A Practical Approach to JAK Inhibitors in IBD 2020 · 0.5 0 0 NMSC (%) 0.5 0 1.5 Sandborn WJ et al, ECCO 2017 Oral ... Thromboembolism • FDA-required safety study of tofacitinib

A Practical Approach to JAK Inhibitors in IBD 2020

Edward V Loftus Jr MDProfessor of Medicine

Division of Gastroenterology and HepatologyMayo Clinic

Rochester, Minnesota, USA

©2010 MFMER | slide-1

Binding of Cytokine Receptors by Cytokines Activates JAK Pathways Signaling

CP123456- 4

Consequence of JAK Inhibition on Signaling by Key Immunoregulatory Cytokines

O’Shea J. Immunity 2012

Tofacitinib for Induction of Remission in UC—2 Phase 3 Trials (n=1139)

• Mod-severe UC• Randomized 4:1 to tofacitinib 10 mg

BID or PBO• Primary endpoint: remission at week 8

(total Mayo ≤2, no subscore>1, rectal bleed 0)

• Results similar regardless of prior anti-TNF

• Rapid improvements• Infections higher in tofa groups (18-

23% vs 15%)

18.516.6

8.2

3.6

02468

101214161820

OCTAVE 1 OCTAVE 2

Tofacitinib10 mg BID

Placebo

Sandborn WJ et al, J Crohns Colitis Suppl 2016; Gastroenterology 2016 SupplSandborn WJ et al, N Engl J Med 2017;376:1723-36

7

32.8 29

59.9 55

0

20

40

60

80

OCTAVE 1 OCTAVE 2

Tofacitinib in Moderate to Severe UC:Clinical Response and Remission at 8 Weeks

Placebo Tofacitinib 10 mg BID

Patie

nts,

%

Clinical Response

8.2 4

25.2 22.112.6 12

0

20

40

60

80

OCTAVE 1 OCTAVE 2

Placebo Tofacitinib 10 mg BID, anti-TNF naïveTofacitinib 10 mg BID, anti-TNF experienced

P<0.001

Patie

nts,

%

P<0.001

Clinical Remission

P<0.01P<0.01

*Total Mayo score ≤2, no subscore >1, rectal bleeding 0.Sandborn WJ et al. N Engl J Med. 2017;376:1723-1736.

8

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID(n=198) (n=198) (n=197)

OCTAVE Sustain:Clinical Response and Remission at 52 Weeks

20.211 6.6 5.1

51.5

34.3 27.835.4

61.9

40.633

47.3

0

20

40

60

80

Patie

nts,

%

P<0.001

Clinical response Remission Sustained* mucosal healing

Sustained steroid-free†

remission among remitters at baseline

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

*Sustained endpoints defined as achieving response/remission at both Week 24 and Week 52.†Steroid-free defined as not requiring corticosteroids for ≥4 weeks prior to each visit.Sandborn WJ et al. N Engl J Med. 2017;376:1723-1736.

Tofacitinib Maintenance UC Trial-Safety• Prescribing info for RA has black

boxed warning about serious infections and malignancies

• Adverse events, serious adverse events, serious infection rates similar in all treatment arms

• Overall infections higher, but withdrawal due to AE was lower

• Zoster signal at 10 BID dose• No deaths• No intestinal perforations• Expected changes in lipids, CK

PBOBID

Tofa 5 mg BID

Tofa 10 mg BID

AEs (%) 75.3 72.2 79.6Withdrawal due to AE (%)

18.7 9.1 9.7

SAEs (%) 6.6 5.1 5.6Any Infections (%) 24.2 35.9 39.8

Serious infections (%)

1.0 1.0 0.5

Herpes zoster (%) 0.5 1.5 5.1

Malignancy exclNMSC (%)

0.5 0 0

NMSC (%) 0.5 0 1.5

Sandborn WJ et al, ECCO 2017 Oral Presentation (OP032) and DDW 2017 Oral Presentation 1080; Sandborn WJ et al, N EnglJ Med 2017;376:1723-36.

