorax 2016;0:1–7. doi:10.1136/thoraxjnl-2016-208710

Nintedanib had a similar effect on FVC decline

in patients with FVC >90% and ≤90%

Post hoc subgroup analyses of pooled data from the two replicate phase III INPULSIS trials

Albera C et al. Eur Respir J

2016;48:843

Pirfenidone had a similar effect

in patients with FVC ≥80% vs

<80% and GAP stage I vs II/III

Pirfenidone is efficacious in

patients with more preserved

lung function

• These data go against a ‘watch and wait’ approach for the treatment of IPF and support the importance of prompt diagnosis of IPF to enable patients to receive treatment to slow disease progression as soon as possible.

WHEN TO STOP ANTIFIBROTIC THERAPY?

• SHOULD TREATMENT BE STOPPED IF WE HAVE FUNCTIONAL DECLINE?

• NO!

Nathan SD et al. Thorax 2016;71:429-435

*Rank analysis of covariance with ranked change from baseline as the outcome variable; study, treatment, and

region as fixed effects; and ranked baseline FVC as a covariate. Deaths are ranked worst according to time until

death†Fisher’s exact test‡Either no decline or increase in FVC

Continued treatment with pirfenidone following a ≥10% decline in FVC improved outcomes for patients in the following 6 months

Nathan SD et al. Thorax 2016;71:429-435

Median change in % predicted FVC during the 6-month

period following an initial decline in FVC ≥10%

Patients who have an initial decline

in FVC ≥10% benefit from continued

treatment with pirfenidone

compared with placebo

Conclusions

WHEN TO STOP ANTIFIBROTIC THERAPY?

• SHOULD TREATMENT BE STOPPED BEFORE LUNG TRANPLANTATION?

• NO!

Delanote et al. BMC Pulmonary Medicine (2016) 16:156

A total of 9 IPF patients were treated with antifibrotics and subsequently

underwent LTx:

pirfenidone n = 7 (n = 2 study vs. n = 5 open-label treatment),

nintedanib n = 2 (n=2 study).

28

IPF THERAPY IN THE REAL LIFE

The European IPF registry (eurIPFreg): baseline characteristicsand survival of patients with idiopathic pulmonary fibrosis

.

•Objectives: To describe baseline data of 525

European patients with IPF recruited to eurIPFreg

from November 2009 to October 2016, and to

provide insight into the survival and management

changes in this IPF cohort

A. Gunther et al. Respiratory Research. 2018

These data demostrate a survival benefit with antifibrotics

Pirfenidone in real life: A retrospective observational multicentre study in Italian patients with idiopathic pulmonary fibrosis

Carlo Vancheri, Alfredo Sebastiani, Sara Tomassetti, Alberto Pesci, Paola Rogliani, Laura Tavanti, Fabrizio Luppi, Sergio Harari, Paola Rottoli, Alessandra Ghirardini, Klaus-Uwe Kirchgaessler, Carlo Albera

ConclusionsThe decline in FVC and the safety profile observed in this real-world IPF cohort were consistent with the findings of the Phase III pirfenidone trials.

ResultsThe study included 379 patients (mean age, 67.6 years; 78.1% male). Mean change from baseline in FVC and the percentage of patients with ≥ 10% absolute decline in % predicted FVC at Month 12 were −81.8 mL (SD, 419.6 mL; P = 0.002) and 16.0% (95% CI, 12.2–20.9%), respectively. Disease progression was similar across prespecified subgroups, including patients with definite vs possible UIP. Overall, 211 AEs occurred in 149 patients (39.3%), with serious AEs in 31 patients (8.2%) and 9 discontinuations due to AEs. Skin and gastrointestinal AEs were most frequent. Fifteen patients (4.0%) died.

September 2019 Volume 156, Pages 78–84Respir Med

Real-world evaluation of the effectiveness and safety of pirfenidone: findings from an observational chart review of a large cohort of

IPF patients in italy

IRENE italian team. ERS 2018

The findings of this retrospective analysis of a large observational cohortof Italian patients with IPF was consistent with the previously knownprofile of pirfenidone in delaying disease progression with manageabletreatment-related adverse events.

The effectiveness of pirfenidone was similar in patients with possibleUIP on HRCT and in those with definite UIP pattern.

ANTI FIBROTIC DRUGS:ADVERSE EFFECTS LEADING TO PERMANENT DISCONTINUATION (JAN 2012-SEPTEMBER 2019) 478 PATIENTS follow-up range 5-91 monthsILD UNIT Osp.S.Camillo,Roma) (UNPUBLISHED DATA)

DIARRHEA 9/478 ( 1,9%)

LIVER TOXICITY 2/478 (0,4%)

RASH 3/478 (0,6%)

WEIGHT LOSS/CACHEXIA 7/478 (1,5%)

NAUSEA/ANOREXIA 8/478 (1,7%)

PIASTRINOPENIA 1/478 (0,2%)

PHOTOSENSIVITY REACTIONS

12 /478 (2,5%)

TOTAL AE SWITCH

42/478 (8,78%)18/478 (3,8%)

IPF THERAPY WITH NEW ANTIFIBROTIC DRUGS : WHAT WE WANT TO KNOW

• WHICH DRUG FOR WHICH PATIENT ?

