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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