Tofacitinib Potential Safety Issue: Thromboembolism

• FDA-required safety study of tofacitinib in RA patients >50 yrs old with at least one CV risk factor

• Tofa 5 BID vs tofa 10 BID vs anti-TNF• Based on interim analysis, 10 BID

discontinued, changed to 5 BID• Awaiting final results of this trial• Boxed warning about DVT/PE added

to tofacitinib label• Indication in UC changed to

moderately to severely active UC, failed anti-TNF therapy

Tofacitinib 10 mg BID

Anti-TNF IncidenceRate Ratio

DVT/PE Incidence (cases per PY)

19/3884 =

0.49/100

3/3982 =

0.07/100 7

Death Incidence(per PY)

45/3884 =

1.16/100

25/3982 =

0.63/100 1.8

FDA Drug Safety Communication, July 26, 2019

Tofacitinib for Crohn’s Disease—Two Negative Trials• Two phase 2b studies of

moderate-severe Crohn’s (n=280 for induction, 180 for maintenance)

• PBO vs tofacitinib 5, 10, or 15 mg PO BID (highest dose dropped) for 8 weeks

• Primary endpoint: CDAI<150• Responders re-randomized to

PBO or tofacitinib 5 or 10 mg BID for 26 weeks

• Forced steroid taper to 10 mg daily for those on steroids

• Primary endpoint: CDAI<150 or CR100

• Drops in CRP but not FCP in tofacitinib groups were significant in induction

• Both CRP and FCP dropped in tofacitinib groups in maintenance

36.7

54.462.2

43.5

70.676.5

43

68.674.4

0

10

20

30

40

50

60

70

80

90

CDAI<150

CR 100

CR 70

Week 8

Panes J et al, Gut 2017;66:1049-59.

38.1

28.6

35.739.5

37.2 37.2

55.8

41.9

55.8

0

10

20

30

40

50

60

CR100 o

r CDAI<1

50

CDAI<150

CR100

Maintenance Week 26

PBOTofa 5 BIDTofa 10 BID

Vermeire S, et al. DDW Late-Breaker May 2016. Abstract 812c.Vermeire S, et al. Lancet 2017;389(10066):266-75.

23

4741

59

0

10

20

30

40

50

60

70

80

Clinicalremission

100-pointsclinical

responsePe

rcen

t Re

spon

ders

p<0.01

p<0.05

Placebo Filgotinib Placebo Filgotinib

Remission (CDAI <150)

Response (CDAI Reduction ≥100)

• Filgotinib is a selective once-daily oral JAK1 inhibitor

• FITZROY study: randomized to treatment with filgotinib 200 mg QD or placebo for 10 weeks

• All immunosuppressants were discontinued

• Primary endpoint: CDAI <150 at 10 weeks

• Endoscopic response (Reduced SES-CD>50%): 25% vs. 14% (NS)

• Serious AEs: 9% vs. 4%• Serious infections: 3% vs. 0%

Filgotinib (Selective JAK1 Inhibitor) Induction Rx for Moderate to Severe Crohn’s (n=174)

‡SES-CD, Endoscopic Response (Improvement by at least 50%, ITT-NRI, Wk 10)FITZROY

% s

ubje

cts

14%

(6/44)

23%

(10/44)

25%(32/128)

39%

(50/128)

05

101520253035404550

Central Reading Local Reading

Placebo FILG 200 mg+

+: p<0.10

∆=11%

∆=16%

Vermeire, S et al., Lancet 2017.

Digestive Disease Week, 2-5 June 2018, Washington DC, USA 15

CELEST Study Design

• Adult patients 18-75 years of age• Moderate to severe Crohn’s disease:

• CDAI 220-450• Average (7-day) daily very soft or liquid stool frequency (SF) > 2.5 and/or abdominal pain (AP) score > 2.0• Simplified Endoscopic Score for CD (SES-CD) > 6 (or > 4 in isolated ileal disease), confirmed by a central reader

• Inadequate response or intolerance to an immunosupressant or tumor necrosis factor antagonist

Week 0 5216

Rand

omiz

atio

n 1:

1:1:

1:1:

1N

=220

UPA 3mg BID

UPA 6 mg BID

UPA 12 mg BID

UPA 24 mg QD

2

UPA 24 mg QD

UPA 24 mg BID

PlaceboUPA 3 mg BID

UPA 6 mg BIDUPA 12 mg BID

Amendment 2: 6 mg BID: Initiated

Amendment 2: 24 mg QD: Stopped randomization, subjects previously enrolled continued

Com

plet

ers:

Re-r

ando

miz

atio

n N

=180

12Colonoscopy or

Upadacitinib (ABT-494)-Selective JAK1 Inhibitor-Induction Rx for Moderate to Severe Crohn’s Disease: CELEST (n=220)

• 96% were refractory to anti-TNF• Randomized to PBO vs ABT-494

at 3 mg, 6 mg, 12 mg, or 24 mg BID or 24 mg QD x 16 weeks

• Co-primary endpoints• Clinical remission (stool

frequency≤1.5, abd pain≤1) week 16• Endoscopic remission (SES-CD≤4)

at week 12/16

• AEs:76-86% vs. 73% PBO• SAEs: 5-28% vs. 5% PBO• Serious infections: 0-8% vs. 0% PBO

11

0

32

141310

44

2327

8

57

43

118

47

39

22 22

61

50

14 14

49 49

0

10

20

30

40

50

60

70

ClinicalRemission

EndoscopicRemission

ClinicalResponse

EndoscopicResponse

PBO3 mg BID6 mg BID12 mg BID24 mg BID24 mg QD

*

©2010 MFMER | slide-16Sandborn WJ et al, DDW 2017 Late-Breaker (874h)

*

**

**

* *

* p<0.05

Sandborn WJ et al, DDW 2017 Late-Breaker (874h)

UPA Ph 2 CD: CELEST

Sandborn WJ et al, DDW 2017 Late-Breaker (874h)

UPA Ph 2 CD: CELEST

Digestive Disease Week, 2-5 June 2018, Washington DC, USA 19

Modified Clinical Remission and Endoscopic Response 50% at Week 52 in Patients Who Were Responders or Clinical Responders at Week 16

† statistically significant at ≤0.1 level.

M o d if ie d C lin ic a l

R e m is s io n

E n d o s c o p ic

R e s p o n s e

0

2 0

4 0

6 0

8 0

1 0 0

Pe

rce

ne

tage

of

pa

tie

nts

4 1 . 2

6 2 . 5

†7 3 . 3

4 0 . 0

5 0 . 0 5 0 . 0

6 8 . 8

3 0 . 0

7 / 1 7 5 / 8 1 1 / 1 5 4 / 1 0 1 0 / 2 0 4 / 8 1 1 / 1 6 3 / 1 0

M o d if ie d C lin ic a l

R e m is s io n

E n d o s c o p ic

R e s p o n s e

0

2 0

4 0

6 0

8 0

1 0 0

Pe

rce

ne

tage

of

pa

tie

nts

2 8 . 6

4 2 . 9

†5 1 . 9

3 8 . 93 4 . 4 3 5 . 7

4 4 . 8

3 6 . 8

8 / 2 8 6 / 1 4 1 4 / 2 7 7 / 1 8 1 1 / 3 2 5 / 1 4 1 3 / 2 9 7 / 1 9

† s ta tis tic a lly s ig n if ic a n t a t £ 0 .1 le v e l.

R e s p o n d e r s ( IT T -R ) C lin ic a l R e s p o n d e r s ( IT T -C R )

3 m g B ID 6 m g B ID 1 2 m g B ID 2 4 m g Q D

Panes J et al, DDW 2018

Upadacitinib for Moderate to Severe UC: U-ACHEIVE

• 250 mod-severe UC• Randomized to PBO, UPA

7.5,15, 30,or 45 mg daily• Primary endpoint: clinical

remission per adapted Mayo score at week 8

0 2

13 11915

30

0

14

31

45

2

14

27

44

0

20

36

50

4

0102030405060

Clin Rem

Endo im

provemen

t

Clin Res

pSAE

PBOUPA 7.5UPA 15UPA 30UPA 45

20

Sandborn WJ et al, UEGW 2018, Abstract OP195

U-ACHIEVE Primary Endpoint: Clinical Remission per Adapted Mayo Score at Week 8 (NRI). Overall Population