• WHICH THERAPY IN ACUTE EXACERBATIONS?

• NEW DRUGS ( IN COMBINATION ?)

• DO THE DRUGS WORK IN NON-IPF ILDS?

WHICH DRUG SHOULD I CHOOSE ?

• SIMILAR EFFICACY (50% SLOWING PROGRESSION)

• PARTIALLY DIFFERENT ADVERSE EFFECTS (DIARRHEA VS PHOTOSENSITIVITY)

• DIFFERENT DOSING AND SCHEDULE /COMORBIDITIES

• PATIENTS PREFERENCE- LIFE STYLE

• PATIENT TYPE (IN ITALY PIRFENIDONE IS PRECLUDED IF > 80 YEAR OLD

AND DLCO <35%, NINTEDANIB HAS NO AGE LIMITED INDICATION AND DLCO< 30%)

THERE REMAIN NO PROVEN,

EFFECTIVE THERAPIES FOR

ACUTE EXACERBATIONS OF IPF

38

Nintedanib in patients with chronic

fibrosing interstitial lung diseases with

progressive phenotype: the INBUILD® trial

September 2019

Adjusted annual rate of decline in FVC (mL/year) over 52 weeks

(primary endpoint)

-80,8

-187,8

-82,9

-211,1-250

-200

-150

-100

-50

0

Adju

ste

d m

ean (

SE

) annual ra

te

of

declin

e in F

VC

(m

L/y

ear)

Difference: 107.0 mL/year

(95% CI: 65.4, 148.5); p<0.001

Relative reduction: 57%

Difference: 128.2 mL/year

(95% CI: 70.8, 185.6); p<0.001

Relative reduction: 61%

Nintedanib

(n=332)

Placebo

(n=331)

Nintedanib

(n=206)

Placebo

(n=206)

Overall populationPatients with UIP-like fibrotic

pattern on HRCT

Based on random coefficient regression with fixed effects for treatment, HRCT pattern (only for the overall population), and baseline FVC (mL), and terms for treatment-by-time and baseline-by-time interactions. Flaherty KR, et al. N Engl J Med 2019; doi: 10.1056/NEJMoa1908681.

Unmeet need of patientsand olistic approach of care

L. Richeldi et al. Lancet. 2017 May 13;389(10082):1941-1952

La Carta Europea ha individuato cinque

temi chiave:

1) la necessità di una diagnosi più rapida e di un più

facile accesso ai centri specialistici di riferimento

2)l’urgenza di assicurare a tutti i pazienti un accesso a tutte le

terapie farmacologiche innovative ed efficaci ed al trapianto di

polmone

3) la possibilità per tutti i pazienti di ricevere un approccio globale

e integrato alla terapia, comprendente oltre ai farmaci anche la

riabilitazione respiratoria, il trattamento delle comorbidità, la

disassuefazione dal fumo, l’ottimizzazione dell’ossigenoterapia,

l’educazione nutrizionale e il supporto psicologico e sociale.

4) l’importanza di ricevere informazioni chiare e dettagliate sulla

malattia, la sua evoluzione e tutte le cure disponibili

5) la possibilità di ricevere cure palliative, per vivere con dignità le fasi finali della malattia.

Modello assistenziale centrato sul paziente

Le associazioni che fanno parte della FIMARP

LombardiaEmilia Romagna

Toscana Toscana

Dott. Alfredo Sebastiani

Dipartimento Malattie Polmonari

UOS Interstiziopatie Polmonari

Az. Osp. S.Camillo – Forlanini Roma

UN ESPERIENZA

ITALIANA DI

COUNSELING NEI

PAZIENTI CON IPF

COUNSELING

• Il termine counseling indica un'attività professionale che tende ad orientare, sostenere e sviluppare le potenzialità del paziente, promuovendone atteggiamenti attivi, propositivi e stimolando le capacità di scelta. Si occupa di problemi non specifici (prendere decisioni, miglioramento delle relazioni interpersonali) e contestualmente circoscritti.

Wikipedia

Obiettivi

⚫ Informare ed educare il paziente e i suoi familiari sulla malattia

⚫ Garantire aderenza alla terapia

⚫ Gestire gli effetti collaterali

⚫ Migliorare la gestione complessiva della malattia

⚫ Organizzare un corretto follow up

⚫ Pianificare la terapia palliativa

Grazie!

UOSD DAY HOSPITAL E INTERSTIZIOPATIE POLMONARI

Az. Osp. San Camillo-Forlanini Roma