The experience with tofacitinib in Humanitas IBD center, from … · 2019-06-01 · Study design: OCTAVE Induction studies Primary Objectives 1. Compare the efficacy of tofacitinib

The experience with tofacitinib in Humanitas IBD center, from theory to clinical practice

Silvio Danese, MD, PhD

IBD Center, Istituto Clinico Humanitas,

Milan, Italy

PP-XEL-SWE-0419_sept-2018

Conflicts of Interest

• Consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring Pharmaceuticals Inc., Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB Inc., and Vifor.

• “The opinions expressed in this presentation belong to the presenter and do not necessarily reflect the views of the company. For all medicinal products mentioned, please refer to the approved Summaries of Product Characteristics”

FAQs in IBD clinic at tofacitinib launch

• How should we use a new drugonce we have it in the clinic?

• What are the differentiatorsfor a new drug?

FAQ, frequently asked question; IBD, inflammatory bowel disease.

What are the decision drivers?

Data at launch

Treatment

strategies

Positioning

Disease/patient

features

?


Data at launch

Treatment

strategies

Positioning

Disease/patient

features

UC clinical development programme

Study Name/ Number Objective Endpoints Duration Study Completion

Phase 2

A39210631 Dose-finding study to find optimal dose for Phase 3

Primary endpoint:clinical response at Week 8

8 weeks September 2010

Phase 3

OCTAVE Induction 12,3

(A3921094)Assess the efficacy and safety of

tofacitinib as induction therapy for UC

Primary endpoint: remission at Week 8

Key secondary endpoint: mucosal healing at Week 8

8 weeks* May 2015



tofacitinib as induction therapy for UC


Key secondary endpoint: mucosal healing at Week 8

8 weeks* May 2015

OCTAVE Sustain5,6


tofacitinib as maintenance therapy for UC


Key secondary endpoints: mucosal healing at Week 52 and sustained steroid-free remission†

at Week 52

52 weeks* May 2016

OCTAVE Open7

(A3921139)Open-label LTE study to assess the long-

term use of tofacitinibPrimary endpoint:

Safety measured by number of reported AEs

>12 months (ending with first market

authorisation)July 2018 (estimated)

Final complete efficacy assessment at Week 8/52; treatment continued up to Week 9/53. * Among subjects in remission at baseline.

The tofacitinib clinical development programme in UC comprises a phase 2 dose-finding trial,

two identical phase 3 induction studies, a phase 3 maintenance study, and a long-term extension study

AEs, adverse events; LTE, long-term extension; UC, ulcerative colitis

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Tofacitinib UC Phase 3 programme

Completers

& Treatment

Failures


(A391094)

10 mg BID

Placebo

8 weeks*

N=598 (4:1)

Ran

do

mis

ati

on

As

se

ss

me

nt Nonresponders

Responders†


(A3921095)

10 mg BID

Placebo

8 weeks*

N=541 (4:1)

Ran

do

mis

ati

on

As

se

ss

me

nt

Responders†

Nonresponders

OCTAVE Sustain2,4

(A3921096)

52 weeks*

N=593 (1:1:1)

5 mg BID

10 mg BID

Re

-ra

nd

om

isa

tio

n

As

se

ss

me

nt

Placebo

OCTAVE Open5

(A3921139)

Up to 1st approval

N=946

10 mg BID‡

5 mg BID‡

En

rolm

en

t

As

se

ss

me

nt

* Final complete efficacy assessment at Week 8/52. Treatment continued up to Week 9/53. † “Responders” refers to subjects who achieved clinical response during OCTAVE Induction 1 or 2. ‡ Subjects in remission at Week 52 of OCTAVE Sustain were assigned to tofacitinib 5 mg BID. Subjects who completed 8 weeks of treatment in OCTAVE Induction 1 or 2 and were classified as nonresponders, and subjects who completed OCTAVE Sustain but did not meet remission or who withdrew from the study early due to treatment failure, were assigned to tofacitinib 10 mg BID.

The OCTAVE Phase 3 program for UC consists of two identical induction studies (OCTAVE Induction

1 and 2), a maintenance study (OCTAVE Sustain), and a long-term extension study (OCTAVE Open).

BID, twice daily

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Study design: OCTAVE Induction studies

Primary Objectives

1. Compare the efficacy of tofacitinib vs placebo in inducing remission (primary endpoint) and achieving mucosal healing (key secondary endpoint) in subjects

with moderately to severely active UC after 8 weeks of treatment

2. Evaluate the safety and tolerability of tofacitinib after 8 weeks of treatment

Screening (3

weeks)1,2

2 4 8 9 130

Tofacitinib 10 mg BID3

(OCTAVE Induction 1: N=476)


Placebo BID3


(OCTAVE Induction 2: N=112)Ran

do

mis

ati

on

(4:1

)3

En

d o

f tr

ea

tme

nt

Double-blind,

placebo-controlled treatment

8 weeks*

Non-responders

Responders

Others

OCTAVE Sustain

OCTAVE Open

4-week follow-upFollow-up

4 weeks

The induction studies initially included a tofacitinib 15 mg BID dose group, which was removed after a total of 22 subjects were randomised and

completed the studies3

Subjects required to have

prior failure or intolerance to

≥1 of the following

therapies:3

‒ Oral or IV corticosteroids

‒ AZA or 6-MP

‒ TNFi

The primary endpoint was

remission at Week 8

* Subjects received double-blind treatment for up to 9 weeks, with the final efficacy evaluation at Week 8.