21U-ACHIEVE sub-group analysis| OP064 | UEGW 2019

0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s (

%)

P l a c e b o

( 0 / 4 6 )

0 . 0

+

8 . 5

*

1 4 . 3

*

1 3 . 5

* *

1 9 . 6

U P A Q D

7 . 5 m g

( 4 / 4 7 )

U P A Q D

4 5 m g

( 1 1 / 5 6 )

U P A Q D

3 0 m g

( 7 / 5 2 )

U P A Q D

1 5 m g

( 7 / 4 9 )

T r e a t m e n t a r m

( n / N )+<0.1; *p<0.05; **p<0.01UPA: upadacitinib; QD: once daily

Clinical remission per Adapted Mayo score: stool frequency subscore (SFS) ≤ 1, rectal bleeding subscore (RBS) = 0, and endoscopic subscore ≤ 1.

Sandborn WJ et al, UEGW 2018, Abstract OP195

U-ACHIEVE: Endoscopic and histologic outcomes at Week 8 | Oral 800 | DDW 2019 22

0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s (

%)

P l a c e b o

( 0 / 4 6 )

06 . 4 4 . 1

*

9 . 6

* *

1 7 . 9

U P A

7 . 5 m g Q D

( 3 / 4 7 )

U P A

4 5 m g Q D

( 1 0 / 5 6 )

U P A

3 0 m g Q D

( 5 / 5 2 )

U P A

1 5 m g Q D

( 2 / 4 9 )

0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s (

%)

P l a c e b o

( 1 / 4 6 )

2 . 2

*

1 4 . 9

* * *

3 0 . 6* * *

2 6 . 9

* * *

3 5 . 7

U P A

7 . 5 m g Q D

( 7 / 4 7 )

U P A

4 5 m g Q D

( 2 0 / 5 6 )

U P A

3 0 m g Q D

( 1 4 / 5 2 )

U P A

1 5 m g Q D

( 1 5 / 4 9 )


( n / N )

U-ACHIEVE: Endoscopic outcomes at Week 8 (NRI)

Endoscopic improvement(endoscopic subscore ≤ 1)

Endoscopic remission(endoscopic subscore = 0)

*p<0.05; **p<0.01; ***p<0.001UPA: upadacitinib; QD: once daily

Sandborn WJ et al, DDW 2019


0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s (

%)

P l a c e b o

( 1 / 4 6 )

2 . 2

+

1 2 . 8

* *

2 2 . 4

* * *

3 0 . 8

* * *

4 1 . 1

U P A

7 . 5 m g Q D

( 6 / 4 7 )

U P A

4 5 m g Q D

( 2 3 / 5 6 )

U P A

3 0 m g Q D

( 1 6 / 5 2 )

U P A

1 5 m g Q D

( 1 1 / 4 9 )

0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s (

%)

P l a c e b o

( 3 / 4 6 )

6 . 5

* *

3 1 . 9

* * *

5 1 . 0 * * *

4 4 . 2

* * *

4 8 . 2

U P A

7 . 5 m g Q D

( 1 5 / 4 7 )

U P A

4 5 m g Q D

( 2 7 / 5 6 )

U P A

3 0 m g Q D

( 2 3 / 5 2 )

U P A

1 5 m g Q D

( 2 5 / 4 9 )


( n / N )

U-ACHIEVE: Histologic outcomes at Week 8 (NRI)

Histologic remission(Geboes score < 2)

Histologic improvement (any decrease from baseline in Geboes score)

+p<0.1; **p<0.01; ***p<0.001UPA: upadacitinib; QD: once daily



0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s (

%)

P l a c e b o

( 0 / 4 6 )

0 2 . 1 2 . 0

*

5 . 8

*

1 4 . 3

U P A

7 . 5 m g Q D

( 1 / 4 7 )

U P A

4 5 m g Q D

( 8 / 5 6 )

U P A

3 0 m g Q D

( 3 / 5 2 )

U P A

1 5 m g Q D

( 1 / 4 9 )


( n / N )

U-ACHIEVE: Mucosal healing at Week 8 (NRI)

