C0362 - Major Cardiovascular Adverse Events by Baseline Cardiovascular Risk Stratification in Patients With Ulcerative Colitis Treated With Tofacitinib: Data From the OCTAVE Clinical Program

Monday, October 24, 2022

3:00 PM – 5:00 PM ET

Location: Crown Ballroom

Presenting Author(s)

Marla C. Dubinsky, MD

Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai
New York, New York

Stefan Schreiber, MD¹, David T. Rubin, MD, FACG², Siew C. Ng, MD, PhD³, Irene Modesto, MD⁴, Xiang Guo, PharmD, MS⁵, Chinyu Su, MD⁵, Kenneth K. Kwok, MS⁴, Hyejin Jo, ⁴, Yan Chen, ⁴, Arne Yndestad, ⁶, Walter Reinisch, MD, PhD⁷, Marla C. Dubinsky, MD⁸
¹University Hospital Schleswig-Holstein, Kiel University, Kiel, Schleswig-Holstein, Germany; ²University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL; ³Institute of Digestive Disease, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong, Hong Kong; ⁴Pfizer Inc, New York, NY; ⁵Pfizer Inc, Collegeville, PA; ⁶Pfizer Inc, Oslo, Oslo, Norway; ⁷Medical University of Vienna, Vienna, Wien, Austria; ⁸Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY

Introduction: Tofacitinib is an oral small molecule JAK inhibitor for the treatment of UC. Results from ORAL Surveillance, a post-authorization safety study in patients (pts) with RA aged ≥ 50 years with ≥ 1 additional cardiovascular (CV) risk factor indicated increased risk of major adverse CV events (MACE) and malignancies (excluding NMSC) with tofacitinib vs tumor necrosis factor inhibitors. Pts with IBD are at increased risk of atherosclerotic CV disease (ASCVD; coronary artery disease, cerebrovascular disease, or peripheral artery disease) vs the general population. The ASCVD-pooled cohort equations calculator, a validated risk-prediction tool recommended by the ACC, considers traditional CV risk factors to estimate 10-year risk of primary ASCVD. This study evaluated MACE occurrence stratified by baseline CV risk in the tofacitinib OCTAVE clinical program.

Methods: 1,157 pts (median treatment duration 623 [range 1–2,850] days; 2,814.4 pt-years [PY] of exposure) who received tofacitinib 5 or 10 mg BID in a Phase(P)2 induction study (NCT00787202) and P3 studies (OCTAVE Induction 1&2 [NCT01465763; NCT01458951], OCTAVE Sustain [NCT01458574], and OCTAVE Open [NCT01470612]) were included. Proportions and incidence rates (IRs; unique pts with events / 100 PY of exposure) were evaluated for MACE. MACE IRs were stratified by baseline (first tofacitinib exposure) CV risk profile: first by history of ASCVD (HxASCVD), then pts without HxASCVD were categorized by 10-year ASCVD risk.

Results: Of 1,109 pts in which baseline CV risk was assessed, 4% had a HxASCVD, and most (87%) pts without a HxASCVD had a low / borderline risk of ASCVD (Figure). 8 pts had an adjudicated MACE; 1 event occurred in a pt with a HxASCVD, 5 in pts in intermediate / high ASCVD risk categories, and 2 in pts in the low ASCVD risk category. MACE IR in pts with a HxASCVD was 0.95 (0.02, 5.27) and IRs in pts without a HxASCVD by ASCVD risk were: high 1.81 (0.05, 10.07); intermediate 1.54 (0.42, 3.95); borderline 0.00 (0.00, 2.85); and low 0.09 (0.01, 0.32). 7 pts with MACE had a medical history of CV risk factors, and 7 were receiving statins (Table).

Discussion: In the tofacitinib OCTAVE clinical program, MACE were infrequent. Most pts had a low baseline ASCVD risk. This analysis highlights a potential association between baseline CV risk and MACE incidence in pts with UC treated with tofacitinib. Interpretation of these data was limited by the low number of events and short median treatment duration vs assessment of long-latency events.

