Traitement médical de la fibrose pulmonaire idiopathique : de nouvelles perspectives

Traitement médical de la fibrose pulmonaire idiopathique : de nouvelles perspectives

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A Dallas IPF cohort (n = 135) 100



B Chicago IPF cohort (n = 135)

C San Francisco IPF cohort (n = 135)

Q1 Q2 Q3 Q4

80 60 40 20 p = 0,0048

0 0

10

Number at risk Q4 34 Q3 33 Q2 34 Q1 34

p = 0,029

p = 0,00066

20

30 40 Months

20 8 16 12

8 3 5 5

50

60 0 4 1 0 3

10

31 30 31 31

20

30 40 Months

26 22 21 18

50

17 13 8 9

60 0 10 5 3 0

10

12 12 12 13

20

30 40 Months

10 10 7 9

50

10 7 6 5

60 9 6 6 4

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A Ageing-related susceptible lung

Recurring microinjuries Alveolar epithelium Capillaries

B Wound clot

C Aberrant activation of epithelial cells

Caveolin 1 RAGE

EGFs MMP1, MMP7

AEC migration and proliferation Epithelial cell apoptosis

Epithelial recapitulation of developmental pathways (Wnt, Shh)

FXa D Fibroblast focus MMP2 MMP9

E Hypercoagulable milieu Fibroblast recapitulatin of developmental pathways (PTEN, gremlin, FAPα)

F

Exaggerated ECM accumulatin

PDGF CXCL12 TGFβ

Progressive lung remodelling

Local fibroblasts Fibrocytes EMT, myofibroblast differentiation

Honeycomb changes

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B

A Change from baseline in FVC

After alert

0,0

Outcome

• Placebo

• •

FVC (liters)

-0,05

-0,10

• Acetylcysteine • •

-0,15

••

-0,20

Base- 15 line No. at risk Acety|cysteine 133 Placebo 131

127 127

30

45

60

Week 118 119

113 118

102 109

All patients

Before alert

P Value for Interaction

t-Statistic

FVC

0,16

DLCO corrected

0,02

CPI

0,04

Alveolar-arterial gradient

0,70

Walk distance

0,20

Oxygen saturation AUC

0,72

Walk distance to desaturation

0,65

Minutes walked

0,76

SF-36 aggregate physical score

0,89

SF-36 aggregate mental score

0,08

EuroQoL score

0,51

EuroQoL thermometer response

0,56

St. George’s total score

0,19

St. George’s symptoms score

0,45

St. George’s activity score

0,20

St. George’s impacts score

0,29

UCSD SOBQ total score

0,10 0,10

ICECAP summary score -3

-2

-1

Placebo better

0

1

2

3

Acetylcysteine better

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Mean Observed Change from Baseline in FVC (ml)

B INPULSIS-1 50

– 50 – 100 – 150

– 114,7

– 200 Difference, 125,3 (95 % CI, 77,7 – 172,8) – 250 P < 0,001 – 239,9 – 300

Nintedanib, 150 mg Twice Daily (N = 309)

Placebo (N = 204)

Adjusted Annual Rate of Change in FVC (ml/yr)

C INPULSIS-2 0

Nintedanib, 150 mg twice daily

– 50 – 100

Placebo

– 150

Adjusted mean difference, 109,9 (95 % CI, 71,3 – 148,6) P < 0,001

– 200 – 250

0 2 4 6

12

24 Week 292 194

284 192

36 274 187

52 250 165

D INPULSIS-1 50

– 50 – 100 – 150

0

No. of Patients Nintedanib 303 301 298 Placebo 202 198 200

– 113,6

Difference, 93,7 (95 % CI, 44,8 – 142,7 ) – 250 P < 0,001 – 207,3 – 200

Mean Observed Change from Baseline in FVC (ml)

Adjusted Annual Rate of Change in FVC (ml/yr)

A INPULSIS-1 0

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0 Nintedanib, 150 mg twice daily – 50 – 100 – 150 – 200