OCTAVE Induction 1 and 2 were identically designed Phase 3 studies.

The primary endpoint in OCTAVE Induction 1 and 2 was remission at Week 8.6-MP, 6-mercaptopurine; AZA, azathioprine; BID, twice daily; TNF, tumour

necrosis factor inhibitors; IV, intravenous1. A3921094 and A3921095 Final Protocols; 2. A3921094 and A3921095 Study Report Output; 3. Sandborn WJ, et al. N Engl J Med. 2017;376(18):1723–36.

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Significantly more patients achieved primary endpointat Week 8 with tofacitinib vs placebo

Treatment effect was observed in TNFi-treated and TNFi-naïve patients(% difference from placebo [95% confidence intervals]):• OCTAVE Induction 1: TNFi-treated (11.1 [6.0, 16.1]); TNFi-naïve (9.4 [-1.6, 20.5])• OCTAVE Induction 2: TNFi-treated (12.0 [7.8, 16.1]); TNFi-naïve (13.5 [3.7, 23.4])

Data are full analysis set with non-responder imputation**p<0.01; ***p<0.001 vs placebo (Cochran-Mantel-Haenszel chi-square test)Sanborn WJ, et al. NEJM 2017.

3.6

***

16.6

0

10

20

30

40

50

60

Placebo Tofacitinib10 mg BID

Pat

ien

ts w

ith

re

mis

sio

n (

%) OCTAVE Induction 2

8.2

**

18.5

0

10

20

30

40

50

60


Pat

ien

ts w

ith

re

mis

sio

n (

%) OCTAVE Induction 1

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Primary endpoint: remission at week 8 by prior TNFitreatment

1.5

15.8

0

8.512.6

25.2

12.0

22.1

0

10

20

30

40

50

60

70

80

90

100

TNFi treated TNFi naive TNFi treated TNFi naive

Pat

ien

ts w

ith

re

mis

sio

n (

%)

* *

*Δ=11.1

Δ=9.4

Δ=12.0

Δ=13.5

OCTAVE Induction 1 OCTAVE Induction 2

*P≤0.05

The treatment effect for remission was similar in patients who were TNFi treated and TNFi naive.

Tofacitinib 10 mg BIDPlacebo

n 1 32 9 56 0 28 4 43

N 65 254 57 222 65 234 47 195

BID, twice daily; TNFi, tumour necrosis factor inhibitorsSandborn WJ, et al. N Engl J Med. 2017;376(18):1723–36 (appendix)

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Tofacitinib had a significant effect vs placebo onmucosal healing at Week 8

Treatment effect was observed in TNFi-treated and TNFi-naïve patients(% difference from placebo [95% confidence intervals]):• OCTAVE Induction 1: TNFi-treated (17.9 [10.0, 25.77]); TNFi-naïve (13.3 [0.2, 26.4])• OCTAVE Induction 2: TNFi-treated (15.6 [7.8, 23.5]); TNFi-naïve (17.3 [4.1, 30.4])

Data are full analysis set with non-responder imputation**p<0.01; ***p<0.001 vs placebo (Cochran-Mantel-Haenszel chi-square test)Sanborn WJ, et al. ECCO 2016; OPO19.

11.6

***

28.4

0

10

20

30

40

50

60


Pat

ien

ts w

ith

mu

cosa

l he

alin

g (%

)

OCTAVE Induction 2

15.6

***

31.3

0

10

20

30

40

50

60


Pat

ien

ts w

ith

mu

cosa

l he

alin

g (%

)

OCTAVE Induction 1

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Key secondary endpoint: mucosal healing at week 8 by prior TNFi treatment

P values based on Cochran-Mantel-Haenszel chi-square test stratified by prior treatment with TNFi, corticosteroid use at baseline, and geographic region.Efficacy data are full analysis set with nonresponder imputation (central read).

6.2

26.3

6.2

19.124.0

39.6

21.8

36.4

0

10

20

30

40

50

60

70

80

90

100

TNFi treated TNFi naive TNFi treated TNFi naive

Pat

ien

ts w

ith

mu

cosa

l he

alin

g (%

)

n2 4 61 15 88 4 51 9 71

N1 65 254 57 222 65 234 47 195

**

*Δ=17.9

Δ=13.3

Δ=15.6

Δ=17.3

*P≤0.05

OCTAVE Induction 1 OCTAVE Induction 2

Placebo Tofacitinib 10 mg BID

BID, twice daily; TNFi, tumour necrosis factor inhibitors1. Sandborn WJ, et al. N Engl J Med. 2017;376(18):1723–36; 2. A3921094 and A3921095 Study Report Output; Table 14.2.3.3.

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Primary endpoint: remission at Week 52 (FAS, NRI; central read )

• A significantly greater proportion of patients receiving tofacitinib were in remission at Week 52 vs patients receiving placebo

13

11.1

34.340.6

0

10

20

30

40

50

60

70

80

90

100

Remission at Week 52

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID

n/N 22/198 68/198 80/197

Diff. from placebo(95% CI)

- 23.2(15.3, 31.2)

29.5(21.4, 37.6)

p<0.001p<0.001

∆=29.5

∆=23.2

Data are FAS with NRI, central read. FAS consisted of all randomized subjects

p<0.001 vs placebo; calculated by Cochran-Mantel-Haenszel chi-square test

Remission is defined as total Mayo score ≤2; no subscore >1; rectal bleeding subscore of 0

BID, twice daily; CI, confidence interval; Diff., difference; FAS, full analysis set; NRI, non-responder imputation; N, total number of patients in the analysis set; n, number of

patients meeting endpoint criteria

Pro

po

rtio

n o

f p

atie

nts

(%

)

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Primary endpoint: Remission at week 52 by prior TNFi treatment

A3921096 Study Report Output; Tables 14.2.2.4 and 14.2.2.5.