Figure: Figure. a) Proportion of patients in each baseline CV risk category[a], and b) IRs (unique patients with events/100 PY of exposure) for MACE baseline CV risk category in the tofacitinib UC clinical trial program[b].
MACE were adjudicated by an independent review committee and defined as any myocardial infarction, stroke, or CV death.
HxASCVD was defined as a history of any of coronary artery disease (including myocardial infarction), cerebrovascular disease (including stroke), or peripheral artery disease
[a] Patients without a HxASCVD were categorized according to their 10-year risk of ASCVD, per the ASCVD PCE calculator, as recommended by the ACC. Baseline was defined as first tofacitinib exposure.
[b] Includes data from the P2 induction study (NCT00787202) and P3 studies (OCTAVE Induction 1&2 [NCT01465763; NCT01458951], OCTAVE Sustain [NCT01458574], and OCTAVE Open [NCT01470612]) from patients who received at least one dose of tofacitinib 5 mg or 10 mg twice daily
[c] Includes patients with a HxASCVD and patients for which baseline CV risk could be determined (N=1,109; 48 pts had a missing score due to missing components).
[d] Excludes data from the Phase 2 study. Events that occurred >28 days after the last dose of the study drug were excluded.
ACC, American College of Cardiology; ASCVD, atherosclerotic CV disease; ASCVD-PCE, ASCVD-pooled cohort equations; CI, confidence interval; CV, cardiovascular; HxASCVD, history of ASCVD; IR, incidence rate (unique patients with events/100 PY of exposure); MACE, major adverse CV events; N, number of patients with a HxASCVD or non-missing baseline ASCVD score; n, number of unique patients with a MACE; P, Phase; PY, patient-years; UC, ulcerative colitis

