World Congress at ACG2017

Simultaneous Plenary Session 4C: IBD

78 - Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib

Wednesday, October 18
9:20 AM - 9:30 AM
Location: W414 (Level 4)



Category: IBD       

Kevin L. Winthrop, MD, PhD1, Gil Y. Melmed, MD, MS2, Séverine Vermeire, MD, PhD3, Millie D. Long, MD, MPH4, Gary Chan, PharmD, MS5, Ronald D. Pedersen, MS6, Nervin Lawendy, PharmD6, Andrew J. Thorpe, PhD6, Chudy I. Nduaka, DVM, PhD6, Chinyu Su, MD6
1Oregon Health and Science University, Portland, OR; 2Cedars-Sinai Medical Center, Los Angeles, CA; 3University Hospitals Leuven, Leuven, Vlaams-Brabant, Belgium; 4University of North Carolina, Center for Gastrointestinal Biology and Disease, Chapel Hill, NC; 5Pfizer Inc., Groton, CT; 6Pfizer Inc., Collegeville, PA
Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). We present details of herpes zoster (HZ) infection events in the tofacitinib Phase (P) 2/3 UC program.

Methods: Pooled analyses were performed for 3 cohorts (C): C1, 3 8-week placebo-controlled double-blind induction studies (1 P2 and 2 P3 [OCTAVE Induction 1 & 2]);1,2 C2, a 52-week placebo-controlled P3 maintenance study (OCTAVE Sustain); and C3, all patients (pts) treated with tofacitinib 5 or 10 mg twice daily (BID) in P2/3 and in the ongoing, open-label long-term extension study (OCTAVE Open). Tofacitinib 10 mg BID was evaluated in C1, and tofacitinib 5 and 10 mg BID were evaluated in C2 and 3. Cox regression was used for risk factor analysis. No HZ vaccination was required before treatment.

Results: As of July 2016, 1156 pts received ≥1 dose of tofacitinib 5 or 10 mg BID, with a mean age of 41.3 years (yrs), mean treatment duration of 1.2 yrs (treatment up to 3.9 yrs), and a total of 1365.5 pt-yrs (PY) of exposure. In C1, HZ events ( < 1%) were similar between placebo and tofacitinib. In C2, HZ incidence rates (IRs; pts with events/100 PY) for tofacitinib 5 mg BID (2.05/100 PY) or 10 mg BID (6.64/100 PY) were higher than placebo (0.97/100 PY); the difference in IR from placebo was statistically significant for 10 mg BID. The IR in C3 (4.33/100 PY) was in the range of IRs in C2, which suggests that there is not an increasing risk of HZ with longer duration of treatment with tofacitinib. In C3, a total of 63 events of HZ occurred in 59 pts. HZ meeting serious AE criteria was reported in 1 pt; HZ meeting severe AE criteria was reported in another pt. Over 98% of the events were mild/moderate in severity, over 98% were considered non-serious AEs, and 2 (3.6%) events resulted in discontinuation from treatment. With the exception of 2 ophthalmic HZ events, all were limited to cutaneous involvement, with most (>75%) HZ events limited to 1–2 dermatomes. Cox proportional hazard analysis identified increased age and Asian race as statistically significant risk factors for HZ.

Discussion: In the tofacitinib UC program, HZ risk was dose-dependent, but did not increase with longer treatment duration. HZ events were mostly mild/moderate infections, limited to cutaneous involvement, and did not require treatment discontinuation in most pts.

Funded by Pfizer Inc.

1. Sandborn WJ et al. N Engl J Med 2012;367:616-24.

2. Sandborn WJ et al. N Engl J Med 2017;376:1723-36.

Supported by Industry Grant: Yes

Disclosures: Does Disclose

Kevin Winthrop: Pfizer Inc – Consultant, Investigator.
Gil Melmed: AbbVie – Consultant. Boehringer Ingelheim – Consultant. Celgene – Consultant. Genentech – Consultant. Janssen – Consultant. Pfizer Inc – Consultant. Prometheus Labs – Grant/Research Support. Takeda – Consultant. UCB Pharma – Consultant.
Séverine Vermeire: AbbVie – Consultant, Grant/Research Support, Speaker's Bureau. Celgene – Consultant. Dr Falk Pharma – Speaker's Bureau. Ferring – Consultant, Speaker's Bureau. Galapagos – Consultant. Genentech/Roche – Consultant. Hospira – Consultant, Speaker's Bureau. Janssen – Consultant. MSD – Consultant, Grant/Research Support, Speaker's Bureau. Mundipharma – Consultant. Pfizer Inc – Consultant. Second Genome – Consultant. Shire – Consultant. Takeda – Consultant, Grant/Research Support, Speaker's Bureau. Tillots – Speaker's Bureau.
Millie Long: AbbVie – Consultant. Pfizer Inc – Consultant. Salix – Consultant. Theravance Pharmaceuticals – Consultant.
Gary Chan: Pfizer Inc – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Ronald Pedersen: Pfizer Inc – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Nervin Lawendy: Pfizer Inc – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Andrew Thorpe: Pfizer Inc – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Chudy Nduaka: Pfizer Inc – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).
Chinyu Su: Pfizer Inc – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Demographic and baseline characteristics of pts, and proportions and IRs (pts with events per 100 PY) for HZ, in P2, P3, and LTE studies of tofacitinib, by Cohorts































































































































