Safety and Efficacy of Tofacitinib for Treatment of Ulcerative Colitis

Final Analysis of OCTAVE Open, an Open-label, Long-term Extension Study With Up to 7.0 Years of Treatment

William J. Sandborn; Nervin Lawendy; Silvio Danese; Chinyu Su; Edward V. Loftus Jr.; Ailsa Hart; Iris Dotan; Adérson O. M. C. Damião; Donna T. Judd; Xiang Guo; Irene Modesto; Wenjin Wang; Julian Panés

Disclosures

Aliment Pharmacol Ther. 2022;55(4):464-478.

Abstract and Introduction

Abstract

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present final data from OCTAVE Open, an open-label, long-term extension study.

Aims: The primary objective of OCTAVE Open was to assess the safety and tolerability of long-term tofacitinib in patients with ulcerative colitis; evaluating efficacy was a secondary objective.

Methods: Eligible patients included OCTAVE Induction 1&2 non-responders and OCTAVE Sustain completers/treatment failures. Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. Incidence rates (unique patients with events/100 patient-years) for adverse events of special interest were calculated; ≤7.0 years of observation. Efficacy endpoints derived from Mayo score were reported ≤36 months (last scheduled endoscopy visit).

Results: In OCTAVE Open, 769 of 944 patients (81.5%) initially received tofacitinib 10 mg b.d. Among all patients (2440.8 patient-years of exposure), incidence rates (IRs; 95% confidence intervals) for deaths and adverse events of special interest were: deaths, 0.25 (0.09–0.54); serious infections, 1.61 (1.14–2.20); herpes zoster (non-serious and serious), 3.16 (2.47–3.97); opportunistic infections, 0.87 (0.54–1.33); major adverse cardiovascular events, 0.16 (0.04–0.42); malignancies (excluding non-melanoma skin cancer), 1.03 (0.67–1.52); non-melanoma skin cancer, 0.75 (0.45–1.19); deep vein thrombosis, 0.04 (0.00–0.23); pulmonary embolism, 0.21 (0.07–0.48). At Month 36, 66.9% and 40.3% showed clinical response, 64.6% and 37.1% had endoscopic improvement, and 58.9% and 33.7% maintained or achieved remission, with tofacitinib 5 and 10 mg b.d. respectively.

Conclusion: Tofacitinib demonstrated consistent safety up to 7.0 years. Data collected up to Month 36 support long-term efficacy beyond the 52-week maintenance study.

Introduction

Ulcerative colitis is a chronic, immune-mediated, idiopathic inflammatory bowel disease that is characterised by mucosal inflammation in the rectum and colon.^[1,2] The management of patients with moderate to severe ulcerative colitis often requires long-term maintenance treatment, the aims of which are to achieve sustained steroid-free remission, improve quality of life, reduce morbidity and prevent colorectal cancer.^[2–4]

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. The efficacy and safety of tofacitinib were demonstrated in a phase 2, double-blind, placebo-controlled, 8-week induction study (NCT00787202),^[5] two identical phase 3, randomised, double-blind, placebo-controlled, 8-week induction studies (OCTAVE Induction 1 and 2; NCT01465763 and NCT01458951) and one phase 3, randomised, double-blind, placebo-controlled, 52-week maintenance study (OCTAVE Sustain; NCT01458574).^[6]

The safety and efficacy of tofacitinib in patients with ulcerative colitis have been further evaluated in a phase 3, multicentre, open-label, long-term extension study (OCTAVE Open; ClinicalTrials.gov: NCT01470612).^[7] Patients enrolled in OCTAVE Open received tofacitinib for up to 7.0 years. The primary objective of OCTAVE Open was to assess the safety and tolerability of long-term tofacitinib therapy in patients with ulcerative colitis. A secondary objective was to evaluate the efficacy of long-term tofacitinib therapy in patients with ulcerative colitis. Here, we report the final safety and efficacy data from OCTAVE Open.