Table. Demographics and clinical characteristics of pts with MACE in the tofacitinib UC clinical program
MACE	Adjudicated event preferred term	Baseline CV risk category (ASCVD risk score, %)^a	CV risk category prior to first MACE (ASCVD risk score, %)^b	Induction baseline age (years) and gender	Day of onset^c and predominant tofacitinib dose^d	Smoking status and CV risk factors	Prior and concomitant CV medication and LLA	Induction baseline serum lipid concen-trations (mg/dL)^e	Serum lipid concen-trations at last recorded study time point (mg/dL)^e
Myocardial infarction	Acute coronary syndrome	HxASCVD	HxASCVD	66 Male	Day 28^f 5 mg BID	Ex-smoker Medical history of myocardial infarction, angina pectoris, arrhythmia, hyper-cholesterolemia and hypertension	CV medication: acetylsalicylic acid, perindopril and verapamil LLA: rosuvastatin	TC: 192 HDL-c: 112 LDL-c: 59 TG: 105	TC: 151 HDL-c: 65 LDL-c: 70 TG: 82
Myocardial infarction	Acute myocardial infarction	Inter-mediate (9.6)	Inter-mediate (14.3)	64 Male	Day 1,540^h 5 mg BID	Non-smoker None reported	CV medication: acetylsalicylic acid and perindopril LLA: atorvastatin	TC: 167 HDL-c:59 LDL-c: 92 TG: 80	TC: 151 HDL-c: 51 LDL-c: 82 TG: 88
Myocardial infarction	Myocardial infarction	Inter-mediate (17.9)	Inter-mediate (17.9)	74 Male	Day 142^g 5 mg BID	Ex-smoker Medical history of hyperlipidemia, hypertension and deep vein thrombosis	CV medication: acetylsalicylic acid and warfarin LLA: simvastatin	TC: 161 HDL-c: 63 LDL-c: 71 TG: 134	TC: 172 HDL-c: 44 LDL-c: 96 TG: 159
CV death	Aortic dissection	Low (1.4)	Low (1.4)	39 Male	Day 31^f 10 mg BID	Non-smoker Medical history of hyperlipidemia	None reported	TC: 309 HDL-c: 80 LDL-c: 189 TG: 194	Not assessed
CV death	Cardiac arrest	Inter-mediate (15.2)	High (25.7)	67 Male	Day 1,725^h 10 mg BID	Ex-smoker Medical history of dyslipidemia and pulmonary embolism	CV medication: none reported LLA: atorvastatin	TC: 172 HDL-c: 39 LDL-c: 103 TG: 150	TC: 214 HDL-c: 54 LDL-c: 128 TG: 159
Stroke	Hemorrhagic stroke	Low (4.2)	Borderline (5.5)	55 Female	Day 148^g 10 mg BID	Non-smoker Medical history of hypertension, hyper-cholesterolemia and diabetes mellitus	CV medication: irbesartan LLA: atorvastatin	TC: 183 HDL-c: 63 LDL-c: 94 TG: 132	TC: 205 HDL-c: 71 LDL-c: 111 TG: 117
Stroke	Cerebro-vascular accident	High (36.3)	High (49.6)	56 Male	Day 857^h 10 mg BID	Smoker Medical history of hypertension and diabetes mellitus	CV medication: amlodipine and enalapril LLA: atorvastatin	TC: 230 HDL-c: 39 LDL-c: 132 TG: 297	TC: 181 HDL-c: 56 LDL-c: 73 TG: 258
Stroke	Cerebellar hemorrhage	Inter-mediate (9.9)	Inter-mediate (14.0)	55 Male	Day 1,438^h 5 mg BID	Non-smoker Medical history of left ventricular hypertrophy and hypertension	CV medication: amlodipine LLA: atorvastatin	TC: 216 HDL-c: 34 LDL-c: 150 TG: 161	TC: 282 HDL-c: 51 LDL-c: 191 TG: 194
MACE were adjudicated by an independent review committee and defined as any myocardial infarction, stroke, or CV death HxASCVD was defined as a history of any of coronary artery disease (including myocardial infarction), cerebrovascular disease (including stroke), or peripheral artery disease ^aPts without HxASCVD were categorized according to their 10‑year risk of ASCVD, per the ASCVD-PCE risk calculator (as recommended by the ACC). Baseline was defined as first tofacitinib exposure ^bLatest CV risk score prior to MACE ^cStudy onset day in relation to first day of tofacitinib exposure ^dPts were categorized based on the average daily dose of tofacitinib (placebo exposure was not included): predominant dose tofacitinib 5 mg BID (average total daily dose < 15 mg) and predominant dose tofacitinib 10 mg BID (average total daily dose ≥ 15 mg) ^eReference ranges: TC, 130–200 mg/dL; HDL-c, 40–80 mg/dL; LDL-c, 0–130 mg/dL; TG, 45–250 mg/dL ^fEvent onset during OCTAVE Induction 1 or 2 ^gEvent onset during OCTAVE Sustain ^hEvent onset during OCTAVE Open ACC, American College of Cardiology; ASCVD, atherosclerotic CV disease; ASCVD-PCE, ASCVD-pooled cohort equations; BID, twice daily; CV, cardiovascular; HDL-c, high-density lipoprotein-cholesterol; HxASCVD, history of ASCVD; LDL‑c, low-density lipoprotein-cholesterol; LLA, lipid-lowering agent; MACE, major adverse cardiovascular events; TC, total cholesterol; TG, triglycerides; UC, ulcerative colitis

Disclosures:

Stefan Schreiber: AbbVie – Consultant, Personal fees. Arena – Consultant, Personal fees. Biogen – Consultant, Personal fees. Bristol-Myers Squibb – Consultant, Personal fees. Celgene – Consultant, Personal fees. Celltrion – Consultant, Personal fees. Eli Lilly and Company – Consultant, Personal fees. Falk – Consultant, Personal fees. Ferring – Consultant, Personal fees. Fresenius – Consultant, Personal fees. Galapagos/Gilead Sciences – Consultant, Personal fees. IMAB – Consultant, Personal fees. Janssen – Consultant, Personal fees. MSD – Consultant, Personal fees. Mylan – Consultant, Personal fees. Pfizer Inc – Consultant, Personal fees. Protagonist – Consultant, Personal fees. Provention Bio – Consultant, Personal fees. Takeda – Consultant, Personal fees. Theravance – Consultant, Personal fees.