12.0 10.4

26.7

40.736.6

44.8

0

20

40

60

80

100

TNFi treated TNFi naive

Pat

ien

ts w

ith

re

mis

sio

n (

%)

n 11 24 37 11 44 43

N 92 90 101 106 108 96

Δ=14.7

Δ=24.7

Δ=30.4

Δ=34.4


BID, twice daily; TNFi, tumour necrosis factor inhibitor

Efficacy data are full analysis set with non-responder imputation (central read).

Key secondary endpoints: mucosal healing (FAS, NRI; central read)

15

13.1

37.445.7

0

10

20

30

40

50

60

70

80

90

100

Mucosal healing at Week 52


n/N 26/198 74/198 90/197

Diff. from placebo(95% CI)

- 24.2(16.0, 32.5)

32.6(24.2,41.0)

p<0.001p<0.001

∆=32.6

∆=24.2

Mucosal healing at Week 52 was observed in a significantly greater proportion of patients receiving tofacitinib vs patients receiving placebo

Data are FAS with NRI, central read. FAS consisted of all randomized subjects

p<0.001 vs placebo; calculated by Cochran-Mantel-Haenszel chi-square test

Mucosal healing defined as Mayo endoscopic subscore of 0 or 1.

BID, twice daily; CI, confidence interval; Diff., difference; FAS, full analysis set; NRI, non-responder imputation; N, total number of patients in the analysis set; n, number of

patients meeting endpoint criteria

Pro

po

rtio

n o

f p

atie

nts

(%

)

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Key secondary endpoint: Mucosal healing at week 52 by prior TNFitreatment

A3921096 Study Report Output; Tables 14.2.3.4 and 14.2.3.5.

13.0 13.2

32.2

41.739.6

52.1

0

20

40

60

80

100

TNFi treated TNFi naive

Pat

ien

ts w

ith

m

uco

sal h

eal

ing

(%)

n 12 29 40 14 45 50

N 92 90 101 106 108 96

Δ=19.2

Δ=26.6Δ=28.5

Δ=38.9


BID, twice daily; TNFi, tumour necrosis factor inhibitor.

Efficacy data are full analysis set with non-responder imputation (central read).

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FAQ in IBD clinic at tofacitinib launch

• Before or after anti-TNF?

There is definitely a place for tofacitinib useas a first-line biologic after failure of, or contraindications to,

a conventional therapy, beside second line after failure on anti-TNFs

Tofacitinib Summary of product characteristics (SmPC). .


Data at launch

Treatment

strategies

Positioning

Disease/patient

features

Placebo

What sources are available to inform positioning of a new drug vs competitors?

There is a paucity of head-to-head trials that inform clinicians on the appropriate efficacious and safe treatment regimens for IBD

Head-to-head trials in other IMIDs

Moderate-to-severe rheumatoid arthritis

• Abatacept (CTLA4Ig) is not inferior to adalimumab (anti-TNF)

• Adalimumab (anti-TNF) is superior to pateclizumaba (anti-lymphotoxin-α)

• Certolizumab pegol (anti-TNF) is not inferior to adalimumab (anti-TNF)

• Tofactinib (anti-JAK) is not inferior to adalimumab (anti-TNF)

Moderate-to-severe (plaque) psoriasis

• Ustekinumab (anti-IL-12/23) is superior to etanercept (anti-TNF)

• Secukinumab (anti-IL-17A) is superior to etanercept (anti-TNF)

• Secukinumab (anti-IL-17A) is superior to ustekinumab (anti-IL-12/23)

• Ixekizumab (anti-IL-17A) is superior to etanercept (anti-TNF) and superior to ustekinumab (anti-IL-12/23)

• Guselkumab is superior to adalimumab and superior to ustekinumab in UST-IR

• Risankizumabb (anti-IL-23) is superior to ustekinumab (anti-IL-12/23)

a Currently not indicated for the treatment of rheumatoid arthritis.b Currently not indicated for the treatment of psoriasis.CTLA4, cytotoxic t-lymphocyte-associated protein 4; IMID, immune-mediated inflammatory disease; JAK, Janus kinase, UST-IR, ustekinumab immediate release.

Schiff M, et al. Ann Rheum Dis. 2014;73:86-94.Kennedy WP, et al. Arthritis Res Ther. 2014;16:467.

Smolen JS, et al. Lancet. 2016;388:2763-74.Fleischmann R, et al. Lancet. 2017;390:457-68.

Griffiths CE, et al. N Engl J Med. 2010;362:118-28.Langley RG, et al. N Engl J Med. 2014;371:326-38.

Thaçi D, et al. J Am Acad Dermatol. 2015;73:400-9.Reich K, et al. Br J Dermatol. 2017;177:1014-23.Papp KA, et al. N Engl J Med. 2017;376:1551-60.

Ixekizumab Summary of product characteristics (SmPC). EMA. Date of revision: 3 August 2018.Guselkumab Summary of product characteristics (SmPC). EMA. Date of revision: 30 November 2017.

ClinicalTrials.gov. NCT02694523, NCT03478787, NCT02684370, and NCT02684357.