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Next Section

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Baseline demographics and disease characteristics in OCTAVE Open
	Tofacitinib 5 mg b.d. (N = 175)	Tofacitinib 10 mg b.d. (N = 769)	Tofacitinib All (N = 944)
Remission, n (%)^a,b,c	163 (93.1)^d	1 (0.1)^e	164 (17.4)
Total Mayo score, mean (SD)^a,c	1.2 (0.9)	8.1 (2.3)	6.8 (3.4)
Age (years), mean (SD)	44.5 (14.6)	40.5 (13.5)	41.2 (13.8)
Female, n (%)	79 (45.1)	310 (40.3)	389 (41.2)
Race, n (%)
White	136 (77.7)	615 (80.0)	751 (79.6)
Asian	25 (14.3)	97 (12.6)	122 (12.9)
Weight (kg), mean (SD)^f,g	75.6 (15.7)	73.4 (16.4)	73.8 (16.3)
BMI (kg/m²), mean (SD)^f,h	25.8 (5.2)	24.8 (4.7)	25.0 (4.8)
Disease duration (years), median (range)^c	6.6 (1.6–32.8)	6.5 (0.6–42.9)	6.5 (0.6–42.9)
Corticosteroid use, n (%)^c	1 (0.6)ⁱ	212 (27.6)	213 (22.6)
5-ASA use, n (%)^c	133 (76.0)	539 (70.1)	672 (71.2)
Prior TNFi exposure, n (%)^j	74 (42.3)	441 (57.3)	515 (54.6)
Prior TNFi failure, n (%)^j	66 (37.7)	425 (55.3)	491 (52.0)
Prior immunosuppressant use, n (%)^j,k	116 (66.3)	602 (78.3)	718 (76.1)
Prior immunosuppressant failure, n (%)^j,k	110 (62.9)	588 (76.5)	698 (73.9)
Extent of disease, n (%)^j,l
Proctosigmoiditis	38 (21.8)	98 (12.8)	136 (14.5)
Left-sided colitis	56 (32.2)	261 (34.0)	317 (33.7)
Extensive colitis/pancolitis	80 (46.0)	407 (53.1)	487 (51.8)
Proctitis^m	0 (0.0)	1 (0.1)	1 (0.1)

Abbreviations: 5-ASA, 5-aminosalicylates; b.d., twice daily; BMI, body mass index; N, number of patients in the treatment group; n, number of patients within the given category; SD, standard deviation; TNFi, tumour necrosis factor inhibitor.
^aAssessment based on 767 and 942 evaluable patients receiving tofacitinib 10 mg b.d. and tofacitinib all respectively.
^bBased on centrally read endoscopic subscore.
^cBaseline and clinical characteristics data per data from baseline of OCTAVE Open.
^dTwelve patients not in remission at OCTAVE Open baseline were assigned to tofacitinib 5 mg b.d. as protocol deviations.
^eOne patient in remission at OCTAVE Open baseline was assigned to tofacitinib 10 mg b.d. in error by the clinical trial site.
^fAssessment based on 765 and 940 evaluable patients receiving tofacitinib 10 mg b.d. and tofacitinib all respectively.
^gFrom the last patient visit in the previous study.
^hBMI was calculated using weight (from the last patient visit in the previous study) and height (from screening of the induction studies).
ⁱOne patient was receiving prednisone 7.5 mg daily at baseline of OCTAVE Open.
^jBaseline and clinical characteristics data per data from baseline of induction studies.
^kImmunosuppressant use was defined as taking non-biologic agents such as azathioprine, 6-mercaptopurine, methotrexate, thioguanine, cyclosporine, tacrolimus and mycophenolic acid products and leukapheresis, but excludes TNFi agents.
^lAssessment based on 174, 767 and 941 evaluable patients receiving tofacitinib 5 mg b.d., tofacitinib 10 mg b.d. and tofacitinib all respectively.
^mOne patient with proctitis was enrolled into the induction study as a protocol deviation.