David Rubin: AbbVie – Consultant. Alimentiv Inc. – Consultant. AltruBio – Consultant. Arena Pharmaceuticals – Consultant. Aslan Pharmaceuticals – Consultant. Athos Therapeutics – Consultant. Bellatrix Pharmaceuticals – Consultant. Boehringer Ingelheim, Ltd. – Consultant. Bristol Myers Squibb – Consultant. Celgene Corp/Syneos – Consultant. ClostraBio – Consultant. Connect BioPharma – Consultant. EcoR1 – Consultant. Genentech/Roche – Consultant. Gilead Sciences – Consultant. Ironwood Pharmaceuticals – Consultant. Iterative Scopes – Consultant. Janssen – Consultant. Kaleido Biosciences – Consultant. Lilly, Eli & Co – Consultant. Materia Prima – Consultant. Pfizer – Consultant. Prometheus Biosciences – Consultant. Reistone Biopharma – Consultant. Seres Therapeutics, Inc – Consultant. Takeda – Consultant, Grant/Research Support. Target RWE – Consultant. Techlab – Consultant. Trellus Health – Consultant.

Siew Ng: AbbVie – Advisory Committee/Board Member, Grant/Research Support, Speaker fees. Ferring – Advisory Committee/Board Member, Grant/Research Support, Speaker fees. GenieBiome Limited – Scientific co-founder; Shareholder. Janssen – Advisory Committee/Board Member, Grant/Research Support, Speaker fees. Menarini – Speaker fees. Microbiota I Center – Directorship. Olympus – Grant/Research Support. Pfizer Inc – Advisory Committee/Board Member, Speaker fees. Takeda – Speaker fees. Tillotts – Speaker fees.

Irene Modesto: Pfizer Inc – Employee, Stock Options.

Xiang Guo: Pfizer Inc – Employee, Stock Options.

Chinyu Su: Pfizer Inc – Employee, Stock Options.

Kenneth Kwok: Pfizer Inc – Employee, Stock Options.

Hyejin Jo: Pfizer – Paid contractor. Syneos Health – Employee.

Yan Chen: Eli Lilly – Stock Options. Pfizer Inc – Employee, Stock Options.

Arne Yndestad: Pfizer Inc – Employee, Stock Options.