Head-to-head trials of biologics with different MoAs in ulcerative colitis are underway

MoAs, mechanisms of action.1. ClinicalTrials.gov NCT02497469. 2. ClinicalTrials.gov NCT02171429. 3. ClinicalTrials.gov NCT02163759. 4, ClinicalTrials.gov NCT03616821. 5. ClinicalTrials.gov NCT02136069.

21

Etrolizumab

vs adalimumab2,3

Etrolizumab

vs infliximab5

Estimated primary completion date

HIBISCUS 1&2Induction: 10 weeks

GARDENIAMaintenance: 54 weeks

VARSITYMaintenance: 52 weeks

Vedolizumab

vs adalimumab1

EXPEDITIONMaintenance: 54 weeks

October MarchFebruary

20202019 2021 2022 2023

February

Brazikumab4

vs vedolizumab

What have we learned from indirect comparisons of ulcerative colitis clinical trials?

PBO, placebo; pts, patients; RCTs, randomised controlled trials, TNF, tumour necrosis factor.1. Danese S et al. Ann Intern Med. 2014;160:704-11. 2. Vickers AD et al. PLoS One. 2016;11:e0165435. 3. Cholapranee A et al. Aliment Pharmacol Ther. 2017;45:1291-302.4. Bonovas S et al. Aliment Pharmacol Ther. 2018;47:454-65. 5. Singh S et al. Aliment Pharmacol Ther. 2018;47:162-75.Head-to-head trials are needed to inform clinical decision-making with greater confidence.

22

2014 2016 2017 2018

Danese et al1 Vickers et al 2 Cholapranee et al 3 Bonovas et al 4 Singh et al 5

RCTs, n 7 7 5 15 14

Endpoints

(Population)

Induction and

maintenance, safety

(no separate analysis

for biologic-naïve vs

prior anti-TNF

exposure pts)

Induction and

maintenance

(analysis for biologic-

naïve vs prior anti-

TNF exposure)

Mucosal healing

(no separate analysis

for biologic-naïve vs

prior anti-TNF

exposure pts)

Induction and

maintenance, safety

(analysis only for pts

without prior anti-

TNF exposure)

Induction and

maintenance, safety

(analysis for biologic-

naïve vs prior anti-

TNF exposure)

ComparisonBiologic vs PBO;

biologic vs biologic

Biologic vs PBO;


Biologic vs PBO;


Drug vs PBO;

drug vs drug

Drug vs PBO;

drug vs drug

Comparators Infliximab Infliximab Infliximab Infliximab Infliximab

Adalimumab Adalimumab Adalimumab Adalimumab Adalimumab

Golimumab Golimumab Golimumab Golimumab Golimumab

Vedolizumab Vedolizumab Vedolizumab Vedolizumab Vedolizumab

Tofacitinib Tofacitinib

Systematic review anddirect comparison

Induction efficacy in biologic-naïve UC patients: Tofacitinib and all biologics studied were superior to placebo

CI, confidence interval; OR, odds ratio; UC, ulcerative colitis.Bonovas S, et al. Aliment Pharmacol Ther. 2018;47:454-465.Head-to-head trials are needed to inform clinical decision-making with greater confidence.

23

▪ 15 randomised controlled trials

included in network meta-

analysis (N=3130)

▪ All the treatments under

evaluation (tofacitinib,

adalimumab, golimumab,

infliximab and vedolizumab)

demonstrated superiority over

placebo

Induction of clinical remission

Comparison Study or Subgroup

Adalimumab

vs. placebo

Reinisch ULTRA 1, ITT-A3 (2011)

Reinisch ULTRA 1, ITT-E (2011)

Sandborn ULTRA 2 (2012)

Suzuki (2014)

Fixed effect model

Random effects model

Golimumab

vs. placebo

Sandborn PURSUIT-SC Ph2 (2014)

Sandborn PURSUIT-SC Ph2 add. (2014)

Sandborn PURSUIT-SC Ph3 (2014)

Fixed effect model


Infliximab

vs. placebo

Rutgeerts ACT 1 (2005)

Rutgeerts ACT 2 (2005)

Kobayashi Japic CTI-060298 (2016)

Jiang (2015)

Fixed effect model


Tofacitinib

vs. placebo

Sandborn OCTAVE Induction 1 (2017)

Sandborn OCTAVE Induction 2 (2017)

Sandborn Study A39221063 (2012)

Fixed effect model


Vedolizumab

vs. placebo

Feagan GEMINI 1 (2016)

Fixed effect model


0.1 0.5 1 2 10Odds ratio (95% CI)*

OR [95% CI]*

2.23 [1.06, 4.67]

2.98 [0.91, 9.74]

2.19 [1.14, 4.19]

0.86 [0.34, 2.18]

1.92 [1.29, 2.86]

1.89 [1.19, 3.00]

1.90 [0.51, 7.08]

2.08 [0.47, 9.29]

3.18 [1.74, 5.79]

2.81 [1.69, 4.69]

2.80 [1.67, 4.67]

3.63 [1.96, 6.76]

8.49 [3.63, 19.88]

2.14 [0.97, 4.70]

4.12 [1.57, 10.76]

4.03 [2.75, 5.89]

3.97 [2.32, 6.79]

1.80 [0.83, 3.90]

3.04 [1.03, 8.95]

4.31 [1.22, 15.17]

2.47 [1.40, 4.34]

2.47 [1.41, 4.34]

4.26 [1.58, 11.52]

4.26 [1.58, 11.52]