Table 2. Summary of safety in OCTAVE Open
	Tofacitinib 5 mg b.d. (N = 175)	Tofacitinib 10 mg b.d. (N = 769)^a	Tofacitinib All (N = 944)
Total PY of exposure	643.7	1797.0	2440.8
Treatment duration (days), median (range)	1529 (36–2422)	668 (1–2561)	–
Discontinuations, n (%)^b	84 (48.0)	665 (86.5)	749 (79.3)
Due to adverse event excluding worsening ulcerative colitis^c	20 (11.4)^d	80 (10.4)^d	100 (10.6)
Due to insufficient clinical response^c
Prior to or at Month 2	0 (0.0)	172 (22.4)	172 (18.2)
OCTAVE Open final analysis (cumulative)	20 (11.4)	326 (42.4)	346 (36.7)
Due to enrolment into another study/regulatory approval
Enrolled into RIVETING (NCT03281304)	2 (1.1)^e	138 (17.9)	140 (14.8)
Enrolled into post-marketing surveillance (Japan only)	8 (4.6)	4 (0.5)	12 (1.3)
Regulatory approval in Japan	1 (0.6)	2 (0.3)	3 (0.3)
Dose adjustments, n (%)
Dose escalation	50 (28.6)	—	—
Dose de-escalation	—	98 (12.7)	—
All-causality treatment-emergent adverse events, n (%)
Adverse events	154 (88.0)	626 (81.4)	780 (82.6)
Serious adverse events	39 (22.3)	147 (19.1)	186 (19.7)
Severe adverse events	25 (14.3)	104 (13.5)	129 (13.7)
All-causality treatment-emergent adverse events, by preferred term occurring in ≥10% of patients in any treatment group, n (%)
Worsening ulcerative colitis	47 (26.9)	159 (20.7)	206 (21.8)
Nasopharyngitis	41 (23.4)	157 (20.4)	198 (21.0)
Blood creatine phosphokinase increased	19 (10.9)	85 (11.1)	104 (11.0)
Upper respiratory tract infection	19 (10.9)	77 (10.0)	96 (10.2)
Influenza	23 (13.1)	65 (8.5)	88 (9.3)

Abbreviations: b.d., twice daily; N, number of patients in the treatment group; n, number of unique patients with a particular adverse event; PY, patient-years.
^aAll patients underwent endoscopy at Month 2; induction non-responders were mandated to discontinue if they failed to achieve clinical response by Month 2.
^bOther reasons for withdrawal from OCTAVE Open included: no longer willing to participate in study, pregnancy, protocol violation, lost to follow-up, not meeting entrance criteria, adverse events not related to study drug, other.
^cAdverse events of worsening ulcerative colitis leading to discontinuation were designated as insufficient clinical response.
^dRelated to study drug in 12 (6.9%) patients who received tofacitinib 5 mg b.d., and 46 (6.0%) patients who received tofacitinib 10 mg b.d.
^eTwo patients in the 5 mg b.d. arm of OCTAVE Open were enrolled in RIVETING in error.

Table 3. Proportions and IRs of deaths and adverse events of special interest in OCTAVE Open
	Tofacitinib 5 mg b.d. (N = 175; 643.7 PY)		Tofacitinib 10 mg b.d. (N = 769; 1797.0 PY)		Tofacitinib All (N = 944; 2440.8 PY)
	n (%)	IR^a (95% CI)	n (%)	IR^a (95% CI)	n (%)	IR^a (95% CI)
Deaths^b	0 (0.0)	0.00 (0.00–0.57)	6 (0.8)	0.33 (0.12–0.73)	6 (0.6)	0.25 (0.09–0.54)
Serious infections^c	8 (4.6)^d	1.25 (0.54–2.46)	31 (4.0)^e	1.74 (1.18–2.47)	39 (4.1)	1.61 (1.14–2.20)
Herpes zoster (non-serious and serious)^c,f	13 (7.4)	2.08 (1.11–3.55)	60 (7.8)^g	3.55 (2.71–4.58)	73 (7.7)	3.16 (2.47–3.97)
Serious herpes zoster^c	1 (0.6)	0.16 (0.00–0.87)	6 (0.8)	0.33 (0.12–0.73)	7 (0.7)	0.29 (0.12–0.59)
Opportunistic infections^c,h,i,j	4 (2.3)	0.63 (0.17–1.60)	17 (2.2)	0.96 (0.56–1.53)	21 (2.2)	0.87 (0.54–1.33)
Malignancies excluding NMSC^b,h	7 (4.0)	1.09 (0.44–2.25)	18 (2.3)	1.00 (0.60–1.59)	25 (2.6)	1.03 (0.67–1.52)
NMSC^b,h	6 (3.4)	0.96 (0.35–2.08)	12 (1.6)	0.68 (0.35–1.19)	18 (1.9)	0.75 (0.45–1.19)
MACE^b,h	2 (1.1)	0.31 (0.04–1.13)	2 (0.3)	0.11 (0.01–0.40)	4 (0.4)	0.16 (0.04–0.42)
Gastrointestinal perforations^c,h,k	1 (0.6)	0.16 (0.00–0.87)	1 (0.1)	0.06 (0.00–0.31)	2 (0.2)	0.08 (0.01–0.30)
Deep vein thrombosis^c	0 (0.0)	0.00 (0.00–0.57)	1 (0.1)	0.06 (0.00–0.31)	1 (0.1)	0.04 (0.00–0.23)
Pulmonary embolism^c	0 (0.0)	0.00 (0.00–0.57)	5 (0.7)	0.28 (0.09–0.65)	5 (0.5)	0.21 (0.07–0.48)