Placebo Adjusted mean difference, 109,8 (95 % CI, 70,9 – 148,6) P < 0,001

– 250 0 2 4 6

– 300 Nintedanib, 150 mg Twice Daily (N = 329)

Placebo (N = 219)

No. of Patients Nintedanib 323 315 315 Placebo 215 210 207

12

24 Week 312 209

303 203

36 295 196

52 269 180

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Cumulative incidence of first confirmed/suspected acute exacerbation (%)

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15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Nintedanib 150 mg × 2/j Placebo HR 0,32 (95 % Cl ; 0,16, 0,65) p = 0,0010

0

30

60

90

120

150

180

210

240

270

300

330

360 373

572 380

563 371

548 503 363 345

Time to first confirmed/suspected acute exacerbation (days) No. of patients Nintedanib 638 Placebo 423

634 419

629 416

613 409

610 408

602 404

597 396

593 393

589 390

580 384

Nintedanib 150 mg × 2/j (n = 638) Patients avec ≥ 1 exacerbatuion aigue, n (%)

Placebo (n = 423)

12 (1,9)

24 (5,7)

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Kaplan-Meier estimate of death (%)

Nintedanib 150 mg × 2/j 100 99 98 97 96 95 94 93 92 91 90

Placebo

HR 0,70 (95 % Cl ; 0,43, 1,12) p = 0,1399

0 0

30

60

90

120

150

180

210

240

270

300

330

360 373

617 406

612 403

606 400

601 394

591 532 388 358

Time to death (days) No. of patients Nintedanib 638 Placebo 423

637 422

635 420

632 418

628 418

623 416

620 414

619 408

Nintedanib 150 mg × 2/j (n = 638) Patients décédés, n (%)

35 (5,5)

Placebo (n = 423) 33 (7,8)

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A



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B

C

0 –2 –4 –6 –8 – 10 Pirfenidone 2 403 mg/day (n = 174) Pirfenidone 1 197 mg/day (n = 87) Placebo (n = 174)

– 12 – 14 0

Absolute difference* Relative difference* p value†

12

24

36

48

60

1,4 % 2,5 % 4,6 % 4,8 % 4,1 % 53,5 % 65,2 % 63,7 % 52,3 % 38,3 % 0,061 0,014 0,0001 0,0009 0,0002

72

Pirfenidone 2 403 mg/day (n = 171) Placebo (n = 173) 0

12

24

36

48

60

72

– 4,4 % 2,8 % 2,4 % 1,9 % 0,6 % 0,6 % 4,4 % – 31,5 % 62,1 % 48,2 % 27,3 % 7,6 % 6,5 % 35,3 % 0,021 0,001 0,011 0,005 0,172 0,501 0,001

Pirfenidone 2 403 mg/day (n = 345) Placebo (n = 347) 0

12

24

36

48

60

72

0,5 % 2,7 % 3,5 % 3,3 % 2,4 % 2,5 % 28,5 % 63,6 % 57,5 % 41,6 % 25,1 % 22,8 % 0,003 < 0,0001 < 0,0001 < 0,0001 0,0003 0,005

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A Decreased FVC or Death 35 Pirfenidone (N = 278)

P < 0,001

Placebo (N = 277)

Pirfenidone (N = 278)

25

P < 0,001

20 P < 0,001

15 10 5

P < 0,001

0 26

39 Week

– 200 – 300 – 400

13

26 Week

39

52

D Progression-free Survival

Pirfenidone (N = 278) P = 0,04 Placebo (N = 277)

30

P = 0,12

P = 0,04 Patients (%)

35

25 20 P = 0,40 15

100 90 80 70 60 50 40 30

Pirfenidone (N = 278)

Placebo (N = 277) Hazard ratio, 0,57 (95 %, 0,43 –0,77) P < 0,001

20 10

10 5 0

Placebo (N = 277) 0

52

C Decreased Walk Distance or Death

Patients (%)

– 100

– 500 13

40

B Change in FVC 0 Mean Change (ml)

Patients (%)

30

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243 225

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