4.26 [1.58, 11.52]

Favors interventionFavors control

General safety

• In the Induction and Maintenance Cohorts, the most frequent reason for discontinuation was insufficient clinical response, including the AE of worsening UC

• In Cohort 3, the SOCs in which AEs most frequently occurred (all causality) were Gastrointestinal disorders SOC and Infections and infestations SOC

Induction Cohort1 Maintenance Cohort1,2 Overall

Cohort1

AEs, n (%)

Placebo

(N=282)

Tofacitinib

10 mg BID

(N=938)

Placebo

(N=198)

Tofacitinib

5 mg BID

(N=198)

Tofacitinib

10 mg BID

(N=196)

Tofacitinib

All

(N=1156)

Patients with AEs 155 (55.0) 515 (54.9) 149 (75.3) 143 (72.2) 156 (79.6) 939 (81.2)

Patients with SAEs 18 (6.4) 36 (3.8) 13 (6.6) 10 (5.1) 11 (5.6) 149 (12.9)

Patients with severe AEs1 15 (5.3) 38 (4.1) 19 (9.6) 14 (7.1) 15 (7.7) 135 (11.7)

Discontinuations due to AEs 14 (5.0) 36 (3.8) 37 (18.7) 18 (9.1) 19 (9.7) 74 (6.4)a

Most frequently occurring AEs ≥10% of patients

HeadacheNasopharyngitisWorsening UC

19 (6.7)14 (5.0)20 (7.1)

73 (7.8)56 (6.0)26 (2.8)

12 (6.1)11 (5.6)

71 (35.9)

17 (8.6)19 (9.6)

36 (18.2)

6 (3.1)27 (13.8)29 (14.8)

118 (10.2)194 (16.8)212 (18.3)

Most frequent SAE – worsening UC 9 (3.2) 14 (1.5) 8 (4.0) 2 (1.0) 1 (0.5) 51 (4.4)

Only events occurring within 28 days after the last dose are included in this table for calculation of proportion; AEs and SAEs were coded using MedDRA, version 19.0; severe AE intensity was described by the investigators aData for the Overall

Cohort are n (%) of patients with dose reduction or temporary discontinuation due to AE

AE, adverse event; BID, twice daily; MedDRA, Medical Dictionary for Regulatory

Activities; N, number of patients in the treatment group; n, number of unique

patients with a particular adverse event; SAE, serious adverse event; UC,

ulcerative colitis

1. Pfizer Data on File; 2. Sandborn WJ, et al. N Engl J Med. 2017;376(18):1723–36.

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• Infections

– Serious infections

– Herpes zoster

– Opportunistic infections

• Malignancies

• Cardiovascular events

• Gastrointestinal perforations

Safety events of special interest

Sandborn WT, et al. Safety manuscript

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1.86 1.83

3.29

1.652.22

4.79

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Thiopurine Biologic Combination Thiopurine Biologic Combination

Risk of herpes zoster associated with treatments in patients with IBD

aAdjusted for health care utilization, comorbidities, 5-ASA, and corticosteroid use as appropriate. bThiopurine defined as mercaptopurines or azathioprine. cBiologic defined as infliximab, adalimumab, or certolizumab pegol. dCombination therapy defined as both thiopurine and biologic.

IBD Overall (n=13,129) Ulcerative Colitis (n=6381)

Ad

jus

ted

Od

ds

Rati

oa

(95

% C

I)

b bc c dd

◼ Retrospective, nested case-control study using procedural and retail pharmacy claims data from IMS LifeLink®

Information Assets-Health Plan Claims Database from January 1997 through December 2009 to assess the

independent effects of medication use on herpes zoster risk among patients with IBD

CI, confidence interval; IBD, inflammatory bowel disease.Long MD, et al. Aliment Pharmacol Ther 2013;37(4):420-429.

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Incidence rates of herpes zoster (shingles) (serious and non-serious)

1.0 2.1

6.6

4.1

0

2

4

6

8

10

12

14


Tofacitinib10 mg BID

Tofacitinib All

Patients 198 198 196 1157

Total PY 103 146 151 1596

Patients with

events1 3 10 65

Cohort 3Cohort 2

Inc

ide

nc

e R

ate

, /1

00

PY

(9

5%

CI)

Events are counted up to 28 days(except subjects that are Ongoing in A3921139) beyond the last dose.PY: Total follow up time calculated up to the earliest of: day of the first event, time to data cutoff or progression to next study, or time to last dose + 28 days. Exact Poisson (adjusted for PY) CI are provided for the crude IR.

BID, twice daily; CI, confidence interval; PY, patient years.Sandborn et al. Safety manuscript.

PP

-XE

L-S

WE

-0419_sep

t-2018

Herpes zoster events in Cohort 3: clinical characterisation

95.7

2.9 1.4

0

20

40

60

80

100

Cutaneous Only Ocular Meningitis

Herpes Zoster Events by Number of

Dermatomes and OI Categories

Herpes Zoster Events by Cutaneous

Involvement

Pe

rce

nt

of

HZ

Eve

nts 73.9

17.4

8.7

0

20

40

60

80

100

1 or 2 AdjacentDermatomes

Multi-dermatomal

Disseminated

n= 51 12 6 66 2 1

Pe

rce

nt

of

HZ

Eve

nts

n=

HZ, herpes zoster.Pfizer Data on File

PP

-XE

L-S

WE

-0419_sep

t-2018

HDL-C, LDL-C, and LDL-C/HDL-C Ratio Over Time (Observed): OCTAVE Sustain

BID=twice daily; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; SD=standard deviation.A3921096 Study Report Output; Table 14.3.4.1.6. Data as of June 2016.