Abbreviations: b.d., twice daily; CI, confidence interval; IR, incidence rate; MACE, major adverse cardiovascular events; N, number of patients who received at least one dose of study drug; n, number of patients with the specified event within the given category; NMSC, non-melanoma skin cancer; PY, patient-years.
^aIRs were calculated as the number of unique patients with events per 100 PY.
^bAll events, including those outside the 28-day risk period, were included.
^cAll events occurred within 28 days after the last dose of study drug.
^dThree events were reported as severe (number of events): complicated appendicitis (1), gastroenteritis norovirus (1), necrotising fasciitis (1).
^eSixteen events were reported as severe in a total of 13 patients (number of events): appendicitis (3), arthritis bacterial (1), atypical pneumonia (1), herpes zoster (3), herpes zoster meningitis (1), mastoiditis (1), meningitis viral (1), ophthalmic herpes zoster (1), osteomyelitis (1), perirectal abscess (1) sinusitis (1), wound infection (1).
^fIncludes all herpes zoster events, including those classified as opportunistic infections.
^gFive events were reported as severe.
^hAdjudicated events.
ⁱExcludes tuberculosis and herpes zoster with two adjacent dermatomes; only multidermatomal herpes zoster (events that were non-adjacent or with more than two adjacent dermatomes that were not considered disseminated) and disseminated herpes zoster (defined as any of: diffuse rash [>6 dermatomes], encephalitis, pneumonia or other non-skin organ involvement) were classified as opportunistic infections.
^jNon-herpes zoster opportunistic infections included a pulmonary mycosis (invasive cryptococcosis) case in the tofacitinib 5 mg b.d. group, and one case each of histoplasmosis, cytomegalovirus (CMV) infection and CMV hepatitis in the tofacitinib 10 mg b.d. group.
^kExcludes preferred terms of pilonidal cyst, perirectal abscess, rectal abscess, anal abscess, perineal abscess and any preferred terms containing the term fistula.

Table 4. Summary of liver function test values as multiples of the upper limit of normal and laboratory data meeting criteria for discontinuation in OCTAVE Open
n (%)	Tofacitinib 5 mg b.d. (N = 175)	Tofacitinib 10 mg b.d. (N = 769)	Tofacitinib All (N = 944)
ALT
≥1 ×ULN	86 (49.1)	211 (27.4)	297 (31.5)
≥2 ×ULN	25 (14.3)	52 (6.8)	77 (8.2)
≥3 ×ULN	14 (8.0)	19 (2.5)	33 (3.5)
AST
≥1 ×ULN	72 (41.1)	180 (23.4)	252 (26.7)
≥2 ×ULN	22 (12.6)	35 (4.6)	57 (6.0)
≥3 ×ULN	10 (5.7)	13 (1.7)	23 (2.4)
Laboratory data for discontinuations
Two sequential Hgb <8.0 g/dL or >30% decrease from baseline	0 (0.0)	11 (1.4)	11 (1.2)
Two sequential ANC <750 neutrophils/mm³	0 (0.0)	1 (0.1)	1 (0.1)
Two sequential ALC <500 lymphocytes/mm³	1 (0.6)	14 (1.8)	15 (1.6)
Two sequential creatine phosphokinase elevations >10 ×ULN^a	2 (1.1)	4 (0.5)	6 (0.6)
Two sequential AST or ALT elevations
≥3 ×ULN with at least one total bilirubin value ≥2 ×ULN^b	1 (0.6)	0 (0.0)	1 (0.1)
Two sequential AST or ALT elevations
≥5 ×ULN	1 (0.6)	1 (0.1)	2 (0.2)

Reference ranges for ULN parameters were dependent on patient sex and age.
Abbreviations: ALC, absolute lymphocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; b.d., twice daily; Hgb, haemoglobin; N, number of patients in the treatment group; n, number of patients meeting criteria; ULN, upper limit of normal.
^aDiscontinuation was required unless the causality was known not to be medically serious (e.g. exercise induced).
^bTwo sequential AST or ALT elevations ≥3 ×ULN alone was not a reason for discontinuation. Discontinuation was only required if accompanied by at least one total bilirubin value ≥2 ×ULN, or signs or symptoms consistent with hepatic injury.