Walter Reinisch: 4SC – Advisory Committee/Board Member, Consultant. Abbott Laboratories – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. AbbVie – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. Aesca – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. Algernon – Consultant. AM Pharma – Advisory Committee/Board Member, Consultant. Amgen – Advisory Committee/Board Member, Consultant. AMT – Consultant. AOP Orphan – Consultant. Aptalis – Speakers Bureau. Arena Pharmaceuticals – Consultant. Astellas – Advisory Committee/Board Member, Consultant, Speakers Bureau. AstraZeneca – Advisory Committee/Board Member, Consultant. Avaxia – Advisory Committee/Board Member, Consultant. Bioclinica – Consultant. Biogen IDEC – Advisory Committee/Board Member, Consultant. Boehringer Ingelheim – Advisory Committee/Board Member, Consultant. Bristol Myers Squibb – Advisory Committee/Board Member, Consultant. Celgene – Advisory Committee/Board Member, Consultant. Cellerix – Advisory Committee/Board Member, Consultant. Celltrion – Advisory Committee/Board Member, Consultant, Speakers Bureau. Centocor – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. ChemoCentryx – Advisory Committee/Board Member, Consultant. Covance – Consultant. Danone Austria – Advisory Committee/Board Member, Consultant, Speakers Bureau. DSM – Advisory Committee/Board Member, Consultant. Elan – Advisory Committee/Board Member, Consultant, Speakers Bureau. Eli Lilly – Consultant. Ernest & Young – Consultant. Falk Pharma GmbH – Consultant, Grant/Research Support, Speakers Bureau. Ferring – Advisory Committee/Board Member, Consultant, Speakers Bureau. Galapagos – Advisory Committee/Board Member, Consultant. Gatehouse Bio – Consultant. Genentech – Advisory Committee/Board Member, Consultant. Gilead – Consultant. Grünenthal – Advisory Committee/Board Member, Consultant. ICON – Consultant. Immundiagnostik – Grant/Research Support, Speaker. Index Pharma – Consultant. Inova – Advisory Committee/Board Member, Consultant. Intrinsic Imaging – Consultant. Janssen – Advisory Committee/Board Member, Consultant, Grant/Research Support. Johnson & Johnson – Advisory Committee/Board Member, Consultant. Kyowa Hakko Kirin Pharma – Advisory Committee/Board Member, Consultant. Lipid Therapeutics – Advisory Committee/Board Member, Consultant. LivaNova – Consultant. Mallinckrodt – Consultant. Medahead – Consultant. MedImmune – Advisory Committee/Board Member, Consultant. Millenium – Advisory Committee/Board Member, Consultant. Mitsubishi Tanabe Pharma Corporation – Advisory Committee/Board Member, Consultant, Speakers Bureau. MSD – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. Nash Pharmaceuticals – Consultant. Nestle – Advisory Committee/Board Member, Consultant. Nippon Kayaku – Consultant. Novartis – Advisory Committee/Board Member, Consultant. Ocera – Advisory Committee/Board Member, Consultant. OMass – Consultant. Otsuka – Advisory Committee/Board Member, Consultant, Speakers Bureau. Parexel – Consultant. PDL – Advisory Committee/Board Member, Consultant, Speakers Bureau. Periconsulting – Consultant. Pfizer – Advisory Committee/Board Member, Consultant. Pharmacosmos – Advisory Committee/Board Member, Consultant, Speakers Bureau. Philip Morris Institute – Consultant. PLS Education – Speakers Bureau. Procter & Gamble – Advisory Committee/Board Member, Consultant. Prometheus – Advisory Committee/Board Member, Consultant. Protagonist – Consultant. Provention – Consultant. Quell Therapeutics – Consultant. Robarts Clinical Trial – Consultant. Roland Berger GmbH – Consultant. Sandoz – Advisory Committee/Board Member, Consultant, Grant/Research Support. Schering-Plough – Advisory Committee/Board Member, Consultant, Speakers Bureau. Second Genome – Advisory Committee/Board Member, Consultant. Seres Therapeutics – Consultant. Setpoint Medical – Advisory Committee/Board Member, Consultant. Shire – Speakers Bureau. Sigmoid – Consultant. Sublimity – Consultant. Takeda – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. Therakos – Advisory Committee/Board Member, Consultant, Speakers Bureau. Theravance – Consultant. TiGenix – Advisory Committee/Board Member, Consultant. UCB – Advisory Committee/Board Member, Consultant. Vifor – Consultant, Speakers Bureau. Yakult – Speakers Bureau. Zealand – Advisory Committee/Board Member, Consultant. Zyngenia – Advisory Committee/Board Member, Consultant.

Marla Dubinsky: AbbVie – Consultant. Arena Pharmaceuticals – Consultant. Bristol Myers Squibb – Consultant. Celgene – Consultant. Eli Lilly – Consultant. Galapagos – Consultant. Genetech – Consultant. Gilead Sciences – Consultant. Janssen Pharmaceuticals – Consultant. Pfizer Inc – Consultant. Prometheus Laboratories – Consultant. Takeda – Consultant. Trellus Health – Shareholder. UCB – Consultant.

Stefan Schreiber, MD¹, David T. Rubin, MD, FACG², Siew C. Ng, MD, PhD³, Irene Modesto, MD⁴, Xiang Guo, PharmD, MS⁵, Chinyu Su, MD⁵, Kenneth K. Kwok, MS⁴, Hyejin Jo, ⁴, Yan Chen, ⁴, Arne Yndestad, ⁶, Walter Reinisch, MD, PhD⁷, Marla C. Dubinsky, MD⁸. C0362 - Major Cardiovascular Adverse Events by Baseline Cardiovascular Risk Stratification in Patients With Ulcerative Colitis Treated With Tofacitinib: Data From the OCTAVE Clinical Program, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.