60

80

100

120

140

160

180

Ob

se

rve

d M

ea

n

(SD

)20

40

60

80

100

Ob

se

rve

d M

ea

n

(SD

)

0

1

2

3

4

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Ob

se

rve

d M

ea

n

(SD

)

29

Maintenance

Week

HDL-C (mg/dL)

Ratio of LDL-C/HDL-C

LDL-C (mg/dL)

Placebo Tofacitinib 10 mg BIDTofacitinib 5 mg BID

PP

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L-S

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t-2018

Treatment With Tofacitinib Was Associated With Early, Nonprogressive Increases in Lipid Parameters

That Were Responsive to Statin Treatment

Changes in Lipid Parameters1,2

▪ Treatment with tofacitinib was associated with changes in lipid parameters*:

▪ No change in the LDL/HDL ratio

▪ Maximum effects generally observed within 6 weeks and responsive to statin treatment2

12%-15% 9%-14%

HDL

11%-15%

LDL TC

LDL-c

Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e (

mg

/dL

)

Month

0

10

20

30

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Change Observed Over Time in Lipid Parameters†,1 HDL

TC

* Mean percent change from baseline, observed in patients in the LTE. Data as of 2016. † Beyond Month 90, fewer than 100 patients are included in the analysis.HDL=high-density lipoprotein; LDL=low-density lipoprotein; TC=total cholesterol.

3

0

PP

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t-2018


Data at launch

Treatment

strategies

Positioning

Disease/patient

features

…..let’s move from theory to practice

Patient case study: John, 34 years• 2013: E3 UC (up to hepatic flexure)

– Mild activity at diagnosis

– Oral 5-ASA 3–4.5 g ± rectal 5-ASA 1–4 g

– One course of oral steroids

• 2014: azathioprine 150–200 mg/day(~2.5 mg/kg/day)

– Disease still active after 3 months’ treatment

– Visits hospital for consultation

• pMayo = 8

– 5–6 BMs/day, bloody diarrhoea, tenesmus, urgency, cramps, no fever

– Hb = 11.5 g/dL, CRP = 24.7 mg/L

33

• Latent TB screening: negative

• CMV negative (IHC and PCR)

• Sigmoidoscopy (eMayo = 3)

E3=extensive colitis; 5-ASA=5-aminosalicylic acid; BM=bowel movement; CMV=cytomegalovirus; CRP=C-reactive protein; eMayo=endoscopic Mayo subscore; Hb=haemoglobin;IHC=immunohistochemistry; PCR=polymerise chain reaction; pMayo=partial Mayo score; TB=tuberculosis

How do we choose which drug to prescribe?

Lack of head-to-head trials…

34

Multiple options for patients…

Active

UC

Vedolizumab

Infliximab

Adalimumab

GolimumabTofacitinib

Azathioprine

Combination

Benefits of tofacitinib treatment in moderate-to-severe ulcerative colitis1

Oral administration

Rapid onset of action

Benefits of tofacitinib

1. Danese S, et al. Inflamm Bowel Dis. 2018;24:2106-2112.

Stool frequency Rectal bleeding

Number of daily

bowel movements

Rapid response: Significant improvement in symptomsversus placebo evident by Day 31

*P<0.01 vs placebo; **P<0.0001 vs placebo.BID=twice daily; LS=least squares; SE=standard error.1. Hanauer S, et al. Clin Gastroenterol Hepatol. 2018 doi: 10.1016/j.cgh.2018.07.009 [Epub ahead of print].

-0.27

–0.11

P<0.01

Tofacitinib 10 mg BID

Placebo

*

*

***

**** **

** **** **

** **

152 3 4 5 6 7 8 9 10 11 12 13 140 1

Time (days)

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

-0.8

-0.9LS m

ean

ch

ange

fro

m b

asel

ine

in

May

o s

too

l fre

qu

ency

su

bsc

ore

(SE

)

-0.30

-0.14

P<0.01

*

*

**

**** **

** ** **** ** **

**


Placebo

152 3 4 5 6 7 8 9 10 11 12 13 140 1

Time (days)

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

-0.8

-0.9LS m

ean

ch

ange

fro

m b

asel

ine

in

May

o r

ecta

l ble

ed

ing

sub

sco

re (

SE)

-1.06

-0.27

P<0.0001

2 3 4 5 156 7 8 9 10 11 12 13 140 1

Time (days)

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0LS m

ean

ch

ange

fro

m b

asel

ine

in

tota

l nu

mb

er o

f d

aily

bo

wel

mo

vem

en

ts (

SE)


Placebo

**

** ****

** ****

** ** **

**

**

**

Short serum half-life

Immunogenicity not expected


1. Danese S, et al. Inflamm Bowel Dis. 2018;24:2106–2112.


Characteristics of biologic and small molecule therapies1

38

Biologics Small molecules

Chemical composition Protein Synthetic

Administration Parenteral Oral

Molecular size

Adalimumab = 144.19 kDa Tofacitinib = 0.3123 kDa

Target Extracellular Intracellular

Immunogenicity Possible Not expected

kDa=kilodalton.1. Olivera P, et al. Gut. 2017;66(2):199–209.