Authors and Disclosures

William J. Sandborn¹, Nervin Lawendy², Silvio Danese³, Chinyu Su², Edward V. Loftus Jr.⁴, Ailsa Hart⁵, Iris Dotan^6,7, Adérson O. M. C. Damião⁸, Donna T. Judd², Xiang Guo², Irene Modesto⁹, Wenjin Wang² and Julian Panés¹⁰

¹Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
²Pfizer Inc, Collegeville, PA, USA
³Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
⁴Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
⁵IBD Unit, St Mark's Hospital, London, UK
⁶Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
⁷Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
⁸Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
⁹Pfizer Inc, New York, NY, USA
¹⁰Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain

Correspondence
Xiang Guo, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USA. Email: xiang.guo@pfizer.com

Author contributions
WJ Sandborn, S Danese, EV Loftus Jr. and J Panés were investigators for this study. N Lawendy, C Su and W Wang contributed to the conceptualisation of the study. N Lawendy, C Su and W Wang contributed to the methodology. N Lawendy, C Su, DT Judd, X Guo, I Modesto and W Wang contributed to data curation, project administration and validation. All authors contributed equally to formal analysis of the data and writing, reviewing and editing the manuscript. All authors approved the final version of the article, including the authorship list.

Declaration of personal interests
WJ Sandborn has received grant support, personal fees and non-financial support from Pfizer Inc during the conduct of the study; research support from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer Inc, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda and Theravance Biopharma; consultancy fees from AbbVie, Abivax, AdMIRx, Alfasigma, Alimentiv (Robarts Clinical Trials, owned by Health Academic Research Trust [HART]), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), BeiGene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Equillium, Escalier Biosciences, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer Inc, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vedanta Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences and Zealand Pharma; and has stock or stock options in Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Progenity, Prometheus Biosciences, Shoreline Biosciences, Ventyx Biosciences and Vimalan Biosciences. WJ Sandborn's spouse has received consultancy fees from Iveric Bio and Oppilan Pharma; is an employee of Prometheus Biosciences; and has stock or stock options in Iveric Bio, Oppilan Pharma Progenity, Prometheus Biosciences, Ventyx Biosciences and Vimalan Biosciences. N Lawendy, C Su, DT Judd, X Guo, I Modesto and W Wang are all employees and stockholders of Pfizer Inc. S Danese has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB and Vifor. EV Loftus Jr. has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead Sciences, Janssen, Pfizer Inc, Receptos, Robarts Clinical Trials, Takeda, Theravance and UCB; and consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, Calibr, Celgene, Lilly, Genentech, Gilead Sciences, Gossamer Bio, Iterative Scopes, Janssen, Lilly, Ono Pharma, Pfizer Inc, Sun Pharma, Takeda and UCB. A Hart has received consultancy fees from AbbVie, Allergan, Atlantic, Bristol-Myers Squibb, Celltrion, Falk Pharma, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer Inc, Pharmacosmos, Shire and Takeda; lecture fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk Pharma, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer Inc, Pharmacosmos, Shire and Takeda; other fees from Genentech (Global Steering Committee); and has served as an advisory board member for AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk Pharma, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer Inc, Pharmacosmos, Shire and Takeda. I Dotan has received personal fees from AbbVie, Abbott, Altman Research, Arena Pharmaceuticals, Athos, Cambridge Healthcare, Celgene/Bristol-Myers Squibb, Celltrion, DSM, Falk Pharma, Ferring, Food Industries Organisation, Genentech/Roche, Gilead Sciences, Janssen, MSD, Neopharm, Nestlé, Pfizer Inc, Rafa Laboratories, Sandoz, Sangamo, Sublimity, Takeda and Wildbio. AOMC Damião has received personal fees from AbbVie, Ferring, Janssen, Takeda and Pfizer Inc. J Panés has received research support from AbbVie and Pfizer Inc; and personal fees from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Celltrion, F. Hoffmann-La Roche, Genentech, Gilead Sciences, GlaxoSmithKline, Immunic, Janssen, Origo, Pandion, Pfizer Inc, Progenity, Robarts Clinical Trials, Takeda, Theravance and Wassermann.