Endoscopic subscore = 0 AND Geboes score < 2

+p<0.1; *p<0.05; **p<0.01UPA: upadacitinib; QD: once daily

0

2 0

4 0

6 0

8 0

1 0 0

Pa

tie

nt

s,

%

06 . 4

+

1 6 . 3+

1 3 . 5

* *

2 5 . 0

P l a c e b o

( 0 / 4 6 )

U P A

7 . 5 m g Q D

( 3 / 4 7 )

U P A

4 5 m g Q D

( 1 4 / 5 6 )

U P A

3 0 m g Q D

( 7 / 5 2 )

U P A

1 5 m g Q D

( 8 / 4 9 )

Endoscopic subscore ≤ 1 AND Geboes score < 2 (post-hoc analysis)



U-ACHIEVE: Safety Overview

Event, n (%) PlaceboN = 46

UPA 7.5 mg QDN = 47

UPA 15 mg QDN = 49

UPA 30 mg QDN = 52

UPA 45 mg QDN = 56

Any AEs 33 (71.7) 29 (61.7) 29 (59.2) 34 (65.4) 35 (62.5)

Severe AEs 7 (15.2) 3 (6.4) 3 (6.1) 3 (5.8) 4 (7.1)

Serious AEs 5 (10.9) 0 2 (4.1) 3 (5.8) 3 (5.4)

AEs Leading to Discontinuation 4 (8.7) 2 (4.3) 2 (4.1) 4 (7.7) 4 (7.1)

No deaths were reported as of the date of database lock.



U-ACHIEVE: Adverse Events of Special Interest

AE, n (%) PlaceboN = 46

UPA 7.5 mg QDN = 47

UPA 15 mg QDN = 49

UPA 30 mg QDN = 52

UPA 45 mg QDN = 56

Serious Infections 2 (4.3) 0 1 (2.0) 0 2 (3.6)

Opportunistic Infections 1 (2.2) 0 0 0 1 (1.8)

Herpes Zoster 0 0 0 0 1 (1.8)

Malignancya 0 1 (2.1) 0 0 0

Hepatic Disorderb 1 (2.2) 2 (4.3) 0 0 6 (10.7)

Gastrointestinal Perforations 0 0 0 0 0

Anemia 3 (6.5) 1 (2.1) 4 (8.2) 1 (1.9) 0

a. One case of malignant melanoma was reported.b. All were reported as liver enzyme abnormalities except for one case of drug-induced liver injury due to isoniazid therapy.


Phase 1b. Colonic Release, Pan-JAK Inhibitor TD-1473 is Efficacious Moderate-Severe UC§ Aim- TD-1473 is an orally

administered and gut-selective pan-Janus kinase (JAK) inhibitor

- Assess the safety, clinical and molecular effects of TD-1473 in UC after 4 weeks

§ Method- Double-blind, placebo-

controlled, multicenterPhase 1b

- 40 subjects enrolled- Placebo n=9- 20mg n=10- 80mg n=10- 270mg n=11

§ Results- Higher rates of clinical response,

endoscopic healing, and improvement by ≥ 1 point in rectal bleeding and endoscopy subscores

- Reduction in CRP + FCAL- Well tolerated and minimal risk for

systemic immunosuppression

Sandborn W, et al. Presented at DDW, May 2019. Abstract 801.

1

10

100

1000

10000

100000

270 mg

Time PointsDay 1 Day 28

1

10

100

1000

10000

100000

Placebo

Time Points

Feca

l Calp

rotec

tin Le

vel

Day 1 Day 28

27

Conclusions• JAK inhibition represents a potent, fast-acting

mechanism of action for reducing inflammation in IBD

• Tofacitinib approved for moderately to severely active UC in patients who have failed anti-TNF therapy

• The selective JAK1 inhibitors appear to have efficacy in moderately to severely active CD, and upadacitinib appears efficacious in UC

©2010 MFMER | slide-28

Documents

A Practical Approach to JAK Inhibitors in IBD 2020 · 0.5 0 0 NMSC (%) 0.5 0 1.5 Sandborn WJ et al, ECCO 2017 Oral ... Thromboembolism • FDA-required safety study of tofacitinib