• Potential first-line advanced therapy after 5-ASAs and steroids

• Effective in patients previously treated with TNF inhibitors

• Experience in RA



5-ASA=5-aminosalicylic acid; RA= rheumatoid arthritis; TNF=tumour necrosis factor.1. Danese S, et al. Inflamm Bowel Dis. 2018;24:2106-2112.

Prior TNFi failure: Remission at Week 8 and Week 521

Week 8* Week 52

12%

1%

24%

11%

0

20

40

60

80

100

Pro

po

rtio

n o

f p

atie

nts

in

rem

issi

on

at

We

ek

8 (

%)

n/N 13/110 106/440 1/124 53/465

11% 11%

42%

24%

44%

37%

0

20

40

60

80

100

Pro

po

rtio

n o

f p

atie

nts

in

rem

issi

on

at

We

ek

52

(%

)

n/N 12/109 48/115 46/104 10/89 20/83 34/93

*Data combined from OCTAVE Induction study 1 and 2.BID=twice daily; TNFi=tumour necrosis factor inhibitor.

1. XELJANZ SmPC August 2018. Pfizer Ltd; 2018.

Placebo



Without prior TNFi failure

With prior TNFi failure



Prior TNFi failure: Mucosal healing at Week 8 and Week 521*

Week 8† Week 52

Pro

po

rtio

n o

f p

atie

nts

wit

h

mu

cosa

l he

alin

g at

We

ek

8 (

%)

22%

38%

22%

0

20

40

60

80

100

6%

n/N 24/110 168/440 8/124 103/465

Pro

po

rtio

n o

f p

atie

nts

wit

h

mu

cosa

l he

alin

g at

We

ek

52

(%

)

14% 12%

43%

30%

51%

40%

0

20

40

60

80

100

n/N 15/109 49/115 53/104 11/89 25/83 37/93





*Improvement in mucosal appearance determined endoscopically/by central endoscopy read; †Data combined from OCTAVE Induction study 1 and 2.

BID=twice daily; TNFi=tumour necrosis factor inhibitor.1. XELJANZ SmPC August 2018. Pfizer Ltd; 2018.

Placebo



…Back to the patient, John

• One of the very first patients included in the OCTAVE trials

• Induction with tofacitinib 10 mg BID

4

2

Clinical improvement observed by Day 5

Continued remission since 2014 at tofacitinib 5 mg BID

No steroid use since then; repeat blood tests every 3 months

BID=twice daily.

Advantages of tofacitinib use in patients with ulcerative colitis

Oral administration 1

Advantages of tofacitinib



Rapid absorptiontime 2


Danese S, et al. Inflamm Bowel Dis 2018; doi:10.1093/ibd/izy076






Short serum half-life 3







No immunogenicity4







No immunogenicity4

Potential firstline therapy after 5--ASA and steroids 5







No immunogenicity4


Effective in patients previously treated with anti-TNF agents 5







No immunogenicity4



Potential for use in mild moderate, and severe UC 6







No immunogenicity4



Potential for use in mild moderate, and severe UC 6

Experience in RA 8

BACK UP SLIDES

• Deep vein thrombosis (DVT) and pulmonary embolism (PE) in general population

– Reported to occur in 1-2 in 1000 patients in the general population1-5

– The risk with increasing age or with fracture of lower extremities, immobilisation, joint replacement surgery, major general surgery, major trauma, malignancy, heart or respiratory failure, pregnancy, history of VTE, hormone replacement therapy, oral contraceptive use, obesity, smoking and inherited thrombophilias.1,6

• Risk of DVT and PE in ulcerative colitis

– In a review of the Manitoba Health administrative database, the incidence rates of DVT and PE for patients with UC were 0.30 and0.20 per 100 patient-years, respectively.7

– From Danish Civil Registration System, an increased risk of DVT and PE in patients with ulcerative colitis as noted by the following hazard ratios: DVT (1.8 [95% CI: 1.6-2.0]); unprovoked* DVT (1.5 [95% CI: 1.3-1.7]); PE (2.0 [95% CI: 1.8-2.2]); and unprovoked PE (1.6 [95% CI: 1.4-1.9]). The IRs of DVT and PE for patients with UC in this analysis were 0.14 and 0.10 events per 100 patient-years, respectively.8

52

Background

Reference:

1. Kim SC, Schneeweiss S, Liu J, et al. The risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res. 2013;65(10):1600-1607.

2. Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb. Haemost.

2000;83:657–660.

3. Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am. J. Med. 2013;126:832.e13–832.e21.

4. Naess IA, et al. Incidence and mortality of venous thrombosis: a population-based study. J. Thromb. Haemost. 2007;5:692–699

5. Lee LH, Gallus A, Jindal R, Wang C, Wu CC. Incidence of Venous Thromboembolism in Asian Populations: A Systematic Review. Thromb Haemost. 2017 Dec;117(12):2243-2260. doi: 10.1160/TH17-02-0134.

6. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003 Jun 17

7. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of venous thromboembolic disease among patients with IBD: a population-based study. Thromb Haemost, 85 (2001), pp. 430-434.

8. Thromb Haemost, 85 (2001), pp. 430-434Kappelman MD, Horvath-Puho E, Sandler RS, et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based

nationwide study. Gut. 2011;60:937-943.

• Signs and Symptoms for DVT1,2

– Asymmetrical swelling, warmth, or pain in the extremity

– Red or discolored skin on the extremity

• Signs and Symptoms for PE3

– Sudden shortness of breath or difficulty breathing

– Chest pain or pain in the back

– Coughing up blood

– Tachycardia

– Excessive sweating

– Cyanosis

53

Signs and Symptoms for Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)

1. Stone J, Hangge P, Albadawi H, et al. Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther. 2017;7(Suppl

3):S276-S284.