 

Cohort 1
(P2/P3 induction)



Cohort 2
(P3 maintenance)



Cohort 3
(P2/P3/LTE)


 

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)


Age, mean (range) 

41.4
(18–81)



41.3
(18–80)



43.4
(19–80)



41.9
(18–79)



43.0
(18–79)



41.3
(18–81)


Female, %  45.0  40.6  41.4  48.0  43.9  41.3 

Geographic region, n (%)
   Asia
   Eastern Europe
   North America
   Western Europe
   Rest of the world




26 (9.2)
90 (31.9)
53 (18.8)
79 (28.0)
34 (12.1)




95 (10.1)
283 (30.2)
187 (19.9)
281 (30.0)
92 (9.8)




20 (10.1)
57 (28.8)
45 (22.7)
55 (27.8)
21 (10.6)




22 (11.1)
66 (33.3)
39 (19.7)
47 (23.7)
24 (12.1)



21 (10.7)
63 (32.1)
44 (22.4)
57 (29.1)
11 (5.6)




123 (10.6)
342 (29.6)
240 (20.8)
344 (29.8)
107 (9.3)


Mayo score at baseline, mean (SD)  8.9 (1.5)  9.0 (1.5)  3.3 (1.8)  3.3 (1.8)  3.4 (1.8)  8.6 (2.0) 
Total PY of exposure  44.8  156.2  100.4  146.2  154.3  1365.5
Treatment duration, days, mean (SD) [range] 

57.9 (13.7)
[7–80]



60.8 (11.0)
[1–96]



185.1 (127.9)
[14–382]



269.7 (125.1)
[22–420]



287.4 (123.1)
[1–399]



431.4 (327.5)
[1–1431]


  n (%)  n (%)  n (%)  IR
(95% CI)
n (%)  IR
(95% CI) 
n (%)  IR
(95% CI) 
n (%)  IR
(95% CI) 
HZ (all)  1 (0.4)  6 (0.6)  1 (0.5) 

0.97
(0.02, 5.42)


3 (1.5) 

2.05
(0.42, 6.00)


10 (5.1) 

6.64
(3.19, 12.22)


59 (5.1) 

4.33
(3.29, 5.58)


HZ multi-dermatomal†*  0 (0.0)  1 (0.1)  1 (0.5) 

0.97
(0.02, 5.42)


1 (0.5) 

0.68
(0.02, 3.77)


4 (2.0)

2.60
(0.71, 6.65)


10 (0.9)

0.71
(0.34, 1.31)


HZ disseminated*^  0 (0.0)  1 (0.1)  0 (0.0) 

0.00
(0.00, 3.57)


1 (0.5) 

0.68
(0.02, 3.77)


0 (0.0)

0.00
(0.00, 2.35)


3 (0.3)

0.21
(0.04, 0.62)


Only events occurring within 28 days after the last dose are included in this table for calculation of proportion and IR;
Multi-dermatomal HZ = non-adjacent dermatomes or >2 adjacent dermatomes
*Confirmed by independent adjudication;
^Refers to diffuse skin rash events;
BID, twice daily; CI, confidence interval; HZ, herpes zoster; IR, incidence rate; LTE, long-term extension; N, number of patients in the treatment group; n, number of unique patients with HZ infection; P, Phase; pts, patients; PY, pt-years; SD, standard deviation.

Citation: . HERPES ZOSTER INFECTION IN PATIENTS WITH ULCERATIVE COLITIS RECEIVING TOFACITINIB. Program No. 78. World Congress of Gastroenterology at ACG2017 Meeting Abstracts. Orlando, FL: American College of Gastroenterology.

Gil Melmed

Associate Professor of Medicine
Cedars-Sinai Medical Center
Los Angeles, California

Gil Y. Melmed, MD, MS is Director of Clinical Inflammatory Bowel Disease at Cedars-Sinai Medical Center and Associate Professor of Medicine at Cedars-Sinai and the David Geffen School of Medicine at UCLA. He received his medical degree from Albert Einstein College of Medicine. He completed his residency at Cedars-Sinai Medical Center and his gastroenterology fellowship at UCLA, where he also received a master's of science in clinical research. He is board certified by the American Board of Internal Medicine in gastroenterology.
Dr. Melmed's research interests include clinical outcomes in inflammatory bowel disease including health-related quality of life, post-operative outcomes, vaccination and health maintenance issues in patients with IBD, and quality of care for IBD. He has authored or co-authored over 70 publications and serves as a review editor for Inflammatory Bowel Disease. He co-chairs the Quality of Care Committee at the Crohn's and Colitis Foundation of America.

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