2. Hudgens SA, Cella D, Caprini CA, Caprini JA. Deep vein thrombosis: validation of a patient-reported leg symptom index. Health Qual Life Outcomes.

2003;1:76. Published 2003 Dec 15. doi:10.1186/1477-7525-1-76

3. Shonyela FS, Yang S, Liu B, Jiao J. Postoperative Acute Pulmonary Embolism Following Pulmonary Resections. Ann Thorac Cardiovasc Surg.

2015;21(5):409-17.

54

Deep Vein Thrombosis and Pulmonary Embolism in Tofacitinib UC Development Program

Induction P2P3 Maintenance P3 All Tofacitinib doses (P2P3LTE)*

Placebo(N = 282, PY=45)

Tofacitinib 10 mg BID(N = 938, PY= 156)


Tofacitinib5 mg BID(N = 198, PY=146)


Predominant Tofacitinib 5 mg BID(N=197,PY=596)

Predominant Tofacitinib 10 mg BID(N=960, PY= 1801)

All Tofacitinib(N=1157, PY= 2404 )

Subjects with Deep Vein Thrombosisn (%)

IR (95% CI)

1 (0.4)

1.99 (0.05, 11.07)

0 (0.0)

0.00 (0.00,2.22)

1 (0.5)

0.97 (0.02, 5.39)

0 (0.0)

0.00 (0.00, 2.48)

0 (0.0)

0.00 (0.00, 2.35)

0 (0.0)

0.00 (0.00, 0.61)

1 (0.1)

0.05 (0.00, 0.30)

1 (0.1)

0.04 (0.00, 0.23)

Subjects with Pulmonary Embolismn (%)

IR (95% CI)

1 (0.4)

1.98 (0.05, 11.04)

0 (0.0)

0.00 (0.00, 2.22)

1 (0.5)

0.98 (0.02, 5.44)

0 (0.0)

0.00 (0.00, 2.48)

0 (0.0)

0.00 (0.00, 2.35)

0 (0.0)

0.00(0.00, 0.61)

4 (0.4)

0.21 (0.06, 0.55)

4 (0.3)

0.16 (0.04, 0.41)

1. Data on file. Pfizer Inc, New York, NY.

*Data cut-off date September 2018

55

Deep Vein Thrombosis and Pulmonary Embolism in Tofacitinib UC Development Program Treated with Tofacitinib

• U.S. Prescribing Information: Four cases of pulmonary embolism were reported in patients

taking Xeljanz 10 mg twice daily within the tofacitinib UC development program, including

one fatality in a patient with advanced cancer.1*

• OCTAVE Open2**

• Deep vein thrombosis: • 58 years of age at DVT event (PD tofacitinib 10mg BID)

• 1149 days following the first dose of tofacitinib

• Following a long haul flight and management of an infected leg wound sustained in a recent

motorbike accident

• Pulmonary embolism:• 70 years of age at PE event (PD Tofacitinib 10mg BID)

• 383 days following the first dose of tofacitinib with cholangiocarcinoma and metastases to the

peritoneum

• Died due to PE

• 57 years of age at PE event (PD Tofacitinib 10mg BID)

• 236 days following the first dose of tofacitinib with prior phlebothrombosis and stroke

• 25 years of age at PE event (PD Tofacitinib 10mg BID)

• 216 days following the first dose of tofacitinib with prior DVT and PE

• 21 years of age at PE event (PD tofacitinib 10mg BID)

• 569 days following the first dose of tofacitinib

• Receiving oral contraceptives for dysfunctional uterine bleeding

Reference:

1. Tofacitinib USPI, Pfizer Inc, New York, NY, 2018.


*Data cut-off date July 2016; **Data cut-off date September 2018

56

Mortality in UC Tofacitinib Development Program Treated with Tofacitinib

Induction P2P3 Maintenance P3 All Tofacitinib doses (P2P3LTE)*


Tofacitinib 10 mg BID(N = 938, PY=166)




PredominantTofacitinib 5 mg BID

(N=197,

PY= 606)

Predominant Tofacitinib 10 mg BID(N=960,PY=1867)

All Tofacitinib (N=1157,PY=2473)

Subjects with events

n (%)

IR (CI)

0 (0.0)

0.00 (0.00, 7.30)

1 (0.1)

0.60 (0.02, 3.35)

0

0.00 (0.00, 3.57)

0

0.00 (0.00, 2.48)

0

0.00 (0.00, 2.35)

0

0.00 (0.00, 0.61)

5 (0.5)

0.27 (0.09, 0.63)

5 (0.4)

0. 20 (0.07, 0.47)

*Data cut-off date September 2018

Listing of all deaths• Aortic Dissection: 40-year-old male died on Day 31; last known does on Day 31

• Hepatic angiosarcoma: 54-year-old male died on Day 232; last known does on Day 187

• Acute myeloid leukemia: 54-year-old male died on Day 398; last known does on Day 347

• Pulmonary embolism complicating cholangiocarcinoma with metastases: 70-year-old male died on Day 384;

last known does on Day 378

• Malignant Melanoma: 66-year-old-male died on Day 1518; last known does on Day 1359


Documents

The experience with tofacitinib in Humanitas IBD center, from … · 2019-06-01 · Study design: OCTAVE Induction studies Primary Objectives 1. Compare the efficacy of tofacitinib